Cirrhosis File - Related Information

Cirrhosis File


Patients all over the world have used the information in The Cirrhosis File since 1992, when the Center for Current Research—one of the first 80 companies on the Internet—was founded. Their highly trained researchers (all of whom hold Ph.D.s) have searched the advanced medical database at the National Library of Medicine and compiled a comprehensive collection of research descriptions on Cirrhosis and its care.
   
The following research descriptions detail the findings published in the most respected journals in the field. Because the research descriptions are written in medical terms, you may come across them in your medical transcription. We at ProfitMTFuture medical transcription education/medical word editing education are hoping this compilation of articles on cirrhosis will be helpful to you if you come across some of these terms.  We commend you in your medical transcription education search for terms! Medical transcriptionists, good ones, really become detectives! See the American Association for Medical transcription site regarding great qualities for medical transcriptionists: http://www.aamt.org/scriptcontent/rjobdesc.cfm

Welcome to the Cirrhosis File
Patients all over the world have used the information in The Cirrhosis File since 1992, when the Center for Current Research—one of the first 80 companies on the Internet—was founded. Our highly trained researchers (all of whom hold Ph.D.s) have searched the advanced medical database at the National Library of Medicine and compiled a comprehensive collection of research descriptions on Cirrhosis and its care.

As you will see, the following research descriptions detail the findings published in the most respected journals in the field. Because the research descriptions are written in medical terms, most people will bring all or parts of the Cirrhosis File to their doctor for further explanation and discussion. Often your doctor will have access to full-text articles and other information that could be useful in planning a successful course of treatment and prevention. Note that the titles of the journals are abbreviated according to the National Library of Medicine's format; your doctor can provide the full title if you need it.

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Director of Research

Cirrhosis File - Related Information
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   Latest Research on Cirrhosis
Cardiovasc Intervent Radiol. 2006 Sep-Oct;29(5):785-90.
Transjugular intrahepatic portosystemic shunt placement in patients with cirrhosis and concomitant portal vein thrombosis.
Van Ha TG, Hodge J, Funaki B, Lorenz J, Rosenblum J, Straus C, Leef J.
Department of Radiology, Section of Interventional Radiology, The University of Chicago, 5841 South Maryland Avenue MC 2026, Chicago, IL 60637, USA. tgvanha@radiology.bsd.uchicago.edu

PURPOSE: To determine the safety and efficacy of transjugular intrahepatic portosystemic shunt (TIPS) creation in patients with liver cirrhosis complicated by thrombosed portal vein. METHODS: This study reviewed 15 cases of TIPS creation in 15 cirrhotic patients with portal vein thrombosis at our institution over an 8-year period. There were 2 women and 13 men with a mean age of 53 years. Indications were refractory ascites, variceal hemorrhage, and refractory pleural effusion. Clinical follow-up was performed in all patients. RESULTS: The technical success rate was 75% (3/4) in patients with chronic portal vein thrombosis associated with cavernomatous transformation and 91% (10/11) in patients with acute thrombosis or partial thrombosis, giving an overall success rate of 87%. Complications included postprocedural encephalopathy and localized hematoma at the access site. In patients with successful shunt placement, the total follow-up time was 223 months. The 30-day mortality rate was 13%. Two patients underwent liver transplantation at 35 days and 7 months, respectively, after TIPS insertion. One patient had an occluded shunt at 4 months with an unsuccessful revision. The remaining patients had functioning shunts at follow-up. CONCLUSION: TIPS creation in thrombosed portal vein is possible and might be a treatment option in certain patients.


Endoscopy. 2006 Sep;38(9):896-901.
The use of self-expanding metal stents to treat acute esophageal variceal bleeding.
Hubmann R, Bodlaj G, Czompo M, Benko L, Pichler P, Al-Kathib S, Kiblbock P, Shamyieh A, Biesenbach G.
2nd Dept. of Internal Medicine, Linz General Hospital, Linz, Austria. rainer.hubmann@akh.linz.at

BACKGROUND AND STUDY AIMS: Acute variceal bleeding is a life-threatening complication of liver cirrhosis. Essential factors for survival after variceal bleeding are the rapidity and efficacy of initial primary hemostasis. Endoscopic and vasoactive therapy is the gold standard in the management of acute variceal hemorrhage. The primary aim of this study was to evaluate the use of self-expandable metallic stents to arrest uncontrollable acute variceal bleeding. PATIENTS AND METHODS: Between November 2002 and May 2005, esophageal stents were implanted in 20 patients (18 men, two women; mean age 52, range 27-87) with massive ongoing bleeding from esophageal varices, as an alternative treatment to balloon tamponade. The patients had not been successfully managed with prior pharmacologic or endoscopic therapy. They had had one to five previous bleeding episodes (mean 2.4). Eight of the patients were in Child-Pugh grade B and 12 in grade C. A new type of stent with special introducers was developed that allowed placement without radiographic assistance. RESULTS: The stents were successfully placed in all of the patients and were left in place for 2-14 days. Bleeding from the esophageal varices ceased immediately after implantation of the stent in all cases. While the stent was in place, further diagnostic steps were carried out to optimize management of the patients' illness and portal hypertension. No recurrent bleeding, morbidity, or mortality occurred during treatment with the esophageal stent. All of the stents were extracted without any complications after definitive treatment had been started. CONCLUSIONS: In this pilot study, the new method of implantation of an esophageal stent was found to be a safe and effective treatment for massive bleeding from esophageal varices in patients with liver cirrhosis. These initial clinical results will of course have to be confirmed in comparative studies including a large number of patients.

Hepatology. 2006 Sep;44(3):640-9.
The effect of single oral low-dose losartan on posture-related sodium handling in post-TIPS ascites-free cirrhosis.
Therapondos G, Hol L, Benjaminov F, Wong F.
Division of Gastroenterology, Department of Medicine, Toronto General Hospital, University of Toronto, Canada.

Post-TIPS ascites-free patients with cirrhosis and previous refractory ascites demonstrate subtle sodium retention when challenged with a high sodium load. This is also observed in pre-ascitic patients with cirrhosis. This phenomenon is dependent on an intrarenal angiotensin II (ANG II) mechanism related to the assumption of erect posture. We investigated whether similar mechanisms were involved in post-TIPS ascites-free patients, by studying 10 patients with functioning TIPS and no ascites. We measured the effect of changing from supine to erect posture on sodium excretion at baseline and after single oral low dose losartan (7.5 mg) which has been shown to blunt proximal and distal tubular sodium reabsorption in pre-ascites. At baseline, the assumption of erect posture produced a reduction in sodium excretion (from 0.30+/-0.06 to 0.13+/-0.02 mmol/min, P=.05), which was mainly due to an increase in proximal tubular reabsorption of sodium (PTRNa) (69.7+/-3.1% to 81.1+/-1.8%, P=.003). The administration of losartan resulted in a blunting of PTRNa (supine 69.7+/-3.1% to 63.9+/-3.9%, P=.01 and erect 81.1+/-1.8% to 73.8+/-2.4%, P=.01), accompanied by an increased distal tubular reabsorption of sodium in both postures, with no overall improvement in sodium excretion on standing. In conclusion, post-TIPS ascites-free patients with cirrhosis exhibit erect posture-induced sodium retention. We speculate that (1) this effect is partly mediated by the effect of ANG II on PTRNa and (2) that the inability of low dose losartan to block the erect posture-induced sodium retention may be related to the erect posture-induced rise in aldosterone which is unmodified by losartan.

Can J Gastroenterol. 2006 Aug;20(8):531-4.
Acute management and secondary prophylaxis of esophageal variceal bleeding: a western Canadian survey.
Cheung J, Wong W, Zandieh I, Leung Y, Lee SS, Ramji A, Yoshida EM.
Department of Medicine, University of Alberta, Edmonton.

BACKGROUND: Acute esophageal variceal bleeding (EVB) is a major cause of morbidity and mortality in patients with liver cirrhosis. Guidelines have been published in 1997; however, variability in the acute management and prevention of EVB rebleeding may occur. METHODS: Gastroenterologists in the provinces of British Columbia, Alberta, Manitoba and Saskatchewan were sent a self-reporting questionnaire. RESULTS: The response rate was 70.4% (86 of 122). Intravenous octreotide was recommended by 93% for EVB patients but the duration was variable. The preferred timing for endoscopy in suspected acute EVB was within 12 h in 75.6% of respondents and within 24 h in 24.6% of respondents. Most (52.3%) gastroenterologists do not routinely use antibiotic prophylaxis in acute EVB patients. The preferred duration of antibiotic therapy was less than three days (35.7%), three to seven days (44.6%), seven to 10 days (10.7%) and throughout hospitalization (8.9%). Methods of secondary prophylaxis included repeat endoscopic therapy (93%) and beta-blocker therapy (84.9%). Most gastroenterologists (80.2%) routinely attempted to titrate beta-blockers to a heart rate of 55 beats/min or a 25% reduction from baseline. The most common form of secondary prophylaxis was a combination of endoscopic and pharmacological therapy (70.9%). CONCLUSIONS: Variability exists in some areas of EVB treatment, especially in areas for which evidence was lacking at the time of the last guideline publication. Gastroenterologists varied in the use of prophylactic antibiotics for acute EVB. More gastroenterologists used combination secondary prophylaxis in the form of band ligation eradication and beta-blocker therapy rather than either treatment alone. Future guidelines may be needed to address these practice differences.

J Am Coll Surg. 2006 Aug;203(2):145-51. Epub 2006 Jun 22.
Laparoscopic cholecystectomy in cirrhotic patients: the role of subtotal cholecystectomy and its variants.
Palanivelu C, Rajan PS, Jani K, Shetty AR, Sendhilkumar K, Senthilnathan P, Parthasarthi R.
Department of GI and Minimal Access Surgery, Gem Hospital, Coimbatore, Tamilnadu, India.

BACKGROUND: Open cholecystectomy is associated with considerable morbidity and mortality in cirrhotic patients. Laparoscopic cholecystectomy may offer a better option because of the magnification available and the availability of newer instruments like the ultrasonic shears. We present our experience of 265 laparoscopic cholecystectomies and attempt to identify the difficulties encountered in this group of patients. STUDY DESIGN: Between 1991 and 2005, 265 cirrhotic patients of Child-Pugh Classification A and B, with symptomatic gallstones, were subjected to laparoscopic cholecystectomy. We describe here our tailored approach and our techniques of subtotal cholecystectomy. RESULTS: Features of acute cholecystitis were present in 35.1% of the patients, and 64.9% presented with chronic cholecystitis. In 81.5% of the patients, the diagnosis of cirrhosis was established preoperatively. In 8.3% of the patients, a fundus first method was adopted when the hilum could not be approached despite additional ports. Modified subtotal cholecystectomy was performed in a total of 206 patients. Mean operative time in the subtotal cholecystectomy group was 72 minutes; in the standard group, it was 41 minutes. There was no mortality. In 15% of patients, postoperative deterioration in liver function occurred. Worsening of ascites, port site infection, port site bleeding, intraoperative hemorrhage, bilious drainage, and stone formation in the remnant were the other complications encountered. CONCLUSIONS: Laparoscopic cholecystectomy is a safe and effective treatment for calculous cholecystitis in cirrhotic patients. Appropriate modification of subtotal cholecystectomy should be practiced, depending on the risk factors present, to avoid complications.

Transplant Proc. 2006 Jul-Aug;38(6):1659-63.
Total parenteral nutrition: challenges and practice in the cirrhotic patient.
Buchman AL.
Division of Gastroenterology, Intestinal Rehabilitation Center, Feinberg School of Medicine, Northwestern University, 676 N. St. Clair Street, Chicago, Illinois, USA. a-buchman@northwestern.edu

Patients with cirrhosis develop metabolic derangements of protein, carbohydrate, and lipid metabolism. Malnutrition is commonplace and is associated with morbidity and mortality. Specific nutrient deficiencies may occur and enteral or parenteral nutritional support may improve outcome in appropriately selected patients. Parenteral nutrition itself has been associated with hepatic dysfunction, although the preponderance of evidence suggests that hepatic dysfunction is more a function of the underlying disorder and malabsorption. Intravenously infused organic nutrients may be metabolized differently than the same nutrient consumed enterally. The pathophysiology of total parenteral nutrition-associated liver disease is discussed as well as potential management options.

Am J Transplant. 2006 Jun;6(6):1398-406.
No Improvement in Long-Term Liver Transplant Graft Survival in the Last Decade: An Analysis of the UNOS Data.
Futagawa Y, Terasaki PI, Waki K, Cai J, Gjertson DW.
Terasaki Foundation Laboratory, Los Angeles, California, USA.

We analyzed change in outcomes during two successive 5-year periods (period I = 1992-1996 vs period II = 1997-2002) among 35 186 deceased adult liver transplant recipients reported to the United Network for Organ Sharing (UNOS) Registry. The 5-year graft survival was 67.4% in the first period and 67.5% in the second, though the 1-year survival had improved from 81.0 to 83.5%. Comparison of blended survival rates during the two study periods showed decreased long-term graft survival in period II, explicable by an increased number of hepatitis C virus cirrhosis (HCV) patients and an increase in patients with HCV antibodies (HCVab) during this later period. Analysis wherein these patients with HCV were excluded revealed the same long-term graft survival during both periods. Non-HCV patients who had HCVab also had worse 5-year graft survival. We conclude that hepatitis C prevented improved outcomes during period II and that improved, more effective, treatment for hepatitis C virus would have great positive impact on overall survival of liver transplant recipients.

Arch Surg. 2006 Apr;141(4):385-8; discussion 388.
Distal splenorenal shunt: preferred treatment for recurrent variceal hemorrhage in the patient with well-compensated cirrhosis.
Elwood DR, Pomposelli JJ, Pomfret EA, Lewis WD, Jenkins RL.
Division of Hepatobiliary Surgery and Liver Transplantation, Lahey Clinic Medical Center, Burlington, Mass.

HYPOTHESIS: Distal splenorenal shunt (DSRS) is a safe and effective treatment for patients with Child-Pugh class A and B cirrhosis with recurrent variceal hemorrhage after failed transjugular intrahepatic portosystemic shunt. DESIGN: Retrospective case review. SETTING: Hepatobiliary surgery and liver transplantation department in a tertiary referral medical center. PATIENTS: Between August 1, 1985, and May 1, 2005, 119 patients with Child-Pugh class A and B cirrhosis underwent DSRS for recurrent variceal hemorrhage. Of these, 17 (14.3%) had thrombosed or failing transjugular intrahepatic portosystemic shunt prior to DSRS. INTERVENTION: Distal splenorenal shunt for recurrent variceal hemorrhage after failure of conservative management. MAIN OUTCOME MEASURES: Morbidity, mortality, and subsequent liver transplantation rate. RESULTS: The overall perioperative morbidity rate was 31.5%. Thirteen patients (11.7%) developed encephalopathy and 6 (5.4%) had recurrent variceal hemorrhage. Other complications included portal vein thrombosis, pancreatitis, pancreatic pseudocyst, pneumonia, and wound infection. The 30-day operative mortality rate was 6.4% (n = 7). The 1-year survival rate was 85.9%. The incidence of DSRS for failed transjugular intrahepatic portosystemic shunt during the first 12 years of the study (1985-1997) was 11.1% (9/81). This proportion increased to 26.7% (8/30) during the second half of the study (1997-2005). During the 20-year period, 15 patients (13.5%) underwent liver transplantation a mean of 5.1 years after DSRS without an increase in morbidity or mortality after transplantation. CONCLUSIONS: Distal splenorenal shunt may be the preferred treatment for recurrent variceal hemorrhage in the patient with well-compensated cirrhosis. In addition, DSRS does not cause increased morbidity or mortality in subsequent liver transplantation.

Transpl Infect Dis. 2006 Mar;8(1):3-12.
Rejection rates in a randomised trial of tacrolimus monotherapy versus triple therapy in liver transplant recipients with hepatitis C virus cirrhosis.
Samonakis DN, Mela M, Quaglia A, Triantos CK, Thalheimer U, Leandro G, Pesci A, Raimondo ML, Dhillon AP, Rolles K, Davidson BR, Patch DW, Burroughs AK.
Liver Transplantation and Hepatobiliary Unit, Royal Free Hospital, Hampstead, London, UK.

Background. Reducing immunosuppression not only reduces complications but also may lessen recurrent hepatitis C virus (HCV) infection after liver transplantation. Patients/Methods. HCV-infected cirrhotic patients randomised to tacrolimus monotherapy (MT) or triple therapy (TT) using tacrolimus 0.1 mg/kg/day, azathioprine 1 mg/kg/day, and prednisolone 20 mg/day, tapering over 3 months. Results. Twenty-seven patients (MT) and 29 (TT) - median follow up 661 days (range, 1-1603). Rejection episodes (protocol/further biopsies) within first 3 months and use of empirical treatment were evaluated. New rejection was diagnosed if repeat biopsy (5-day interval) did not show improvement. Treated rejection episodes: 20 MT (15 biopsy-proven) vs. 24 TT (21 biopsy-proven), with 19 (MT) vs. 24 (TT) methylprednisolone boluses. Overall: 35 episodes (MT) and 46 (TT). Fewer MT patients had histological rejection (70%) than TT patients (86%), with fewer episodes of rejection (18.5% vs. 10%), and more moderate rejection (22% vs. 41%). The MT group had higher early tacrolimus levels. Rates of renal dysfunction, retransplantation, and death were not significantly different. Conclusion. Tacrolimus monotherapy is a viable immunosuppressive strategy in HCV-infected liver transplant recipients.

Clin Transplant. 2006 Mar;20(2):211-20.
Long-term follow-up after recurrence of primary biliary cirrhosis after liver transplantation in 100 patients.
Jacob DA, Neumann UP, Bahra M, Klupp J, Puhl G, Neuhaus R, Langrehr JM.
Department of General, Visceral and Transplantation Surgery, Humboldt University of Berlin, Charite Virchow Clinic, Berlin, Germany.

Orthotopic liver transplantation (OLT) is the only effective curative therapy for end-stage primary biliary cirrhosis (PBC). Survival after OLT is excellent, although recent data have shown a recurrence rate of PBC of up to 32% after transplantation. The aim of this study is to investigate the course after disease recurrence, particularly with regard to liver function and survival in a long-term follow-up. Between April 1989 and April 2003, 1553 liver transplantations were performed in 1415 patients at the Charite, Virchow Clinic. Protocol liver biopsies were taken after one, three, five, seven, 10 and 13 yr. One hundred (7%) patients suffered from histologically proven PBC. Primary immunosuppression consisted of cyclosporine (n=54) or tacrolimus (Tac) (n=46). Immediately after OLT, all patients received ursodeoxycholic acid. Corticosteroids were withdrawn three to six months after OLT. The median age of the 85 women and 15 men was 55 yr (range 25-66 yr). The median follow-up after liver transplantation was 118 months (range 16-187 months) and after recurrence 30 months (range 4-79 months). Actuarial patient survival after five, 10 and 15 yr was 87, 84 and 82% respectively. Ten patients (10%) died after a median survival time of 32 months. Two of these patients developed organ dysfunction owing to recurrence of PBC. Histological recurrence was found in 14 patients (14%) after a median time of 61 months (range 36-122 months). Patients with Tac immunosuppression developed PBC recurrence more often (p<0.05) and also earlier (p<0.05). Fifty-seven patients developed an acute rejection and two patients a chronic rejection episode. Liver function did not alter within the first five yr after histologically proven PBC recurrence. Multivariate analysis of the investigated patients showed that the recipient's age and Tac immunosuppression were significant risk factors for PBC recurrence. Long-term follow-up of up to 15 yr after liver transplantation, owing to PBC, in addition to maintenance of liver function, shows excellent organ and patient survival rates. Although protocol liver biopsies revealed histological recurrence in 14 (14%) patients, only two patients developed graft dysfunction. Tac-treated patients showed more frequently and also earlier histologically proven PBC recurrence; however, in our population we could not observe an impact on graft dysfunction and patient's survival.

Gastroenterology. 2006 Mar;130(3):715-20.
Excellent long-term survival in patients with primary biliary cirrhosis and biochemical response to ursodeoxycholic Acid.
Pares A, Caballeria L, Rodes J.
Liver Unit, Digestive Diseases Institute, Hospital Clinic, IDIBAPS, Barcelona, Spain. pares@ub.edu

BACKGROUND & AIMS: Because the efficacy of UDCA on long-term outcome of primary biliary cirrhosis (PBC) has not been completely elucidated, we have assessed the course and survival of patients with PBC treated with UDCA and compared with the survival predicted by the Mayo model and the estimated survival of a standardized population. METHODS: (One hundred ninety-two patients [181 women] with PBC treated with UDCA [15 mg/kg per day] for 1.5-14 years.) Response to treatment was defined by an alkaline phosphatase decrease greater than 40% of baseline values or normal levels after 1 year of treatment. The predicted survival was obtained by the Mayo model and the estimated survival was taken from the standardized matched Spanish population. RESULTS: Seventeen patients died or fulfilled criteria for liver transplantation (8.9%). The observed survival was higher than that predicted by the Mayo model and lower than that of the control population (P < .001). One hundred seventeen patients (61%) responded to treatment. The survival of responders was significantly higher than that predicted by the Mayo model and similar to that estimated for the control population (P = .15). By contrast, the survival of patients without biochemical response was lower than that estimated for the Spanish population (P < .001) although higher than that predicted by the Mayo model. CONCLUSIONS: Biochemical response to UDCA after 1 year is associated with a similar survival to the matched control population, clearly supporting the favorable effects of this treatment in PBC. The suboptimal survival of nonresponders identifies the group for further treatments.

Liver Transpl. 2006 Feb;12(2):320-3.
Indications for chronic albumin infusion.
Perkins JD.
Liver Transplantation Worldwide, University of Washington Medical Center, Seattle, WA.

While transjugular intrahepatic portosystemic shunt (TIPS) is a common therapy for cirrhotic patients with diuretic-resistant or diuretic-refractory ascites, some patients are unsuitable for the procedure for technical or medical reasons. We report our experience with the use of chronic intravenous albumin infusions to achieve diuresis in this difficult patient population and review the historic experience of chronic albumin infusions as a treatment for ascites. Nineteen patients with cirrhosis and diuretic-resistant or diuretic-refractory ascites who were deemed unsuitable for TIPS received outpatient intravenous albumin infusions (50 g) weekly for at least 4 weeks. The following endpoints were retrospectively recorded: serum sodium, serum creatinine, blood urea nitrogen, hematocrit, bilirubin, albumin, international normalized ratio, body weight, and Model for End-stage Liver Disease (MELD) score. The contraindications for TIPS included the following: portal vein thrombosis, two; advanced age, one; encephalopathy, nine; hyperbilirubinemia, five; and other, two. Compared to pretreatment, posttreatment weight decreased in 17 patients, remained unchanged in 0 patients, and increased in 2 patients. The overall mean change in body weight (before vs. after therapy) was 8 lb (P < 0.05). The only significant change in biochemistries was an increase in serum albumin from 2.5 g/dl before therapy to 3.5 g/dl after therapy (P < 0.05). We conclude that (1) recurrent intravenous weekly albumin infusions resulted in significant loss of edema and ascites as measured by loss of body weight, and (2) clinicians may want to consider chronic albumin infusions for selected patients with refractory ascites who are not candidates for TIPS.

J Hepatol. 2006 Feb;44(2):400-6. Epub 2005 Nov 15.
Long term outcome and response to therapy of primary biliary cirrhosis-autoimmune hepatitis overlap syndrome.
Chazouilleres O, Wendum D, Serfaty L, Rosmorduc O, Poupon R.
Service d'Hepatologie, Centre de reference des maladies inflammatoires du foie et des voies biliaires, Hopital Saint Antoine, Assistance Publique-Hopitaux de Paris, Faculte de Medecine Pierre et Marie Curie, Paris, France.

BACKGROUND/AIMS: Whether primary biliary cirrhosis (PBC)-autoimmune hepatitis (AIH) overlap syndrome requires immunosuppressive therapy in addition to ursodeoxycholic acid (UDCA) is a controversial issue. METHODS: Seventeen patients with simultaneous form of strictly defined overlap were followed for 7.5 years. First-line treatment was UDCA alone (UDCA) in 11 and combination of immunosuppressors and UDCA (UDCA+IS) in 6. RESULTS: Characteristics at presentation were not significantly different between the 2 groups. In the UDCA+IS group (f-up 7.3 years), biochemical response in terms of AIH features (ALT<2ULN and IgG<16g/L) was achieved in 4/6 and fibrosis did not progress. In the UDCA group, biochemical response was observed in three patients together with stable or decreased fibrosis (f-up 4.5 years) whereas the eight others were non-responders with increased fibrosis in four (f-up 1.6 years). Seven of these eight patients subsequently received combined therapy for 3 years. Biochemical response was obtained in 6/7 and no further increase of fibrosis was demonstrated. Overall, fibrosis progression in non-cirrhotic patients occurred more frequently under UDCA monotherapy (4/8) than under combined therapy (0/6) (P=0.04). CONCLUSIONS: Combination of UDCA and immunosuppressors appears to be the best therapeutic option for strictly defined PBC-AIH overlap syndrome.

J Gastroenterol Hepatol. 2006 Jan;21(1):303-7.
Terlipressin versus albumin in paracentesis-induced circulatory dysfunction in cirrhosis: A randomized study.
Singh V, Kumar R, Nain CK, Singh B, Sharma AK.
Department of Hepatology, Postgraduate Institute of Medical Education and Research, Chandigarh, India.

Background: Therapeutic paracentesis in patients with cirrhosis induces arterial vasodilatation, causes a decrease in effective arterial blood volume and leads to circulatory dysfunction, which can be prevented by intravenous albumin. However, the use of albumin, being a blood product, is controversial. Recently, terlipressin, a vasoconstrictor, has been successfully used to combat this adverse effect of therapeutic paracentesis. Therefore, the aim of the present study was to investigate the preventive effect of terlipressin on paracentesis-induced circulatory dysfunction in patients with cirrhosis after therapeutic paracentesis and compared with that of intravenous albumin. Methods: Forty patients with cirrhosis and tense ascites underwent therapeutic paracentesis with albumin or terlipressin in a randomized pilot study at a tertiary center. Effective arterial blood volume was assessed by measuring plasma renin activity at baseline and at 4-6 days after treatment. Results: Effective arterial blood volumes as indicated by plasma renin activity before and 4-6 days after paracentesis did not differ in the two groups (19.15 +/- 12.1 to 20.33 +/- 12.8 ng/mL per h, P = 0.46 in the albumin group; and 20.11 +/- 10.6 to 21.08 +/- 10.52 ng/mL per h, P = 0.44 in the terlipressin group). Plasma aldosterone concentrations before and 4-6 days after paracentesis were also similar in both groups (1334.75 +/- 1058 to 1440.0 +/- 1161 pg/mL, P = 0.06 in the albumin group; and 1473.0 +/- 1168 to 1572.29 +/- 1182 pg/mL, P = 0.24 in the terlipressin group). Both terlipressin and albumin prevented paracentesis-induced renal impairment in these patients. Conclusions: Terlipressin may be as effective as intravenous albumin in preventing paracentesis-induced circulatory dysfunction in patients with cirrhosis after therapeutic paracentesis.

Hepatology. 2006 Jan 30;43(S1):S99-S112 [Epub ahead of print]
Nonalcoholic fatty liver disease: From steatosis to cirrhosis.
Farrell GC, Larter CZ.
The Storr Liver Unit, Westmead's Millennium Institute, University of Sydney at Westmead Hospital, Westmead, NSW, Australia.

Nonalcoholic steatohepatitis (NASH), the lynchpin between steatosis and cirrhosis in the spectrum of nonalcoholic fatty liver disorders (NAFLD), was barely recognized in 1981. NAFLD is now present in 17% to 33% of Americans, has a worldwide distribution, and parallels the frequency of central adiposity, obesity, insulin resistance, metabolic syndrome and type 2 diabetes. NASH could be present in one third of NAFLD cases. Age, activity of steatohepatitis, and established fibrosis predispose to cirrhosis, which has a 7- to 10-year liver-related mortality of 12% to 25%. Many cases of cryptogenic cirrhosis are likely endstage NASH. While endstage NAFLD currently accounts for 4% to 10% of liver transplants, this may soon rise. Pathogenic concepts for NAFLD/NASH must account for the strong links with overnutrition and underactivity, insulin resistance, and genetic factors. Lipotoxicity, oxidative stress, cytokines, and other proinflammatory mediators may each play a role in transition of steatosis to NASH. The present "gold standard" management of NASH is modest weight reduction, particularly correction of central obesity achieved by combining dietary measures with increased physical activity. Whether achieved by "lifestyle adjustment" or anti-obesity surgery, this improves insulin resistance and reverses steatosis, hepatocellular injury, inflammation, and fibrosis. The same potential for "unwinding" fibrotic NASH is indicated by studies of the peroxisome proliferation activator receptor (PPAR)-gamma agonist "glitazones," but these agents may improve liver disease at the expense of worsening obesity. Future challenges are to approach NAFLD as a preventive public health initiative and to motivate affected persons to adopt a healthier lifestyle. (Hepatology 2006;43:S99-S112.).

Wien Klin Wochenschr. 2005 Dec;117 Suppl 6:54-9.
[Peritoneal dialysis in patients with liver cirrhosis and/or ascites.]
[Article in German]
Paul G.
3. Medizinische Abteilung, Donauspital, Sozialmedizinisches Zentrum Ost der Stadt Wien, Wien, Austria, gernot.paul@wienkav.at.

In older textbooks the use of peritoneal dialysis (PD) in patients with liver cirrhosis and/or ascites was contraindicated. Only a small number of papers have focused on this problem and they mainly consist of case reports and retrospective studies of small numbers of patients. In addition, most nephrologists' experience of performing PD in patients with liver diseases is rather limited. Nevertheless, for these patients PD offers a wide range of advantages, such as a simplified ascites management, since repeated abdominal punctures become unnecessary. Furthermore, because of continuous peritoneal ultrafiltration, hemodynamic tolerance during PD is significantly better than in hemodialysis and results in a markedly lower frequency of hypotensive episodes. The risk of nosocomial infection with hepatitis B or C viruses can also be reduced by treating these patients with home PD. Although some authors suggest that PD patients with liver cirrhosis have an especially increased risk of Gram-negative peritonitis, currently available data show controversial results. There is also little information in the literature on the impact of increased peritoneal protein loss on malnutrition and outcome of these patients. Nevertheless, recent studies have shown that protein loss into the peritoneal cavity in PD patients with liver cirrhosis is high only initially, stabilizing at a lower level in the further course of treatment. In conclusion, in patients with end-stage renal disease suffering from liver cirrhosis and/or ascites, PD can be considered as a good or adequate treatment option.

Am Surg. 2005 Dec;71(12):996-1000.
Cirrhosis and trauma: a deadly duo.
Christmas AB, Wilson AK, Franklin GA, Miller FB, Richardson JD, Rodriguez JL.
Department of Surgery, University of Louisville, Louisville, Kentucky 40292, USA.

It has been previously reported that trauma patients with cirrhosis undergoing emergency abdominal operations exhibit a fourfold increase in mortality independent of their Child's classification. We undertook this review to assess the impact of cirrhosis on trauma patients. We reviewed the records of patients from 1993 to 2003 with documented hepatic cirrhosis and compared them to a 2:1 control population without hepatic cirrhosis and matched for age, sex, Injury Severity Score (ISS), and Glasgow Coma Score (GCS). Demographic, severity of injury, and outcome data were recorded. Student's t test and X2 were used for statistical analysis and a P < 0.05 was significant. Sixty-one patients had documented cirrhosis and were compared to 156 matched controls. Comparing the two groups demonstrates there was no difference in age, ISS, or GCS. Intensive care stay, hospital length of stay, blood requirements in the first 24 hours postinjury, and mortality (33% vs 1%) was significantly greater in the trauma patients with cirrhosis. Fifty-five per cent of deaths in the cirrhosis group was due to sepsis, and, as the Child's class increases, so does the mortality (Child's A, 15%; B, 37%; and C, 63%). In 64 per cent of cirrhotics without an emergent abdominal operation, mortality was 21 per cent. In the 36 per cent of cirrhotics who had emergent abdominal operation, mortality was 55 per cent. Hepatic cirrhosis in trauma patients, regardless of severity of injury or the need for an abdominal intervention, is a poor prognostic indicator. The necessity of an abdominal operative intervention further amplifies this effect. Trauma and cirrhosis is, in fact, a deadly duo.

Arq Gastroenterol. 2005 Oct-Dec;42(4):256-62. Epub 2006 Jan 19.
Trimethoprim-sulfamethoxazole versus norfloxacin in the prophylaxis of spontaneous bacterial peritonitis in cirrhosis.
Alvarez RF, Mattos AA, Correa EB, Cotrim HP, Nascimento TV.
Department of Gastroenterology and Hepatology, Federal School of Medical Sciences of Porto Alegre, Porto Alegre, RS, Brazil.

BACKGROUND: The prognosis of patients with chronic liver disease and spontaneous bacterial peritonitis is poor, being of great importance its prevention. AIM: To compare the effectiveness of trimethoprim-sulfamethoxazole versus norfloxacin for prevention of spontaneous bacterial peritonitis in patients with cirrhosis and ascites. PATIENTS AND METHODS: Fifty seven patients with cirrhosis and ascites were evaluated between March 1999 and March 2001. All of them had a previous episode of spontaneous bacterial peritonitis or had ascitic fluid protein concentration < or = 1 g/dL and/or serum bilirubin > or = 2.5 mg/dL. The patients were randomly assigned to receive either 800/160 mg/day of trimethoprim-sulfamethoxazole 5 days a week or 400 mg of norfloxacin daily. The mean time of observation was 163 days for the norfloxacin group and 182 days for the trimethoprim-sulfamethoxazole group. In the statistical analysis, differences were considered significant at the level of 0.05. RESULTS: According to the inclusion criteria, 32 patients (56%) were treated with norfloxacin and 25 (44%) with trimethoprim-sulfamethoxazole. Spontaneous bacterial peritonitis occurred in three patients receiving norfloxacin (9.4%) and in four patients receiving trimethoprim-sulfamethoxazole (16.0%). Extraperitoneal infections occurred in 10 patients receiving norfloxacin (31.3%) and in 6 patients receiving trimethoprim-sulfamethoxazole (24.0%). Death occurred in seven patients (21.9%) who received norfloxacin and in five (20.0%) who received trimethoprim-sulfamethoxazole. Side effects occurred only in the trimethoprim-sulfamethoxazole group. CONCLUSION: In spite of the reduced number of patients and time of observation, trimethoprim-sulfamethoxazole and norfloxacin were equally effective in spontaneous bacterial peritonitis prophylaxis, suggesting that trimethoprim-sulfamethoxazole is a valid alternative to norfloxacin.

Radiologe. 2005 Nov;45(11):1012-9.
[Interventions for benign biliary strictures.]
[Article in German]
Lubienski A, Duex M, Lubienski K, Blietz J, Kauffmann GW, Helmberger T.
Institut fur Radiologie, Campus Lubeck des Universitatsklinikums Schleswig-Holstein.

Due to their potential for serious consequences, even including biliary liver cirrhosis, benign biliary strictures pose a considerable diagnostic and therapeutic challenge. In addition to inflammatory disease or an acute liver injury, iatrogenically caused biliary strictures following hepatobiliary surgery represent in 95% of cases the main cause for all benign entities.The diagnosis should be determined noninvasively with magnetic resonance cholangiopancreaticography (MRCP). Invasive techniques such as ERCP or percutaneous transhepatic cholangiography (PTC) should be reserved for unclear cases and first performed before the scheduled intervention.Depending on the site and cause of the stricture, surgical and interventional procedures are employed in the treatment of biliary strictures. The best results are obtained in short-segment strictures of the main bile duct. Interventional methods such as balloon dilation and/or stent application with concomitant drain insertion achieve patency rates of up to 75% after 5 and 55% after 12 years with a total complication rate of 5-8%. Due to the fact that most of the cases involve cicatricial fibroses, predisposition for recurrence of biliary strictures after interventional therapy can be very high, ranging up to 66% depending on the localization.

Hepatology. 2005 Nov;42(5):1184-93.
Methotrexate (MTX) plus ursodeoxycholic acid (UDCA) in the treatment of primary biliary cirrhosis.
Combes B, Emerson SS, Flye NL, Munoz SJ, Luketic VA, Mayo MJ, McCashland TM, Zetterman RK, Peters MG, Di Bisceglie AM, Benner KG, Kowdley KV, Carithers RL Jr, Rosoff L Jr, Garcia-Tsao G, Boyer JL, Boyer TD, Martinez EJ, Bass NM, Lake JR, Barnes DS, Bonacini M, Lindsay KL, Mills AS, Markin RS, Rubin R, West AB, Wheeler DE, Contos MJ, Hofmann AF.
The University of Texas Southwestern Medical Center at Dallas, Dallas, TX.

This placebo-controlled, randomized, multicenter trial compared the effects of MTX plus UDCA to UDCA alone on the course of primary biliary cirrhosis (PBC). Two hundred and sixty five AMA positive patients without ascites, variceal bleeding, or encephalopathy; a serum bilirubin less than 3 mg/dL; serum albumin 3 g/dL or greater, who had taken UDCA 15 mg/kg daily for at least 6 months, were stratified by Ludwig's histological staging and then randomized to MTX 15 mg/m(2) body surface area (maximum dose 20 mg) once a week while continuing on UDCA. The median time from randomization to closure of the study was 7.6 years (range: 4.6-8.8 years). Treatment failure was defined as death without liver transplantation; transplantation; variceal bleeding; development of ascites, encephalopathy, or varices; a doubling of serum bilirubin to 2.5 mg/dL or greater; a fall in serum albumin to 2.5 g/dL or less; histological progression by at least two stages or to cirrhosis. Patients were continued on treatment despite failure of treatment, unless transplantation ensued, drug toxicity necessitated withdrawal, or the patient developed a cancer. There were no significant differences in these parameters nor to the time of development of treatment failures observed for patients taking UDCA plus MTX, or UDCA plus placebo. The trial was conducted with a stopping rule, and was stopped early by the National Institutes of Health at the advice of our Data Safety Monitoring Board for reasons of futility. In conclusion, methotrexate when added to UDCA for a median period of 7.6 years had no effect on the course of PBC treated with UDCA alone. Supplementary material for this article can be found on the HEPATOLOGY website (http://www.interscience.wiley.com/jpages/0270-9139/suppmat/index.html). (HEPATOLOGY 2005;42:1184-1193.).

Liver Transpl. 2005 Oct;11(10):1252-7.
Recurrent primary biliary cirrhosis: Peritransplant factors and ursodeoxycholic acid treatment post-liver transplant.
Guy JE, Qian P, Lowell JA, Peters MG.
Department of Medicine University of California San Francisco, CA.

Primary biliary cirrhosis (PBC) recurs after orthotopic liver transplantation (OLT) in up to one-third of patients. These patients are typically asymptomatic, can be identified by abnormal liver biochemistries, and have evidence of histologic recurrence on liver biopsy. The effect of treatment on recurrence has not been determined. This pilot study evaluates the factors associated with recurrent PBC and describes our experience using ursodeoxycholic acid treatment in this patient population. Forty-eight patients with PBC were followed for at least 1 yr post-OLT, and 27 patients (56%) developed abnormal serum alkaline phosphatase. Seventeen patients (35%) had evidence of recurrent PBC by liver biopsy. Patients with recurrent PBC had a trend toward longer warm ischemia times and more episodes of acute cellular rejection in the first year posttransplant, but this was not significant in multivariate analysis. Donor or recipient age, donor and recipient cytomegalovirus status, and dose of immunosuppression did not correlate with recurrence of PBC. Those patients diagnosed with recurrent PBC were placed on ursodeoxycholic acid, 15 mg/kg daily, with improvement in serum alkaline phosphatase in the majority. In conclusion, recurrent PBC is not infrequent post-OLT, and ursodeoxycholic acid can be used with some benefit post-OLT. Treatment effects on long-term survival are not known. (Liver Transpl 2005;11:1252-1257.).

Rev Prat. 2005 Sep 30;55(14):1539-48.
[Liver cirrhosis in adults: etiology and specific treatments]
[Article in French]
Fartoux L, Serfaty L.
Service d'hepatologie, hopital Saint-Antoine, 75571 Paris. laetitia.fartoux@sat.ap-hop.paris.fr

Cirrhosis is the result of chronic inflammation and of the progressive increase of fibrosis. In France, hepatitis C infection is the second cause of cirrhosis after alcohol abuse. The other causes of cirrhosis are: hepatitis B infection, genetic haemochromatosis, autoimmune hepatitis, primary biliary cirrhosis, drug-induced cirrhosis, secondary biliary cirrhosis, Wilson's disease and al-antitrypsin deficiency. Etiological treatment is based upon: abstinence in case of alcoholic cirrhosis, the combination of pegylated interferon alpha (PEG IFN) with ribavirin in case of C viral cirrhosis, the PEG IFN and the nucleoside analogs in case of B viral cause; corticosteroids and immunosuppressive drugs in case of autoimmune cirrhosis; venesections in case of genetic haemochromatosis and stopping the drug in case of drug-induced cirrhosis. The complications of cirrhosis such as ascites, oesophageal varices, bleeding, hepatic encephalopathy and hepatocellular carcinoma mainly explain the high rate of morbidity and mortality. Liver transplantation is the established therapy for decompensated liver disease of any etiology significantly changed the outcome of patients with advanced cirrhosis.

Z Gastroenterol. 2005 Sep;43(9):1051-9.
Ursodeoxycholic acid in the therapy for primary biliary cirrhosis: effects on progression and prognosis.
Leuschner U, Manns MP, Eisebitt R.
Medizinische Klinik der Johann Wolfgang Goethe Universitat, Frankfurt am Main, Germany. U.Leuschner@em.uni-Frankfurt.de

The effects in clinical studies of UDCA on the endpoints "death" or "pre-transplantation survival" can only be shown when UDCA therapy is started in an early disease phase, preferably in stage I but no later than stage II, and is then continued into stages III/IV, or preferably stage IV. The reasons for this lie in the observation that, in stages I/II, no patient suffers from progressive disease that irrevocably leads to death or transplantation, while a measurable effect of UDCA, as is true for other drugs and other hepatic diseases, continues to dwindle and finally disappears as patients progress through the fibrotic and cirrhotic stages III and IV. Hence, administration of UDCA must begin in the phase of progressive inflammation (stages I and II) and the outcome documented after many years of long-term therapy. This requires very large, probably unattainable, patient collectives. Whether it is justified to administer placebo to one-half of these patients over such an extended period of time represents a profound ethical dilemma. Because these arguments were not considered in the two meta-analyses cited above or in any other study, they do not allow a definitive statement on the life expectancy of patients on UDCA therapy. On the other hand, it is possible using generally accepted, independent prognostic variables and mathematical models, whose limitations are well-known and must be considered, to predict with a high degree of accuracy the disease course of treated and untreated patients and calculate their life expectancy and/or pre-transplantation survival. Because UDCA exerts a significant positive effect on the most important prognostic markers for PBC, such as serum bilirubin, piecemeal necroses, histological disease progression, ascites and edema, and apparently the scores for pruritus and fatigue, this permits us to demonstrate not only a decrease in the incidence of transplantation but also to calculate a prolongation in life expectancy.

Semin Liver Dis. 2005 Aug;25(3):321-6.
The natural history of PBC: has it changed?
Lee YM, Kaplan MM.
Tufts-New England Medical Center, Boston, MA 02111, USA. ylee@tufts-nemc.org

The prognosis and natural history of primary biliary cirrhosis (PBC) have improved significantly during the last few decades. Patients are diagnosed at earlier stages, are more likely to be asymptomatic at diagnosis, and are more likely to receive medical treatment. The survival of asymptomatic patients is longer than the median survival of symptomatic patients. The natural history of PBC has been assessed in the presence of effective therapy, ursodeoxycholic acid (UDCA). Evidence suggests that UDCA delays histological progression in PBC and decreases the risk of development of esophageal varices. Survival of UDCA-treated patients is better than that of untreated patients and also is better than that predicted by the Mayo model. For patients in early stages of PBC, UDCA treatment may normalize survival. However, patients with stage III and IV PBC do not respond as well to UDCA. Therefore, there is a continued need for additional treatment in patients with advanced disease.

Semin Liver Dis. 2005 Aug;25(3):311-20.
Overlap syndromes.
Beuers U, Rust C.
Department of Medicine II-Grosshadern, Ludwig Maximilians-University of Munich, Germany. Beuers@med.uni-muenchen.de

In hepatology, the term overlap syndrome describes variant forms of the major hepatobiliary autoimmune diseases, autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), and primary sclerosing cholangitis (PSC). Patients with overlap syndromes present with both hepatitic and cholestatic biochemical and histological features of AIH, PBC, and/or PSC, and usually show a progressive course toward liver cirrhosis and liver failure without adequate treatment. AIH-PBC overlap syndromes have been reported in almost 10% of adults with AIH or PBC, whereas AIH-PSC overlap syndromes were found in 6 to 8% of children, adolescents, and young adults with AIH or PSC. A minority of patients may also show transition from stable PBC to AIH, AIH to PBC, or AIH to PSC, as documented by single case reports and small case series. Single cases of AIH and autoimmune cholangitis (antimitochondrial antibody-negative PBC) overlap have also been reported. Empiric medical treatment of AIH-PBC and AIH-PSC overlap syndromes includes anticholestatic therapy with ursodeoxycholic acid and immunosuppressive therapy with corticosteroids and azathioprine. In end-stage disease, liver transplantation is the treatment of choice.

Am J Gastroenterol. 2005 Aug;100(8):1876-85.
Colchicine for primary biliary cirrhosis: a cochrane hepato-biliary group systematic review of randomized clinical trials.
Gong Y, Gluud C.
The Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Center for Clinical Intervention Research, H:S Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.

OBJECTIVES: Colchicine is used for patients with primary biliary cirrhosis due to its immunomodulatory and antifibrotic potential. The results from randomized clinical trials have, however, been inconsistent. We conducted a systematical review to evaluate the effect of colchicine for primary biliary cirrhosis. METHODS: We identified randomized clinical trials comparing colchicine with placebo/no intervention. We analyzed effects by fixed and random effects model. We investigated heterogeneity by subgroup and sensitivity analyses. RESULTS: We included 10 trials involving 631 patients, four of which were high-quality trials. No significant differences were detected between colchicine and placebo/no intervention regarding mortality (relative risk (RR), 1.21; 95% confidence interval (CI), 0.71-2.06), mortality or liver transplantation (RR = 1.00; 95% CI, 0.67-1.49), liver complications, liver biochemical variables, liver histology, or adverse events. Regarding mortality, an extreme case analysis favoring colchicine did not demonstrate beneficial effects of colchicine, whereas an extreme case analysis favoring placebo/no intervention demonstrated a detrimental effect of colchicine (RR = 2.28; 95% CI, 1.17-4.44). The number of patients without improvement of pruritus significantly decreased in the colchicine group (RR = 0.75; 95% CI, 0.65-0.87). However, this estimate was based on only 156 patients from three trials. CONCLUSIONS: There is insufficient evidence to support the use of colchicine for patients with primary biliary cirrhosis. As we are unable to exclude a risk of increased mortality, we recommend to use colchicine only in randomized clinical trials. (Am J Gastroenterol 2005;100:1-10).

Hepatogastroenterology. 2005 Jul-Aug;52(64):1180-5.
Clinical outcome of 214 liver resections using microwave tissue coagulation.
Satoi S, Kamiyama Y, Matsui Y, Kitade H, Kaibori M, Yamamoto H, Yanagimoto H, Takai S, Kwon AH.
Department of Surgery, Kansai Medical University, Osaka, Japan. satoi@takii.kmu.ac.jp

BACKGROUND/AIMS: Liver resection is the most effective form of treatment for patients with hepatocellular carcinoma. The use of a microwave tissue coagulator has been reported to enable limited liver resections for the patients with poor hepatic reserve. Herein, we report the clinical outcome of 214 patients with HCC who underwent non-anatomical liver resection using MTC in accordance with the tumor size. METHODOLOGY: A consecutive series of 214 patients who underwent liver resections using MTC were observed over a 10-year study period. The clinical characteristics of patients were evaluated. The operative mortality and morbidity, overall patient survival and disease-free survival were calculated. RESULTS: Seventy-two percent of patients suffered from type C hepatitis and 47% of patients had pathologically proven liver cirrhosis. The overall patient survival rates were 91, 72, and 58% at 1, 3 and 5 years, respectively. Disease-free survival rates were 74, 46, and 28% at 1, 3 and 5 years, respectively. Postoperative morbidity was 36% and hospital mortality was 2.8%. Complications in most patients were well controlled. CONCLUSIONS: Non-anatomical liver resections using MTC, in accordance with tumor sizes, can be achieved safely with acceptable results and without the need to use special techniques.

Cochrane Database Syst Rev. 2005 Jul 20;(3):CD004385.
Methotrexate for primary biliary cirrhosis.
Gong Y, Gluud C.
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Dept. 7102, Blegdamsvej 9, H:S Rigshospitalet, Copenhagen, DENMARK, DK-2100.

BACKGROUND: Methotrexate, a folic acid antagonist with immunosuppressive properties, has been used to treat patients with primary biliary cirrhosis. The therapeutic responses to methotrexate in randomised clinical trials have been heterogeneous. OBJECTIVES: To assess the beneficial and harmful effects of methotrexate for patients with primary biliary cirrhosis. SEARCH STRATEGY: Relevant randomised clinical trials were identified by searching The Cochrane Hepato-Biliary Group Controlled Trials Register (June 2004), The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 2, 2004), MEDLINE (January 1966 to August 2004), EMBASE (January 1980 to August 2004), and manual searches of bibliographies. We contacted authors of trials and pharmaceutical companies. SELECTION CRITERIA: Randomised clinical trials comparing methotrexate with placebo, no intervention, or another drug were included irrespective of blinding, language, year of publication, and publication status. DATA COLLECTION AND ANALYSIS: Our primary outcomes were mortality and mortality or liver transplantation. Dichotomous outcomes were reported as relative risk (RR) and hazard ratio (HR) if applicable. Continuous outcomes were reported as weighted mean difference (WMD). We examined intervention effects by using both a random-effects model and a fixed-effect model. Heterogeneity was investigated by subgroup analyses and sensitivity analyses. MAIN RESULTS: We identified four trials (370 patients) that compared methotrexate with placebo with or without ursodeoxycholic acid as co-intervention. One additional trial (87 patients) compared methotrexate with colchicine without and later with ursodeoxycholic acid as co-intervention. The methodological quality of the trials was low. We did not find significant effects of methotrexate on pruritus, fatigue, liver complications, liver biochemistry, liver histology, or adverse events. The pruritus score (WMD - 0.68, 95% CI - 1.11 to - 0.25), the levels of serum alkaline phosphatases (WMD - 0.41, 95% CI - 0.70 to - 0.12) and plasma immunoglobulin M (WMD - 0.47, 95% CI - 0.74 to - 0.20) were significantly lower in the patients receiving methotrexate. AUTHORS' CONCLUSIONS: Methotrexate increased mortality in patients with primary biliary cirrhosis. We do not recommend methotrexate for patients with primary biliary cirrhosis outside randomised trials.

Cochrane Database Syst Rev. 2005 Jul 20;(3):CD004792.
Vitamin K for upper gastrointestinal bleeding in patients with liver diseases.
Marti-Carvajal A, Marti-Pena A.

BACKGROUND: Upper gastrointestinal bleeding is one of the most frequent causes of morbidity and mortality in the course of liver cirrhosis. Several treatments are used for upper gastrointestinal bleeding in patients with liver diseases. However, supplementary interventions are often used as well. One of them is vitamin K administration, but it is unknown whether it benefits or harms patients with liver disease and upper gastrointestinal bleeding. OBJECTIVES: To assess the beneficial and harmful effects of vitamin K for patients with liver disease and upper gastrointestinal bleeding. SEARCH STRATEGY: We searched The Cochrane Hepato-Biliary Group Controlled Trials Register (February 2004), which comprises references identified from comprehensive electronic database searches and handsearching of relevant journals and abstract books of conference proceedings, The Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (Issue 1, 2004), MEDLINE (1966 to March 2004), EMBASE (1988 to March 2004), and LILACS (1982 to March 2004). Additional randomised trials were sought from the reference lists of the trials found and reviews identified by the electronic searches. SELECTION CRITERIA: We intended to include randomised clinical trials. DATA COLLECTION AND ANALYSIS: We intended to summarise data by standard Cochrane Collaboration methodologies. MAIN RESULTS: We could not find any randomised trials on vitamin K for upper gastrointestinal bleeding in patients with liver diseases. AUTHORS' CONCLUSIONS: We were unable to identify randomised trials on the safety and efficacy of vitamin K for upper gastrointestinal bleeding in patients with liver diseases. The effects of vitamin K need to be tested in randomised clinical trials.

Arch Surg. 2005 Jul;140(7):650-4; discussion 655.
The safety of intra-abdominal surgery in patients with cirrhosis: model for end-stage liver disease score is superior to Child-Turcotte-Pugh classification in predicting outcome.
Befeler AS, Palmer DE, Hoffman M, Longo W, Solomon H, Di Bisceglie AM.
Division of Gastroenterology and Hepatology, Department of Internal Medicine, Saint Louis University, St Louis, MO 63110, USA.

HYPOTHESIS: We hypothesized that the model for end-stage liver disease (MELD) score may be a better and less subjective method than the Child-Turcotte-Pugh score for stratifying patients with cirrhosis before abdominal surgery. DESIGN: Retrospective medical record review. SETTING: Tertiary care institution. PATIENTS: Fifty-three adult patients with histologically proven cirrhosis undergoing abdominal surgery at Saint Louis University Hospital, St Louis, Mo, between 1991 and 2001. Those undergoing hepatic surgery (such as resection or transplantation) or closed abdominal surgery (such as hernia repair) were excluded. MAIN OUTCOME MEASURE: A poor outcome after surgery was defined as death or liver transplantation within 90 days of the operative procedure or a hospital stay of longer than 21 days. Demographic, clinical, and laboratory features predictive of poor outcome were assessed by multivariate analysis. RESULTS: A total of 13 patients (25%) had poor outcomes including 9 deaths (17%). Model for end-stage liver disease score and plasma hemoglobin levels lower than 10 g/dL were found to be independent predictors of poor outcomes. A MELD score of 14 or greater was a better clinical predictor of poor outcome than Child-Turcotte-Pugh class C. CONCLUSIONS: A MELD score of 14 or greater should be considered as a replacement for Child-Turcotte-Pugh class C as a predictor of being very high risk for abdominal surgery. Patients with cirrhosis with hemoglobin levels lower than 10 g/dL should receive corrective blood transfusions before abdominal surgery.

Hepatology. 2005 Jun;41(6):1305-12.
A randomized, controlled crossover trial of ondansetron in patients with primary biliary cirrhosis and fatigue.
Theal JJ, Toosi MN, Girlan L, Heslegrave RJ, Huet PM, Burak KW, Swain M, Tomlinson GA, Heathcote EJ.
Department of Medicine, University Health Network, University of Toronto, Toronto, Canada.

Fatigue is common in primary biliary cirrhosis (PBC). Altered central serotonergic neurotransmission may be involved in its pathogenesis. This multicenter, randomized, double-blind, placebo-controlled, crossover trial evaluated the efficacy of ondansetron, a selective 5-HT3 receptor subtype antagonist, for treating fatigue in PBC. A crossover design was chosen, allowing subjects to serve as their own controls-appropriate to evaluate fatigue, a subjective symptom. Sixty patients with clinically stable PBC, a Fatigue Severity Score (FSS) > 4, and no other identifiable cause for fatigue were enrolled. Subjects were randomized to receive ondansetron (4 mg) or placebo orally 3 times daily for 4 weeks (period 1). Subjects then crossed over, after a minimum 1-week washout period, for a further 4 weeks of ondansetron or placebo (period 2). Fatigue was measured at the beginning and end of each period by using the FSS and Fatigue Impact Scale (FIS). Six patients withdrew; the remaining 54 subjects had a mean baseline FSS of 5.55 (+/-0.1). Response to study medication in period 1 versus period 2 was not uniform; thus, it was necessary to analyze the trial periods separately. In period 1, there was no significant additional fatigue reduction on ondansetron over placebo. During period 2, FSS and FIS decreased significantly on ondansetron versus placebo (P = .001). However, period 2 results were invalidated because drug side effects unblinded subjects (constipation affected 63.0% of patients taking ondansetron, versus 13.3% on placebo). In conclusion, ondansetron administration did not confer clinically significant fatigue reduction when compared with placebo in our study population.Dig Liver Dis. 2005 Mar;37(3):176-180. Epub 2004 Dec 15.

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Quantitative treatment of the hyponatremia of cirrhosis.
Castello L, Pirisi M, Sainaghi PP, Bartoli E.
Department of Internal Medicine, Piemonte Orientale Hospital, 'Amedeo Avogadro', Via Solaroli, 17, 28100 Novara, Italy.

BACKGROUND.: Hyponatremia represents a frequent complication of liver cirrhosis, associated with adverse events and death. It is caused either by excessive water retention or solute depletion, or a combination of both. AIMS.: To determine the cause of hyponatremia clinically and to examine the usefulness of quantitative calculations of water excess and Na deficit to guide treatment. METHODS.: We studied 23 patients with liver cirrhosis and PNa</=131meq/L to determine the cause of hyponatremia and results of quantitative treatment. RESULTS.: The most frequent cause of hyponatremia was diuretic-induced Na depletion, which occurred in 14 out of 23 instances, while four patients had water excess. Hyponatremia was corrected after a quantitative estimate of the Na deficit or relative water excess by algebraic formulas. The former was quantitatively replenished as 3% NaCl, the latter was excreted with the technique of furosemide-induced diuresis and re-infusion of solute, but not water, losses. After quantitative replacement, there was a significant correlation (R=0.98, P<0.001) between the Na concentration predicted mathematically and that actually measured. CONCLUSIONS.: The hyponatremia of cirrhosis is frequently caused by diuretics. Its treatment can be effectively guided with the aid of quantitative estimates of Na deficit and/or water excess in all instances, although the methods of correction described are indicated in severe clinical conditions.

Clin Rev Allergy Immunol. 2005 Apr;28(2):167-74.
Surgical treatment of primary biliary cirrhosis and primary sclerosing cholangitis.
Loehe F, Schauer RJ.
Department of Surgery, Ludwig-Maximilians-University of Munich, Klinikum Grosshadern, Munich, Germany.

Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are progressivecholestatic liver diseases of supposed auto-immune etiology. The clinical course is unpredictableand, in many patients, leads to end-stage liver disease or a poor quality of life. Conservativetherapy only has a limited effect on the natural history, but orthotopic liver transplantation(OLT) offers a definitive therapeutic option.Retrospective analysis was performed for 38 patients with PBC and 17 patients with PSCwho underwent OLT between January 1986 and June 2003 at our institution. Median followupafter OLT was 72 mo.Cumulative survival at 5 yr post-OLT was 84% in the PBC group and 73% in the PSCgroup. Compared with OLT for other benign diseases, actuarial survival rates at 5 and 10 yrpost-OLT were significantly better for patients with PBC, whereas there was no difference insurvival after OLT for patients with PSC. Survival rate at 5 yr post-OLT was significantlyincreased for patients with PBC who had a Child-Pugh B liver cirrhosis (93%) compared withthose who had Child-Pugh C cirrhosis (60%). Retransplantation rate was 18.2% (resulting frombiliary complications in three cases). Surgical techniques had no effect on outcome after OLTin both groups.We concluded that liver transplantation represents a safe and beneficial therapy forpatients with end-stage PBC. Cirrhotic patients with PSC also benefit from OLT, with an outcomecomparable to that of liver cirrhosis of other etiologies.

Cochrane Database Syst Rev. 2005 Apr 18;(2):CD002148.
Colchicine for alcoholic and non-alcoholic liver fibrosis and cirrhosis.
Rambaldi A, Gluud C.
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Department 7102, H:S Rigshospitalet,, Copenhagen University Hospital, Blegdamsvej 9, Copenhagen, DENMARK, DK-2100.

BACKGROUND: Alcohol and hepatotropic viruses cause the majority of liver cirrhosis cases in the Western World. Colchicine is an anti-inflammatory and anti-fibrotic medication. Several randomised clinical trials have addressed the question whether colchicine has any efficacy in patients with alcoholic or non-alcoholic fibrosis and cirrhosis. OBJECTIVES: To assess the beneficial and harmful effects of colchicine in patients with alcoholic or non-alcoholic fibrosis or cirrhosis, excluding primary biliary cirrhosis. SEARCH STRATEGY: The Cochrane Hepato-Biliary Group Controlled Trials Register, The Cochrane Controlled Trials Register on The Cochrane Library, MEDLINE, EMBASE, Web of Science, and full text searches were combined (September 2004). Manufacturers and researchers in the field were also contacted. SELECTION CRITERIA: We included randomised trials irrespective of blinding, language, or publication status comparing per oral colchicine with placebo or no intervention for patients with fibrosis or cirrhosis induced by either alcohol, virus, or unknown factors (cryptogenic). DATA COLLECTION AND ANALYSIS: The statistical package (RevMan Analyses) provided by The Cochrane Collaboration was used. The methodological quality of the randomised clinical trials was evaluated. MAIN RESULTS: We could include fifteen randomised clinical trials in which 1714 patients were randomised. We found no significant effects of colchicine on mortality (relative risks (RR) 1.00, 95% confidence interval (CI) 0.87 to 1.16), liver-related mortality (RR 1.08, 95% CI 0.88 to 1.33), complications (RR 1.01, 95% CI 0.74 to 1.38), liver biochemistry, liver histology, and alcohol consumption (RR 1.03, 95% CI 0.77 to 1.39). Colchicine was associated with a significantly increased risk of adverse events (RR 4.35, 95% CI 2.16 to 8.77). AUTHORS' CONCLUSIONS: Colchicine should not be used for alcoholic, viral, or cryptogenic liver fibrosis or liver cirrhosis outside randomised clinical trials.

Gastroenterology. 2005 Apr;128(4):882-90.
Colchicine treatment of alcoholic cirrhosis: a randomized, placebo-controlled clinical trial of patient survival.
Morgan TR, Weiss DG, Nemchausky B, Schiff ER, Anand B, Simon F, Kidao J, Cecil B, Mendenhall CL, Nelson D, Lieber C, Pedrosa M, Jeffers L, Bloor J, Lumeng L, Marsano L, McClain C, Mishra G, Myers B, Leo M, Ponomarenko Y, Taylor D, Chedid A, French S, Kanel G, Murray N, Pinto P, Fong TL, Sather MR.
VA Long Beach Healthcare Systems, Long Beach, CA 90822, USA. timothy.morgan@med.va.gov

BACKGROUND & AIMS: Colchicine improved survival and reversed cirrhosis in several small clinical trials. We compared the efficacy and safety of long-term colchicine, as compared with placebo, in patients with advanced alcoholic cirrhosis. METHODS: Five hundred forty-nine patients with advanced (Pugh B or C) alcoholic cirrhosis were randomized to receive either colchicine 0.6 mg twice per day (n = 274) or placebo (n = 275). Treatment lasted from 2 to 6 years. The primary outcome was all-cause mortality. Secondary outcomes were liver-related morbidity and mortality. Liver biopsy was requested prior to entry and after 24 months of treatment. RESULTS: Attendance at scheduled clinic visits and adherence with study medication were similar in colchicine and placebo groups. Alcohol intake was less than 1 drink per day in 69% of patients. In an intention-to-treat analysis, all-cause mortality was similar in colchicine (49%) and placebo (45%) patients (P = .371). Mortality attributed to liver disease was 32% in colchicine and 28% in placebo patients (P = .337). Fewer patients receiving colchicine developed hepatorenal syndrome. In 54 patients with repeat liver biopsies after 24 or more months of treatment, cirrhosis improved to septal fibrosis in 7 patients (3 colchicine, 4 placebo) and to portal fibrosis in 1 patient (colchicine). CONCLUSIONS: In patients with advanced alcoholic cirrhosis, colchicine does not reduce overall or liver-specific mortality. Liver histology improves to septal fibrosis in a minority of patients after 24 months of treatment, with similar rates of improvement in patients receiving placebo and colchicine. Colchicine is not recommended for patients with advanced alcoholic cirrhosis.

Gastroenterology. 2005 Apr;128(4):870-81.
Randomized study comparing banding and propranolol to prevent initial variceal hemorrhage in cirrhotics with high-risk
esophageal varices.
Jutabha R, Jensen DM, Martin P, Savides T, Han SH, Gornbein J.
Division of Digestive Diseases, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.

BACKGROUND & AIMS: Standard care for prevention of first esophageal variceal hemorrhage is beta-blockade, but this may be ineffective or unsafe. Our purpose was to compare endoscopic banding with propranolol for prevention of first variceal hemorrhage. METHODS: In a multicenter, prospective trial, 62 patients with cirrhosis with high-risk esophageal varices were randomized to propranolol (titrated to reducing resting pulse by > or =25%) or banding (performed monthly until varices were eradicated) and were followed up on the same schedule for a mean duration of 15 months. The primary end point was treatment failure, defined as the development of endoscopically documented variceal hemorrhage or a severe medical complication requiring discontinuation of therapy. Direct costs were estimated from Medicare reimbursements and fixed or variable charges for services up to treatment failure. RESULTS: Background variables of the treatment groups were similar. The trial was stopped early after an interim analysis showed that the failure rate of propranolol was significantly higher than that of banding (6/31 vs. 0/31; difference, 19.4%; P = .0098; 95% confidence interval for true difference, 6.4%-37.2%). Significantly more propranolol than banding patients had esophageal variceal hemorrhage (4/31 vs. 0/31; difference, 12.9%; P = .0443; 95% confidence interval for true difference, 0.8%-29%), and the cumulative mortality rate was significantly higher in the propranolol than in the banding group (4/31 vs. 0/31; difference, 12.9%; P = .0443; 95% confidence interval for true difference, 0.8%-29%). Direct costs of care were not significantly different. CONCLUSIONS: For patients with cirrhosis with high-risk esophageal varices and no history of variceal hemorrhage, propranolol-treated patients had significantly higher failure rates of failure, first esophageal varix hemorrhage, and cumulative mortality than banding patients. Direct costs of medical care were not significantly different.

Rev Med Suisse. 2005 Jan 19;1(3):242, 245-7.
[Auto-immune liver diseases and their treatment]
[Article in French]
Hess J, Thorens J, Pache I, Troillet FX, Moradpour D, Gonvers JJ.
Service de gastro-enterologie et d'hepatologie, CHUV, Rue du Bugnon 44, 1011 Lausanne. jurghess@bluewin.ch

There are three main types of auto-immune liver disease, auto-immune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis. In the case of auto-immune hepatitis, prednisone therapy, with or without azathioprine, can improve quality of life and halt progression to cirrhosis. If there is no response or if the therapy is poorly tolerated, mycophenolate mofetil or cyclosporin should be considered. Ursodeoxycholic acid (UDCA), at a dosage of 13 to 15 mg/kg/day slows the progression of fibrosis in patients with primary biliary cirrhosis. Pruritis may be treated with cholestyramine, rifampicin or opiate antagonists. Ursodeoxycholic acid at a dosage of 20 to 30 mg/kg/day will slow the evolution of fibrosis.

Rev Med Suisse. 2005 Jan 19;1(3):249-50, 252-5.
[Complications of liver cirrhosis: oesophageal varices, ascites and hepato-cellular carcinoma]
[Article in French]
Troillet FX, Halkic N, Froehlich F, Moradpour D, Gonvers JJ, Denys A.
Service de chirurgie viscerale, CHUV, Lausanne. Francois-Xavier.Troillet@chuv.hospvd.ch

The principal treatment for bleeding oesophageal varices is endoscopic ligation. Non-cardioselective beta-blockers are the gold-standard of primary prophylaxis. The principal treatment for ascites is a salt-free diet and diuretics, mainly spironolactone, if necessary associated with a loop diuretic. In refractory ascites, paracentesis or installation of a transjugular intrahepatic portosystemic shunt (TIPS) are two possible treatment options. Cirrhosis patients are at higher risk of developing hepato-cellular carcinoma. Surgery is only possible in a small number of cases. Percutaneous destruction techniques have nearly the same survival rate as that obtained by surgery and should be proposed to patients where surgery is not an option.

Liver Int. 2005 Feb;25(1):117-21.
Raloxifene improves bone mass in osteopenic women with primary biliary cirrhosis: results of a pilot study.
Levy C, Harnois DM, Angulo P, Jorgensen R, Lindor KD.
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.

Levy C, Harnois DM, Angulo P, Jorgensen R, Lindor KD. Raloxifene improves bone mass in osteopenic women with primary biliary cirrhosis - results of a pilot study. Liver International 2005: 25: 117-121. (c) Blackwell Munksgaard 2005 Abstract: Background/Aims: Bone disease is common in patients with primary biliary cirrhosis (PBC). Our aim was to evaluate safety and efficacy of raloxifene in this population. Methods: Nine postmenopausal women with PBC were enrolled and seven completed the study. Subjects received raloxifene 60 mg daily for 1 year. Each patient on raloxifene was age-matched to three controls. Liver biochemistries were monitored periodically; bone mineral density (BMD) of the lumbar spine (LS) and femoral neck (FN) was measured at baseline and at 1 year. Results: No significant adverse effects were reported. Liver biochemistries remained unchanged. Baseline LS-BMD was similar in the treatment group and controls [median 0.720 g/cm(2) (range 0.620-0.867) vs. 0.740 g/cm(2) (0.570-1.040), P=0.5]. Conclusion: Compared with baseline, LS-BMD improved significantly with 1 year of therapy [0.72 g/cm(2) (0.62-0.87) vs. 0.74 g/cm(2) (0.63-0.97), P=0.02]. FN-BMD remained stable [0.53 g/cm(2) (0.50-0.60) vs. 0.54 g/cm(2) (0.49-0.63), P=0.6]. Improvement in LS BMD was seen in patients on raloxifene but not in matched controls [0.02 g/cm(2) (0.01-0.10) vs. 0.00 g/cm(2) (-0.120-0.040), P=0.06)]. In conclusion, raloxifene appears safe and of benefit in preventing bone loss in patients with PBC. Larger studies with longer follow-up are warranted.

Aliment Pharmacol Ther. 2005 Feb 1;21(3):217-26.
Long-term ursodeoxycholic acid therapy for primary biliary cirrhosis: a follow-up to 12 years.
Chan CW, Gunsar F, Feudjo M, Rigamonti C, Vlachogiannakos J, Carpenter JR, Burroughs AK.
Liver Transplantation and Hepatobiliary Medicine, Royal Free Hospital, London, UK.

Summary Background : It is uncertain whether ursodeoxycholic acid therapy slows down the progression of primary biliary cirrhosis, according to two meta-analyses. However, the randomized trials evaluated had only a median of 24 months of follow-up. Aim : To evaluate long-term ursodeoxycholic acid therapy in primary biliary cirrhosis. Methods : We evaluated 209 consecutive primary biliary cirrhosis patients, 69 compliant with ursodeoxycholic acid and 140 untreated [mean follow-up 5.79 (s.d. = 4.73) and 4.87 (s.d. = 5.21) years, respectively] with onset of all complications documented. Comparison was made following adjustment for baseline differences according to Cox modelling, Mayo and Royal Free prognostic models. Results : Bilirubin and alkaline phosphatase concentrations improved with ursodeoxycholic acid (at 36 months, P = 0.007 and 0.018, respectively). Unadjusted Kaplan-Meier analysis showed benefit (P = 0.028), as 44 (31%) untreated and 15 (22%) ursodeoxycholic acid patients died or had liver transplantation. However, there was no difference when adjusted by Cox modelling (P = 0.267), Mayo (P = 0.698) and Royal Free models (P = 0.559). New pruritus or fatigue or other complications were not different, either before or after adjustment for baseline characteristics. Conclusions : Long-term ursodeoxycholic acid therapy did not alter disease progression in primary biliary cirrhosis patients despite a significant improvement in serum bilirubin and alkaline phosphatase consistent with, and similar to, those seen in ursodeoxycholic acid cohorts in randomized trials.

Gastroenterology. 2005 Feb;128(2):297-303.
The effect of ursodeoxycholic acid therapy on the natural course of primary biliary cirrhosis.
Corpechot C, Carrat F, Bahr A, Chretien Y, Poupon RE, Poupon R.

Background & Aims: We used a multistate modeling approach to assess the effect of ursodeoxycholic acid (UDCA) therapy on the natural course of primary biliary cirrhosis (PBC), which remains controversial. Methods: Our population included 262 patients with PBC who had received 13-15 mg/kg UDCA daily for a mean of 8 years (range, 1-22 years). Data were analyzed using a multistate Markov model, with histologic stage progression, death, and orthotopic liver transplantation (OLT) as main end points. Survival without OLT was compared with that predicted by the updated Mayo model and with the expected survival in the control population. Results: Forty-five patients developed cirrhosis, 20 underwent OLT, and 16 died by the censor date. Ten deaths were due to liver disease. The overall survival rates were 92% at 10 years and 82% at 20 years. Survival rates without OLT were 84% and 66% at 10 and 20 years, respectively, which were slightly lower than the survival rate of an age- and sex-matched control population (relative risk [RR], 1.4; P = .1) but better than the spontaneous survival rate as predicted by the updated Mayo model (RR, .5; P < .01). The survival rate of patients in stage 1 and 2 was similar to that in the control population (RR, .8; P = .5), whereas the probability of death or OLT remained significantly increased in treated patients in late histologic stages (RR, 2.2; P < .05). Conclusions: Treatment with UDCA alone normalizes the survival rate of patients with PBC when given at early stages. However, there is a continued need for new therapeutic options in patients with advanced disease.

Am J Gastroenterol. 2004 Dec;99(12):2348-55.
Pilot studies of single and combination antiretroviral therapy in patients with primary biliary cirrhosis.
Mason AL, Farr GH, Xu L, Hubscher SG, Neuberger JM.
Section of Gastroenterology and Hepatology, Ochsner Clinic Foundation, New Orleans, Louisiana, USA.

OBJECTIVE: Preliminary reports suggest that patients with primary biliary cirrhosis (PBC) have evidence of human betaretrovirus infection. The aim of this study was to determine whether antiviral therapy impacts on the disease process. METHODS: We conducted two consecutive open-labeled, nonrandomized, 1-yr pilot studies; the first with lamivudine 150 mg/day and the second with Combivir combination therapy using lamivudine 150 mg and zidovudine 300 mg twice a day. Eleven PBC patients enrolled in each study, seven patients were entered into both studies, and one patient was withdrawn from each study due to side effects. RESULTS: Evaluation of liver biopsies before and after lamivudine therapy showed a 4-5 increase in necroinflammatory score, a 1-1.5 elevation in bile duct injury, with little change in the percentage of portal tracts with bile ducts (50-52%). None of the patients in the lamivudine study normalized alkaline phosphatase. Histological assessment following Combivir therapy revealed a 6 to 4 improvement in necroinflammatory score (p < 0.03, 95% CI: 0.53-2.33), a 3 to 1 reduction in bile duct injury (p < 0.02, 95% CI: 1.08-2.07), and a 45-75% increase in portal tracts with bile ducts (p < 0.05, 95% CI: 0.02-0.29). In the Combivir cohort, five patients normalized alkaline phosphatase and four developed normal AST, ALT, and alkaline phosphatase. CONCLUSIONS: Histological and biochemical endpoints were achieved in the Combivir pilot study suggesting a larger placebo-controlled trial is required as a proof of principle to assess whether antiviral therapy impacts the PBC disease process.

Hepatol Res. 2004 Dec;30S:25-29. Epub 2004 Nov 11.
Branched-chain amino acid treatment in patients with liver cirrhosis.
Suzuki K, Kato A, Iwai M.
First Department of Internal Medicine, Iwate Medical University, 19-1 Uchimaru, Morioka 020-8505, Japan.

We discuss branched-chain amino acid (BCAA) treatment for the management of hepatic encephalopathy (HE) and protein-energy malnutrition (PEM) in patients with liver cirrhosis (LC). PEM is closely associated with the prognosis of patients with LC independently of liver function. Therefore, adequate protein and energy intake is a fundamental management to improve the status of PEM in patients with LC. However, it is difficult to maintain good nutritional status with diet therapy alone in patients with LC, because the majority of these patients have disturbances of the nutritious metabolism including urea synthesis in the liver, together with the existence of portal-systemic shunt which is related with the pathogenesis of HE. BCAA enriched amino acid solution was administered at first to treat chronic HE based on amino acid imbalance and neurotransmitter theory. Furthermore, recent studies have suggested that the supplement of BCAA enriched oral mixture and BCAA granules with diet therapy might improve the status of PEM in patients with LC. However, as the effects of these BCAA supplements are basically related to the severity of liver damage, further investigations are required to identify the efficacy of these treatments.

Rev Gastroenterol Disord. 2004 Fall;4(4):175-85.
Management of ascites in patients with end-stage liver disease.
Saadeh S, Davis GL.
Division of Hepatology, Baylor University Medical Center, Dallas, Texas, USA.

Ascites is the most common complication in patients with decompensated cirrhosis. Approximately 50% of patients with compensated cirrhosis will develop ascites over a 10-year period. This occurrence is an important milestone in the natural history of end-stage liver disease because only 50% of patients survive 2 to 5 years (depending on the cause of cirrhosis) after its onset. Salt restriction and diuretics are the mainstays of therapy, and these measures are effective in approximately 90% of patients. Large-volume paracentesis or transjugular intrahepatic portosystemic shunt can be used in patients with refractory ascites as either a bridge to transplant or as palliation. Cirrhotic patients with ascites should be carefully monitored for the development of bacterial peritonitis, and those at greatest risk should receive antibiotic prophylaxis. When spontaneous bacterial peritonitis is suspected, prompt diagnostic paracentesis followed by broad-spectrum antibiotics and albumin infusion can be life saving. Orthotopic liver transplantation should be considered in all patients with decompensated liver disease with or without ascites.

Med Hypotheses. 2005;64(1):118-119.
Bupropion for fatigue and as a tumor necrosis factor-alpha lowering agent in primary biliary cirrhosis.
Altschuler EL, Kast RE.
Mount Sinai School of Medicine, 1425 Madison Avenue, Box 1240, New York, NY 10029, USA.

Primary biliary cirrhosis (PBC) is a chronic cholestatic disease which can often be severe, progressive and necessitate liver transplantation. The cause of PBC is not known, and treatments other than liver transplantation are often not effective. Among the more common and troublesome symptoms of PBC is fatigue. The etiology of fatigue in PBC is not well-understood, and there is no known treatment for it. Here, we suggest that for a number of reasons that the safe and commonly used oral antidepressant bupropion might be effective for fatigue in PBC: (1) increased monoaminergic and dopaminergic tone to combat fatigue, (2) treatment of concomitant depression, (3) in general for PBC as a tumor necrosis factor-alpha (TNF) lowering agent, if TNF is eventually found to play a role in PBC pathogenesis.

Yakugaku Zasshi. 2004 Nov;124(11):711-24.
Wilson's Disease and Its Pharmacological Treatment.
Hayashi H, Suzuki R, Wakusawa S.
Department of Medicine, Faculty of Pharmaceutical Sciences of Hokuriku University.

Wilson's disease is an inherited copper toxicosis caused by defective putative copper transporting ATPase in the liver. Because of impaired biliary secretion, copper remains in the liver, resulting in chronic hepatic lesions including fatty metamorphosis, chronic hepatitis and cirrhosis. In the latter stage, extrapyramidal syndromes may develop with and without symptomatic hepatic lesions. Acute liver damage associated with hemolysis and deep jaundice may be the first manifestation. The majority of patients show hypoceruloplasminemia, which has been used as a screening test for the disease. A large number of mutations in the ATP7B gene have been reported. Thus, genetic diagnosis might be limitedly used to presymptomatic diagnosis of siblings when mutations are identified in an index patient. Introduction of penicillamine caused a revolution in the treatment of patients. Another chelater, trientine, is now available for those intolerant of penicillamine. Tetrathiomolibdate and zinc acetate are additional alternatives currently being tested. Hypoceruloplasminemia and further reduction after chelation therapy may be associated with iron overload. This complication is closely related with impaired transport of ferrous ion due to ferroxidase deficiency. Noncompliance and teratogenicity are other major concerns because any treatment with the agents listed above is a life long regimen. Despite various side effects of penicillamine, its teratogenicity is negligible. These data indicate that penicillamine is the first choice of drug for this disease.

Cochrane Database Syst Rev. 2004 Oct 18(4):CD004789.
D-penicillamine for primary biliary cirrhosis.
Gong Y, Frederiksen S, Gluud C.
Copenhagen Trial Unit, Centre for Clinical Intervention Research, Copenhagen University Hospital, Dept. 7102, Blegdamsvej 9, H:S Rigshospitalet, Copenhagen, DENMARK, DK-2100.

BACKGROUND: D-penicillamine is used for patients with primary biliary cirrhosis due to its hepatic copper decreasing and immunomodulatory potentials. The results from randomised clinical trials have been inconsistent. OBJECTIVES: To systematically review the beneficial and harmful effects of D-penicillamine for patients with primary biliary cirrhosis. SEARCH STRATEGY: We identified trials through electronic searches of The Cochrane Hepato-Biliary Group Controlled Trials Register (September 2003), The Cochrane Central Register of Controlled Trials on The Cochrane Library (Issue 3, 2003), MEDLINE (January 1966 to September 2003), EMBASE (January 1980 to September 2003), The Chinese Biomedical CD Database (January 1979 to August 2003), and LILACS (1982 to 2003); through manual searches of bibliographies; and by contacting authors of the trials and pharmaceutical companies. SELECTION CRITERIA: We included randomised clinical trials comparing D-penicillamine with placebo/no intervention or other control intervention irrespective of language, year of publication, and publication status. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed the methodological quality of the trials and extracted data, validated by a third reviewer. The primary outcomes were 1) mortality and 2) a combination of those who died or underwent liver transplantation. We analysed dichotomous outcomes as relative risk (RR) with 95% confidence interval (CI) by a fixed effect model and a random effects model. We investigated sources of heterogeneity by subgroup analyses and tested the robustness of our findings by sensitivity analyses. MAIN RESULTS: We included seven trials randomising 706 patients with primary biliary cirrhosis. D-penicillamine compared with placebo/no intervention tended to increase mortality (RR 1.34, 95% CI 1.09 to 1.64, fixed; RR 1.46, 95% CI 0.85 to 2.50, random). However, there was substantial heterogeneity. No significant differences were detected regarding the risks of mortality or liver transplantation, pruritus, liver complications, progression of liver histological stage, or the levels of liver biochemical variables (except alanine aminotransferase). D-penicillamine versus placebo/no intervention significantly increased the risk of adverse events (RR 3.11, 95% CI 2.33 to 4.16, fixed; RR 4.18, 95% CI 1.38 to 12.69, random). REVIEWERS' CONCLUSIONS: D-penicillamine did not appear to reduce the risk of mortality, but significantly increased the occurrences of adverse events in patients with primary biliary cirrhosis. We do not support the use of D-penicillamine for patients with primary biliary cirrhosis.

Nippon Geka Gakkai Zasshi. 2004 Oct;105(10):669-73.
[Hepatic failure after liver resection in patients with cirrhosis]
[Article in Japanese]
Kubo S, Tanaka H, Shuto T, Takemura S, Uenishi T, Tanaka S, Hirohashi K.
Department of Gastroenterological and Hepato-Biliary-Pancreatic Surgery, Osaka City University Graduate School of Medicine, Osaka, Japan.

Despite improvements in the preoperative assessment of liver function and advances in surgical techniques, liver resection for hepatocellular carcinoma still holds a risk for postoperative hepatic failure, especially in patients with cirrhosis. Physiologic characteristics in patients with cirrhosis include hyperdynamic state of the systemic circulation, decrease in hepatic blood flow, portal hypertension, metabolic disorders, dysfunction of the reticuloendothelial system, and thrombocytopenia. Surgical stress including massive bleeding, disturbance of hepatic circulation, and infection are risk factors for postoperative hepatic failure. The risk of hepatic failure also correlates with the severity of active hepatitis and the degree of hepatic fibrosis. To prevent postoperative hepatic failure, dopamine, prostaglandin, and hydrocortisone have been used. Although various treatments including plasma exchange have been tried in hepatic failure, the results have often been unsatisfactory. Careful preoperative evaluation of the hepatic functional reserve and the severity of active hepatitis, and adequate selection of surgical method are important to prevent postoperative hepatic failure.

Gastroenterology. 2004 Oct;127(4):1123-30.
Recombinant factor VIIa for upper gastrointestinal bleeding in patients with cirrhosis: a randomized, double-blind trial.
Bosch J, Thabut D, Bendtsen F, D'Amico G, Albillos A, Gonzalez Abraldes J, Fabricius S, Erhardtsen E, de Franchis R; European Study Group on rFVIIa in UGI Haemorrhage.
Hospital Clinic, Liver Unit, Barcelona, Spain. jbosch@medicina.ub.es

BACKGROUND & AIMS: Upper gastrointestinal bleeding (UGIB) is a severe and frequent complication of cirrhosis. Recombinant coagulation factor VIIa (rFVIIa) has been shown to correct the prolonged prothrombin time in patients with cirrhosis and UGIB. This trial aimed to determine efficacy and safety of rFVIIa in cirrhotic patients with variceal and nonvariceal UGIB. METHODS: A total of 245 cirrhotic patients (Child-Pugh < 13; Child-Pugh A = 20%, B = 52%, C = 28%) with UGIB (variceal = 66%, nonvariceal = 29%, bleeding source unknown = 5%) were randomized equally to receive 8 doses of 100 microg/kg rFVIIa or placebo in addition to pharmacologic and endoscopic treatment. The primary end point was a composite including: (1) failure to control UGIB within 24 hours after first dose, or (2) failure to prevent rebleeding between 24 hours and day 5, or (3) death within 5 days. RESULTS: Baseline characteristics were similar between rFVIIa and placebo groups. rFVIIa showed no advantage over standard treatment in the whole trial population. Exploratory analyses, however, showed that rFVIIa significantly decreased the number of failures on the composite end point (P = 0.03) and the 24-hour bleeding control end point (P = 0.01) in the subgroup of Child-Pugh B and C variceal bleeders. There were no significant differences between rFVIIa and placebo groups in mortality (5- or 42-day) or incidence of adverse events including thromboembolic events. CONCLUSIONS: Although no overall effect of rFVIIa was observed, exploratory analyses in Child-Pugh B and C cirrhotic patients indicated that administration of rFVIIa significantly decreased the proportion of patients who failed to control variceal bleeding. Dosing with rFVIIa appeared safe. Further studies are needed to verify these findings.

Annu Rev Pharmacol Toxicol. 2004 Oct 07 [Epub ahead of print]
Hepatic Fibrosis: Molecular Mechanisms and Drug Targets.
Lotersztajn S, Julien B, Teixeira-Clerc F, Grenard P, Mallat A.
Unite INSERM 581 Hopital Henri Mondor, 94010 Creteil, France sophie.lotersztajn@im3.inserm.fr, Unite INSERM 581 Hopital Henri Mondor, 94010 Creteil, France boris.julien@im3.inserm.fr, Unite INSERM 581 Hopital Henri Mondor, 94010 Creteil, France fatima.clerc@im3.inserm.fr, Unite INSERM 581 Hopital Henri Mondor, 94010 Creteil, France pascale.grenard@im3.inserm.fr, Unite INSERM 581 et Service d'Hepatologie et de Gastroenterologie, Hopital Henri Mondor, 94010 Creteil, ariane.mallat@hmn.ap-hop-paris.fr.

Liver fibrosis is the common response to chronic liver injury, ultimately leading to cirrhosis and its complications, portal hypertension, liver failure, and hepatocellular carcinoma. Efficient and well-tolerated antifibrotic drugs are currently lacking, and current treatment of hepatic fibrosis is limited to withdrawal of the noxious agent. Efforts over the past decade have mainly focused on fibrogenic cells generating the scarring response, although promising data on inhibition of parenchymal injury and/or reduction of liver inflammation have also been obtained. A large number of approaches have been validated in culture studies and in animal models, and several clinical trials are underway or anticipated for a growing number of molecules. This review highlights recent advances in the molecular mechanisms of liver fibrosis and discusses mechanistically based strategies that have recently emerged. Expected online publication date for the Annual Review of Pharmacology and Toxicology Volume 45 is January 6, 2005. Please see http://www.annualreviews.org/catalog/pub_dates.asp for revised estimates.

Expert Opin Ther Targets. 2004 Oct;8(5):423-35.
Targeted treatments for cirrhosis.
Fallowfield JA, Iredale JP.
Liver Research Group, Division of Infection, Inflammation and Repair, Southampton General Hospital, Mailpoint 811, D Level, Southampton, SO16 6YD, UK. jonfalluk@yahoo.co.uk

The causes of hepatic scarring (fibrosis) are protean but, unchecked, all result in a common fate--the development of cirrhosis--with gross disruption of the normal liver architecture. Subsequent liver cell dysfunction and portal hypertension give rise to major systemic complications and premature death. Cirrhosis and its sequelae represent a huge, and global, healthcare burden. The success of liver transplantation and the development of efficacious antiviral regimens for hepatitis B and C should not be underestimated, but they also serve to highlight our current inability to manipulate the underlying fibrotic process in many patients with liver disease. Moreover, transplantation as a treatment is limited by organ availability, among other factors. The development of antifibrotic therapies is urgently needed and for this we require a mechanistic and evidence-based approach. Accumulating data from clinical and laboratory studies demonstrate that even advanced fibrosis and cirrhosis are potentially reversible. The hepatic stellate cells have been identified as the pivotal effector cells orchestrating the fibrotic process and, furthermore, reversibility appears to hinge upon their elimination. This review draws on recent scientific advances, and highlights emerging therapeutic interventions in liver fibrosis.

Surgery. 2004 Oct;136(4):804-11.
An initial experience and evolution of laparoscopic hepatic resectional surgery.
Buell JF, Thomas MJ, Doty TC, Gersin KS, Merchen TD, Gupta M, Rudich SM, Woodle ES.
Division of Transplantation, University of Cincinnati, OH 45267-0558, USA.

BACKGROUND: The use of minimally invasive procedures has revolutionized modern surgery. Only recently has laparoscopy been introduced for use in hepatic surgery. METHODS: Patient demographics, tumor characteristics, and outcomes were evaluated for all initial cases of laparoscopic hepatic resection. RESULTS: Twenty-one resections were performed in 17 patients; 5 were performed for malignancy, of which 3 had underlying cirrhosis, and the remaining 12 for benign symptomatic disease. Mean patient age was 55.4 (range, 24-82 years). The mean number of lesions was 1.4 (range, 1-5), having an average size of 7.6 cm (range, 2-30 cm). Mean operative time was 2.8 hours (range, 2-5 hours) hours. Most resections involved 1 or more Couinaud segments. Mean blood loss was 288 cc (range, 50-150 cc). Complications included re-operation for hemorrhage (n=2), biliary leakage (n=1), and death from hepatic failure (n=1). Mean length of stay was 2.9 days (range, 1-14). When compared with our series of 100 patients who underwent open hepatic resection for benign tumors, significantly greater means ( P <.05) were noted for blood loss (485 cc), operative time (4.5 hours), and length of stay (6.5 days). CONCLUSIONS: Laparoscopic hepatic surgery, though complex, can be performed safely and efficaciously. Minimally invasive surgery appears to provide several distinct advantages over traditional open hepatic surgery. However, techniques for the laparoscopic control of bleeding and bile leak remain in their infancy.

J Hepatol. 2004 Oct;41(4):560-6.
Bleeding ectopic varices-treatment with transjugular intrahepatic porto-systemic shunt (TIPS) and embolisation.
Vangeli M, Patch D, Terreni N, Tibballs J, Watkinson A, Davies N, Burroughs AK.
Liver Transplantation and Hepatobiliary Unit, Royal Free Hospital and NHS Hampstead Trust, London, UK.

BACKGROUND/AIMS: Bleeding ectopic varices due to cirrhosis can be difficult to manage. We report our experience of uncontrolled bleeding from ectopic varices treated with transjugular intrahepatic porto-systemic shunt (TIPS). METHODS: We selected the 21 cirrhotics who underwent TIPS for bleeding ectopic varices from our database: Child-Pugh grade A (2), B (11) and C (8). Site of bleeding was rectal (11), colonic (2), ileal 1, jejunal 1, duodenal 1, and stomal (5). RESULTS: TIPS was performed successfully in 19/21 (90%) patients. All except 1 had either a reduction in portosystemic pressure gradient </= 12mmHg (n=12) or reduction by 25-50% of baseline (n=6). TIPS alone was used in 12/19: 7 of these 12 had no further bleeding; 5 (42%) rebled within 48h, and had embolisation, 4 without further bleeding. In 7 of 19, TIPS and embolisation were performed together: 2 patients (28%) rebled; further embolisation stopped the bleeding. CONCLUSIONS: Ectopic varices do rebleed despite a reduction of porto-systemic pressure gradient </= 12mmHg or by 25-50% of baseline, following TIPS. Embolisation stopped bleeding in all but 1 patient. We recommend performing embolisation at the time of the initial TIPS to control bleeding from ectopic varices.

Gastrointest Endosc. 2004 Aug;60(2):180-5.
Endoscopic sphincterotomy vs. endoscopic papillary balloon dilation for choledocholithiasis in patients with liver cirrhosis and coagulopathy.
Park do H, Kim MH, Lee SK, Lee SS, Choi JS, Song MH, Seo DW, Min YI.
Current affiliation: Department of Internal Medicine, University of Ulsan College of Medicine, Asan Medical Center, Seoul, Korea.

BACKGROUND: To determine whether endoscopic papillary balloon dilation decreases the risk of hemorrhage without increasing the risk of acute pancreatitis, the results of endoscopic papillary balloon dilation were compared with those of endoscopic biliary sphincterotomy in patients with cirrhosis and coagulopathy. METHODS: Twenty-one patients with liver cirrhosis with coagulopathy had endoscopic papillary balloon dilation for choledocholithiasis from January 2001 to September 2003. Twenty patients with cirrhosis and coagulopathy who underwent endoscopic biliary sphincterotomy from January 1998 to December 2000, served as a historical control group. RESULTS: The rate of endoscopic biliary sphincterotomy related hemorrhage was 30% (6/20), whereas the rate for endoscopic papillary balloon dilation related hemorrhage was 0% (p=0.009). With regard to rates of hemorrhage in relation to Child-Pugh class, most (n=5) of the bleeding complications occurred in patients with Child-Pugh class C cirrhosis; bleeding occurred in only one patient with Child-Pugh B cirrhosis. There was no significant difference between the endoscopic biliary sphincterotomy and the endoscopic papillary balloon dilation groups for procedure-related pancreatitis (10% vs. 4.7%, respectively; p>0.05). CONCLUSIONS: Endoscopic papillary balloon dilation may significantly reduce the risk of bleeding compared with endoscopic biliary sphincterotomy in patients with advanced cirrhosis and coagulopathy. In these patients, the substitution of endoscopic papillary balloon dilation for endoscopic biliary sphincterotomy is recommended for treatment of choledocholithiasis.

Expert Opin Biol Ther. 2004 Jul;4(7):1073-91.
Gene therapy of liver diseases.
Prieto J, Qian C, Hernandez-Alcoceba R, Gonzalez-Aseguinolaza G, Mazzolini G, Sangro B, Kramer MG.
Clinica Universitaria de Navarra, Department of Internal Medicine, Avda. Pio XII 36, 31008 Pamplona, Spain. mgkramer@unav.es

Many liver diseases lack satisfactory treatment and alternative therapeutic options are urgently needed. Gene therapy is a new mode of treatment for both inherited and acquired diseases, based on the transfer of genetic material to the tissues. Genes are incorporated into appropriate vectors in order to facilitate their entrance and function inside the target cells. Gene therapy vectors can be constructed on the basis of viral or non-viral molecular structures. Viral vectors are frequently used, due to their higher transduction efficiency. Both the type of vector and the expression cassette determine the duration, specificity and inducibility of gene expression. A considerable number of preclinical studies indicate that a great variety of liver diseases, including inherited metabolic defects, chronic viral hepatitis, liver cirrhosis and primary and metastatic liver cancer, are amenable to gene therapy. Gene transfer to the liver can also be used to convert this organ into a factory of secreted proteins needed to treat conditions that do not affect the liver itself. Clinical trials of gene therapy for the treatment of inherited diseases and liver cancer have been initiated but human gene therapy is still in its infancy. Recent progress in vector technology and imaging techniques, allowing in vivo assessment of gene expression, will facilitate the development of clinical applications of gene therapy.

- Chest. 2004 Jul;126(1):142-8.
Outcome analysis of cirrhotic patients undergoing chest tube placement.
Liu LU, Haddadin HA, Bodian CA, Sigal SH, Korman JD, Bodenheimer HC Jr, Schiano TD.
Division of Liver Diseases, Mount Sinai Medical Center, New York, NY 10029, USA.

OBJECTIVES: Patients with cirrhosis can acquire pulmonary conditions that may or may not be related to their illness. Although posing a greater risk for complications, chest tubes are sometimes placed as treatment for hepatic hydrothorax and other pulmonary conditions. The aim of this study was to analyze the outcomes of chest tube placement in cirrhotic patients. METHODS: A retrospective analysis was performed of 59 adults with cirrhosis undergoing chest tube placement. Variables that were investigated included reason for chest tube placement, complications developing while having the tube in place, and outcome. RESULTS: The 59 subjects were classified as having Child-Turcotte-Pugh (CTP) class A cirrhosis (n = 3), CTP class B cirrhosis (n = 31), and CTP class C cirrhosis (n = 25). Indications for having a chest tube placed were hepatic hydrothorax (n = 24), pneumothorax (n = 9), empyema (n = 8), video-assisted thoracoscopy (VAT) [n = 7], non-VAT (n = 5), and hemothorax (n = 3). The CTP class A subjects had their chest tubes removed without further complications early in the course, and were excluded from further statistical analysis. Twenty-five subjects (42%) had significant pleural effusions requiring chest tube placement. Among the CTP class B and class C subjects, the median duration with chest tube in place was 5.0 days (range, 1 to 53 days). Serum total bilirubin levels, presence of portosystemic encephalopathy, and CTP C classification were predictors of mortality. Mortalities were seen in 5 of 31 CTP class B subjects (16%), and 10 of 25 CTP class C subjects (40%). The tubes were successfully removed in a total of 39 subjects (66%) with no further procedure. Forty-seven subjects (80%) acquired one or more of the following complications: renal dysfunction, electrolyte imbalances, and infection. CONCLUSIONS: When placed for all indications, chest tubes may be successfully removed in the majority of cirrhotic patients. However, a third of all patients still die with the chest tube still in place. Failure to remove the chest tube increases mortality in patients with increasing severity of liver disease.

Hepatology. 2004 Jul;40(1):65-72.
Ligation versus propranolol for the primary prophylaxis of variceal bleeding in cirrhosis.
Schepke M, Kleber G, Nurnberg D, Willert J, Koch L, Veltzke-Schlieker W, Hellerbrand C, Kuth J, Schanz S, Kahl S, Fleig WE, Sauerbruch T; German Study Group for the Primary Prophylaxis of Variceal Bleeding.
Department of Internal Medicine I, University of Bonn, Bonn, Germany.

In this randomized controlled multicenter trial, we compared endoscopic variceal banding ligation (VBL) with propranolol (PPL) for primary prophylaxis of variceal bleeding. One hundred fifty-two cirrhotic patients with 2 or more esophageal varices (diameter >5 mm) without prior bleeding were randomized to VBL (n = 75) or PPL (n = 77). The groups were well matched with respect to baseline characteristics (age 56 +/- 10 years, alcoholic etiology 51%, Child-Pugh score 7.2 +/- 1.8). The mean follow-up was 34 +/- 19 months. Data were analyzed on an intention-to-treat basis. Neither bleeding incidence nor mortality differed significantly between the 2 groups. Variceal bleeding occurred in 25% of the VBL group and in 29% of the PPL group. The actuarial risks of bleeding after 2 years were 20% (VBL) and 18% (PPL). Fatal bleeding was observed in 12% (VBL) and 10% (PPL). It was associated with the ligation procedure in 2 patients (2.6%). Overall mortality was 45% (VBL) and 43% (PPL) with the 2-year actuarial risks being 28% (VBL) and 22% (PPL). 25% of patients withdrew from PPL treatment, 16% due to side effects. In conclusion, VBL and PPL were similarly effective for primary prophylaxis of variceal bleeding. VBL should be offered to patients who are not candidates for long-term PPL treatment.

Hepatology. 2004 Jul;40(1):55-64.
Midodrine, octreotide, albumin, and TIPS in selected patients with cirrhosis and type 1 hepatorenal syndrome.
Wong F, Pantea L, Sniderman K.
Division of Gastroenterology, Department of Medicine, Toronto General Hospital, University of Toronto, Toronto, Ontario, Canada. florence.wong@utoronto.ca

Hepatorenal syndrome (HRS) is a functional renal disorder complicating decompensated cirrhosis. Treatments to date, except liver transplantation, have been able to improve but not normalize renal function. The aim of this study was to determine the efficacy of transjugular intrahepatic portosystemic stent shunt (TIPS) as a treatment for type 1 HRS in ascitic cirrhotic patients, following improvement in systemic hemodynamics with a combination of midodrine, octreotide, and albumin (medical treatment). Fourteen ascitic cirrhotic patients with type 1 HRS received medical therapy until their serum creatinine reached below 135 micromol/L for at least 3 days, followed by a TIPS if there were no contraindications. Patients were assessed before and after medical treatment, as well as at 1 week and 1, 3, 6, and 12 months post-TIPS with measurements of renal function, sodium handling, systemic hemodynamics, central blood volume, and hormonal markers. Medical therapy for 14 +/- 3 days improved renal function (serum creatinine: 233 +/- 29 micromol/L vs. 112 +/- 8 micromol/L, P =.001) and renal sodium excretion (5 +/- 2 mmol/d vs. 9 +/- 2 mmol/d, P =.002) in 10 of the 14 patients. TIPS insertion in five of the responders further improved renal function and sodium excretion, so that by 12 months post-TIPS, glomerular filtration rate (96 +/- 20 mL/min, P <.01 vs. pre-TIPS) and urinary sodium excretion (119 +/- 15 mmol/d, P <.01 vs. pre-TIPS) were normal, associated with normalization of plasma renin and aldosterone levels and elimination of ascites. In conclusion, TIPS is an effective treatment for type 1 HRS in suitable patients with cirrhosis and ascites, following the improvement of renal function with combination therapy of midodrine, octreotide, and albumin.

Gastroenterology. 2004 Jun;126(7):1740-9.
Long-term benefit of interferon alpha therapy of chronic hepatitis D: regression of advanced hepatic fibrosis.
Farci P, Roskams T, Chessa L, Peddis G, Mazzoleni AP, Scioscia R, Serra G, Lai ME, Loy M, Caruso L, Desmet V, Purcell RH, Balestrieri A.
Dipartimento di Scienze Mediche, Universita di Cagliari, SS 554 Bivio Sestu, 09042 Cagliari, Italy. farcip@pacs.unica.it

BACKGROUND & AIMS: Little is known about the long-term effects of interferon alpha on clinical outcome and survival of patients with chronic hepatitis D. METHODS: Thirty-six patients with chronic hepatitis D who participated in a randomized controlled trial of a 48-week course of high (9 million units) or low (3 million units) doses of interferon alpha or no treatment were followed for an additional 2 to 14 years. RESULTS: Long-term survival was significantly longer in the high-dose group than in untreated controls (P = 0.003) or in the low-dose group (P = 0.019) but did not differ between patients treated with 3 million units and controls. Among surviving patients at 12 years of follow-up, a biochemical response was present in 7 of 12 treated with 9 million units, in 2 of 4 who received 3 million units, and in none of 3 controls. Long-term alanine aminotransferase (ALT) normalization correlated with improved hepatic function and loss of IgM antibody to hepatitis delta antigen (anti-HD). Patients in the high-dose group had a sustained decrease in HDV replication (P = 0.008), leading to clearance of HDV RNA and, eventually, hepatitis B virus (HBV) in some patients, as well as a dramatic improvement in liver histology with respect to activity grade (P = 0.0004) and fibrosis stage (P = 0.007). Strikingly, we documented an absence of fibrosis in the final biopsy of 4 patients with a long-term biochemical response and an initial diagnosis of active cirrhosis. CONCLUSIONS: High doses of interferon alpha-2a significantly improved the long-term clinical outcome and survival of patients with chronic hepatitis D, even though the majority had active cirrhosis before the onset of therapy.

Am J Gastroenterol. 2004 Jun;99(6):1105-10.
Extracorporeal albumin dialysis: a procedure for prolonged relief of intractable pruritus in patients with primary biliary cirrhosis.
Pares A, Cisneros L, Salmeron JM, Caballeria L, Mas A, Torras A, Rodes J.
Liver Unit, Institut Clinic de Malalties Digestives, Hospital Clinic, Barcelona, Spain.

BACKGROUND AND AIMS: Pruritus is a distressing symptom in patients with primary biliary cirrhosis, and when uncontrollable it is an indication for liver transplantation. Since pruritus can result from unknown substances that accumulate systemically as a consequence of impaired biliary secretion, we have assessed whether a new extracorporeal albumin dialysis (ECAD) procedure, the molecular-adsorbing recirculating system-MARS, has any effect on pruritus of cholestasis. METHODS: Four patients with primary biliary cirrhosis and resistant pruritus were treated with two 7-h ECAD sessions 1 day apart. Pruritus was recorded from 15 days before the first session, before and after each session, and during the follow-up using a visual analogue scale (VAS). Standard liver tests as well as serum bile acid levels were also measured. RESULTS: There was a clear association between ECAD treatment and relief of itching, which promptly disappeared in two patients, or decreased markedly in the other two. One patient was free of pruritus for 18 months except for short periods with mild pruritus. The second patient experienced amelioration of itching, which almost disappeared completely and recurred mildly 4 months later. In the other two patients pruritus was alleviated markedly after ECAD but gradually recurred. These two patients were treated again 9 and 7 months later with favorable effects on pruritus. The scratching skin lesions improved or disappeared in parallel with the alleviation of itching. The albumin dialysis procedure did not result in liver test changes, except for circulating bile acids, which decreased in all the patients. No significant adverse effects were observed. CONCLUSIONS: The ECAD procedure seems to be an effective alternative for the treatment of patients with pruritus of cholestasis who do not respond to other therapeutic methods.

Eur J Gastroenterol Hepatol. 2004 Jun;16(6):567-70.
Nitric oxide and renal function in cirrhotic patients with ascites: from physiopathology to practice.
Grange JD, Amiot X.
Department of Gastroenterology and Hepatology, Hopital Tenon, Paris, France. jean-didier.grange@tnn.ap-hop-paris.fr

Patients with cirrhosis and ascites show systemic and splanchnic arterial vasodilation, which causes a reduction in effective arterial blood volume and the activation of hormonal anti-natriuretic systems. Renal impairment is the most important predictor of hospital mortality in cirrhotic patients with SBP. In patients with SBP, the inflammatory response to the infection (TNF-alpha, IL-6) may be an important mechanism of renal dysfunction. Ascitic-fluid NO metabolites are related independently to the development of renal impairment. Treatment of SBP with intravenous albumin in addition to cefotaxime prevents renal impairment and reduces mortality in comparison with treatment with cefotaxime alone. As soon as ascites develops, liver transplantation should be considered in eligible patients, especially when local mean waiting times exceed life expectancy. Nitric oxide (NO), tumour necrosis factor alpha (TNF-alpha) and interleukin-6 (IL-6) have been implicated in the pathogenesis of circulatory alterations observed in cirrhotic patients with ascites. Kidney failure is one of the main factors associated with mortality in patients with end-stage liver disease developing complications, particularly severe infections and variceal haemorrhage. Renal impairment occurs in patients with the highest concentration of cytokines in plasma and ascitic fluid and is associated with marked activation of the renin-angiotensin system. In patients with spontaneous bacterial peritonitis (SBP), serum and ascitic fluid levels of NO metabolites (nitrites and nitrates) were higher than those of patients with sterile ascites, and renal impairment is considered to be caused by a decrease in effective arterial blood volume as a result of the infection. The administration of albumin prevents deterioration of renal function and reduces mortality in these patients. However, SBP and renal dysfunction are late complications in the course of liver cirrhosis. As soon as ascites develops, liver transplantation should be considered in eligible patients, especially when local mean waiting times exceed life expectancy. A better knowledge of metabolic disorders associated with the early stage of cirrhosis is essential for the development of optimal therapeutic strategies for the prophylaxis and treatment of portal hypertension and its complications.

Hepatology. 2004 Apr;39(4):915-23.
A randomized controlled trial of colchicine plus ursodiol versus methotrexate plus ursodiol in primary biliary cirrhosis: ten-year results.
Kaplan MM, Cheng S, Price LL, Bonis PA.
Division of Gastroenterology, Department of Medicine and the Tupper Research Institute, New England Medical Center and Tufts University School of Medicine, Boston, Massachusetts, USA. mkaplan@tufts-nemc.org Primary biliary cirrhosis frequently progresses despite treatment with ursodeoxycholic acid (UDCA), the only approved therapy. Previous studies suggested that colchicine and methotrexate may improve biochemical tests of liver function, symptoms, and liver histology. The aim of the present study was to determine if the addition of colchicine or methotrexate to UDCA would improve survival free of liver transplantation. Eighty-five patients with histologically confirmed primary biliary cirrhosis whose serum alkaline phosphatase levels were at least twice the normal level and who were not yet candidates for liver transplantation were randomly assigned to receive colchicine or methotrexate in a double-blind study. UDCA was administered to all patients after 2 years. The primary end point was survival free of liver transplantation. Patients were followed up for a total of up to 10 years or until treatment failure. Data were analyzed on an intention-to-treat basis. Transplant-free survival was similar in both groups: 0.57 for colchicine plus UDCA and 0.44 for methotrexate plus UDCA, results that are similar to those predicted by the Mayo prognostic model. Significant improvement in liver biochemical tests and liver histology was observed in a subset of patients in both treatment groups who remained in the study for all 10 years. In conclusion, neither colchcine plus UDCA nor methotrexate plus UDCA improved survival beyond that predicted by the Mayo prognostic model. However, clinical, histologic, and biochemical improvement observed among those who remained in the study for 10 years suggests a possible benefit of these drugs in a subset of patients.

Liver Transpl. 2004 Apr;10(4):564-70.
Two-stage total hepatectomy and liver transplantation for acute deterioration of chronic liver disease: A new bridge to transplantation.
Guirl MJ, Weinstein JS, Goldstein RM, Levy MF, Klintmalm GB.
Department of Internal Medicine, Division of Gastroenterology, Methodist Dallas Hospital, Dallas, TX.

Two-stage total hepatectomy and liver transplantation has been reported for acute liver disease such as fulminant hepatic failure, primary graft failure, severe hepatic trauma, and spontaneous hepatic rupture secondary to hemolysis, elevated liver function tests, low platelets syndrome, and preeclampsia. This is the first report of patients with cirrhosis to undergo a 2-stage total hepatectomy and liver transplantation. From 1984 to 2002, our institution performed 2008 orthotopic liver transplantations. We identified 4 patients with chronic liver disease who underwent a 2-stage hepatectomy and liver transplantation. This is a retrospective review of these 4 patients and a review of the literature on this procedure. All 4 patients were young men with an age range of 29-31 years and had underlying cirrhosis as well as a previous transjugular intrahepatic portosystemic shunt (TIPS)procedure. Acute decompensation fulfilling Ringes' criteria for toxic liver syndrome secondary to an upper gastrointestinal bleed occurred in all patients. The approximate average time between hepatectomy and liver transplantation was 20 hours (range: 8-42 hours). In all cases, the explanted liver showed histological changes of acute hepatic necrosis within the background of cirrhosis. After hepatectomy, vasopressor requirements were well documented in 2 patients. For 1 patient, there was a clear improvement in their hemodynamic status. The mean hospital stay of the 4 patients was 63 days. All patients were discharged from the hospital and are alive and well with adequate liver function at 6 to 37 months follow-up. Two-stage total hepatectomy and liver transplantation may be a life-saving procedure in highly selected cirrhotic patients with acute hepatic decompensation and multiorgan dysfunction. (Liver Transpl 2004;10:564-570.)

Liver Transpl. 2004 Apr;10(4):488-91.
Immunosuppression affects the rate of recurrent primary biliary cirrhosis after liver transplantation.
Neuberger J, Gunson B, Hubscher S, Nightingale P.
Liver Unit, Queen Elizabeth Hospital, Birmingham, UK.

Identifying the risk factors associated with recurrence of primary biliary cirrhosis after liver transplantation may affect immunosuppression and increase understanding of the pathogenesis. Four hundred eighty-five patients with PBC were followed for a median of 79 months after transplantation; histological evidence of recurrence was found in 23%. On multivariate analysis, the only risk factor identified with recurrence was the type of calcineurin inhibitor used. The odds ratio for recurrence on tacrolimus was 2.73 (95% confidence interval: 1.84-4.10) compared with cyclosporine. For those receiving cyclosporine, the median time to recurrence was 123 months and for those on tacrolimus 62 months (P <.001). Reasons for this difference between the 2 calcineurin inhibitors are not clear. (Liver Transpl 2004;10:488-491.)

Ann Surg. 2004 Feb;239(2):194-201.
Abdominal drainage after hepatic resection is contraindicated in patients with chronic liver diseases.
Liu CL, Fan ST, Lo CM, Wong Y, Ng IO, Lam CM, Poon RT, Wong J.
Department of Surgery, University of Hong Kong Medical Centre, Queen Mary Hospital, Hong Kong, China. clliu@hkucc.hku.hk

OBJECTIVE: The aim of this study was to determine whether abdominal drainage is beneficial after elective hepatic resection in patients with underlying chronic liver diseases. SUMMARY BACKGROUND DATA: Traditionally, in patients with chronic liver diseases, an abdominal drainage catheter is routinely inserted after hepatic resection to drain ascitic fluid and to detect postoperative hemorrhage and bile leakage. However, the benefits of this surgical practice have not been evaluated prospectively. PATIENTS AND METHODS: Between January 1999 and March 2002, 104 patients who had underlying chronic liver diseases were prospectively randomized to have either closed suction abdominal drainage (drainage group, n = 52) or no drainage (nondrainage group, n = 52) after elective hepatic resection. The operative outcomes of the 2 groups of patients were compared. RESULTS: Fifty-seven (55%) patients had major hepatic resection with resection of 3 Coiunaud's segments or more. Sixty-nine (66%) patients had liver cirrhosis and 35 (34%) had chronic hepatitis. Demographic, surgical, and pathologic details were similar between both groups. The primary indication for hepatic resection was hepatocellular carcinoma (n = 100, 96%). There was no difference in hospital mortality between the 2 groups of patients (drainage group, 6% vs. nondrainage group, 2%; P = 0.618). However, there was a significantly higher overall operative morbidity in the drainage group (73% vs. 38%, P < 0.001). This was related to a significantly higher incidence of wound complications in the drainage group compared with the nondrainage group (62% vs. 21%, P < 0.001). In addition, a trend toward a higher incidence of septic complications in the drainage group was observed (33% vs. 17%, P = 0.07). The mean (+/- standard error of mean) postoperative hospital stay of the drainage group was 19.0 +/- 2.2 days, which was significantly longer than that of the nondrainage group (12.5 +/- 1.1 days, P = 0.005). With a median follow-up of 15 months, none of the 51 patients with hepatocellular carcinoma in the drainage group developed metastasis at the drain sites. On multivariate analysis, abdominal drainage, underlying liver cirrhosis, major hepatic resection, and intraoperative blood loss of >1.5L were independent and significant factors associated with postoperative morbidity. CONCLUSION: Routine abdominal drainage after hepatic resection is contraindicated in patients with chronic liver diseases.

Rom J Gastroenterol. 2003 Dec;12(4):297-302.
Cirrhosis and bacterial infections.
Vilstrup H.
Department of Medicine V, Aarhus University Hospital, Denmark. vilstrup@akh.aaa.dk

Half of cirrhosis patients die within two years after diagnosis, in most cases from cirrhosis related causes; most frequently variceal bleeding closely followed by infections. There seems to exist associations between infection and other complications such as malnutrition, hepatic encephalopathy and variceal bleeding. Cirrhosis patients have an acquired immune deficiency because of dyshomeostasis and malnutrition. All host defence systems are compromised, e.g. the acute phase response, and macrophage, neutrocyte, and lymphocyte functions. Simultaneously, there is increased microbiotic invasion, due to increased nosocomial exposure, intestinal translocation, aspiration, skin lesions, and trauma. Compared to the background population, the mortality of infections is more than 20 times increased in cirrhosis. The incidence of peritonitis, bacteremia, urinary tract infection, pneumonia, meningitis, tuberculosis, liver abscess is increased more than tenfold, and the mortality of each episode 3-10 times higher. The systemic response and accompanying classical symptoms are usually weakened. When positive isolates can be obtained the flora tends to be of an opportunistic nature. Infection should be suspected in any cirrhotic patient with an unexpected deterioration of clinical course. Treatment should be started on suspicion and with large dose broad-spectrum antibiotics (avoiding aminoglycosides). Antibiotic prophylaxis is efficacious at variceal bleeding, recurrent peritonitis, and at very low protein ascites, but otherwise is associated with risk of infection with multi-resistant strains.

Acta Med Croatica. 2003;57(3):221-5.
[Primary biliary cirrhosis]
[Article in Croatian]
Cukovic-Cavka S.
Zavod za gastroenterologiju, Klinicki bolnicki centar Zagreb, Kispaticeva 12, 10000 Zagreb, Hrvatska.

Primary biliary cirrhosis is an autoimmune chronic cholestatic liver disease of unknown cause that usually affects middle-aged women. It is characterized by inflammatory destruction of the interlobular and septal bile ducts, which leads to chronic cholestasis and cirrhosis. The diagnosis should be considered in the setting of elevated alkaline phosphatase, immunoglobulin M level and the presence of antimitochondrial antibody in serum. Ursodeoxycholic acid is the only medication of proven benefit for these patients. Liver transplantation is only therapeutic option for patients who have end-stage disease.

Hepatogastroenterology. 2003 Nov-Dec;50(54):2013-6.
Long-term follow-up of patients with liver cirrhosis after endoscopic esophageal varices ligation therapy: comparison with ethanol injection therapy.
Okano H, Shiraki K, Inoue H, Kawakita T, Deguchi M, Sugimoto K, Sakai T, Ohmori S, Murata K, Nakano T.
First Department of Internal Medicine, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.

BACKGROUND/AIMS: Esophageal variceal hemorrhage is the most dreaded complication of liver disease. Prevention or emergency therapy of bleeding is important. METHODOLOGY: A group of 217 patients underwent endoscopic esophageal variceal therapy including endoscopic ethanol injection, endoscopic esophageal variceal ligation, or a combination of the two. RESULTS: Esophageal varices were eradicated by endoscopic esophageal variceal ligation with the least sessions required, and associated complications with endoscopic esophageal variceal ligation therapy were lower than with the other two approaches. However, the cumulative recurrence-free period of esophageal varices was significantly higher after endoscopic ethanol injection than after endoscopic esophageal variceal ligation and in some cases F3 varices were observed post-endoscopic esophageal variceal ligation hemorrhage. A combined endoscopic esophageal variceal ligation and endoscopic ethanol injection therapy had no advantage with respect to cumulative recurrence-free rate, session number, or complication frequency, relative to either therapy alone. CONCLUSIONS: While the combined observations indicate that endoscopic esophageal variceal ligation is safe and simple, we should consider additional therapy to achieve complete mucosal fibrosis of the esophagus after endoscopic esophageal variceal ligation.

Intervirology. 2003;46(6):388-93.
Lamivudine therapy for decompensated liver cirrhosis related to hepatitis B virus infection.
Lee HC, Suh DJ.
Division of Gastroenterology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine, 388-1 Pungnap-song, Songpa-gu, Seoul, Korea.

Chronic hepatitis B virus (HBV) infection is the major cause of chronic liver disease worldwide. Although the clinical course of HBV infection varies widely, the prognosis of decompensated liver cirrhosis is quite poor and the 5-year survival rate has been estimated to be only 14-35%. While the ultimate treatment of decompensated cirrhosis is orthotopic liver transplantation (OLT), recent studies have suggested that lamivudine can also improve the clinical outcomes in this group of patients. Lamivudine rapidly suppresses HBV replication and can improve several parameters of liver function tests and afford prolonged periods of pretransplantation survival. However, the proportion of clinical improvement as defined by a decrease in Child-Pugh score as well as the prolonged survival rate varied widely from study to study. These discrepancies might result from differences in the severity of cirrhosis at entry, the presence of active viral replication or inflammation, and the proportions of patients who received OLT during the study period. Overall, about half of the patients achieved a clinical improvement with lamivudine therapy. However, data are still lacking on whether lamivudine can prolong survival before OLT and even replace OLT. Most of the deaths or clinical improvement occurred or started to occur within the first 6 months of treatment. Therefore, OLT should be actively considered in patients with risk factors for early mortality or those without clinical improvement within the first 6 months of lamivudine treatment. Copyright 2003 S. Karger AG, Basel

Am J Gastroenterol. 2003 Nov;98(11):2485-90.
Vitamin E and vitamin C treatment improves fibrosis in patients with nonalcoholic steatohepatitis.
Harrison SA, Torgerson S, Hayashi P, Ward J, Schenker S.
Brooke Army Medical Center, University of Texas Health Science Center San Antonio, San Antonio, Texas, USA.

OBJECTIVE: Nonalcoholic steatohepatitis (NASH) is a common cause of liver disease. Although usually indolent, this disease can progress to cirrhosis in some patients. There is currently no proven medical therapy for the treatment of NASH. The aim of our study was to evaluate the efficacy of combination alpha-tocopherol (vitamin E) and vitamin C in reducing histologic inflammation and fibrosis. METHODS: This was a prospective, double-blind, randomized, placebo-controlled trial with a total enrollment of 49 patients; 45 patients completed the study. All patients were randomized to receive either vitamins E and C (1000 IU and 1000 mg, respectively) or placebo daily for 6 months, based on their initial histologic diagnosis of NASH. Additionally, all patients were given standard weight-loss counseling and encouraged to follow a low fat diet (<30 fat g/day). The pre- and posttreatment liver biopsies were reviewed by a single pathologist, who was blinded to the patient's medication. Biopsies were scored based on a modification of the scoring system published by Brunt et al. (Am J Gastroenterol 1999;94:2467-74). A score of 0-4 was possible for fibrosis, and a score of 0-6 was possible for inflammation and hepatocyte degeneration and necrosis. In addition, body mass index, glycohemoglobin, lipids, and liver enzymes were followed throughout the study. RESULTS: Forty-five patients completed 6 months of therapy without significant side effects. Vitamin treatment resulted in a statistically significant improvement in fibrosis score (p=0.002). No changes were noted in inflammation with treatment.Vitamin E and vitamin C, in the doses used in this study, were well tolerated and were effective in improving fibrosis scores in NASH patients. No improvement in necroinflammatory activity or ALT was seen with this combination of drug therapy. A larger, multicenter, longer-term trial with vitamin E and vitamin C seems to be warranted.

Int J Vitam Nutr Res. 2003 Nov;73(6):411-5.
Pilot clinical trial of the use of alpha-tocopherol for the prevention of hepatocellular carcinoma in patients with liver cirrhosis.
Takagi H, Kakizaki S, Sohara N, Sato K, Tsukioka G, Tago Y, Konaka K, Kabeya K, Kaneko M, Takayama H, Hashimoto Y, Yamada T, Takahashi H, Shimojo H, Nagamine T, Mori M.
First Department of Internal Medicine, Gunma University Faculty of Medicine, 3-39-15, Showa Machi Maebashi, 371-8511, Japan. htakagi@med.gunma-u.ac.jp

Patients with chronic hepatitis C virus (HCV) infection often develop liver cirrhosis and hepatocellular carcinoma (HCC). The purpose of this study was to test the chemopreventive effect of alpha-tocopherol on hepatocarcinogenesis in patients with liver cirrhosis and a history of HCV infection. Eighty-three patients with liver cirrhosis and with positive history of HCV infection were divided at random into two groups. Forty-four patients were treated with alpha-tocopherol (Vit E group) while the other 39 were followed as controls. The clinical background (gender, age, and laboratory data) was similar in the two groups. Serum levels of alpha-tocopherol, albumin, alanine aminotransferase (ALT), and total cholesterol and platelet count were measured serially over a period of five years. The mean serum concentration of alpha-tocopherol was low in both groups at entry and was significantly higher in the Vit E group than in the control group one month after treatment. Platelet count, serum albumin, ALT, and total cholesterol were not different between the two groups during the five-year period. Cumulative tumor-free survival and cumulative survival rate tended to be higher in the Vit E group than in controls, albeit statistically insignificant. The serum level of alpha-tocopherol was low in patients with liver cirrhosis and positive for HCV. Although the administration of alpha-tocopherol normalized the level one month later, it could neither improve liver function, suppress hepatocarcinogenesis, nor improve cumulative survival. Patients treated with alpha-tocopherol tended to live longer without development of HCC but the difference was not statistically significant.

Dig Liver Dis. 2003 Sep;35(9):660-3.
Is the use of albumin of value in the treatment of ascites in cirrhosis? The case in favour.
Laffi G, Gentilini P, Romanelli RG, La Villa G.
Department of Internal Medicine, University of Florence School of Medicine, Viale Morgagni 85, 1-50134 Florence, Italy.

In patients with cirrhosis, ascites accumulates because of sodium retention, triggered by a reduction of the effective arterial blood volume, and imbalanced Starling forces in the splanchnic area due to portal hypertension and hypoalbuminemia. Albumin is the ideal plasma expander in this setting, since it ameliorates systemic and reneal haemodynamics, so reducing sodium retention, and increases oncotic pressure in the splanchnic compartment. In particular, albumin proved useful in patients treated with diuretics, as demonstrated by a randomised study performed at our Instituition in which 126 ascitic inpatients were treated according to a stepped-care diuretic regimen. In fact, patients receiving diuretics plus albumin (n = 63) had a higher cummulative rate of response (p < 0.05) and a shorter hospital stay (20 +/- 1 versus 24 +/- 2 days, p < 0.05) than those given diuretics alone. Treatment with albumin on an outpatient basis (25 g/week) resulted in a lower probability of developing ascites (p < 0.02 vs. patients not given albumin) and a lower probability of readmission (p < 0.02). Patients given albumin also had a better quality of life. As discussed in another article, evidence also supports the use of albumin in patients treated for paracentesis, as well as in patients with spontaneous peritonitis or hepatorenal syndrome.

Schweiz Rundsch Med Prax. 2003 Aug 27;92(35):1427-34.
[Complications of liver cirrhosis: portal hypertension, gastroesophageal varices and ascites]
[Article in German]
Schuster MJ.
Medizinische Klinik Fachbereich Gastroenterologie Stadtische Kliniken Esslingen Akademisches Lehrkrankenhaus der Universitat Tubingen Hirschlandstrasse 97 D-73730 Esslingen.

Patients with cirrhosis of the liver are at high risk of a large variety of complications. Especially the development of portal hypertension, followed by gastroesophageal varicosis and ascites are potentially life threatening problems. In the treatment of gastroesophageal varicosis primary prophylaxis to prevent a first bleeding episode, acute therapy for bleeding varices, and secondary prophylaxis to prevent patients from rebleeding have to be considered. While treating patients with ascites the high frequency of side effects induced by diuretics has to be taken into account. In addition, the diagnosis of spontaneous bacterial peritonitis must not be missed. Hepatorenal syndrome, a typical complication of advanced cirrhosis is especially difficult to treat and is considered an indication for liver transplantation.

Hepatogastroenterology. 2003 Sep-Oct;50(53):1556-9.
Long-term follow-up of patients with liver cirrhosis after endoscopic ethanol injection sclerotherapy for esophageal varices.
Okano H, Shiraki K, Inoue H, Kawakita T, Deguchi M, Sugimoto K, Sakai T, Ohmori S, Murata K, Nakano T.
First Department of Internal Medicine, Mie University School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan.

BACKGROUND/AIMS: Esophageal variceal hemorrhage is a severe complication of liver cirrhosis, and therapy for acute bleeding and prevention of hemorrhage are important. In this study, we evaluated the long-term cumulative survival rate of patients with esophageal varices after treatment with endoscopic ethanol injection sclerotherapy (EIS group) or pharmacological therapy (non-EIS group). METHODOLOGY: All 110 patients were treated for their esophageal varices and their prognosis and complications were analyzed during the follow-up period. RESULTS: The cumulative survival rate in the primary preventive EIS group was superior to that in the non-EIS group. The preventive EIS group had greater long-term survival rate than those treated on an emergency group. With respect to emergency therapy, the EIS group had better survival rates than the non-EIS group during the two-year follow-up period after esophageal variceal therapy. CONCLUSIONS: We conclude that primary preventive EIS is an effective therapy for survival of patients with esophageal varices over a long-term period.

Br J Surg. 2003 Aug;90(8):950-5.
Interstitial laser coagulation with temporary hepatic artery occlusion for patients with cirrhosis and irresectable hepatoma.
Verhoef C, Kuiper JW, Heisterkamp J, de Man RA, Pattynama PM, IJzermans JN.
Department of Surgery, Erasmus Medical Centre, Rotterdam, The Netherlands.

BACKGROUND: The aim was to determine the degree of local control of hepatocellular carcinoma (HCC) in patients with cirrhotic liver disease when treated with ultrasonographically guided interstitial laser coagulation (ILC) with temporary hepatic artery occlusion. METHODS: Sixteen patients with 24 HCC tumours were treated. Follow-up was by computed tomography or magnetic resonance imaging every 3 months. RESULTS: Nineteen of 24 tumours showed complete necrosis immediately after treatment, and there was no tumour recurrence during follow-up (mean 14 months, median 12 months). No effect on liver function was observed after 1 week and there was no death. In 13 of the 16 patients, new HCC foci developed at other sites. CONCLUSION: Percutaneous ILC combined with temporary hepatic artery occlusion during a single session is an effective local treatment for HCC nodules smaller than 5 cm. However, new HCC lesions develop in the majority of patients, which underscores the need for adjuvant therapy or repeated treatment in these patients. Copyright 2003 British Journal of Surgery Society Ltd. Published by John Wiley & Sons, Ltd.

Ann Intern Med. 2003 Aug 5;139(3):186-93.
The effect of selective intestinal decontamination on the hyperdynamic circulatory state in cirrhosis. A randomized trial.
Rasaratnam B, Kaye D, Jennings G, Dudley F, Chin-Dusting J.
Alfred Hospital and Baker Medical Research Institute, Prahran, Victoria, Australia.

BACKGROUND: Peripheral vasodilatation is central to the pathogenesis of the accompanying hyperkinetic circulatory state and portal hypertension in cirrhotic patients. Selective intestinal decontamination with norfloxacin has been demonstrated to partially correct nitric oxide production in the forearm vasculature of cirrhotic patients. OBJECTIVE: To examine the effects of selective intestinal decontamination on regional and systemic hemodynamics in cirrhotic patients. DESIGN: Randomized, double-blind, placebo-controlled, crossover study. SETTING: Alfred Hospital, Melbourne, Australia. PATIENTS: 14 patients with alcohol-related cirrhosis and 14 matched healthy controls. INTERVENTION: Norfloxacin, 400 mg twice daily, for 4 weeks. MEASUREMENTS: Venous occlusion plethysmography was used to determine forearm blood flow. Cardiac output and the hepatic venous pressure gradient were determined after cardiac catheterization. Glomerular filtration rate was assessed by measuring inulin clearance. Serum levels of endotoxin were determined by chromogenic Limulus amebocytelysate assay. RESULTS: Norfloxacin significantly diminished serum endotoxin levels (average change, -2.14 EU/mL [95% CI, -3.6 to -0.68 EU/mL]). Derived systemic vascular resistance increased significantly with norfloxacin (2.94 units [CI, 0.74 to 5.11 units]) and was accompanied by an increase in mean arterial pressure (8.70 mm Hg [CI, 2.65 to 14.73]), a trend toward decreased cardiac output (-1.207 L/min [range, 0.05 to -2.37 L/min]), a decrease in forearm blood flow (-0.99 mL/100 mL per min [CI, -1.80 to -0.17 mL/100 mL per min]), and a trend toward reduced hepatic venous pressure gradient (-2.43 mm Hg [CI, -5.2 to 0.34 mm Hg]). Norfloxacin did not significantly alter glomerular filtration rate. CONCLUSION: Selective intestinal decontamination with norfloxacin partially reverses the hyperdynamic circulatory state in cirrhotic patients without harming splanchnic or renal hemodynamics.

Dig Dis Sci. 2003 Jul;48(7):1425-30.
Regression of fibrosis in chronic hepatitis C after therapy with interferon and ribavirin.
Arif A, Levine RA, Sanderson SO, Bank L, Velu RP, Shah A, Mahl TC, Gregory DH.
Department of Medicine, Division of Gastroenterology, State University of New York, Upstate Medical University, Syracuse, New York 13210, USA.

Interferon and ribavirin decrease necroinflammation in chronic hepatitis C with or without virological clearance; however, reversibility of fibrosis remains to be established. We evaluated the effect of combination therapy on virological and liver histopathological outcomes in 52 naive patients and 79 patients unresponsive to interferon monotherapy with predominantly genotype 1 chronic hepatitis C. One hundred four patients completed interferon and ribavirin treatment after 24-48 weeks. Fifty-six paired liver biopsies (mean biopsy interval 28 months) were assessed by the Ishak score. Sustained virological responses were 37% in naive patients and 22% in re-treated patients. In virological responders and nonresponders, fibrosis and necroinflammation scores decreased by -0.91 (P = 0.04) and -0.5 (P = 0.02) and by -2.8 (P = 0.001) and -0.66 (P = 0.06), respectively. Interferon and ribavirin had greater benefit on fibrosis when associated with clearance of HCV RNA. Treatment strategies in virological nonresponders who show fibrosis regression should include consideration of maintenance therapy, if such treatment eventually proves to benefit histological outcomes.

Lancet. 2003 Jul 5;362(9377):53-61.
Primary biliary cirrhosis.
Talwalkar JA, Lindor KD.
Division of Gastroenterology and Hepatology, Mayo Clinic and Foundation, Rochester, MN 55905, USA.

Primary biliary cirrhosis is a chronic cholestatic liver disease of adults. This disorder is characterised histologically by chronic non-suppurative destruction of interlobular bile ducts leading to advanced fibrosis, cirrhosis, and liver failure. The precise aetiopathogenesis of primary biliary cirrhosis remains unknown, although dysregulation of the immune system and genetic susceptibility both seem to be important. Affected patients are typically middle-aged women with abnormal serum concentrations of alkaline phosphatase. Presence of antimitochondrial antibody in serum is almost diagnostic of the disorder. Identification of primary biliary cirrhosis is important, because effective treatment with ursodeoxycholic acid has been shown to halt disease progression and improve survival without need for liver transplantation. However, therapeutic options for disease-related complications-including fatigue and metabolic bone disease-remain unavailable. Mathematical models have been developed that accurately predict the natural history of primary biliary cirrhosis in individuals. Despite advances in understanding of the disease, it remains one of the major indications for liver transplantation worldwide.

Hepatology. 2003 Jul;38(1):203-9.
Ursodeoxycholic acid therapy and the risk of colorectal adenoma in patients with primary biliary cirrhosis: an observational study.
Serfaty L, De Leusse A, Rosmorduc O, Desaint B, Flejou JF, Chazouilleres O, Poupon RE, Poupon R.
Service d'Hepato-gastroenterologie, Service d'Anatomopathologie, Hopital Saint-Antoine, INSERM U370, Paris, France. lawrence.serfaty@sat.ap-hop-paris.fr

Ursodeoxycholic acid (UDCA) is the first-line treatment for primary biliary cirrhosis (PBC). The long-term administration of UDCA might indirectly favor colon carcinogenesis by increasing the fecal excretion of secondary bile acids or, in contrast, it might inhibit colon carcinogenesis, as demonstrated in animal models. In patients with PBC, we examined the effect of prolonged UDCA administration on the prevalence and recurrence of colorectal adenoma and on the proliferation of colon epithelial cells. One hundred fourteen patients (103 women, 11 men; mean age, 55 years) with PBC, were enrolled in a colonoscopic surveillance program. The prevalence of colon adenoma was compared in patients already treated with UDCA (mean duration 46 months) at the time of colonoscopy (treated group, n = 52) and in patients undergoing colonoscopy just prior to treatment initiation (untreated group, n = 62). The recurrence of adenoma following removal (mean follow-up, 35 months) was compared between UDCA-treated patients and appropriate age- and gender-matched controls (2/1) selected from a cohort of 205 patients undergoing polypectomy. Epithelial cell proliferation was assessed using anti-Ki67 antibodies on colon biopsies from both treated and untreated patients. Treated and untreated patients displayed similar demographic characteristics. The prevalence of colorectal adenomas was 13% in the treated group versus 24% in the untreated group (P =.16). The colon epithelial cell proliferation index was significantly lower in treated patients than in untreated patients (P =.001). Following removal of the adenoma, the probability of recurrence was significantly lower in patients treated with UDCA than in controls (7% vs. 28% at 3 years, P =.04). In conclusion, this study suggests that, in patients with PBC, the prolonged administration of UDCA (1) is not associated with an increased prevalence of colorectal adenomas, and (2) significantly decreases the probability of colorectal adenoma recurrence following removal. These results are strengthened by the significant reduction in colon epithelial cell proliferation seen in patients treated with UDCA.

Hepatology. 2003 Jul;38(1):196-202.
Pharmacokinetics and pharmacodynamic action of budesonide in early- and late-stage primary
biliary cirrhosis.
Hempfling W, Grunhage F, Dilger K, Reichel C, Beuers U, Sauerbruch T.
Department of Medicine II, Klinikum Grosshadern, University of Munich, Munich, Germany. Budesonide has been discussed as a potential treatment option in primary biliary cirrhosis (PBC). Therefore, we studied the pharmacokinetics and pharmacodynamics of budesonide in patients with PBC stage I/II and stage IV. Twelve patients with early PBC stage I/II and 7 patients with PBC stage IV under continuous treatment with ursodeoxycholic acid (UDCA) were enrolled in an exploratory trial. Each patient received oral budesonide for 3 weeks at weekly increasing dosages of 3 mg once to thrice per day. Budesonide and cortisol plasma levels, urinary cortisol excretion, serum liver tests, and immunoglobulins were determined on days 1, 7, and 21 of the study. Patients with PBC stage IV showed significantly higher peak plasma concentrations (4.9 +/- 3.5 vs. 1.5 +/- 0.4 ng/mL; P <.05) and areas under the plasma concentration-time curves (AUC) (23.2 +/- 16.8 vs. 5.1 +/- 1.4 hours. ng/mL, P <.01, total AUC extrapolated to infinity [AUC(0- infinity )]) after a single dose of 3 mg budesonide when compared with patients with PBC stage I/II. Equally, AUC of budesonide were significantly increased under a multiple dose regimen on day 21 (14.0 +/- 11.6 vs. 5.0 +/- 1.9 hours. ng/mL, P <.01, AUC at steady state from dosing time to 8 hours [AUC(ss,0-8 h)]). Higher levels of budesonide were related to a significant decrease in plasma cortisol and reduction of urinary cortisol excretion in patients with stage IV disease. Two patients with stage IV disease developed portal vein thrombosis (PVT). In conclusion, administration of budesonide leads to markedly elevated plasma levels in cirrhotic patients with PBC associated with serious adverse drug reactions. Thus, further evaluation of combined treatment with UDCA may be considered in early-stage PBC but not in cirrhotic patients with PBC.

Liver Transpl. 2003 Jul;9(7):733-6.
The effect of immunosuppressive regimens on the recurrence of primary biliary cirrhosis after liver transplantation.
Levitsky J, Hart J, Cohen SM, Te HS.
Center for Liver Diseases, The University of Chicago Hospitals, IL 60637, USA.

Recurrence of primary biliary cirrhosis (PBC) has been described in liver transplant recipients. Type of immunosuppression has been reported to influence the frequency of recurrence. The aim of this study is to evaluate the occurrence and pattern of recurrent PBC in our liver transplant recipients and determine any association of immunosuppressive agents with its recurrence. Patients who underwent orthotopic liver transplantation (OLT) for PBC were identified from the University of Chicago Liver Transplant Database. Recurrent PBC was diagnosed based on specific pathological criteria. Of 46 patients who underwent OLT for PBC between 1984 and 2000, a total of 7 patients (15%) were diagnosed with recurrent PBC at a median of 78 months (range, 27 to 120 months) after OLT. Forty-three percent of patients were administered cyclosporine, whereas 57% were administered tacrolimus before disease recurrence. Rates of recurrence were not different between patients maintained on cyclosporine therapy (16%) compared with those maintained on tacrolimus therapy (18%; P = 1.0). There also was no difference in frequency of rejection episodes or duration of corticosteroid therapy between those who did and did not have recurrent PBC. In conclusion, recurrent PBC developed in a small number of patients 2 years or longer after OLT. In our population, there was no difference in recurrence rates between those administered cyclosporine or tacrolimus for immunosuppression.

J Gastroenterol. 2003;38(6):573-8.
Bezafibrate treatment: a new medical approach for PBC patients?
Kanda T, Yokosuka O, Imazeki F, Saisho H.
First Department of Medicine, Chiba University School of Medicine, Japan.

BACKGROUND: A new medical approach to primary biliary cirrhosis (PBC) has been desired. We investigated the feasibility of using combination ursodeoxycholic acid (UDCA)-bezafibrate therapy in patients with PBC nonresponsive to UDCA monotherapy. METHODS: During a 6-month period, 22 PBC patients with elevated serum alkaline phosphatase (ALP) despite UDCA monotherapy received either UDCA at 600 mg/day (control group) or UDCA at 600 mg/day plus bezafibrate at 400 mg/day (bezafibrate group). Each patient underwent detailed clinical and biochemical evaluation. RESULTS: During treatment, changes in ALP level were greater in the bezafibrate group than in the control group (P< 0.01). During and at the end of treatment, serum ALP levels were significantly lower than those before treatment in patients receiving UDCA plus bezafibrate (P< 0.05). At the end of the 6 months, normalization of serum ALP was observed in 5 of 11 (45.4%) patients given bezafibrate and in 2 of 11 (18.1%) patients not given bezafibrate (P< 0.16). Bile acid proportions during the combination therapy did not change. Pruritus disappeared in 1 of 7 bezafibrate-group patients with this symptom. CONCLUSIONS: UDCA at 600 mg/day plus bezafibrate at 400 mg/day may be considered as a new therapeutic option for patients with PBC.

Gastroenterology. 2003 Jun;124(7):1792-801.
Nutritional supplementation with branched-chain amino acids in advanced cirrhosis: a double-blind, randomized trial.
Marchesini G, Bianchi G, Merli M, Amodio P, Panella C, Loguercio C, Rossi Fanelli F, Abbiati R; Italian BCAA Study Group.
Department of Internal Medicine, Alma Mater Studiorum University of Bologna, Bologna, Italy. marchreg@med.unibo.it

BACKGROUND & AIMS: The role of oral supplementation with branched-chain amino acids (BCAA) in advanced cirrhosis is far from settled. A nutritional approach might prevent progressive liver failure and improve nutritional parameters and quality of life. METHODS: A multicenter, randomized study comparing 1-year nutritional supplementation with BCAA against lactoalbumin or maltodextrins was performed in 174 patients with advanced cirrhosis. Primary outcomes were the prevention of a combined end point (death and deterioration to exclusion criteria), the need for hospital admission, and the duration of hospital stay. Secondary outcomes were nutritional parameters, laboratory data and Child-Pugh score, anorexia, health-related quality of life, and need for therapy. RESULTS: Treatment with BCAA significantly reduced the combined event rates compared with lactoalbumin (odds ratio, 0.43; 95% confidence interval, 0.19-0.96; P = 0.039) and nonsignificantly compared with maltodextrins (odds ratio, 0.51; 95% confidence interval, 0.23-1.17; P = 0.108). The average hospital admission rate was lower in the BCAA arm compared with control treatments (P = 0.006 and P = 0.003, respectively). In patients who remained in the study, nutritional parameters and liver function tests were, on average, stable or improved during treatment with BCAA and the Child-Pugh score decreased (P = 0.013). Also, anorexia and health-related quality of life (SF-36 questionnaire) improved. Long-term compliance with BCAA was poor. CONCLUSIONS: In advanced cirrhosis, long-term nutritional supplementation with oral BCAA is useful to prevent progressive hepatic failure and to improve surrogate markers and perceived health status. New formulas are needed to increase compliance.

Liver Transpl. 2003 Jun;9(6):581-6.
Outcome analysis in adult-to-adult living donor liver transplantation using the left lobe.
Soejima Y, Shimada M, Suehiro T, Hiroshige S, Ninomiya M, Shiotani S, Harada N, Hideki I, Yonemura Y, Maehara Y.
Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. ysoejima@surg2.med.kyushu-u.ac.jp

Graft size problems remain the greatest limiting factor for expansion of living donor liver transplantation (LDLT) to the adult population. The result of adult-to-adult LDLT using the left lobe with special reference to graft size has not been fully evaluated to date. In this study, we evaluated the outcome of adult-to-adult LDLT using the left lobe and also analyze the impact of using small-for-size grafts on outcome. Thirty-six recipients who underwent adult-to-adult LDLT using the left lobe (n = 14) or left lobe plus caudate lobe (n = 22) were included in the study. Variables including preoperative and operative data, patient and graft survival, complications, and causes of graft loss were studied. Furthermore, the incidence of small-for-size syndrome and its impact on graft survival were studied. Mean graft volume (GV) was 420 +/- 85 g (range, 260 to 620 g), which resulted in 38.2% +/- 8.1% (range, 22.8% to 53.8%) of the recipient standard liver volume (SLV). Overall 1-year patient and graft survival rates were 85.7% and 82.9%, respectively. Seven grafts were lost. Small-for-size syndrome occurred in 7 of 16 patients (43.8%) with cirrhosis and only 1 of 20 patients (5.0%) without cirrhosis (P =.005). Recipients who developed small-for-size syndrome had inferior graft survival to those who did not (P =.07). In conclusion, adult-to-adult LDLTs were found to be feasible without affecting patient or graft survival. Small-for-size syndrome developed more frequently in patients with cirrhosis. Minimum GV in adult-to-adult LDLT should be 30% less than the recipient's SLV in patients without cirrhosis, whereas 45% less was required in patients with cirrhosis.

Hepatology. 2003 Jul;38(1):258-66.
The management of ascites in cirrhosis: report on the consensus conference of the International
Ascites Club.
Moore KP, Wong F, Gines P, Bernardi M, Ochs A, Salerno F, Angeli P, Porayko M, Moreau R, Garcia-Tsao G, Jimenez W, Planas R, Arroyo V.
Centre for Hepatology, Royal Free and University College Medical School, UCL, London, United Kingdom. kmoore@rfc.ucl.ac.uk

Ascites is a common complication of cirrhosis, and heralds a new phase of hepatic decompensation in the progression of the cirrhotic process. The development of ascites carries a significant worsening of the prognosis. It is important to diagnose noncirrhotic causes of ascites such as malignancy, tuberculosis, and pancreatic ascites since these occur with increased frequency in patients with liver disease. The International Ascites Club, representing the spectrum of clinical practice from North America to Europe, have developed guidelines by consensus in the management of cirrhotic ascites from the early ascitic stage to the stage of refractory ascites. Mild to moderate ascites should be managed by modest salt restriction and diuretic therapy with spironolactone or an equivalent in the first instance. Diuretics should be added in a stepwise fashion while maintaining sodium restriction. Gross ascites should be treated with therapeutic paracentesis followed by colloid volume expansion, and diuretic therapy. Refractory ascites is managed by repeated large volume paracentesis or insertion of a transjugular intrahepatic portosystemic stent shunt (TIPS). Successful placement of TIPS results in improved renal function, sodium excretion, and general well-being of the patient but without proven survival benefits. Clinicians caring for these patients should be aware of the potential complications of each treatment modality and be prepared to discontinue diuretics or not proceed with TIPS placement should complications or contraindications develop. Liver transplantation should be considered for all ascitic patients, and this should preferably be performed prior to the development of renal dysfunction to prevent further compromise of their prognosis.

Liver Transpl. 2003 Jun;9(6):539-46.
Recurrent primary biliary cirrhosis.
Neuberger J.
Liver Unit, Queen Elizabeth Hospital, Birmingham, United Kingdom. J.M.Neuberger@bham.ac.uk

Liver transplantation remains the only effective treatment for end-stage primary biliary cirrhosis (PBC). It appears now well accepted that the disease recurs in the allograft. The diagnosis of recurrent PBC is made on the basis of a consistent history and demonstrating the histologic features of PBC on liver biopsy and exclusion of other causes of bile duct damage.

Hepatogastroenterology. 2003 May-Jun;50(51):784-8.
Results of modified Sugiura operation in variceal bleeding in cirrhotic and noncirrhotic patients.
Haciyanli M, Genc H, Halici H, Kumkumoglu Y, Gur OS, Ozturk T.
Ataturk Training and Research Hospital, 2nd General Surgery Department, Izmir, Turkey. mhaciyanli@hotmail.com

BACKGROUND/AIMS: Esophageal variceal bleeding is a major complication of portal hypertension and the optimal therapeutic modality for each individual patient differs. We reviewed the results of modified Sugiura procedure in patients with variceal bleeding of esophagus. METHODOLOGY: We retrospectively reviewed the charts of 13 patients who were subjected to modified Sugiura procedure (transabdominal esophagogastric devascularization + esophageal stapled transection + splenectomy) for bleeding esophageal varices between 1996 and 2001. Three patients disappeared from routine follow-up and were excluded from the study. Survival, rebleeding and encephalopathy were evaluated. RESULTS: The mean age was 46 (18-56). The etiology of portal hypertension was cirrhosis of liver in six (60%) and portal vein thrombosis in four (40%). One patient had Child-Pugh's Class A, two had Class B and three had Class C cirrhosis. Previous variceal bleeding were confirmed by endoscopy in all patients who had recurrent variceal bleeding despite treatment with beta-blockers (three patients) or endoscopic sclerotherapy +/- band ligation (seven patients). Two were subjected to emergency surgery while the remaining eight were operated on electively. No postoperative mortality was seen. The bleeders were stopped immediately in the emergent cases. During a mean follow-up of 27 (4-53) months, one (10%) patient suffered from encephalopathy and one (10%) from rebleeding at 20th and 28th months after the operation respectively. Three (30%) patients with Child C cirrhosis died due to bleeding (one) and hepatic failure (two) at 4, 25, and 28 months after the surgery. The prognoses of other patients are well at the present time. CONCLUSIONS: In our small number of patients, modified Sugiura procedure was found to be a safe and effective procedure for urgent and long-term control of bleeding varices in patients with portal hypertension due to cirrhosis and noncirrhotic etiology. The outcomes are encouraging in noncirrhotic patients and cirrhotic patients with good liver functions.

Hepatogastroenterology. 2003 May-Jun;50(51):645-50.
Radiofrequency ablation for treatment of hepatocellular carcinoma with cirrhosis.
Lo HW, Tsai YJ, Chen PH, Chen HY, Ker CG, Juan CC.
Division of Hepatology, Institute of Hepato-Gastroenterology, Yuan's General Hospital, No. 162, Cheng Kung 1st Rd, Kaohsiung 80211, Taiwan.

BACKGROUND/AIMS: The majority of hepatocellular carcinoma patients with cirrhosis are not candidates for surgical resection, and local thermal therapy producing destruction of cancer cells was one of the ideal options for treatment. Heat from radiofrequency ablation is generated through agitation caused by an alternating electrical current. The heat of radiofrequency energy results in local cell coagulation and causes cellular ablation necrosis of tumor tissue. METHODOLOGY: Eighteen cases of hepatocellular carcinoma were treated with radiofrequency ablation in our institute. We used a RFA 2000 generator (Boston Scientific Co, USA) with LeVeen needle with the maximum diameter of 3.5 cm when the array electrodes were fanned out. The indications for this method included; i) normal prothrombin profile, ii) no ascites, iii) tumor can be detected and approached by ultrasound, iv) tumor cannot be resected or patient is not willing to take the operation. RESULTS: No specific complication was noted during or after the procedure. Only two cases needed more analgesics after the procedure. One case was found with burning of the stomach serosa proved by laparoscopic examination, in which radiofrequency ablation was performed to the tumor located in the left lobe of the segment 3. Impedance could not raise up completely in two cases with larger size tumor more than 5 cm. The decreased levels of alpha-fetoprotein were significant (P = 0.005) after radiofrequency ablation treatment. Residual tumor was found in four cases (20%) in the follow-up abdominal computed tomography scan. CONCLUSIONS: Radiofrequency ablation resulted in a higher rate of complete necrosis of tumor tissue and the complication rate was low as well. Therefore, we believed that radiofrequency ablation is an ideal treatment modality for most liver tumors, which cannot tolerate the conventional surgical procedures.

World J Gastroenterol. 2003 May;9(5):1090-3.
A new technique of combined endoscopic sclerotherapy and ligation for variceal bleeding.
Dhiman RK, Chawla YK.
Department of Hepatology, Postgraduate Institute of Medical Education & Research, Chandigarh, India. rkpsdhiman@hotmail.com

AIM: To develop a technique of combined endoscopic sclerotherapy and ligation (ESL) in which both techniques of endoscopic sclerotherapy (ES) and endoscopic variceal ligation (EVL) can be optimally used. METHODS: ESL was performed in 10 patients (age 46.4+/-7.9; 9 males, 1 female) with cirrhosis of liver using sclerotherapy needle and Speedband, Superview multiple band ligater (Boston Scientific, Microvasive, Watertown, MA). A single band was placed 5-10 cm proximal to the gastro-esophageal junction over each varix from proximal to distal margin, followed by intravariceal injection of 1.5 % ethoxysclerol (4 ml each) 2 to 3 cm proximal to the gastroesophageal junction on the ligated varices distal to deployed band. EVL was then performed at the injection site. Similarly other varices were also injected and ligated from distal to proximally. In the subsequent sessions, ES alone was performed to sclerose small varices at the gastroesophageal junction. RESULTS: ESL was successfully performed in all patients. A median of 3 (ESL 1, ES 2) sessions (ranged 1-4) were required to eradicate the varices in 9 (90 %) of 10 patients. Recurrence of varices without bleed was seen in 1 patient during a mean follow-up of 10.3 months (ranged 6-15). Two patients died of liver failure. None died of variceal bleeding. None of the patients had procedure related complications. CONCLUSION: ESL may be useful in the fast eradication of esophageal varices. However, randomised controlled trials are required to find out its relative efficacy and impact on variceal recurrence in comparison to ES or EVL.

Hepatology. 2003 May;37(5):1147-53.
Randomized trial comparing albumin and saline in the prevention of paracentesis-induced circulatory dysfunction in cirrhotic patients with ascites.
Sola-Vera J, Minana J, Ricart E, Planella M, Gonzalez B, Torras X, Rodriguez J, Such J, Pascual S, Soriano G, Perez-Mateo M, Guarner C.
Liver Unit, Internal Medicine Department, Hospital General Universitario de Alicante, Spain.

Paracentesis-induced circulatory dysfunction (PICD) is a recently described complication that can be prevented with the administration of plasma expanders. The aim of this study was to compare the efficacy of saline versus albumin in the prevention of PICD. Patients were randomized to receive albumin or saline after total paracentesis. Patients readmitted as a consequence of a second episode of tense ascites were treated with total paracentesis and the alternative plasma expander. After randomization, 35 patients received saline and 37 received albumin. Twenty-one patients were readmitted for tense ascites and treated with the alternative expander. Significant increases in plasma renin activity (PRA) were found 24 hours and 6 days after paracentesis when saline was used (baseline, 5.6 +/- 5.7; 24 hours, 7.6 +/- 6.9; 6 days, 8.5 +/- 8.0 ng x mL(-1). hr(-1); P <.05 and P <.01 vs. baseline, respectively), whereas no significant changes were observed with albumin. The incidence of PICD was significantly higher in the saline group versus the albumin group (33.3% vs. 11.4%, respectively; P =.03). However, no significant differences were found when less than 6 L of ascitic fluid was evacuated (6.7% vs. 5.6% in the saline and albumin groups, respectively; P =.9). Similar results were observed when analyzing patients who received 2 consecutive paracentesis (i.e., a significant increase in PRA after saline [P <.01] without significant variations after albumin). In conclusion, albumin is more effective than saline in the prevention of PICD. Saline is a valid alternative to albumin when less than 6 L of ascitic fluid is evacuated.

Ann Pharmacother. 2003 May;37(5):695-700.
Combined furosemide and human albumin treatment for diuretic-resistant edema.
Elwell RJ, Spencer AP, Eisele G.
Department of Pharmacy Practice, Albany College of Pharmacy, Albany, NY 12208-3492, USA. elwellr@acp.edu

OBJECTIVE: To evaluate the clinical usefulness of combined furosemide and human albumin for the treatment of diuretic-resistant edema in patients with nephrotic syndrome and cirrhosis. DATA SOURCES: Clinical literature was accessed through MEDLINE (1966-May 2002). Key search terms included furosemide, albumin, human albumin solution, nephrotic syndrome, and cirrhosis. DATA SYNTHESIS: Hypoalbuminemia, edema, and ascites are often manifestations of nephrotic syndrome and cirrhosis of the liver. Many patients with these conditions are resistant to the effects of diuretics. The combination of furosemide and human albumin solution is occasionally used in these patients. An evaluation of published studies focusing on combined furosemide and albumin in the management of nephrotic syndrome and cirrhosis was conducted. CONCLUSIONS: Published studies report conflicting results regarding the efficacy of combined furosemide and albumin. Although it is difficult to generate firm conclusions, it appears the combination may provide clinical benefits for select patients. Given these findings, we believe that the addition of albumin to enhance diuretic efficacy should be reserved for patients with recalcitrant edema or ascites in whom diuretic doses have been maximized and those with severe hypoalbuminemia.

Croat Med J. 2003 Apr;44(2):178-86.
Clinical and neurohumoral response to posture, physical exercise, and ascites treatment in Child-Pugh C liver cirrhosis: randomized prospective trial.
Degoricija V, Zjacic-Rotkvic V, Marout J, Sefer S, Troskot B.
Department of Medicine, Sisters of Mercy University Hospital, Vinogradska cesta 29, 10000 Zagreb, Croatia. vesna.degoricija@zg.tel.hr

AIM: To assess clinical and neurohumoral response to posture, physical exercise, and ascites treatment in patients with Child-Pugh C liver cirrhosis and tense ascites. METHOD: Fifty patients with Child-Pugh C liver cirrhosis and tense ascites were randomly allocated into 5 groups. Thirty patients were treated with paracentesis of 6 L of acites paralleled by plasma volume expansion with 200 mL of 20% low sodium albumin (10 patients), 600 mL fresh frozen plasma (10 patients), or 900 mL solution of synthetic gelatine (10 patients), ie, doses with comparable oncotic power, and bed rest for 24 h before and after the procedure. They were compared with 10 patients treated with paracentesis of 6 L of ascites without plasma volume expansion and no bed rest, and 10 patients treated with 40 mg of furosemide IV daily and no bed rest. Mean arterial pressure, heart rate, body weight loss, urine flow rate, creatinine clearance, plasma renin activity, plasma aldosterone concentration, and plasma atrial natriuretic peptide (ANP) were measured before the procedure and 6 hours, 2, 3, and 6 days after the procedure. RESULTS: Diuretic treatment and paracentesis of 6 L of ascites without plasma volume expansion and no bed rest 24 h before and after the procedure were associated with significant hypotension (p<0.01) during 6 days of the trial, tachycardia (p<0.01) on day 1 and 2 (p=0.012), lower total body weight loss (p=0.007), increase in plasma renin activity 6 hours after the beginning of the study (p=0.025) and on day 6 (p=0.024), increase in plasma aldosterone concentration on day 6 (p=0.030), no significant change in plasma ANP levels, and decrease in creatinine clearance on day 6 (p=0.046). Albumin was superior to the other plasma expanders. Comparison between groups treated with plasma volume expansion did not show significant differences in measured parameters at any time during the study. The differences were found in the amount of needed volume of each substitute, daily sodium balance on day 1 of the trial, increase in plasma aldosterone concentration in bed rest-paracentesis-polygeline group on day 6, and the increase in plasma ANP on day 1 (p=0.077), which was proportional to the amount of infused volume. CONCLUSION: Therapeutic paracentesis of 6 L of ascites, bed rest 24 h before and after the procedure, and intravenous substitution of volume with albumin, fresh frozen plasma, and solution of synthetic gelatine were safe, rapid, and effective treatments, provided that intravascular volume was substituted simultaneously.

Presse Med. 2003 Apr 26;32(15):704-10.
[Regression of hepatic fibrosis physiopathological aspects and clinical reality]
[Article in French]
Bedossa P, Paradis V.
Service d'anatomie pathologique, CNRS ESA 8067, Hopital Bicetre Le Kremlin Bicetre (94). pbedossa@teaser.fr

MANAGING THE RESPONSIBLE AGENT: Hepatic fibrosis with its end-point, cirrhosis, are the principle complications responsible for morbidity and mortality in chronic liver diseases. It is therefore important to address the question of whether these lesions can disappear, once installed in the liver. Regression can only occur when the agent responsible for the fibrosis (virus, alcohol, poison, iron, autoantibodies, etc) is eradicated or controlled. THE FORMS OF REGRESSION: Once the agent controlled, regression of fibrosis can either be spontaneous, a rare situation, although some bona fide cases of fibrosis or even cirrhosis reversion have been reported in the literature, or assisted by specific therapy. It is therefore necessary to take into consideration the development of new treatments based on enhanced knowledge of the mechanisms of fibrosis. THE ACTIVITY AND EFFICACY OF TREATMENTS: These treatments target one of the three following mechanisms: the blockade of hepatic stellate cell activation, enzymatic digestion of fibrous tissue and stimulation of liver cell regeneration. Although these treatments have shown efficacy on experimental models of fibrosis, to date, there are no published results formally confirming the efficacy and safety of these treatments in man.

Hepatogastroenterology. 2003 Mar-Apr;50(50):504-6.
The effect of beta-blocker on intractable ascites in cirrhotic patients undergoing hepatectomy for hepatocellular carcinoma.
Kondo M, Nagano H, Sakon M, Hayashi S, Okami J, Dono K, Umeshita K, Nakamori S, Wakasa K, Monden M.
Department of Surgery and Clinical Oncology, Graduate School of Medicine, Osaka University, 2-2, Yamadaoka, Suita City, Osaka, 565-0871, Japan.

BACKGROUND/AIMS: Intractable ascites is one of the serious complications after hepatectomy. Only little is known about their effect on postoperative ascites in patients with liver cirrhosis although beta-blockers have been used for cirrhotic complications including ascites. METHODOLOGY: Here, we report five cases of intractable ascites after hepatectomy, which were treated by propranolol (1 mg/kg/body). RESULTS: In three patients, plasma renin activity and aldosterone concentrations were markedly increased before propranolol administration, but fell to normal levels thereafter. Ascites subsided in all subjects except one, who developed cardiac dysfunction. CONCLUSIONS: Beta-blockers might be a promising drug for intractable ascites in cirrhotic patients undergoing hepatectomy.

Autoimmun Rev. 2003 Jan;2(1):1-7.
Liver transplantation for primary biliary cirrhosis.
Neuberger J.
Liver Unit, Queen Elizabeth Hospital, Birmingham B15 2TH, UK. j.m.neuberger@bham.ac.uk

Liver transplantation is now the accepted treatment for patients with end-stage disease or intractable symptoms. The success rate is high. Those grafted for PBC are at greater risk of developing acute and chronic rejection and are less likely to be weaned from immunosuppression. Following transplantation, AMA persist and histological features of PBC may be seen in the allograft, in up to 50% by 10 years.

Hepatology. 2003 Apr;37(4):887-92.
A randomized controlled trial of ursodeoxycholic acid in patients with alcohol-induced
cirrhosis and jaundice.
Pelletier G, Roulot D, Davion T, Masliah C, Causse X, Oberti F, Raabe JJ, Van Lemmens C, Labadie H, Serfaty L; URSOMAF Group.
Department of Gastroenterology of Hopital Bicetre, Assistance Publique-Hoopitaux de Paris, Paris, France.

The aim of our multicenter study was to assess the efficacy of ursodeoxycholic acid (UDCA) on the survival of patients with alcohol-induced cirrhosis and jaundice. We included patients with histologically proven alcohol-induced cirrhosis and serum bilirubin >50 micromol/L. After randomization, patients received either UDCA (13-15 mg/kg/d) or a placebo for 6 months. Two hundred twenty-six patients (113 in each group) were included in 24 centers. There were 139 men and 87 women, mean age of 50.3 years. Seventy-four percent had associated alcohol-induced hepatitis, and 24% received a corticosteroid therapy. At inclusion, the 2 groups were comparable for the main clinical and biologic parameters, but serum bilirubin was higher in the UDCA group than in the placebo group (163 micromol/L vs. 145 micromol/L, P <.03). The percentage of patients lost at follow-up or who resumed their alcoholism during the study was comparable in the 2 groups. During the study, 55 patients died, 35 in the UDCA group and 20 in the placebo group. In the intention to treat analysis, the probability of survival at 6 months (Kaplan-Meier method) was lower in the UDCA than in the P group (69% vs. 82%, respectively; P =.04, log-rank test). After adjustment on the bilirubin level at entry (Cox model), the independent predictive value of the treatment group did not reach the statistical level (RR = 1.64, CI 0.85-2.85; P =.077). In conclusion, UDCA administered at the dose recommended in primary biliary cirrhosis has no beneficial effect on the 6-month survival of patients with severe alcohol-induced cirrhosis. An inappropriate dosage of UDCA cannot be excluded as an explanation for the lack of therapeutic benefit.

Am J Gastroenterol. 2002 Oct;97(10):2647-50.
Results of long-term ursodiol treatment for patients with primary biliary cirrhosis.
Jorgensen R, Angulo P, Dickson ER, Lindor KD.
Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota 55905, USA.

OBJECTIVE: When ursodeoxycholic acid (UDCA) is used for the treatment of primary biliary cirrhosis, it has been associated with biochemical improvement, histological stability, reduced risk of esophageal varices, and increased survival free of transplantation. There is limited information available about the long-term outcome of these patients with primary biliary cirrhosis on UDCA treatment. To address this, we reviewed the long-term results from patients enrolled in our original randomized study with up to 12 yr of follow-up. METHODS: From April 1988 to March 1992, a total of 180 patients were enrolled into a randomized, controlled trial evaluating UDCA (n = 89) versus placebo (n = 91). When the randomized portion of the study concluded in May 1992, patients were switched to active medication and followed for up to an additional 8 yr. RESULTS: Twenty-eight patients originally assigned to UDCA and 42 patients originally assigned to placebo have died or undergone transplantation. The patients who died or were transplanted were more histologically advanced at entry (p < 0.001). Seventy-six of the remaining 110 patients return for regular follow-up; mailed questionnaires were returned by an additional 25 patients, and nine patients have been lost to follow-up. Twenty-two of the 76 patients we follow have normal liver tests (ALP, bilirubin, and AST). Patients with normal liver tests had significantly lower levels of ALP and AST at baseline (p < 0.05), but did not differ in histological stage or total bilirubin from those with persistently abnormal tests. CONCLUSIONS: UDCA appears to be of most benefit when instituted in early stage disease. Although a substantial percentage of patients will achieve biochemical normalization on UDCA alone, there is a continued need for therapeutic options for others who have less complete biochemical responses.

Am J Gastroenterol. 2003 Jan;98(1):205-8.
Efficacy of colchicine in patients with primary biliary cirrhosis poorly responsive to ursodiol and methotrexate.
Lee YM, Kaplan MM.
Division of Gastroenterology, New England Medical Center, Tufts University School of Medicine, and the Tupper Research Institute, Boston, Massachusetts 02111, USA.

OBJECTIVE: Approximately 20-30% of patients with primary biliary cirrhosis (PBC) respond fully to treatment with ursodeoxycholic acid (UDCA). The rest have progressive disease and eventually develop cirrhosis and liver failure. More effective treatment is needed. Methotrexate improved biochemical tests of liver function and liver histology in patients with PBC who had failed to respond to UDCA in one report and induced sustained biochemical and histological remission in another. The role of colchicine in PBC is unclear. We describe three patients with symptomatic PBC who responded very well to the addition of colchicine after they had failed to respond to UDCA alone and in combination with methotrexate. We suggest that colchicine should be tried in PBC patients who clearly fail to respond to UDCA. METHODS: Three patients with symptomatic biopsy-proven, antimitochondrial antibody-positive PBC failed to respond to UDCA and then to the addition of methotrexate. Colchicine was eventually added to the regimen. Symptoms, biochemical tests of liver function, and percutaneous liver biopsies were done at baseline, after treatment with UDCA, UDCA plus methotrexate, and UDCA plus methotrexate plus colchicine. RESULTS: All three patients responded after colchicine was added to UDCA and methotrexate. Symptoms, biochemical tests of liver function, and liver histology improved in all, and blood tests normalized in two. CONCLUSIONS: Colchicine may be effective treatment in some symptomatic patients with PBC who respond incompletely to UDCA alone or in combination with methotrexate. Colchicine may be tried in such patients.

Am J Gastroenterol. 2003 Jan;98(1):187-93.
Methotrexate therapy for primary biliary cirrhosis.
Bach N, Bodian C, Bodenheimer H, Croen E, Berk PD, Thung SN, Lindor KD, Therneau T, Schaffner F.
Department of Medicine, Mount Sinai School of Medicine, New York, New York 10029, USA.

OBJECTIVE: Preliminary data suggested possible benefits of methotrexate in primary biliary cirrhosis. We assessed the effectiveness of methotrexate use in primary biliary cirrhosis and its tolerance in patients with this disease. METHODS: A total of 110 primary biliary cirrhosis patients began methotrexate 15 mg/wk; for most, ursodeoxycholic acid was added during the study. We analyzed data from patients completing 5 yr of treatment with methotrexate to assess its effect on biochemical and histologic parameters after 5 yr of therapy. Based on an intent to treat analysis, we also compared survival of our patients (n = 110) with that of patients in a previously published, placebo-controlled trial of ursodeoxycholic acid (n = 180). RESULTS: Only half of the study group completed 5 yr of methotrexate therapy. Therapy did not prevent progression of disease, as indicated by a rising Mayo risk score. Portal fibrosis tended to remain the same. Methotrexate did not diminish the risk of death or liver transplantation when compared with ursodeoxycholic acid or placebo; however, ursodeoxycholic acid use decreased the risk of death or transplant (p = 0.006). CONCLUSIONS: Methotrexate is not well tolerated in primary biliary cirrhosis. The toxicity of methotrexate and its inability to prevent complications of progressive liver disease or improve survival and the need for liver transplantation limits its utility. The benefits of ursodeoxycholic acid were again confirmed.

Eur J Gastroenterol Hepatol. 2002 Dec;14(12):1369-76.
The influence of sulindac on patients with primary biliary cirrhosis that responds incompletely to ursodeoxycholic acid: a pilot study.
Leuschner M, Holtmeier J, Ackermann H, Leuschner U.
Medical Clinic II, Johann Wolfgang Goethe Universitat, Frankfurt am Main, Germany.

OBJECTIVES: In 30% of patients with primary biliary cirrhosis (PBC) ursodeoxycholic acid (UDCA) causes full biochemical normalization, while 70% are incomplete responders. The only differences between the two groups are the significantly higher cholestasis indices in the incomplete responders. In these patients we investigated whether the strongly choleretic sulindac together with UDCA is superior to UDCA monotherapy. DESIGN AND METHODS: Twenty-three patients with PBC incompletely responding to UDCA monotherapy were entered in the open label study for 12 months. Eleven patients (stage II, seven; III, two; and IV, two) received UDCA (10-15 mg/kg/day) plus sulindac (100-300 mg/day) (Group I). Twelve patients (stage I, six; II, four; III, one; and IV, one) were treated with UDCA alone (Group II). Liver biochemistry, analysis of antimitochondrial, antinuclear, smooth muscle, and liver-kidney-microsomal antibodies, ultrasonography and gastroscopy were done in regular intervals. RESULTS: In Group I all liver indices, IgG, IgM and IgA significantly improved although pretreatment data and stages of the disease tended to be higher than in Group II. In five patients of Group I liver histology improved slightly. Sulindac was well tolerated. The biochemical indices did not further improve on UDCA monotherapy. CONCLUSIONS: Sulindac in combination with UDCA further improves liver biochemistries in patients with PBC who responded incompletely to UDCA alone.

Eur J Gastroenterol Hepatol. 2003 Jan;15(1):7-14.
Adult-to-adult living donor liver transplant: UK experience.
Williams RS, Alisa AA, Karani JB, Muiesan P, Rela SM, Heaton ND.
Liver Unit Cromwell Hospital, University College London Hospitals, London, UK. roger.williams@ucl.ac.uk

BACKGROUND: Adult-to-adult living donor liver transplantation (ALDLT) is being adopted widely in the USA and mainland Europe, fueled by the increasing waiting lists for cadaver organs. The present report describes the first UK experience with the procedure in patients from overseas who have the lowest priority for cadaver organ allocation. METHODS: The 16 patients seen over the period November 1998 to March 2002 had end-stage cirrhosis from chronic hepatitis C virus (HCV) or hepatitis B virus (HBV) infection (13 cases), with single instances of cryptogenic cirrhosis, secondary biliary cirrhosis and alcoholic liver disease. Grafts were left lobe in the first two recipients and right lobe in the subsequent 14 recipients, donated by nine sons/daughters and seven brothers/sisters. RESULTS: Twelve of the 16 recipients did well. The four recipients who died had recurrent sepsis; two of these died following hepatic arterial occlusion, and in three major surgical factors were present before transplantation. Serial computed tomography (CT) measurements in the survivors showed regeneration of the grafted lobe with final volumes reaching in each case the calculated standard liver volume for body size. In the donors, liver function tests had returned to normal by day 7-14, with rapid regeneration of the remaining lobe, although the final size attained that estimated before donation in only four donors. CONCLUSIONS: ALDLT, although requiring considerable facilities and organization, can give good results for both recipient and donor. As with cadaver grafts, outcome in the recipient if the larger right lobe is used is dependent on surgical risk factors and the severity of clinical decompensation before transplantation. Measures to ensure the safety of the donors remain the main concern. Copyright 2003 Lippincott Williams & Wilkins

Hepatology. 2003 May;37(5):1147-53.
Randomized trial comparing albumin and saline in the prevention of paracentesis-induced circulatory dysfunction in cirrhotic patients with ascites.
Sola-Vera J, Minana J, Ricart E, Planella M, Gonzalez B, Torras X, Rodriguez J, Such J, Pascual S, Soriano G, Perez-Mateo M, Guarner C.
Liver Unit, Internal Medicine Department, Hospital General Universitario de Alicante, Spain.

Paracentesis-induced circulatory dysfunction (PICD) is a recently described complication that can be prevented with the administration of plasma expanders. The aim of this study was to compare the efficacy of saline versus albumin in the prevention of PICD. Patients were randomized to receive albumin or saline after total paracentesis. Patients readmitted as a consequence of a second episode of tense ascites were treated with total paracentesis and the alternative plasma expander. After randomization, 35 patients received saline and 37 received albumin. Twenty-one patients were readmitted for tense ascites and treated with the alternative expander. Significant increases in plasma renin activity (PRA) were found 24 hours and 6 days after paracentesis when saline was used (baseline, 5.6 +/- 5.7; 24 hours, 7.6 +/- 6.9; 6 days, 8.5 +/- 8.0 ng x mL(-1). hr(-1); P <.05 and P <.01 vs. baseline, respectively), whereas no significant changes were observed with albumin. The incidence of PICD was significantly higher in the saline group versus the albumin group (33.3% vs. 11.4%, respectively; P =.03). However, no significant differences were found when less than 6 L of ascitic fluid was evacuated (6.7% vs. 5.6% in the saline and albumin groups, respectively; P =.9). Similar results were observed when analyzing patients who received 2 consecutive paracentesis (i.e., a significant increase in PRA after saline [P <.01] without significant variations after albumin). In conclusion, albumin is more effective than saline in the prevention of PICD. Saline is a valid alternative to albumin when less than 6 L of ascitic fluid is evacuated.

Rom J Gastroenterol. 2003 Mar;12(1):25-30.
Long term effects of propranolol on portal pressure in cirrhotic patients.
Orban-Schiopu AM, Popescu CR.
Department of Internal Medicine. University Hospital Elias, Bd. Marasti no.17, 71322 Bucharest, Romania.

Bleeding from varices is a very serious complication in cirrhotic patients, with a mean mortality rate around 30 %. If the portal vein pressure is decreased by pharmacological therapy the varices will not bleed and progressively decrease in size. The portal hypertension in cirrhotic patients develops as a consequence of two mechanisms: the increase of portal inflow and the increase of intrahepatic resistance. The aim of our study was to find out if propranolol can prevent the bleeding from esophageal varices and if it acts by reducing the portal inflow due to splanchnic vasodilatation. The study was initiated in 53 patients with portal hypertension, of whom 14 were withdrawn because of adverse effects of propranolol. Abdominal ultrasonography and Doppler of portal vein system were performed in all subjects. The ultrasonographic parameters were measured before and after a 3-year treatment with propranolol. The patients also underwent endoscopy for evaluation of esophageal varices; the endoscopy was repeated at the end-point of treatment. We noted that propranolol reduced the portal blood inflow and the size of esophageal varices, and that the incidence of hemorrhages by variceal rupture was very low in these patients.

Dig Dis Sci. 2003 Jan;48(1):179-86
Effects of orthotopic liver transplantation on vasoactive systems and renal function in patients with advanced liver cirrhosis.
Cassinello C, Moreno E, Gozalo A, Ortuno B, Cuenca B, Solis-Herruzo JA.
Department of Gastroenterology, Hospital Universitario 12 de Octubre, 28041 Madrid, Spain.

The effects of Orthotopic liver transplantation (OLT) on renal function and major vasoactive factors was assessed in end-stage cirrhotic patients. Renal function, mean arterial pressure, and plasma vasoactive hormones were measured In 22 cirrhotic patients with refractory ascites before and after OLT. Before OLT, mean arterial pressure, glomerular filtration rate, free water clearance, and fractional sodium excretion serum sodium levels were decreased. In addition, serum creatinine and plasma levels of vasoactive factors were increased. Ten of these patients fulfilled criteria of hepatorenal syndrome (HRS). Nine to 12 months after transplantation, renal function had improved and plasma levels of vasoactive factors had decreased significantly in all patients, including those with HRS. However, glomerular filtration rate remained subnormal and plasma endothelin-1 levels and plasma renin activity remained increased in most of them. In conclusion, OLT improves renal function in patients with end-stage liver cirrhosis, including those with HRS. However, renal function remains subnormal in most of these patients.

Rev Med Chil. 2002 Dec;130(12):1343-8.
[Laparoscopic and classic cholecystectomy in patients with liver cirrhosis]
[Article in Spanish]
Poniachik J, Castro S, Madrid AM, Quera R, Amat J, Smok G, Cumsille M, Brahm J.
Seccion de Gastroenterologia, Departamento de Cirugia, Instituto de Anatomia Patologica y Departamento de Salud Publica, Hospital Clinico Universidad de Chile, Santos Dumont 999. jponiach@ns.hospital.uchile.cl

BACKGROUND: The prevalence of gallstones is increased in patients with cirrhosis. However the presence of cirrhosis has been generally considered a relative contraindication to cholecystectomy. AIM: To investigate the complications and the outcomes of laparoscopic and open cholecystectomy in patients with cirrhosis. PATIENTS AND METHODS: Sixty seven patients with gallstones with well-documented cirrhosis undergoing cholecystectomy (laparoscopic cholecystectomy (LC) in 35 and open cholecystectomy (OC) in 32), were studied. The mean age was 57.7 + 10.3 years for LC and 58.9 + 11.6 years for OC. In the LC group, 26 were classified as Child-Pugh class A, 8 as Child's B class and 1 as Child's class C. In the OC group, 12 were classified as Child's class A, 15 as Child's B and 5 as Child's C. RESULTS: Complications occurred in 4 of 35 (12.3%) LC patients (1 patients was Child A and 3 were B). In the OC group 14 of 32 patients had complications (4 Child A, 7 B and 3 C, 43.7% p < 0.05 as compared with LC group). Three patients in the OC group died (9.4%). Mean hospital stay was 2.8 + 1.9 and 13 + 12 days in LC and OC patients, respectively (p < 0.05). CONCLUSIONS: LC has a lower rate of complications than OC and is a reasonable option for Child's class A and B patients with cirrhosis and gallstones.

Ugeskr Laeger. 2003 Jan 27;165(5):439-42.
[Transjugular intrahepatic portosystemic shunt (TIPS) for the treatment of complications of portal hypertension in patients with liver cirrhosis]
[Article in Danish]
Gronbaek H, Astrup LB, Nielsen DT, Vilstrup H.
Arhus Universitetshospital, Arhus Kommunehospital, Medicinsk Afdeling V og Radiologisk Afdeling R. henning.gronbaek@dadlnet.dk

Portal hypertension is a main cause for the development of esophago-gastric varices, ascites and hepatic nephropathy in liver cirrhosis. Reduction of portal pressure by a transjugular intrahepatic portosystemic shunt (TIPS) procedure has been possible for the last decade. The treatment reduces the risk for variceal bleeding, reduces ascites formation and may improve renal function in hepatic nephropathy. Improved survival, however, has not yet been documented. Complications comprise procedure related events (puncture of liver capsule, bleeding, infection, hemolysis with mortality 1-5%), shunt stenosis (30-80% during the first year but reversible), and encephalopathy (30% intermittent, 10% chronic). Indications for the procedure are primarily variceal bleeding resistant to conventional pharmacologic and endoscopic treatment. Absolute and relative contraindications are severe hepatic failure, a history of hepatic encephalopathy, infections, respiratory failure, and non-hepatic renal insufficiency.

Zhongguo Zhong Xi Yi Jie He Za Zhi. 2001 Nov;21(11):813-5.
[Clinical and experimental study on anti-liver fibrosis effect of xuelong granule]
[Article in Chinese]
Li ZZ, Wang X, Sui ZY.
Jining Municipal Infectious Diseases Hospital, Shandong 272031.

OBJECTIVE: To study the clinical effect and mechanism of Xuelong Granule (XLG) in antiliver fibrosis. METHODS: Ninety-eight patients with liver cirrhosis were divided into 2 groups randomly. The 58 Patients in the treated group were treated by XLG and the 40 patients in the control group were treated by Shenchai Granule for 3 months. Levels of serum hyaluronic acid (HA) and laminin (LN), and pathological changes of liver tissues were observed before and after treatment. In experimental study on model rats, the liver tissue content of hydroxyproline and pathological changes under light and electron microscope were observed. RESULTS: The total effective rate in the treated group was 72.4%, that in the control group was 40.0%, there was significant difference between the two groups (P < 0.01). The level of serum HA and LN in the treated group declined markedly after treatment, and pathological examination of 8 cases showed the fibrous tissues reduced obviously. Experimental study showed marked reduction of hydroxyproline content and significant lowering of fibrous tissue proliferation, both under light and electron microscope, in liver of model rats after XLG treatment. CONCLUSION: XLG has a definite effect in anti-liver fibrosis.

Hepatology. 2003 Feb;37(2):378-84.
Low doses of isosorbide mononitrate attenuate the postprandial increase in portal pressure in
patients with cirrhosis.
Bellis L, Berzigotti A, Abraldes JG, Moitinho E, Garcia-Pagan JC, Bosch J, Rodes J.
Hepatic Hemodynamic Laboratory, Liver Unit, IMD, Hospital Clinic, Barcelona, Spain.

Postprandial hyperemia is associated with a significant increase in portal pressure in cirrhosis, which may contribute to progressive dilation and rupture of gastroesophageal varices. In cirrhosis, an insufficient hepatic production of nitric oxide (NO) may impair the expected hepatic vasodilatory response to increased blood flow, further exaggerating the postprandial increase in portal pressure. This study was aimed at investigating whether low doses of an oral NO donor might counteract the postprandial peak in portal pressure. Twenty-three portal hypertensive cirrhotics, 8 of them under propranolol therapy, were randomized to receive orally 5-isosorbide mononitrate (ISMN; 10 mg; n = 11) or placebo (n = 12) and a standard liquid meal 15 minutes later. Hepatic venous pressure gradient (HVPG), mean arterial pressure (MAP), and hepatic blood flow (HBF) were measured at baseline and 15, 30, and 45 minutes after a meal. ISMN significantly attenuated the postprandial increase in portal pressure as compared with placebo (peak HVPG increase: 2.4 +/- 1.4 mm Hg vs. 5.2 +/- 2.1 mm Hg, P =.002). Percentual increases in HBF were similar in both groups. MAP decreased slightly in ISMN group (-7.5% +/-.5%; P <.01 vs. baseline). These effects were also observed in patients on chronic propranolol therapy. In conclusion, hepatic NO supplementation by low doses of ISMN effectively reduces the postprandial increase of portal pressure in cirrhosis, with only a mild effect on arterial pressure. The same was observed in patients receiving propranolol. Our results suggest that therapeutic strategies based on selective hepatic NO delivery may improve the treatment of portal hypertension.

Hepatology. 2003 Feb;37(2):359-65.
Nadolol plus spironolactone in the prophylaxis of first variceal bleed in nonascitic cirrhotic patients: A preliminary study.
Abecasis R, Kravetz D, Fassio E, Ameigeiras B, Garcia D, Isla R, Landeira G, Dominguez N, Romero G, Argonz J, Terg R.
Liver Unit, Hospital de Gastroenterologia B. Udaondo, Buenos Aires, Argentina. raquelabecasisabril@hotmail.com

Treatment with beta-blockers fails to decrease portal pressure in nearly 40% of cirrhotic patients. Recent studies have suggested that treatment with spironolactone reduces pressure and flow in the portal and variceal systems. This trial was designed to assess if nadolol plus spironolactone is more effective than nadolol alone to prevent the first variceal bleeding. One hundred patients with medium and large varices who had never bled and were without ascites were included in a prospective, randomized, multicenter, double-blind, placebo-controlled trial. The patients were randomized into 2 groups: 51 received nadolol plus placebo (N + P) and 49 received nadolol plus spironolactone 100 mg/d (N + S). Hepatic venous pressure gradient (HVPG) and activity of the renin-aldosterone system (plasma renin activity/plasma aldosterone levels) were measured in 24 patients. There were no significant differences in the appearance of variceal bleeding and ascites between groups at a mean follow-up of 22 +/- 16 months. However, analyzing both complications together, the incidence was significantly higher in the N + P group than in the N + S group (39% vs. 20%; P <.04). Clinical ascites was also higher in patients in the N + P group than in the N + S group (21% vs. 6%; P <.04). Significant increases in plasma renin activity and plasma aldosterone levels were only observed in patients in the N + S group (P <.01). The cumulative probabilities of remaining free of bleeding and ascites were similar in both groups after 70 months of follow-up. In conclusion, these results suggest that nadolol plus spironolactone does not increase the efficacy of nadolol alone in the prophylaxis of the first variceal bleeding. However, when bleeding and ascites were considered together, the combined therapy effectively reduced the incidence of both portal-hypertensive complications.

Khirurgiia (Sofiia). 2002;58(1):8-10.
[Hepatic resections for hepatocellular carcinoma and cirrhosis]
[Article in Bulgarian]
Frangov T, Gaidarski R, Vasilev S, Mladenov L.

Liver resection in a patient with cirrhosis carries increased risk. The purposes of this study were to review the results of cirrhotic liver resection in the past decade and to propose strategies for low morbidity and mortality. From January 1991 to December 2000 73 patients with primary liver cancer (PLC) were operated and identified in a retrospective database. Twenty five (34%) patients had underlying cirrhosis: 14--Child A and 11--Child B. There were 18 male and 7 female with mean age 60.9 +/- 9.2 (from 44 to 78). There were 16 (64%) resections: 11--stage Child A and 5--stage Child B. Major resections were 7 and minor--9. Eight patients received hemotransfusion--mean 939.13 ml (370-2000 ml). Four patients (25%) died of the hepatic resection--by the 30-th day. Seven patients had postoperative complications. 4 patients developed liver failure. Major resections had 42.86% mortality, minor resections--11.11%. Hepatic resection is potentially curative therapy for HCC and cirrhosis especially in Child A. Child B produce high rate of postoperative morbidity and mortality.

Taehan Kan Hakhoe Chi. 2002 Mar;8(1):52-60.
[Efficacy and safety of large volume paracentesis in cirrhotic patients with spontaneous bacterial peritonitis: a randomized prospective study]
[Article in Korean]
Choi CH, Han KH, Kim do Y, Cho JH, Cheong JY, Song KH, Chon CY, Moon YM.
Department of Internal Medicine, Gastroenterology division, Yonsei University College of Medicine, Seoul, Korea. gihankhys@yumc.yonsei.ac.kr

BACKGROUND/AIMS: Large volume paracentesis (LVP) associated with plasma volume expansion is known to be an effective and safe therapy for tense or refractory ascites in cirrhosis. Spontaneous bacterial peritonitis (SBP) is one of the frequent infections in patients with cirrhosis. We conducted a study to assess the efficacy and safety of large volume paracentesis in cirrhotic patients with SBP. METHODS: We randomly assigned 40 patients with cirrhosis and SBP to either treatment with LVP (21 patients) or general management (19 patients). LVP was defined as drainage of ascitic fluid of more than 4 liters in a single tap or loss of shifting dullness after paracentesis. LVP was performed within 48 hours after the diagnosis of SBP in the LVP group. Cefotaxime was given daily in doses that varied according to the serum creatinine level in both groups. Albumin was given at a dose of 6-8 g per 1 liter of removed ascites in the LVP group. RESULTS: After seven days of treatments, the blood chemistry test, and WBC (PMN) counts and protein concentration in the ascitic fluid were not different between the two groups. Among them, the WBC (PMN) counts were decreased significantly in both groups and protein concentrations tended to increase. Durations of abdominal tenderness and pain were shorter in the LVP group but the differences were statistically not significant. Admission periods, resolution rates of SBP after seven days of treatment, complication rates and in-hospital mortality rates were not different between the two groups. CONCLUSIONS: The two treatment methods demonstrated almost the same effectiveness and safety. The symptoms were improved slightly faster in the LVP group. We concluded that large volume paracentesis is not an absolute contraindication and can be a tolerable and safe therapy in some selected cirrhotic patients with tense ascites and SBP.

Zhonghua Yi Xue Za Zhi. 2002 Sep 10;82(17):1157-9.
[The randomized controlled trial of isosorbide mononitrate plus propranolol compared with propranolol alone for the prevention of variceal rebleeding]
[Article in Chinese]
Zhang Q, Yuan R, Wang H.
Gastroenterology Department, The Branch of Shanghai First People's Hospital. Shanghai 200081, China.

OBJECTIVE: The aim of this study was to test the effectiveness of isosorbide-5-mononitrate (IM) as an adjunct to propranolol (PR) in the prevention of variceal rebleeding. METHODS: Seventy-six cirrhotic patients with variceal bleeding were randomly assigned to treatment with PR + IM (34 patients) or PR alone (32 patients). RESULTS: Seven patients in the PR + IM group and 13 in the PR group had rebleeding during the 1 year after randomization. The actuarial probability of rebleeding 1 years after randomization was lower in the PR + IM group but the difference was not significant (P = 0.09). However, by adding an additional 8 months of follow-up, the decrease in the risk of rebleeding reached statistical significance (P = 0.05). No significant difference was found in rebleeding index and survival. The multivariate Cox analysis indicated both treatment (P = 0.04), severity of liver disease (P = 0.03) and age (P = 0.045) were factors predictive of rebleeding and second, that PR + MI reduced the risk of rebleeding by half (relative risk: 0.54). CONCLUSION: These results suggest that the addition of IM improves the efficacy of PR alone in the prevention of variceal rebleeding in cirrhotic patients. However no beneficial effects were observed on other parameters reflecting the efficacy of treatment.

Int J Artif Organs. 2002 Oct;25(10):935-8.
Clinical outcome of orthotopic liver transplantation.
Berlakovich GA.
g.berlakovich@akh-wien.ac.at

Orthotopic liver transplantation (OLT) has become a standard procedure for end-stage cirrhosis. The purpose of this anlysis is to give a brief overview on the clinical outcome of OLT. According to a current survey of primary indications for liver transplantation in Europe, virus-induced cirrhosis represents the largest proportion with 25%. The next frequent indication is alcoholic cirrhosis with 19%. Cholestatic diseases amount to 13%, malignancy in cirrhosis 10%, and acute hepatic failure 10%. The outcome of these main indications will be discussed and critical considerations pointed out. Patient survival rates demonstrate for cirrhosis at 1-and 5-year about 80% and 70%, respectively. In acute hepatic failure, more patients are lost in the perioperative period. Not surprisingly, patients transplanted for malignancy show decreased long-term survival. Considering an average of 5-year survival in patients with end-stage liver disease of 20% or less, excellent patient survival can be achieved by liver transplantation.

Int J Artif Organs. 2002 Oct;25(10):918-22.
Influence of hydroxy ethyl starch infusion on serum bilirubin levels in cirrhotic patients treated with artificial liver support.
Kramer L, Bauer E, Gendo A, Madl C, Gangl A.
ludwig.kramer@akh-wien.ac.at

Serum bilirubin levels are commonly used to assess extracorporeal detoxification by liver support systems. We tested the hypothesis that intravenous colloids administered before liver support treatment could confound bilirubin values. Eight cirrhotic patients received an infusion of a 6% hydroxy ethyl starch solution (10 ml/kg, 30 minutes) before detoxification using a liver support system (FPSA). Bilirubin was measured before and 1 hour after infusion, and after FPSA treatment (7 hours). Infusion of hydroxy ethyl starch was associated with a drop in bilirubin values (mean, 18%, range, 1-44%, p=0.03 versus baseline values). Bilirubin levels were further reduced during FPSA treatment (mean, 27%, range, 22-34%; p=0.02 versus pretreatment values). In conclusion, hydroxy ethyl starch solution may decrease bilirubin levels in hyperbilirubinemic cirrhotic patients receiving extracorporeal detoxification. The role of potentially confounding factors in liver support studies is discussed further.

Digestion. 2002;66(2):127-30.
Improved quality of life in patients with refractory or recidivant ascites after insertion of transjugular intrahepatic portosystemic shunts.
Gulberg V, Liss I, Bilzer M, Waggershauser T, Reiser M, Gerbes AL.
Department of Medicine II, Klinikum of the University of Munich-Grosshadern, Germany. Viet.Guelberg@med2.med.uni-muenchen.de

BACKGROUND: We have recently shown that the transjugular intrahepatic portosystemic shunt (TIPS) is more effective than paracentesis in the treatment of cirrhotic patients with severe ascites and can prolong survival in selected patients. Although an improved quality of life (QOL) has been suggested in these patients after the TIPS procedure, so far there are no data available to substantiate this assumption. Therefore, the aim of this study was to determine the effect of TIPS on the QOL in cirrhotic patients with refractory or recidivant ascites. METHODS: 21 cirrhotic patients who underwent TIPS for refractory or recidivant ascites were investigated. All patients were pretreated with repeated paracentesis for at least 1 year. Before the procedure and at 3 and 6 months during follow-up, the patients themselves rated QOL, fatigue and physical performance on a visual analogue scale (range 0-100). Furthermore, QOL was determined by the QOL index (range 0-10) according to Spitzer. RESULTS: Patients' rating of the QOL on the visual analogue scale significantly increased from 35 +/- 25 (baseline) to 64 +/- 28 (3 months), and 66 +/- 24 (6 months; p = 0.02). Similarly, the QOL index significantly increased from 6.9 +/- 2.0 (baseline) to 8.3 +/- 2.1 (3 months), and 8.6 +/- 1.7 (6 months; p < 0.001). The increase of QOL was more pronounced in patients with complete response to TIPS. CONCLUSIONS: We demonstrate that TIPS for refractory or recidivant ascites improves the QOL in patients with cirrhosis. Our data indicates that this improvement is dependent on the response to therapy. Copyright 2002 S. Karger AG, Basel

Aliment Pharmacol Ther. 2002 Dec;16 Suppl 5:12-23.
Review article: volume expansion in patients with cirrhosis.
Henriksen JH, Kiszka-Kanowitz M, Bendtsen F.
Department of linical Physiology 239, Hvidovre Hospital, University of Copenhagen, Denmark. jens.h.henriksen@hh.hosp.dk

Adequate size and distribution of the circulating medium are important for cardiovascular function, tissue oxygenation, and fluid homoeostasis. Patients with cirrhosis have cardiovascular dysfunction with a hyperkinetic systemic circulation, abnormal distribution of the blood volume, vasodilation with low systemic vascular resistance, increased whole-body vascular compliance, and increased arterial compliance. The effectiveness and temporal relations of plasma/blood volume expansion depend highly on the type of load (water, saline, oncotic material, red blood cells). Patients with cirrhosis respond in some aspects differently from healthy subjects, owing to their disturbed circulatory function and neurohormonal activation. Thus the increase in cardiac output and suppression of the renin-angiotensin-aldosterone system and sympathetic nervous system during volume expansion may be somewhat blunted, and in advanced cirrhosis, especially the non-central parts of the circulation, including the splanchnic blood volume, are expanded by a volume load. Infusion of oncotic material (preferably albumin) is important in the prevention of post-paracentesis circulatory dysfunction. In conclusion, volume expansion in advanced cirrhosis is qualitatively and quantitatively different from that of healthy subjects, and in those with early cirrhosis. Timely handling is essential, but difficult as it is a balance between the risks of excess extravascular volume loading and further circulatory dysfunction in these patients with a hyperdynamic, but hyporeactive, circulation.

Aliment Pharmacol Ther. 2002 Dec;16 Suppl 5:24-31.
Review article: albumin for circulatory support in patients with cirrhosis.
Gines P, Guevara M, De Las Heras D, Arroyo V.
Liver Unit, Institut de Malalties Digestives, Hospital Clinic, Barcelona, Spain. gines@medicina.ub.es

Renal function abnormalities and ascites in cirrhosis are the final consequence of a circulatory dysfunction characterized by marked splanchnic arterial vasodilation. This causes a reduction in effective arterial blood volume and the homoeostatic activation of vasoconstrictor and sodium-retaining systems. Albumin is very effective in preventing renal failure associated with large-volume paracentesis and spontaneous bacterial peritonitis, conditions that are known to cause an impairment of circulatory function in patients with cirrhosis and ascites. Moreover, albumin administration improves survival in patients with spontaneous bacterial peritonitis. In patients with hepatorenal syndrome the administration of vasoconstrictor drugs in combination with albumin improves circulatory and renal function markedly and survival slightly. By contrast, the administration of albumin without vasoconstrictors has marginal or no effects on renal function in this setting.

Aliment Pharmacol Ther. 2002 Dec;16 Suppl 5:1-5.
Review article: albumin in the treatment of liver diseases—new features of a classical treatment.
Arroyo V.
Liver Unit, Institute of Digestive Diseases, Hospital Clinic, University of Barcelona, Spain. arroyo@medicina.ub.es

Albumin was introduced initially in the treatment of patients with cirrhosis and ascites to increase serum albumin concentration due to its oncotic effect. Although its administration declined some years later, at present it constitutes an essential treatment in clinical hepatology. Several studies have clearly demonstrated its efficacy in the prevention and treatment of circulatory dysfunction and hepatorenal syndrome in patients with cirrhosis. These effects can be due not only to its properties as a plasma expander but also to its capacity to bind numerous substances such as bile acids, nitric oxide and cytokines. Based on this capacity an albumin dialysis system (MARS) has recently been developed. The usefulness of this system in the management of patients with acute and chronic liver failure is, at present, under evaluation.

Hepatology. 2002 Nov;36(5 Suppl 1):S185-94.
Treatment of patients with hepatitis C and cirrhosis.
Wright TL.
Gastroenterology Section, Veterans Affairs Medical Center, University of California, San Francisco, USA. twright@itsa.ucsf.edu

Recommendations for treatment of hepatitis C in patients with cirrhosis are difficult. Few prospective studies have focused on treatment of patients with advanced disease, and response rates appear to be lower and serious side effects more frequent in patients with cirrhosis. In patients with compensated cirrhosis, combination therapy with interferon alfa (3 million units [MU] 3 times a week) and ribavirin (1,000 or 1,200 mg/d) results in a sustained virological response (SVR) in 33% to 41% of patients. Responses to combination therapy are not significantly higher using peginterferon alfa 2a (180 microg/wk; 43%) or peginterferon alfa 2b (1.5 microg /kg/wk; 44%) compared with standard interferon. In using peginterferon in combination therapy, the benefits of once weekly dosing need to be weighed against the higher risks of cytopenias and greater costs with the pegylated formulations. Combination therapy results in some degree of histological improvement even in patients who are virological non-responders. These findings provide the scientific basis for ongoing studies of maintenance therapy with peginterferon to prevent complications of cirrhosis in non-responder patients with hepatitis C. Recommendations for management of decompensated cirrhosis and of recurrent hepatitis C after liver transplantation are difficult because of limitations of data, most of which are derived from uncontrolled case series. Combination therapy is poorly tolerated in both groups and rates of response are low. Thus, while the medical need is great, treatment of patients with decompensated cirrhosis or with recurrent hepatitis C after transplantation should be undertaken cautiously and only within the confines of prospective clinical trials.

Hepatology. 2002 Nov;36(5):1197-205.
Pharmacodynamic effects of a nonpeptide antidiuretic hormone V2 antagonist in cirrhotic
patients with ascites.
Guyader D, Patat A, Ellis-Grosse EJ, Orczyk GP.
Clinique des maladies du foie and Inserm U522, Rennes, France. Dominique.Guyader@univ-rennes1.fr

Water retention and dilutional hyponatremia, mainly attributable to an impairment of free water excretion and increased vasopressin activity, are well-documented complications in cirrhotic patients with ascites. VPA-985 is a selective, nonpeptide, orally active, vasopressin-2-receptor antagonist. The aim of this study was to determine the pharmacodynamics, safety, and pharmacokinetics of ascending single doses (25, 50, 100, 200, and 300 mg) in cirrhotic patients with ascites in a randomized, double-blind, placebo-controlled trial. Each dose level was studied in 5 patients (4 active and 1 placebo). After an overnight fast and fluid restriction (continued for 4 hours after dose administration), all patients were given placebo on baseline day and an oral suspension of VPA or placebo on the following day. VPA produced a significant dose-related increase in daily urine output (1,454 +/- 858 mL to 4,568 +/- 4,385 mL with VPA 300 mg) and a dose-related decrease in urine osmolality. The free water clearance reached greater than 3 mL/min for doses 100 mg or greater. Simultaneously, significant increases in serum osmolality, sodium, and vasopressin levels were found. There was a significant increase in sodium urine excretion. VPA was rapidly absorbed and maximum serum concentrations were achieved within 1 hour after administration. Elimination half-life ranged from 9.0 hours after 100 mg to 22.6 hours after 200 mg. In conclusion, VPA induced a dose-related aquaretic response, suggesting a therapeutic potential in managing water retention in patients with liver cirrhosis with ascites.

J Clin Gastroenterol. 2002 Nov-Dec;35(5):403-5.
The effect of mannitol infusion on the response to diuretic therapy in cirrhotic patients with ascites.
Pamuk ON, Sonsuz A.
Department of Internal Medicine, Cerrahpasa Medical Faculty, University iof Istanbul, Turkey. onpamuk80@hotmail.com

GOALS: A good response to diuretics is obtained initially in the treatment of cirrhotic ascites. However, unresponsiveness to therapy and various complications may develop with disease progression. This makes obligatory the search for new treatment methods that may be alternative to standard diuretics. In our study, we investigated the effect of mannitol infusion on current therapies in patients with cirrhotic ascites who were using diuretic treatment. BACKGROUND: Thirty cirrhotic patients with ascites who were using diuretic treatment were included in the study. The patients were randomly divided into two groups; a dose of 100-mL 20% mannitol was administered to the first group, and 100-mL 5% dextrose solution was administered to the second group. The patients' urinary volumes and serum and urine electrolyte levels (sodium, potassium) were determined before and after the test. RESULTS: In the mannitol group, a significant increase in urinary volume was observed (p < 0.05). However, in the control group no significant differences in urinary sodium excretion were observed after the test (p > 0.05). In the mannitol group, a concomitant increase in urinary volume and sodium excretion was observed in eight cases (53%). The urinary sodium excretions and serum sodium levels before the test were significantly lower in patients who responded to mannitol than in patients who did not respond (p = 0.001 and p = 0.04, respectively). CONCLUSIONS: As a result, short-term mannitol therapy makes a significant contribution to diuretic therapy in approximately half of cases with cirrhotic ascites. The results we obtained suggest that mannitol may be a useful alternative in the treatment of ascites.

Indian J Gastroenterol. 2002 Jul-Aug;21(4):145-8
Hemodynamic effect of spironolactone in liver cirrhosis and propranolol-resistant portal hypertension.
Sen S, De Binay K, Biswas PK, Biswas J, Das D, Maity AK.
Department of Medicine, Institute of Post Graduate Medical Education and Research, Calcutta.

OBJECTIVE: In a proportion of patients with liver cirrhosis, portal pressure does not decrease adequately with propranolol. These patients may benefit from another drug that may reduce portal pressure. We evaluated the role of spironolactone, alone or with propranolol, in such patients. METHODS: Patients with cirrhosis, with or without ascites, with esophageal varices and with hepatic venous pressure gradient exceeding 12 mmHg, which did not show a 20% reduction after an 80-mg oral dose of propranolol, were studied. They were allocated to receive spironolactone 100 mg orally once daily either alone (group 1, n=10) or with propranolol 40 mg orally twice daily (group 2, n=10), for 7 days, after which the hemodynamic study was repeated. RESULTS: Hepatic venous pressure gradient decreased in those receiving spironolactone and propranolol (p=0.007); 5 patients in group 1 and 7 in group 2 showed a reduction in hepatic venous pressure gradient by more than 20%. However, the reduction produced by spironolactone alone (20.5 [31.3]%) was not significantly different from that produced by combination therapy (30.3 [25.9]%; p=0.46). CONCLUSION: Spironolactone in combination with propranolol achieves adequate reduction (> or = 20%) in hepatic venous pressure gradient in propranolol-resistant portal hypertension in patients with liver cirrhosis. Spironolactone alone was also effective in some patients.

Int J Mol Med. 2002 Nov;10(5):647-8.
Additional benefit of lamivudine treatment as a preventive therapy for hepatic encephalopathy in patients with decompensated liver cirrhosis associated with hepatitis B.
Hanada S, Kumashiro R, Kaji R, Harada M, Sata M.
Second Department of Medicine, Kurume University School of Medicine, Kurume, Japan. hanadas@med.kurume-u.ac.jp

Lamivudine has previously been found to be effective not only in patients with compensated liver disease due to hepatitis B virus (HBV) but also in those with hepatic decompensation. However, long-term follow-up of patients with hepatic encephalopathy (HE) has not been previously reported. We describe a patient with recurrent HE associated with decompensated liver cirrhosis due to hepatitis B. After the initiation of treatment with lamivudine, manifestation of HE has not been observed for about 2 years and liver function has improved as well. This experience suggests that improved liver function using lamivudine may contribute to prevention from recurrence of HE.

Hepatology. 2002 Oct;36(4 Pt 1):949-58.
Albumin dialysis in cirrhosis with superimposed acute liver injury: a prospective, controlled study.
Heemann U, Treichel U, Loock J, Philipp T, Gerken G, Malago M, Klammt S, Loehr M, Liebe S, Mitzner S, Schmidt R, Stange J.
Department of Internal Medicine, University of Essen, Germany.

Patients with liver cirrhosis and a superimposed acute injury with progressive hyperbilirubinemia have a high mortality. A prospective, controlled study was performed to test whether hyperbilirubinemia, 30-day survival, and encephalopathy would be improved by extracorporeal albumin dialysis (ECAD). Twenty-four patients were studied; 23 patients had cirrhosis; 1 had a prolonged cholestatic drug reaction and was excluded from per protocol (PP) analysis. Patients had a plasma bilirubin greater than 20 mg/dL and had not responded to prior standard medical therapy (SMT). Patients were randomized to receive SMT with ECAD or without (control). ECAD was performed with an extracorporeal device that dialyzes blood in a hollow fiber dialyzer (MW cutoff < 60 kd) against 15% albumin. Albumin-bound molecules transfer to dialysate albumin that is regenerated continuously by passage through a charcoal and anion exchange column and a conventional dialyzer. ECAD was associated with improved 30-day survival (PP, 11 of 12 ECAD, 6 of 11 controls; log rank P <.05). Plasma bile acids and bilirubin decreased on average by 43% and 29%, respectively, in the ECAD group after 1 week of treatment, but not in the control group. Renal dysfunction and hepatic encephalopathy improved in the ECAD group, but worsened significantly in the control group. ECAD was safe, with adverse events being rare and identical in both groups. In conclusion, ECAD appears to be effective and safe for the short-term treatment of patients with cirrhosis and superimposed acute injury associated with progressive hyperbilirubinemia and may be useful for increasing survival in such patients awaiting liver transplantation.

Hepatogastroenterology. 2002 Sep-Oct;49(47):1445-8.
Long-term hematological and biochemical effects of partial splenic embolization in hepatic cirrhosis.
Tajiri T, Onda M, Yoshida H, Mamada Y, Taniai N, Kumazaki T.
First Department of Surgery, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8603, Japan. tajirit@nms.ac.jp

BACKGROUND/AIMS: Partial splenic embolization was developed as a non-surgical treatment for hypersplenism, but recently splenic embolization has been reported to improve the hepatic function. We undertook long-term evaluation of partial splenic embolization in patients with hepatic cirrhosis in comparison with patients not undergoing embolization. METHODOLOGY: We performed embolization in 26 patients with cirrhosis. The controls consisted of 26 with cirrhosis patients who were not undergone embolization. RESULTS: Red blood cell counts of embolized patients had increased significantly at 6 months after the procedure, remaining increased for up to 7.5 years. Platelet counts increased maximally by 2 weeks after embolization, followed by a gradual decrease. Nonetheless, platelets remained significantly more numerous than before embolization for up to 8 years. Neither aspartate aminotransferase nor alanine aminotransferase activities in serum changed significantly during follow-up. Choline esterase activity increased significantly by 6 months after embolization and remained increased for more than 7 years. Serum albumin concentration increased significantly, beginning at 6 months after embolization; this increase was maintained for 6 years. Survival did not differ between embolized and non-embolized groups. CONCLUSIONS: Partial splenic embolization is a beneficial non-surgical treatment that enhances hepatic protein synthetic capacity as well as alleviating hypersplenism in patients with cirrhosis.

Dig Liver Dis. 2002 Jul;34(7):523-7.
Improved liver tests and greater biliary enrichment with high dose ursodeoxycholic acid in early stage primary biliary cirrhosis.
Roda E, Azzaroli F, Nigro G, Piazza F, Jaboli F, Ferrara F, Liva S, Giovanelli S, Miracolo A, Colecchia A, Festi D, Mazzeo C, Bacchi L, Roda A, Mazzella G.
Department of Internal Medicine and Gastroenterology, University of Bologna, S. Drsola-Malpighi Hospital, Italy.

BACKGROUND: Ursodeoxycholic acid is currently used for the treatment of primary biliary cirrhosis at 13-15 mg/kg/day, but liver tests of some patients do not return to normal at this dose. Studies reported here were designed to test whether a higher dose of ursodeoxycholic acid than is currently used would induce still greater biliary enrichment of ursodeoxycholic acid and whether such enrichment would lead to still further improvement in liver tests in patients with early primary biliary cirrhosis. METHODS: A total of 20 patients with histologically proven primary biliary cirrhosis were enrolled. Patients had early stage primary biliary cirrhosis as serum bilirubin levels were normal and the Mayo risk score 4.2 +/- 0.5. Group 1 received 600, 1200 and 1800 mg/day of ursodeoxycholic acid; group 2 received 900, 1500 and 2100 mg/day. The order of periods was randomized. Each treatment period lasted 3 months followed by a further 3 months during which a standard dose of ursodeoxycholic acid was given. At the end of each treatment period, liver tests were evaluated, and biliary bile acid pattern of duodenal bile was determined using high pressure liquid chromatography. RESULTS: Biliary bile acid became enriched in ursodeoxycholic acid in direct relationship to dosage [r = 0.84, p < 0.001). At doses of 1800 mg/day (25-35 mg/kg/day), biliary ursodeoxycholic acid averaged 69 +/- 6.6%. A progressive decrease of alanine aminotransferase [p < 0.0001), aspartate aminotransferase [p < 0.001) and alkaline phosphatase [p < 0.02) was observed with increasing concentrations of ursodeoxycholic acid in bile. Biochemical liver tests showed a stronger correlation with biliary concentrations of ursodeoxycholic acid than with the administered dose. CONCLUSIONS: In early primary biliary cirrhosis, higher dose ursodeoxycholic acid appears to be more effective than doses currently recommended.

J Gastroenterol Hepatol. 2002 Aug;17(8):882-8.
Clinical course, predictive factors and prognosis in patients with cirrhosis and type 1 hepatorenal syndrome treated with Terlipressin: a retrospective analysis.
Colle I, Durand F, Pessione F, Rassiat E, Bernuau J, Barriere E, Lebrec D, Valla DC, Moreau R.
Laboratoire d'Hemodynamique Splanchmique et de Biologie Vasculaire, Institut National de la Sante et de la Recherge Medicale, Clinchy, France. Isabelle.Colle@rug.ac.be

BACKGROUND AND AIM: Terlipressin has been proposed to treat renal failure in patients with type 1 hepatorenal syndrome (HRS). However, the predictive factors for improved renal function and survival are unknown in patients with type 1 HRS treated with terlipressin. The aim of the present retrospective study was to investigate the predictive factors and prognosis of patients with type 1 HRS treated with terlipressin. METHODS: The clinical charts of 18 consecutive patients with cirrhosis and type 1 HRS treated with terlipressin were studied. The predictive factors for improved renal function and survival were identified using univariate analyses. RESULTS: Improved renal function, indicated by a significant decrease in serum creatinine (61 +/- 4%), occurred in 11 (60%) patients. The only predictive factor for improved renal function was a Child-Pugh's score < or =13 at the time of diagnosis of HRS (P = 0.02). Fifteen patients (83%) died at 45 days and the median survival was 24 days. Of the three patients who survived, two underwent successful orthotopic liver transplantation. Three predictive factors for survival were identified: absence of a precipitating factor for HRS (P = 0.012); improved renal function during terlipressin therapy (P = 0.05); and a dose of terlipressin > or =3 mg/day (P = 0.04). CONCLUSIONS: In patients with type 1 HRS treated with terlipressin, patients with improved renal function had less severe cirrhosis (Child-Pugh >10 but < or =13) than patients without. The predictive factors for survival were the absence of a precipitating factor for HRS, the terlipressin-induced improvement in renal function and a dose of terlipressin of at least 3 mg/day. These findings suggest that a randomized controlled trial investigating the effect of terlipressin on survival in patients with type 1 HRS should be performed. Copyright 2002 Blackwell Publishing Asia Pty Ltd

Hepatogastroenterology. 2002 Jul-Aug;49(46):1102-8.
Antifibrotic properties of botanicals in chronic liver disease.
Stickel F, Brinkhaus B, Krahmer N, Seitz HK, Hahn EG, Schuppan D.
Department of Medicine I, Division of Hepatology, Division of Complementary Medicine, University of Erlangen-Nuremberg, Ulmenweg 18, D-91054 Erlangen, Germany. felix.stickel@med1.imed.uni-erlangen.de

Cirrhosis of the liver is a major complication of various chronic liver diseases and results from excess production and decreased degradation of extracellular matrix. Proinflammatory cytokines, toxic metabolites and certain drugs can trigger enhanced fibrogenesis in hepatic stellate cells and myofibroblasts, the major matrix-producing cells. Since treatment of established cirrhosis is limited, therapeutic interventions that inhibit or mitigate fibrogenesis are needed. Numerous drugs have been investigated for their antifibrotic potential and botanicals constitute a significant fraction of them. Colchicine has been used to treat various chronic liver diseases with controversial results. To date, there is a lack of studies in appropriate animal models and well-controlled human trials to demonstrate its antifibrotic properties. Silymarin has so far failed to clearly show an antifibrotic effect in human studies, whereas animal experiments suggest that this mixture of flavolignanes may be beneficial in patients which have not yet developed cirrhosis. Animal studies indicate an antifibrotic potential of Shosaiko-to, a herbal combination frequently used in China and Japan for the treatment of chronic viral hepatitis, but mechanisms of action need to be further explored. Other botanicals include trans-resveratrol, a flavonoid extracted from grapevine, and Salvia miltiorrhiza which were shown to interfere with the process of hepatic stellate cell activation. Herbal combinations, such as compound 861 and LIV.52 were advocated as antifibrotics or hepatoprotectives, but studies in humans have either been of questionable design or resulted in cessation of the trial due to adverse outcomes.

Liver. 2002 Jun;22(3):235-44.
An electron microscopic and morphometric study of ursodeoxycholic effect in primary biliary cirrhosis.
Neuman MG, Cameron RG, Haber JA, Katz GG, Blendis LM.
Division of Clinical Pharmacology, Sunnybrook and Women's Health Sciences Centre, Toronto, Ontario, Canada. manuela@sten.sunnybrook.utoronto.ca

BACKGROUND/AIMS: Primary biliary cirrhosis (PBC) is a chronic liver disease that results in cholestasis and bile duct loss. Ursodeoxycholic acid (UDCA) has been shown to reduce hepatocellular damage in PBC. The study attempted to quantify perisinusoidal collagenization and the number of apoptotic bodies in PBC liver biopsies from patients in a randomized control trial treated with UDCA compared to those who received placebo. METHODS: Twenty-eight patients with PBC (10 cirrhotic, 18 non-cirrhotic; 13 treated with UDCA, 15 treated with placebo) were compared with 32 controls with normal hepatic histology on light microscopy. Liver biopsies were examined for degree of perisinusoidal fibrosis and apoptotic activity using electron microscopy. RESULTS: The degree of perisinusoidal fibrosis and apoptotic activity was similar in pretreatment biopsies of UDCA and placebo-treated patients. After two years of placebo, patients showed a significant increase in fibrosis (P < 0.001). In contrast, there were no changes in non-cirrhotic and a decrease in fibrosis in cirrhotic patients given UDCA. At baseline, PBC patients had higher numbers (apoptotic cells/100 hepatocytes +/- SE) of apoptotic cells (7 +/- 3), than controls (2 +/- 0.5) (P < 0.05), with no difference between cirrhotic and non-cirrhotic patients in the two groups of patients. After two years, the numbers of apoptotic cells in UDCA-treated patients decreased significantly compared to baseline (3 +/- 2) (P < 0.05); with placebo patients the number of apoptotic cells increased (12 +/- 5) (P < 0.05). CONCLUSION: Treatment with UDCA prevents the deposition of perisinusoidal collagen and reduces the apoptotic activity in PBC patients after 2 years of therapy.

Rev Med Chir Soc Med Nat Iasi. 2001 Jan-Mar;105(1):63-8.
[Portal hypertension in liver cirrhosis]
[Article in Romanian]
Prelipcean CC.
Clinica a II-a Medicala Gastroenterologie, Facultatea de Medicina, Universitatea de Medicina si Farmacie Gr.T. Popa Iasi.

Portal hypertension is a dramatic complication in liver cirrhosis by efraction of the varices localized more frequently in the esophagus. It has been an actual subject due to physiopathological research (endotelin system, nitric system etc), diagnosis (echoendoscopy, color Doppler), and therapeutically progress. Propranolol, available at a low cost, is efficient and unanimously accepted in the prophylactic treatment of medium and large varices which have never bled as well as in the hemorrhage due to variceal efraction which stopped therapeutically or spontaneously. This drug diminishes the risk of rebleeding. Besides the pharmacological treatment, terlipresine, octreotid, sclerotherapy and bandlegation are used in active hemorrhage due to variceal efraction. If this fails other methods for haemostasis are used: portosystemic transjugular shunt, mechanical tamponade, selective surgery and ideally hepatic transplant. Except for the hepatic transplant, none of the mentioned methods can improve the rate of survival in-patients, which depends on the state of the hepatic failure.

J Hepatol. 2002 Jul;37(1):15-21.
Effects of long-term oral misoprostol administration on hepatic amino acid-nitrogen metabolism in patients with cirrhosis.
Bianchi G, Brizi M, Manini R, Fabbri A, Loffreda S, Zoli M, Marchesini G.
Dipartimento di Medicina Interna, Cardioangiologia, Epatologia, Alma Mater Studiorum, Universita di Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy. bianmice@almadns.unibo.it

BACKGROUND: The acute infusion of a Prostaglandin of E series 1 (PGE1) analogue results in nitrogen sparing in cirrhosis. AIMS: To test the effects of long-term oral PGE1 on hepatic and whole-body nitrogen metabolism. PATIENTS AND METHODS: Ten patients with advanced cirrhosis were studied in paired experiments, before and 30-50 days after oral misoprostol therapy. alpha-Amino-nitrogen levels and urea-nitrogen synthesis rate were measured in the post-absorptive state and in response to continuous alanine infusion (2 mmol/kg per hour for 4.5h). Data were used to compute the functional hepatic nitrogen clearance, i.e. the slope of the regression of alpha-amino-N levels to urea-N synthesis rate, and the apparent nitrogen exchange. RESULTS: Misoprostol reduced urea-N synthesis rate (during fasting and in response to alanine), resulting in a positive nitrogen exchange. The functional hepatic nitrogen clearance slightly increased, and the regression line was rightwards shifted, indicating a reduced urea synthesis rate at any alpha-amino-N concentration. Amino acid- and ammonia-N did not accumulate in plasma. No systematic effects on insulin and glucagon were observed. CONCLUSIONS: Data are consistent with a nitrogen sparing mechanism of misoprostol, not mediated by hormone levels. These effects may be beneficial in clinical hepatology, and need to be tested in controlled trials.

Lik Sprava. 2002;(2):64-8.
[Different therapeutic approaches for chronic diffuse liver lesions using ornicetil, lactulose, etimizol and corinfar]
[Article in Ukrainian]
Neiko IeM, Mytnyk ZM, Holovach IIu.

Different therapeutic regimens were tried in 67 patients with hepatic cirrhosis and in 54 patients with chronic hepatitis depending on the leading pathological syndrome. Treatment schemes involved the use of the drug ornicetil in patients having acute episodes of portal systemic encephalopacy, lactulose in those presenting with an increased content of ammonia in the blood and symptoms of chronic portal systemic encephalopacy; etimizol was given to those patients with an apperant antioxidant imbalance. Differentiated approaches to the institution of curative measures permitted improving considerably the patients' medical rehabilitation, achieving regression of pathological manifestations. It has been found out that the above drugs exert a positive effect on the cytolytic and mesenchimal-inflammatory syndromes and will, we believe, come to be widely used for treating diffuse lesions of the liver.

Hepatogastroenterology. 2002 May-Jun;49(45):783-7.
Effects of losartan, somatostatin and losartan plus somatostatin on portal hemodynamics and renal functions in cirrhosis.
Hulagu S, Senturk O, Erdem A, Ozgur O, Celebi A, Karakaya AT, Seyhogullari M, Demirci A.
Department of Gastroenterology, Kocaeli University, Faculty of Medicine, Kocaeli, Turkey. shulagu@hotmail.com

BACKGROUND/AIMS: Several drugs have been used to reduce portal hypertension. Losartan constitutes arteriolar and venous vasodilation by inhibiting the effects of the increased angiotensin II in cirrhotic patients. In this study, we analyzed the effects of losartan, when used alone and when combined with somatostatin, on portal and renal hemodynamics. METHODOLOGY: Seventeen patients with cirrhosis were enrolled. During the study, the patients were administered 250 micrograms of somatostatin i.v. bolus and subsequent infusion at a rate of 250 micrograms/hr for 2 hours on the second day; 25 mg losartan orally on the fourth day; and losartan and somatostatin together, in the same doses as the second and the fourth day, were given on the sixth day. RESULTS: The portal flow volume and the velocity that were measured after the administration of somatostatin, losartan and the combination of each drug, were found to be increased when compared with the initial values (P < 0.001). Additionally, the creatinine clearances were increased and statistically significant with somatostatin. CONCLUSIONS: Considering its low cost, easy usability, long lasting effect, we suggest that losartan can be used as an alternative treatment in the clinical conditions where portal pressure should be reduced and can be combined with somatostatin without any significant adverse effects.

Nippon Geka Gakkai Zasshi. 2002 May;103(5):408-13.
[Liver transplantation for patients with hepatitis B/C virus cirrhosis or hepato cellular carcinoma]
[Article in Japanese]
Todo S, Furukawa H, Matsushita M, Shimamura T, Jin MB, Suzuki T, Taniguchi M.
Hokkaido University School of Medicine, Department of General Surgery.

The outcome of liver transplantation for patients with hepatitis B/C virus (HBV/HBC) cirrhosis or with hepatocellular carcinoma(HCC) was deemed pessimistic until the early 1990s due to the high rate of recurrence and mortality. However, with the advent of new antiviral agents and strict adherence transplant indications, the results of liver transplantation in patients with these disease have improved progressively. Coadministration of lamivudine and anti-HBV immunoglobulin, and of interferon and ribavirin inhibits the recurrence of hepatitis B and hepatitis C, respectively. Excluding HCC patients with extrahepatic or lymph node metastasis, vascular invasion, a single lesion more than 5 cm in diameter, or multiple lesions more than 3 cm in diameter, the 5-year patient survival rate has improved from 30% to 85%, with a disease-free survival rate of more than 90%. However, the development of lamivudineresistant mutants after prolonged use of the agent needs to be overcome, possibly by new antiviral agents such as adefovir. In addition, to expand the current limited transplant indications for HCC, the efficacy of perioperative anticancer treatment and the importance of molecular diagnosis of circulating hepatoma cells must be determined in future.


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