Lia Bellis

Histological and virological features and follow-up of hepatitis C virus carriers with normal aminotransferase levels: the Italian prospective study of the asymptomatic C carriers (ISACC)

BACKGROUND/AIMS To evaluate demographic characteristics, liver histology and virological features of hepatitis C virus (HCV) carriers with normal alanine transaminase (ALT) levels. METHODS A nationwide prospective study was started in 1997. Four Italian centres have participated in this study. RESULTS Eight hundred and eighty subjects entered the study. One hundred and eighty-nine (21.5%) were excluded during the follow-up because of ALT increase. Among the 691 patients with persistent ALT normality, 72% were females. An overall prevalence of genotype 2 was found (52%). Normal liver was found in 17% of the patients; 34% had minimal chronic hepatitis, 44% mild hepatitis, 4% moderate to severe hepatitis, and 1% had cirrhosis. Clinical and virological features did not differ between subjects with ALT flares and those with persistently normal ALT. Baseline ALT levels have no effects on liver histology and clinical outcome. CONCLUSIONS Many HCV carriers have significant chronic liver damage, although in the majority of them liver lesions are minimal or mild. Up to 60% of HCV carriers in Italy harbour non-1 HCV types. Current definition of HCV carriers with persistently normal ALT levels, based upon three normal ALT values over a 6-month period, is not adequate to discriminate between carriers with persistent ALT normality and those with transient biochemical remission. Longer follow-ups are needed.

Plasma Cytokines and Portopulmonary Hypertension in Patients With Cirrhosis Waiting for Orthotopic Liver Transplantation

Portopulmonary hypertension (PPHTN) is a rare complication in patients with portal hypertension. A role of endothelin 1 (ET-1) and other cytokines was demonstrated in primary pulmonary hypertension but not in PPHTN. We evaluated the possible role of ET-1, interleukin 6 (IL-6), interleukin 1β (IL-1β), and tumor necrosis factor alpha (TNF-α) in the pathogenesis of PPHTN. Plasmatic concentrations of ET-1, IL-6, IL-1β, and TNF-α were measured in patients with pulmonary systolic arterial pressure (PAPs) >30 mm Hg and in patients with cirrhosis. In all, Six out of 11 patients with PAPs >30 mm Hg had PPHTN on right heart catheterization. The remaining 10 patients had an hyperdynamic circulation (HC). In PPHTN patients, ET-1 and IL-6 were significantly higher compared with HC and patients with cirrhosis. Endothelin 1 and IL-6 could be implicated in the pathogenesis of PPHTN. On the basis of these results, ET-1 receptor antagonists or anti-IL-6 could have a rationale in the treatment of PPHTN.

Treatment of hepatitis C virus carriers with persistently normal alanine aminotransferase levels with peginterferon α-2a and ribavirin: a multicentric study

Background/Aims: To evaluate, in clinical practice, the efficacy and safety of combined antiviral treatment in hepatitis C virus (HCV) carriers with normal alanine aminotransferase (ALT) levels.

Should we treat HCV carriers with normal ALT levels? The ‘5Ws’ dilemma

Summary.  Approximately 30% of patients with chronic HCV infection have persistently normal ALT levels. Although formerly referred to as ‘healthy’ or ‘asymptomatic’ HCV carriers, and thus historically excluded from antiviral treatment, it has now become clear that the majority of these patients have some degree of histological liver damage that may be significant in up to 20% of cases and might progress towards a more severe degree of liver fibrosis. A significant proportion of patients experience periods of increased serum ALT associated with enhanced disease progression. However, controversies still exist in clinical practice regarding the definition of ‘persistent’ ALT normality, the virological and histological features of these subjects, the need for liver biopsy, the role of noninvasive tools for the assessment of liver fibrosis, the natural history and the usefulness of antiviral treatment. The advent of new therapeutic options (pegylated interferon plus ribavirin) has shifted treatment targets towards the eradication of underlying infection, with therapy decision based on age, severity of disease and likelihood of response rather than on aminotransferase levels. This review is aimed at approaching the main unresolved issues on this topic, trying to give evidence‐based answers to the more frequently asked questions from patients and their physicians.

Diagnosis, management, and treatment of hepatitis C.

We read with great interest the updated American Association for the Study of Liver Diseases practice guideline on the diagnosis, management, and treatment of hepatitis C.1 In particular, the authors should be warmly congratulated for their practical and exhaustive approach to patients with persistently normal alanine aminotransferase (PNALT) levels. However, we have some concerns about the definition and management of hepatitis C virus (HCV) carriers with PNALT proposed by Ghany et al.1 We believe that the definition given in this article (“an ALT value of less than 40 IU/L on 2 to 3 occasions separated by at least a month over a period of six months”), although commonly used in clinical practice, could be misleading, as this observation period is too short and thus not adequate to discriminate between true HCV carriers with PNALT levels and patients with only transient biochemical remission.2 Two or three normal alanine aminotransferase (ALT) values over a short-term period may not be representative of the true pattern of ALT levels for a particular patient.3 Indeed, several studies have shown that many subjects called HCV carriers with PNALT on the basis of a 6-month observation period did suffer from ALT flares during the follow-up, showing histological worsening and fibrosis progression after these flares.4,5 In light of these data, the Italian Association for the Study of the Liver6 suggested that the definition of HCV carriers with PNALT should be made on the basis of at least nine normal ALT values 2 months apart over an 18-month period. We have to be very cautious before we define these persons as subjects with PNALT, given the risks of sudden exacerbation of the disease and a less benign natural history in many of these apparently healthy carriers. Furthermore, we have some comments to offer regarding the suggested management of these patients.1 The authors state that HCVinfected persons with normal ALT values do warrant treatment if liver biopsy shows significant fibrosis. This approach seems to be too restrictive, as it excludes from treatment many patients who might require therapy. An International Clinical Workshop7 suggested that highly motivated, young patients with HCV 2 or 3 might have an excellent response to treatment and thus, in the absence of any contraindication, should receive treatment with pegylated interferon plus ribavirin therapy without the need for liver biopsy. On the contrary, in patients harboring HCV type 1 or 4 (regardless of age) or in older patients (regardless of HCV type), liver biopsy might be invariably offered to decide the need for therapy, with treatment recommended only for patients with evidence of liver disease ( F2). This approach allows more tailored therapy for HCV carriers with PNALT,8 avoiding unnecessary biopsies in many patients and providing the possibility of safe and highly effective treatment of HCV infection for selected patients.9,10 CLAUDIO PUOTI RICCARDO GUARISCO LIA BELLIS LUCIA SPILABOTTI Department of Internal Medicine and Liver Unit Marino General Hospital Rome, Italy

Should we routinely measure portal pressure in patients with cirrhosis, using hepatic venous pressure gradient (HVPG) as a guide for prophylaxis and therapy of bleeding and rebleeding? No.

Portal hypertension (PH) is a severe complication of liver cirrhosis. Measurement of the degree of portal hypertension is usually performed by measuring the hepatic venous pressure gradient (HVPG) which is the difference between the free hepatic venous pressure (FHVP) and the wedged hepatic venous pressure (WHPG). The HVPG accurately reflects the degree of PH in the majority of liver diseases. PH is defined by an increase of HVPG values above the normal upper limit of 5 mm Hg, while clinically significant PH is defined by an HVPG to ≥10 mm Hg. Although measurement of HVPG potentially has several applications, in clinical practice its major use has been related to the assessment of hemodynamic response to pharmacological therapy, in order to evaluate the efficacy of treatment and to predict the risk of rebleeding from esophageal varices. When properly performed, HVPG is a reliable, safe and good predictive tool in the management of portal hypertension. However, the need for appropriate equipment, sufficient and reliable operators and costs, have discouraged its use outside Liver Units specifically devoted to the clinical management of portal hypertension. This has diminished its applicability. Combining its use with transjugular liver biopsy and using the prognostic value of HVPG may help encourage its use.

Antiviral Treatment of HCV Carriers with Persistently Normal ALT Levels

Approximately 30% of patients with chronic HCV infection show persistently normal alanine aminotransferase levels (PNAL). The prevalence of HCV carriers with normal liver seems to be very low (less than 15-20%). Liver disease is usually minimal/mild and fibrosis is generally absent or minimal, although the association of normal alanine aminotransferase (ALT) with cirrhosis or with liver cancer has been reported. In all studies, liver histology was, on average, significantly less severe in subjects with PNAL than with abnormal ALT. Although the majority of data seem to show that HCV carriers with normal ALT have mild and stable disease, with a favourable prognosis, several studies reported a significant progression of fibrosis in approximately 20-30% of the patients with ALT normality, and the development of HCC in some cases has been described, despite persistent ALT normality. Sudden worsening of disease with ALT increase and histological deterioration has been described after up to 15 years of follow-up, in particular in patients harboring genotype 2. As to antiviral treatment, it has been clearly stated that it no longer seems reasonable to affirm that sustained response rates for patients with normal ALT levels are any different than those for patients with elevated ALT levels when the combination of pegylated interferon (IFN) and ribavirin is used. The issue at hand is whether or not patients with mild disease should be treated. There are numerous other factors which impact on this decision, including genotype, histology, patients motivation, symptoms, co-morbid illness, and the age of the patient.

Occurrence of hepatocellular carcinoma in an apparently 'healthy' HCV patient.

Approximately one-third of patients with chronic hepatitis C infection show persistently ‘normal’ alanine aminotransferase (PNALT) levels [1–3]. The extent of liver disease in these patients is usually mild [4–7] and significantly less severe than in patients with abnormal ALT [6–10]. Indeed, severe liver injury in hepatitis C virus (HCV) patients with PNALT levels is unusual with histological changes, monitored by sequential liver biopsies, progressing more slowly than in patients with elevated ALT levels [3]. Nevertheless, most patients with PNALT do have some degree of histological liver damage [11–13], challenging the view that they are ‘healthy’ carriers.

Rapid virological response as a predictor of sustained response in HCV-infected patients with persistently normal alanine aminotransferase levels: A multicenter study

Summary.  Rapid virological response (RVR) is now considered the strongest predictor of sustained virological response (SVR) in patients with HCV undergoing antiviral treatment, and thus, shorter antiviral treatment for these patients has been suggested. However, no data exist on the predictive value of RVR in HCV carriers with normal ALT values. A total of 137 patients with persistently normal ALT treated with peginterferon alfa 2a and ribavirin were studied. Fifteen patients dropped out early because of side effects, and in 10 patients with HCV‐1 treatment was discontinued because of lack of early virological response (EVR). RVR was observed in 68% of the patients (42% patients with HCV‐1, 90% HCV‐2 and 64% HCV‐3). An end‐of‐treatment response was observed in 86% of the patients (68% HCV‐1, 100% HCV‐2 and 91% HCV‐3). SVR was maintained in 91 patients (46% HCV‐1, 97% HCV‐2 and 82% HCV‐3). Overall, 92% patients with rapid response did obtain HCV eradication vs only 38% of those without rapid response. HCV‐1 patients with baseline HCV RNA <400 × 103 IU/mL were more likely to achieve RVR and SVR than those with higher HCV RNA levels. We conclude that patients with genotype 1 and normal ALT who achieve HCV RNA negativity at week 4 may have a higher probability of eradicating their infection. Because of the concomitant favourable demographic and virological features often found in this particular subset of patients, the duration of therapy in these people might be shortened in the case of RVR. Persistently normal alanine aminotransferase levels patients with genotype 2 or 3 have a high chance of achieving SVR, so retesting of HCV RNA during treatment may have no additional practical value in these subjects.

Hepatitis C virus RNA quantitation in hepatic veins and peripheral blood in patients with liver cirrhosis: evidence for low level intrahepatic hepatitis C virus replication in advanced liver disease.

BACKGROUND Very few data exist concerning the level of hepatitis C virus replication within the cirrhotic liver and its relationship to disease severity and progression. AIMS To quantitate hepatitis C virus RNA in hepatic vein blood and peripheral blood in patients with cirrhosis, to evaluate the correlation of hepatitis C virus levels in paired blood samples, and to compare the results with clinical features. PATIENTS A series of 25 patients with hepatitis C virus-related liver cirrhosis undergoing hepatic vein catheterization were studied: 11 belonged to Child Pugh class A, 8 to class B and 6 to class C. RESULTS Hepatitis C virus RNA levels did not differ between hepatic vein blood and peripheral blood (p = 0.26), despite a trend towards higher peripheral hepatitis C virus RNA levels. Hepatitis C virus RNA levels did not differ between patients with genotype 1b and non-1b either in hepatic veins or peripheral blood. Hepatitis C virus loads varied according to the severity of cirrhosis. The patients with more severe liver disease had significantly lower RNA titres than those with less advanced cirrhosis, both in hepatic veins (p = 0.002) and peripheral blood (p = 0.004). No differences in hepatitis C virus load were observed between patients in Child Pugh classes B and C. CONCLUSIONS The present data show that in patients with cirrhosis hepatitis C virus RNA concentrations do not differ between hepatic blood and peripheral blood and, furthermore, confirm that hepatitis C virus replication is reduced in patients with advanced cirrhosis, compared with patients with less severe liver disease. These findings might indicate that patients with liver cirrhosis maintain an efficient intrahepatic hepatitis C virus replication even in end-stage disease, although hepatitis C virus viraemia decreases according to the severity of liver disease.