R. Romeo

The natural history of compensated cirrhosis due to hepatitis C virus: A 17-year cohort study of 214 patients†

Large databases of consecutive patients followed for sufficiently long periods are needed to establish the rates, chronology, and hierarchy of complications of cirrhosis as well as the importance of other potential causes of liver disease. In accordance with this goal, a cohort of patients with compensated cirrhosis due to hepatitis C virus (HCV) was followed for 17 years. Two hundred and fourteen HCV RNA–seropositive patients with Child‐Pugh class A cirrhosis who had no previous clinical decompensation were prospectively recruited and followed up with periodic clinical and abdominal ultrasound examinations. During 114 months (range 1–199), hepatocellular carcinoma (HCC) developed in 68 (32%), ascites in 50 (23%), jaundice in 36 (17%), upper gastrointestinal bleeding in 13 (6%), and encephalopathy in 2 (1%), with annual incidence rates of 3.9%, 2.9%, 2.0%, 0.7%, and 0.1%, respectively. Clinical status remained unchanged in 154 (72%) and progressed to Child‐Pugh class B in 45 (21%) and class C in 15 (7%). HCC was the main cause of death (44%) and the first complication to develop in 58 (27%) patients, followed by ascites in 29 (14%), jaundice in 20 (9%), and upper gastrointestinal bleeding in 3 (1%). The annual mortality rate was 4.0% per year and was higher in patients with other potential causes of liver disease than in those without them (5.7% vs. 3.6%; P = .04). In conclusion, hepatitis C–related cirrhosis is a slowly progressive disease that may be accelerated by other potential causes of liver disease. HCC was the first complication to develop and the dominant cause for increased mortality. (HEPATOLOGY 2006;43:1303–1310.)

A 28-Year Study of the Course of Hepatitis Δ Infection: A Risk Factor for Cirrhosis and Hepatocellular Carcinoma

BACKGROUND & AIMS Chronic infection with hepatitis Delta virus (HDV) is a risk factor for cirrhosis and hepatocellular carcinoma (HCC); predictors of disease outcome are, however, poorly defined. We tracked the course of HDV infection in 299 patients over a mean period of 233 months. METHODS We analyzed data from patients who had been HDV positive for at least 6 months (230 males; mean age, 30 years) admitted from 1978 to 2006 to Maggiore Hospital, Milan. HDV infection was defined by the presence of HDV antigen in liver tissue or serum HDV RNA in anti-HDV/hepatitis B surface antigen seropositive patients. At enrollment, 7 patients had acute hepatitis, 101 had mild-moderate chronic hepatitis, 76 had severe chronic hepatitis, and 104 had histologic or clinical cirrhosis. Ninety patients were treated with interferon, 62 with corticosteroids, and 12 with nucleoside analogues; 135 received no therapy. RESULTS Over a mean period of 233 months, 82 patients developed cirrhosis. Among the 186 total patients with cirrhosis, 46 developed HCC, 43 ascites, 44 jaundice, and 1 encephalopathy. Female sex, alcohol abuse, and HDV replication were associated with liver decompensation; HBV replication and interferon were associated with HCC development. By the end of the study, 186 patients were still alive, 63 had died, and 29 had received liver transplants. The main cause of death was liver failure (n = 37, 59%); HDV replication was the only independent predictor of mortality. CONCLUSIONS Persistent HDV replication leads to cirrhosis and HCC at annual rates of 4% and 2.8%, respectively, and is the only predictor of liver-related mortality.

Production of profibrotic cytokines by invariant NKT cells characterizes cirrhosis progression in chronic viral hepatitis.

Invariant (inv)NKT cells are a subset of autoreactive lymphocytes that recognize endogenous lipid ligands presented by CD1d, and are suspected to regulate the host response to cell stress and tissue damage via the prompt production of cytokines. We investigated invNKT cell response during the progression of chronic viral hepatitis caused by hepatitis B or C virus infection, a major human disease characterized by a diffused hepatic necroinflammation with scarring fibrotic reaction, which can progress toward cirrhosis and cancer. Ex vivo frequency and cytokine production were determined in circulating and intrahepatic invNKT cells from controls (healthy subjects or patients with nonviral benign or malignant focal liver damage and minimal inflammatory response) or chronic viral hepatitis patients without cirrhosis, with cirrhosis, or with cirrhosis and hepatocellular carcinoma. invNKT cells increase in chronically infected livers and undergo a substantial modification in their effector functions, consisting in the production of the type 2 profibrotic IL-4 and IL-13 cytokines, which characterizes the progression of hepatic fibrosis to cirrhosis. CD1d, nearly undetectable in noncirrhotic and control livers, is strongly expressed by APCs in cirrhotic ones. Furthermore, in vitro CD1d-dependent activation of invNKT cells from healthy donors elicits IL-4 and IL-13. Together, these findings show that invNKT cells respond to the progressive liver damage caused by chronic hepatitis virus infection, and suggest that these cells, possibly triggered by the recognition of CD1d associated with viral- or stress-induced lipid ligands, contribute to the pathogenesis of cirrhosis by expressing a set of cytokines involved in the progression of fibrosis.

The natural history of hepatocellular carcinoma.

Prospective studies of patients with cirrhosis who are at risk for developing hepatocellular carcinoma (HCC), have greatly improved our understanding of the natural history of this tumour. Despite many studies, the controversy of whether HCC originates from one or more than one clone of transformed liver cells is still unsettled. The natural history of HCC in many instances is an extension of that of the underlying cirrhosis, although the course of the tumour disease may vary from patient to patient and in different geographical areas. In Oriental and southern European patients with HCC, a longer time may elapse between diagnosis and death, than in African blacks. The information about tumour development in non-cirrhotic liver is scanty, due to the little known risk factors for this type of tumour which has impeded performing prospective cohort studies of high risk patients.

Lack of association between type of hepatitis C virus, serum load and severity of liver disease

SUMMARY. Chronic infection with the hepatitis C virus (HCV) may lead to a variety of hepatic lesions from benign inflammation to liver cancer, but the relationships between infection and development of liver disease are poorly understood. To assess whether virus type and load are of pathogenetic importance, 197 Italian carriers with various hepatic lesions were investigated consecutively. Of these, 187 (95%) patients had serum HCV RNA, by reverse transcription‐polymerase chain reaction (RT‐PCR) with a median level of 1003 × 103 genomic equivalents ml‐1 according to the branched‐DNA assay (b‐DNA). One hundred and seven patients (54%) had serotype 1, 22 (11%) had serotype 2, 9 (5%) had serotype 3, 17 (9%) had mixed serotypes and 42 (21%) had no specified serotype. One hundred and thirty four patients were also tested for genotype. The genotype distribution was as follows: 17 (13%) had genotype 1a; 67 (50%) 1b; 29 (22%) 2a; 12 (9%) 3a; 3 (2%) had genotype 1 not classified (NC); 3 (2%) had genotype 2 NC; 2 (1.4%) had genotype 4 and 1 (1%) had mixed genotype la + 3a. No virus type was associated with any particular histological diagnosis and all were equally distributed between progressive and non‐progressive liver disease groups. Serum HCV‐RNA levels were similar in the liver diseases groups. By analogy to hepatitis B, there was no direct correlation between type and level of viraemia and the severity of the underlying liver damage.

High serum levels of HDV RNA are predictors of cirrhosis and liver cancer in patients with chronic hepatitis delta.

Chronic infection with the hepatitis delta virus (HDV) is a risk factor for cirrhosis and hepatocellular carcinoma (HCC), but little is known whether the outcome of hepatitis is predicted by serum markers of HDV and hepatitis B virus (HBV) infection. The aim of the study was to investigate these correlations in 193 patients with chronic HDV infection who had been followed up for a median of 9.5 years (4.8–19.3). HDV-RNA was first measured by qualitative in-house nested RT-PCR and quantified by in-house real-time PCR. HDV RNA levels only appeared significantly associated to HCC (univariate analysis: OR 1.32, 95% CI 1.02–1.71; p = 0.037; multivariate analysis: OR 1.42, 95% CI 1.04–1.95; p = 0.03). In non-cirrhotics at first presentation (n = 105), HDV RNA levels were associated with progression to cirrhosis (univariate analysis: OR = 1.57, 95% CI 1.20–2.05, p<0.001; multivariate analysis: OR = 1.60, 95% CI 1.20–2.12, p = 0.007) and development of HCC (univariate analysis: OR = 1.66, 95% CI 1.04–2.65, p = 0.033; multivariate analysis: OR = 1.88, 95% CI 1.11–3.19, p = 0.019). ROC analysis showed that approximately 600,000 HDV RNA copies/mL was the optimal cut-off value in our cohort of patients for discriminating the development of cirrhosis. High levels of HDV viremia in non-cirrhotic patients are associated with a considerable likelihood of progression to cirrhosis and the development of HCC. Once cirrhosis has developed, the role of HDV replication as a predictor of a negative outcome lessens.

Long-term titrated recombinant interferon-α2a in chronic hepatitis C: a randomized controlled trial

Summary. The efficacy and tolerability of 12‐month treatment with titrated doses of recombinant interferon‐α2a (IFN‐α2a) in chronic hepatitis C were studied in 67 consecutively recruited patients randomly assigned either to a starting dose of IFN‐α2a 6 MU, subsequently adjusted to the serum alanine aminotransferase (ALT) response (n= 35), or to no therapy (n= 32; controls). End‐of‐treatment ALT levels were normal and hepatitis C virus (HCV) RNA was negative by nested polymerase chain reaction (PCR) in 17 (49%) treated patients compared to none of the controls (P < 0.001). During the 12 months after stopping treatment the number of patients who remained in remission was eight (23%) and one respectively (4%) (P= 0.031). Follow‐up liver biopsy showed reduced hepatic inflammation in 80% of treated patients and in 29% of controls (P < 0.001). The eight sustained responders and 2 7 non‐responders or relapsers received similar mean total doses of IFN (565 MU vs 545 MU) and had a similar incidence of anti‐IFN neutralizing anti‐bodys (13% vs 19%). Absence of cirrhosis was the only independent pretreatment parameter that predicted a sustained response. In conclusion, a mean cumulative dose of IFN 549 MU, titrated over 12 months, was well tolerated, and resulted in the long‐term clearance of HCV RNA and normal ALT levels in 23% of patients.

No hepatitis recurrence using combination prophylaxis in HBV-positive liver transplant recipients with YMDD mutants

Recurrence of hepatitis B impairs the outcome of liver transplantation (OLT). In serum hepatitis B virus (HBV)‐DNA‐positive recipients, prophylaxis using lamivudine and immunoglobulins (HBIg) reduces the risk of recurrence, but it is undefined whether this regimen also protects candidates with YMDD mutants. Seventeen OLT viraemic candidates received pre‐emptive lamivudine followed by post‐OLT prophylaxis with lamivudine and HBIg. Both sera and liver biopsies were prospectively collected and high‐sensitive polymerase chain reaction (PCR) assay was applied for HBV‐DNA detection. Finally, the presence of YMDD mutants was explored in all PCR‐positive samples. All patients remained hepatitis B recurrence‐free after a mean follow up of 32 months. By PCR, serum HBV‐DNA was detectable in 64.3% of cases at OLT‐baseline, in 64.7% under combined prophylaxis and in 58.8% in patients (70.5% of the total) with a minimum follow up of 24 months. At OLT‐baseline, YMDD mutants were found in 44.4% of patients. After OLT, mutants were present in 50% of patients but only in 16.6% of cases in the long period. Although 41% of the native livers and 42.8% of the analysed grafts harboured HBV‐DNA, YMDD mutants were detected in 57% of the native positive livers. YMDD mutants were largely detected both at OLT‐baseline and post‐OLT, but their presence decreased over time. Regardless of the presence of YMDD mutants, no hepatitis B recurrence was observed in our OLT recipients using pre‐emptive lamivudine followed by continuous prophylaxis with lamivudine and HBIg.

Alpha interferon treatment of chronic hepatitis C

Hepatitis C virus infection is a common disease with a high propensity to progress towards chronicity. Alpha interferon has been proposed to halt progression of the disease and prevent the development of more severe liver diseases such as cirrhosis and hepatocellular carcinoma. Unfortunately, less than 20% of treated patients show a long-lasting ALT normalization and HCV-RNA negativity. Factors which might be predictive of a long term response to interferon are debated. Univariate analysis of data collected in randomized clinical studies, has shown that IFN dose, age, duration of disease, cirrhosis and early response (primary) to IFN were all predictors of a sustained response to IFN, but with differences in different studies. When data were analyzed by a multivariate analysis, short duration of the disease and absence of cirrhosis were found to predict long-term response to interferon. Finally, many evidences indicate that response rates to therapy may be better in patients with low pretreatment levels of HCV-RNA measured either by polymerase chain reaction (PCR) or the branched-DNA assay (b-DNA).

Hepatitis C virus and hepatocellular carcinoma

Hepatitis C virus (HCV) is pathogenetically involved in many cases of hepatocellular carcinoma (HCC) worldwide. HCV-related HCC is on the rise in many developed countries as a consequence of past infections with HCV. The time lag between HCV infection and cancer development is several decades. HCV-related tumors arise in older patients, are almost invariably associated with cirrhosis, and often have a less aggressive course than HCC related to other etiologic factors. In most patients, HCC grows as a single hepatic node for years before generating satellite or distant tumor nodes. However, there are tumors that originate as multifocal disease. Tumor progression and hepatic failure are the leading causes of death in most patients. HCV has been almost invariably detected in tumor tissue of anti-HCV patients with HCV, but it is not clear whether the virus promotes cancer through chronic hepatocellular inflammation, which is per se an important risk factor for HCC, or has a direct role in liver carcinogenesis. No reverse transcriptase activity has been found in infected livers, but there are data suggesting that HCV has oncogenic properties, because its interacts with cellular genes regulating cell growth and differentiation.