Miquel Bruguera

PREVALENCE OF ANTIBODIES TO HEPATITIS C VIRUS IN SPANISH PATIENTS WITH HEPATOCELLULAR CARCINOMA AND HEPATIC CIRRHOSIS

The prevalence of antibodies against hepatitis C virus (HCV) was investigated in 96 patients with hepatocellular carcinoma, 106 patients with liver cirrhosis without evidence of cancer, and 177 controls without liver disease. 75% of patients with hepatocellular carcinoma had HCV antibodies (anti-HCV), a significantly higher proportion than that observed in patients with cirrhosis (55.6%), or controls (7.3%). The prevalence of anti-HCV was significantly higher in patients with alcoholic cirrhosis and hepatocellular carcinoma (76%) than in patients with alcoholic cirrhosis alone (38.7%) whereas in patients with cryptogenic cirrhosis there was no significant difference between those with and without primary liver cell cancer (81.4% and 77.5%, respectively). These results indicate that HCV infection may have a role in the pathogenesis of hepatocellular carcinoma, even in patients with chronic liver disease apparently related to other agents such as alcohol, and that this recently identified hepatitis virus may be found in a large proportion of patients with cryptogenic cirrhosis.

Transient elastography for diagnosis of advanced fibrosis and portal hypertension in patients with hepatitis C recurrence after liver transplantation

Recurrence of hepatitis C after liver transplantation (LT) is the main cause of graft loss and retransplantation. Frequent liver biopsies are essential to follow‐up hepatitis C virus (HCV)–induced liver damage. However, liver biopsy is an invasive and expensive procedure. We evaluated prospectively the diagnostic accuracy of noninvasive measurement of liver stiffness (by transient elastography) to assess the severity of hepatitis C recurrence after LT. For this purpose, we included 124 HCV‐infected liver transplant recipients who underwent 169 liver biopsies and 129 hepatic hemodynamic studies with determination of hepatic venous pressure gradient (HVPG). Simultaneously, patients underwent measurement of liver stiffness. Liver fibrosis was mild (F0‐F1) in 96 cases (57%) and significant (F2‐F4) in 73 (43%). HVPG was normal (<6 mm Hg) in 69 cases (54%) and elevated (≥6 mm Hg) in 60 (46%). Using a liver stiffness cutoff value of 8.5 kilopascals, the sensitivity, specificity, negative predictive value, and positive predictive value for diagnosis of fibrosis ≥F2 were 90%, 81%, 79%, and 92%, respectively. The area under the curve (AUC) for diagnosis of fibrosis ≥F2, ≥F3 and F4 were 0.90, 0.93, and 0.98, respectively. There was a close direct correlation between liver stiffness and HVPG (Pearson coefficient, 0.84; P < 0.001) and the AUC for diagnosis of portal hypertension (HVPG ≥6 mm Hg) was 0.93. Importantly, none of the individuals with liver stiffness below the cutoff value had either bridging fibrosis (F3) or cirrhosis (F4) or significant portal hypertension (HVPG ≥10 mm Hg). In conclusion, determination of liver stiffness is an extremely valuable tool to assess the severity of HCV recurrence after LT and in reducing the need of follow‐up liver biopsies. Liver Transpl 12:1791‐1798, 2006.

Using transcriptional profiling to develop a diagnostic test of operational tolerance in liver transplant recipients

A fraction of liver transplant recipients are able to discontinue all immunosuppressive therapies without rejecting their grafts and are said to be operationally tolerant to the transplant. However, accurate identification of these recipients remains a challenge. To design a clinically applicable molecular test of operational tolerance in liver transplantation, we studied transcriptional patterns in the peripheral blood of 80 liver transplant recipients and 16 nontransplanted healthy individuals by employing oligonucleotide microarrays and quantitative real-time PCR. This resulted in the discovery and validation of several gene signatures comprising a modest number of genes capable of identifying tolerant and nontolerant recipients with high accuracy. Multiple peripheral blood lymphocyte subsets contributed to the tolerance-associated transcriptional patterns, although NK and gammadeltaTCR+ T cells exerted the predominant influence. These data suggest that transcriptional profiling of peripheral blood can be employed to identify liver transplant recipients who can discontinue immunosuppressive therapy and that innate immune cells are likely to play a major role in the maintenance of operational tolerance in liver transplantation.

Hepatic venous pressure gradient identifies patients at risk of severe hepatitis C recurrence after liver transplantation

Liver biopsy is essential in the follow‐up of HCV‐infected liver transplant recipients. The aim of this study was to prospectively compare percutaneous (PLB) versus transjugular liver biopsy (TLB) in the assessment of liver damage. We also explored the diagnostic value of hepatic venous pressure gradient (HVPG) to identify patients at risk of severe HCV disease recurrence after liver transplantation (LT). One hundred sixteen paired PLB and TLB (with HVPG measurement) were performed 3 or 12 months after LT in 80 patients. Concordance for necroinflammation and fibrosis was fair or good, particularly 1 year after LT (kappa ≥ 0.6). At this point, a significant positive association was seen between the median HVPG and the fibrosis stage (2.5 mm Hg for F0; 5 mm Hg for F1, 6 mm Hg for F2, and 11.5 mm Hg for F3; Kruscal‐Wallis < 0.001). Despite this strong association, portal hypertension (HVPG ≥ 6 mm Hg) was detected in 1 (5%) of 22, 4 (16%) of 25, and 6 (60%) of 10 patients with fibrosis stages 0, 1, and 2, respectively. After a median follow‐up of 38 months, clinical decompensation occurred in 15 (19%) of 80 patients. Although the presence of significant fibrosis (F2‐F3) 1 year after transplantation was good to predict clinical decompensation (AUC: 0.80), an HVPG of 6 mm Hg or greater was extremely accurate at identifying patients at risk of disease progression (AUC: 0.96). In conclusion, HVPG determination is a valuable tool for follow‐up in patients with HCV recurrence after LT. (HEPATOLOGY 2006;43:492–499.)

Histological course of alcoholic hepatitis. Influence of abstinence, sex and extent of hepatic damage.

The factors influencing the histological evolution of alcoholic hepatitis without cirrhosis have been evaluated in 26 patients (14 males and 12 females) submitted to repeated liver biopsies over a mean period of 1.7 years (1-3). Drinking habits during follow-up were checked by inquiries to patients and relatives and by serial determination of ethanol in urine. At the end of the follow-up, 9 patients (34.6%) had progressed to cirrhosis, 5 (19.2%) still had alcoholic hepatitis and 12 (46.1%) had normal liver or only minimal changes. Nine patients continued drinking heavily, 4 reduced their daily intake markedly and 13 stopped drinking. Improvement of liver lesions was observed in 9 of the abstainers and in 3 non-abstainers that had markedly reduced their alcohol consumption. Among the 9 patients with persistent heavy alcohol consumption, 5 developed cirrhosis and 4 still showed alcoholic hepatitis in their last biopsy. Cirrhosis also developed over 1-2 years in 4 females who had stopped drinking, indicating a marked influence of sex on the course of alcoholic hepatitis. Progression of the disease to cirrhosis despite abstinence occurred in a high proportion of women (4/7) but not in men (0/6). These observations indicate that discontinuation of heavy alcohol consumption often results in improvement of liver lesion in patients with alcoholic hepatitis. However, the risk of progression to cirrhosis remains elevated in women.

Long-term effects of ursodeoxycholic acid in primary biliary cirrhosis: results of a double-blind controlled multicentric trial

Abstract Background/Aim: The aim of this study was to assess the efficacy of ursodeoxycholic acid (UDCA) for primary biliary cirrhosis in a randomized, double-blind placebo-controlled trial. Methods: Consecutive patients ( n =192) were randomized to receive 14–16 mg UDCA/kg/day or placebo. Patients underwent a complete history, physical examination, liver chemistries, immunological determinations and liver biopsy at entry and at the end of the trial, which lasted for at least 2 years. Patients were seen every 3 months and the median follow-up was 3.4 years (range 0.3 to 6.1 years). Results: Patients receiving UDCA (99) or placebo (93) were comparable with regard to age, sex, biochemical parameters and liver histology. UDCA treatment was associated with decreases in alkaline phosphatase, gammaglutamyl transferase, alanine aminotransferase, and cholesterol levels, effects which were conspicuous after 3 months of treatment and remained similar during the follow-up. During the study 31 patients (10 receiving UDCA and 21 placebo) discontinued the trial because of noncompliance ( n =11), voluntary withdrawal ( n =19) or adverse effects ( n =1). Treatment failure (death or liver transplantation) was observed in 17 patients receiving UDCA and in 11 patients receiving placebo. Times to death or liver transplantation and to clinical complications were not significantly different in patients receiving UDCA or placebo. Histological analysis indicates that UDCA improved portal inflammation and prevented histological stage progression. By contrast, histological stage as well as ductular proliferation and ductopenia progressed in patients receiving placebo. Conclusions: Although UDCA treatment did not significantly affect time to death or liver transplantation and to clinical complications, the effects on both cholestasis and liver histology suggest that UDCA is safe and may be useful for preventing the progression of primary biliary cirrhosis.

Hepatitis C recurrence is more severe after living donor compared to cadaveric liver transplantation

Preliminary reports suggested that hepatitis C virus (HCV) infection has a more aggressive course following living donor liver transplantation (LDLT) compared to cadaveric liver transplantation (CLT). The aim of this prospective study was to establish if HCV disease recurrence differs between LDLT and CLT. A cohort of 116 consecutive HCV‐infected patients undergoing 117 LTs in a single center from March 2000 to August 2003 were followed‐up, including systematic liver biopsies. Severe recurrence (SR) was defined as biopsy‐proven cirrhosis and/or the occurrence of clinical decompensation. After a median follow‐up of 22 months (2.6–44 months), 26 (22%) patients developed SR (decompensation in 12), involving 17 (18%) of 95 patients undergoing CLT and 9 (41%) of 22 undergoing LDLT. The 2‐year probability of presenting SR was significantly higher in LDLT compared to CLT (45% vs. 22%, P = .019). By univariate analysis LDLT (P = .019) and an ALT higher than 80 IU/L 3 months after LT (P = .022) were predictors of SR. In 93 patients from whom a liver biopsy was available 3 months after LT, a lobular necroinflammatory score >1 (P < .01), LDLT (P < .01), and biliary complications (P = .046) were associated with SR. However, the only variables independently associated with SR were LDLT (odds ratio [OR], = 2.8; 95% CI,1.19‐6.6; P = .024) and a lobular necroinflammatory score >1 (OR, 3.1; 95% CI, 1.2‐8; P = .013). In conclusion, HCV recurrence is more severe in LDLT compared to CLT. Although our results were based on a single‐center experience, they should be considered in the decision‐making process of transplant programs, since severe HCV recurrence may ultimately compromise graft and patient survival. (HEPATOLOGY 2004; 40:699–707.)

Is Hepatitis C Virus Infection a Trigger of Porphyria Cutanea Tarda

The causes of liver disease, ranging from fatty changes to cirrhosis and hepatocellular carcinoma, in porphyria cutanea tarda (PCT) remain unclear. We tested 100 consecutive PCT patients for antibodies to hepatitis C virus (HCV) by enzyme-linked immunosorbent assay and a recombinant immunoblot assay. 75 (79%) patients with sporadic PCT but none of 5 with familial PCT were positive. HCV RNA was found in serum of all 18 anti-HCV-positive patients tested. There were no significant differences in the prevalence of anti-HCV between treated and untreated patients or between those with and without various HCV risk factors. The frequency of anti-HCV increased with the severity of liver histology. These findings implicate HCV in the aetiology of PCT-associated liver disease.

Impact of the recurrence of hepatitis C virus infection after liver transplantation on the long-term viability of the graft.

BACKGROUND The impact of hepatitis C virus (HCV) infection recurrence after orthotopic liver transplantation (OLT) on graft viability is still not accurately defined. Our study aims to evaluate the magnitude and rate of progression of HCV-induced liver damage after OLT in a single institution cohort of 122 HCV-infected recipients. METHODS All patients transplanted at our institution between 1988 and 1996 with positive serum HCV antibodies before OLT, minimum postoperative survival of 6 months, and without hepatitis B virus coinfection or severe non-HCV-related graft complications were retrospectively included in the study. RESULTS HCV infection recurrence was almost universal, and genotype 1b was observed in 87% of the cases. After a median histological follow-up of 43 months (range: 7-96), evidences of HCV-induced histological damage were found in 94% of the cases. The actuarial rates of severe graft damage (including cirrhosis, fibrosing cholestatic hepatitis, and submassive liver necrosis) were 15%, 33%, and 44% at 3, 5, and 7 years, respectively, and among these patients, 52% developed decompensated liver disease during the follow-up and 36% lost their grafts. The biochemical severity at the onset of the recurrent hepatitis and the development of cholestasis or cytomegalovirus disease were independent predictors of severe HCV-related graft damage. No differences were found in graft and patient survival when positive-HCV OLT recipients were compared with a coetaneous cohort of 215 non-HCV OLT recipients. CONCLUSIONS HCV infection recurrence leads to severe liver damage and subsequently to clinical decompensation in a significant proportion of OLT recipients. Some clinical and biochemical characteristics can predict the severity of HCV-induced graft damage.

Ecstasy: A common cause of severe acute hepatotoxicity

BACKGROUND/AIMS Ecstasy is a synthetic amphetamine recently identified as a possible cause of acute liver injury. This drug is consumed by young people and has a marked effect on improving sociability. The extent of ecstasy-associated severe hepatic damage is unknown to date. METHODS The clinical histories of 62 patients with acute liver failure admitted to the Intensive Care Liver Unit between January 1994 and December 1996 were reviewed to assess the frequency, the epidemiological, clinical and histological characteristics and the outcome of ecstasy-induced severe hepatitis. RESULTS Over this period of time, five patients (8%) were admitted because of ecstasy-induced acute liver failure, representing 31% of the cases with drug hepatotoxicity. Ecstasy was the second most common cause of liver injury in patients under the age of 25 years, being 20% in this subset of patients and 36% after ruling out the cases of viral etiology. All the patients had severe liver disease of acute onset, with jaundice, high peak of serum transaminases activity, hypoglycemia and low prothrombin activity, but no hepatic encephalopathy. Full recovery was observed in all cases from 3 to 12 months. CONCLUSIONS Ecstasy is responsible for a relatively high number of cases of acute liver failure in young people. Therefore, the use of this drug should be investigated in all patients with severe hepatitis of unclear origin. Efforts must be made to advise young people of the risks of ecstasy consumption.