Cirrhosis Research: 2002-2006
     
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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.).

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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.

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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.

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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.

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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.

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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.).

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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.).

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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.

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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.

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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.

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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.

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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).

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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.

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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 major