Should we treat HCV carriers with normal ALT levels? The '5Ws' dilemma.

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.

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

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 <400×10(3) 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.

First-line liver resection and salvage liver transplantation are increasing therapeutic strategies for patients with hepatocellular carcinoma and child a cirrhosis.

AIM: The present study focused on nine patients with hepatocellular carcinoma (HCC) associated with Child A liver cirrhosis undergoing first-line liver resection and salvage liver transplantation (SLT) for liver tumor recurrence. PATIENTS AND METHODS: Forty-six patients with HCC underwent liver transplantation (OLT); 37 (80.5%) were primary liver transplantations (PLTs) and 9 (19.5%) were SLTs. All patients who underwent SLT received minor transabdominal liver resections. RESULTS: The posttransplant 1-, 3-, and 5-year overall survival rates for SLT (88.9%, 88.9%, and 88.9%) were similar to those for PLT (78%, 62.7%, and 62.7%). Four (10.8%) patients in the PLT group had HCC recurrence, while there was zero recurrence in the SLT group. The 1-, 3-, 5-year disease-free survival rates for PLT (89%, 74%, and 74%) were similar to those for SLT (100%, 100%, and 100%). The 1-, 3-, 5-year disease-free survival rates after PLT were 89%, 74%, and 74%, and after SLT were 100%, 100%, and 100%, respectively. The operative mortality, intraperioperative bleeding, operative time, intensive care unit stay, in-hospital stay, and overall incidence of postoperative complications were similar in the two groups. CONCLUSIONS: In our experience, SLT for HCC is a feasible procedure with similar results in terms of overall survival, disease-free survival, and postoperative complications to those reported for patients who underwent PLT at our institute. An important role exists for SLT as shown by the fact that such a strategy has been used in the 20% of the patients undergoing OLT for HCC.

Review article: management of patients with chronic hepatitis C virus infection and "normal" alanine aminotransferase activity.

BACKGROUND: Hepatitis C virus infection, a major cause of chronic liver disease, occurs with normal serum alanine aminotransferase activity in approximately 25% of patients. These patients have historically remained untreated but substantial evidence indicates liver damage, progression of disease and impaired quality of life in some individuals. AIM: To review the current management of patients with chronic hepatitis C and normal alanine aminotransferase activity. METHODS: This review represents the summary of discussions at a Clinical Workshop with a comprehensive literature searching of available databases (PubMed and Embase). RESULTS: Current limits defining normal serum alanine aminotransferase activity are not representative of a "healthy" status. Most patients with hepatitis C and normal alanine aminotransferase levels have histologically proven liver damage that, although generally mild, may be significant (> or =F2) in up to 20% of patients and progresses at approximately 50% of the rate in patients with elevated alanine aminotransferase levels. Some patients have persistently normal alanine aminotransferase activity and may have a more benign outcome, but a significant proportion (> or =20%) experience periods of increased serum alanine aminotransferase activity which may be associated with enhanced disease progression. CONCLUSIONS: A treatment approach that considers host and virus-related variables and optimizes patient and cost benefits may therefore provide more effective management of patients with chronic hepatitis C and normal alanine aminotransferase activity.

Steatosis and portal hypertension.

Non Alcoholic Fatty Liver Disease (NAFLD) is characterized by histologically macrovesicular steatosis in the absence of alcohol consumption. Portal hypertension (PH) is a severe complication of liver cirrhosis leading to a higher risk to develop gastro-esophageal varices, ascites, hepatorenal syndrome, and hepatic encephalopathy. The definition of portal hypertension is based on a pressure measurement. It may be performed directly through portal vein punction or by subtracting the free hepatic venous pressure (FHVP) from the wedged hepatic venous pressure (WHVP). The hepatic venous pressure gradient (HVPG) reflects the degree of PH in the majority of liver diseases. The hepatic vein catheterization with measurement of the HVPG is considered the golden standard for portal pressure evaluation. The mechanisms by which steatosis could induce PH are not fully understood. It is not clear whether the degree of PH differs between patients with viral and alcoholic cirrhosis, and between patients with mild vs severe steatosis, In the majority of the studies subjects with alcoholic cirrhosis were included. Among patients with NASH, the portal hypertensive syndrome appears only in those with advanced cirrhosis. Further, although weight reduction decreases steatosis grade and fibrosis score, it is not clear whether it improves PH in patients with cirrhosis. In contrast, other studies found a correlation between the severity of steatosis and clinical or lab parameters of PH. We can conclude that up to now it is not actually clear whether steatosis in itself might affect portal pressure.

Individual serum bile aids in patients with primary hyperlipoproteinemias.

Fasting serum concentrations of the individual bile acids were measured by gas chromatography in 27 patients with primary hyperlipoproteinemia (8 type IIa, 7 type IIb and 12 type IV) and in 14 healthy subjects. Total serum bile acid levels were 1618 +/- 244 ng/ml (SE) in type IIa, 1296 +/- 251 ng/ml in type IIb and 15609 +/- 263 ng/ml in type IV hyperlipoproteinemia. These values did not differ significantly from values in the control group (1505 +/- 200 ng/ml). Serum levels of cholic acid were significantly higher in patients with type IIa (551 +/- 78 ng/ml) than in those with type IIb (190 +/- 57 ng/ml, P < 0.01) and type IV (240 +/- 57 ng/ml, P < 0.02), while intermediate values were recorded in the control group (384 +/- 49 ng/ml). Ursodeoxycholic acid was found in larger amounts in hyperlipidemic patients than in controls. No significant differences with respect to other bile acids were observed between the groups examined. According to the current concepts on the enterohepatic circulation of bile acids, the findings support the hypothesis that the intestinal absorption of cholic acid may differ in various types of hyperlipoproteinemia.

Effects of ursodeoxycholic acid on serum liver enzymes in patients with hepatitis C virus-related chronic liver disease.

OBJECTIVE: To study the effect of ursodeoxycholic acid (UDCA) on serum liver enzyme levels [alanine aminotransferase (ALT) and gamma-glutamyl transferase (GGT)] in 101 patients with hepatitis C virus-related chronic liver disease. METHODS: Forty-nine patients were assigned to receive UDCA (450 mg/day) over a period of 6 months and 52 to receive no treatment. RESULTS: In the UDCA group, serum ALT and GGT levels significantly improved. ALT values decreased from pre-treatment levels of 157.0 +/- 62.6 IU/l to 82.5 +/- 46.4 IU/l (P < 0.05), and GGT fell from 141.3 +/- 86.2 IU/l to 66.0 +/- 49.5 IU/l (P < 0.001). No significant change occurred in the mean ALT and GGT levels in the control group. CONCLUSION: Although our encouraging preliminary results must be validated by double-blind histological trials, UDCA may be an alternative treatment for patients who fail to respond to interferon therapy.

Hepatitis C virus carriers with persistently normal aminotransferase levels: healthy people or true patients?

Since the discovery of hepatitis C virus, the availability of serological hepatitis C virus screening has led to the identification of many subjects with normal aminotransferase levels who are chronically infected by the hepatitis C virus. To date, the epidemiology and natural history of subjects with normal aminotransferase levels are far from being clarified. Further, whether subjects with persistently normal aminotransferase levels should routinely undergo liver biopsy is still extremely controversial, and benefit from interferon treatment in this group of patients is yet to be proven. On account of the consistent normality of aminotransferases, it is not easy to calculate the rate of persons with normal aminotransferase levels among chronic hepatitis C virus carriers, nor their prevalence in the general population. It has been estimated that up to 25% of patients with chronic hepatitis C virus infection have persistently normal aminotransferase levels (10% to 40%, according to different studies). Most studies showed a clear prevalence of females, ranging from 58% to 90%. Liver biopsy shows some degree of chronic liver disease in up to 80% of these subjects, although in the majority, histological damage is mild and probably does not progress to more severe liver disease, moreover, the progression to fibrosis is slower than in patients with elevated aminotransferase levels. Virological features of these subjects (hepatitis C virus genotype distribution, viral load, quasispecies diversity) do not differ with respect to patients with elevated aminotransferase levels although a higher frequency of non 1 hepatitis C virus types has been reported. To date, no biochemical or virological tools to assess the presence and severity of liver damage exist. Antiviral treatment with interferon may induce a long-term response in only a small proportion of hepatitis C virus carriers with persistently normal aminotransferase levels, and many patients develop aminotransferase-flare-up during or shortly after treatment. Thus, interferon or combination antiviral treatment of hepatitis C virus carriers with normal aminotransferase values should be avoided in clinical practice.

Clinical management of HCV carriers with normal aminotransferase levels.

An ad hoc committee appointed by the Italian Association for the Study of the Liver (AISF) proposed these Practice Guidelines for the management of HCV carriers with persistently normal aminotransferase levels. Only stringent ALT determinations will make it possible to distinguish these subjects from those in temporary biochemical remission. The overall prevalence in Italy has been estimated between 1.5 and 10.6%. HCV RNA quantitation and genotype determination are not predictors of the presence and severity of liver damage nor correlate with the outcome of the disease, and should not be used in clinical practice for the management and surveillance of HCV carriers with normal ALT. Only a minority of HCV carriers with normal ALT levels show a normal morphological picture (true 'healthy carriers'). Disease activity is mild in most cases; fibrosis is generally mild and cirrhosis is very rare. Histological activity, as monitored by sequential liver biopsies, seems to have very slow evolution. HCV carriers should not undergo liver biopsy on a routine basis. Liver biopsy can be reasonably proposed only in selected cases. Until the results of studies with PEG interferon plus ribavirin are available, HCV carriers should not receive antiviral treatment outside controlled experimental studies.

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.

Peripheral blood serum markers for apoptosis and liver fibrosis: are they trustworthy indicators of liver realness?

BACKGROUND/AIMS: No reliable serum markers for liver inflammation, apoptosis and fibrosis have been established yet, although a large number have been evaluated. Moreover, it is not clear if a molecule detected and quantified in peripheral vein blood is a really trustworthy marker of the liver condition. To answer to this question, we had the opportunity to study paired serum samples drawn simultaneously during haemodynamic study from the right hepatic vein and from a peripheral vein from patients with hepatitis C virus related cirrhosis. METHODS: The serum levels of transforming growth factor beta-1, tumour necrosis factor-alpha, hyaluronic acid, soluble (s)human leukocyte class I antigens, soluble FAS ligand, and stumour necrosis factor related ligand were assessed in a consecutive series of 15 patients with hepatitis C virus related cirrhosis. RESULTS: No statistically significant differences were found between hepatic vein and peripheral vein levels for the cytokines, substance or soluble molecules evaluated, excepted for shuman leukocyte class I antigens. Instead a strong correlation between hepatic vein and peripheral vein levels was present for: hepatic vein, shuman leukocyte class I antigens, tumour necrosis factor-alpha, soluble FAS ligand and stumour necrosis factor related ligand, but not for transforming growth factor beta-1. CONCLUSIONS: Our results show that peripheral vein measurements seem to reflect the liver compartment in a large majority of cases, but not for all molecules and probably for any liver diseases. Further studies on this line are warranted in particular for new molecules.

Hospital prevalence of asymptomatic primary biliary cirrhosis: 4-year study based on analysis of 4468 consecutive in-patients.

To assess the hospital prevalence of asymptomatic primary biliary cirrhosis (PBC), routine determination of serum alkaline phosphatase (AP), liver function tests (albumin, bilirubin, prothrombin time) and serum liver biochemistry (aminotransferases, gamma-glutamyltranspeptidase) were performed in 4468 consecutive in-patients (2332 men, 2136 women; mean age 57 years, range 16-94 years) admitted to our medical department from April 1991 to May 1995. In patients with an increase of serum AP levels, antimitochondrial antibody (AMA) testing, ultrasonography or CT scan, HIDA biliary scintiscan, bone scintiscan and endoscopic retrograde cholangio-pancreatography (ERCP) were performed to exclude any disorders other than PBC. Fourteen out of the 4468 patients (0.3%) showed an asymptomatic increase of AP levels (i.e., detected by chance at the entry and not earlier investigated). In 12 of 14 cases the increase of AP was not related to PBC. Asymptomatic PBC was found in 2 of 4468 patients (0.04%). When only the "risk group" (women over 40 years) is considered, the prevalence rate increases to 0.12% (2/1644 women). Our data, while not assessing the true prevalence of asymptomatic PBC in the general population, suggest that symptomless PBC is much more common than has been thus far supposed.

Serum HCV RNA titer does not predict the severity of liver damage in HCV carriers with normal aminotransferase levels.

AIMS/BACKGROUND: Many HCV RNA positive subjects with normal aminotransferase levels have significant liver damage despite normal liver biochemistry. In these patients it is not possible to discriminate between "healthy" carriers and subjects with chronic liver damage, unless liver biopsy is performed. The aim of this study was to evaluate the usefulness of HCV RNA quantitation as a non invasive tool to predict the severity of liver injury in a group of HCV carriers with normal amino-transferase levels. METHODS: 59 HCV RNA positive subjects (20 males) with persistently normal ALT levels were studied. All patients underwent HCV RNA quantitation and percutaneous liver biopsy. RESULTS: No correlation was found between serum HCV RNA titers and grading, while viraemia did correlate with staging. Patients were categorized into four subgroups, according to arbitrary serum HCV RNA cut-offs. Grading was not different between the four groups. Staging was significantly higher among subjects with viraemia > 1000 x 10(3) copies/mL than in patients with HCV RNA titers < 1000 x 10(3) copies/mL. CONCLUSIONS: In HCV carriers with normal aminotransferase levels viraemia does not predict the grade of HCV-related chronic liver disease (CLD), although subjects with higher HCV RNA levels seem to have more severe fibrosis. Although these data suggest that patients with higher viraemia might have more intense architectural changes and more severe progression of liver disease than those with lower levels of HCV replication, the weak and imprecise correlation leads us to conclude that HCV RNA quantitation is not a useful indicator in clinical practice in the selection of patients for liver biopsy.

Risk factors and association with HBV infection in chronic C hepatitis.

The route of transmission in more than 50% of the patients with hepatitis C virus (HCV) infection is unknown. Only a minority of patients have had a previous blood transfusion; sporadic spread seems to be much more important, although the role of inapparent parenteral exposure is yet to be established. Aim of this study was to investigate if a relationship exists between history for exposure to known risk factors, concurrent HBV status and histological findings (presence of cirrhosis) in patients with chronic HCV liver disease. We studied 86 subjects with chronic HCV liver disease, subdivided according to their HBV status. Fifty four patients were anti-HBV negative; in the remaining 32 subjects, antibodies to HBV were found. Our data show that: 1) history for exposure to known risk factors is more likely to be present in patients with chronic HCV liver disease and concurrent positivity for antibodies to HBV than in anti-HCV positive patients without HBV antibodies (62.5% vs 38.9%); and 2) the incidence of liver cirrhosis is higher in anti-HCV positive patients with anti-HBV antibodies than in exclusively anti-HCV positive patients (56.2% vs 12.9%). We conclude that the association of history for exposure to known risk factors and anti-HBV positivity could be a marker of progression from mild to severe liver damage in patients with chronic HCV liver disease (i.e. in the absence of both identifiable risk factors and HBV antibodies, HCV infection could have a less severe clinical outcome). Therefore, in these patients a closer follow-up and earlier interferon therapy are probably needed.

Clinical, histological, and virological features of hepatitis C virus carriers with persistently normal or abnormal alanine transaminase levels.

This study was aimed to evaluate demographic, clinical, histological, and virological characteristics of 46 hepatitis C virus (HCV) carriers with persistently normal alanine transaminase (ALT) levels and to compare the results with those obtained in a group of 52 HCV-RNA-positive patients with elevated ALT levels. Subjects with normal ALT were more often females (P < .001), were more likely to be asymptomatic (P < .001), and have a lower incidence of risk factors for HCV transmission (P < .01). All patients with normal ALT had significant histological liver damage. The mean grading and staging did not differ between patients with normal and those with raised ALT concentrations. Moderate to severe hepatitis was more frequently found among subjects with normal than with elevated ALT. HCV genotype 2a was far more common in subjects with normal (43%) than with abnormal ALT levels (6%; P < .002), genotype 1b being more frequent in these latter (50% vs. 17%; P < .001). Patients with normal ALT levels had similar serum HCV-RNA titers than subjects with raised ALT. Neither HCV genotype distribution nor viral load correlated with the severity of liver damage. We conclude that significant liver disease may occur irrespective of clinical symptoms, ALT levels, HCV genotypes, and viral load.

Influence of portacaval anastomosis on serum and biliary unsulfated bile acid composition in patients with liver cirrhosis.

UNLABELLED: Serum and biliary unsulfated bile acids were studied using a gas chromatographic method in 8 patients before and 2 months after portacaval anastomosis. Total serum bile acids were 21.6 +/- 3.6 mumol/liter before and 68.0 +/- 8.6 mumol/liter after surgery (P less than 0.005). Cholic acid rose from 26.5 +/- 3.4% to 33.8 +/- 4.8% (P less than 0.02) of the total serum bile acids, while chenodeoxycholic acid decreased from 67.9 +/- 4.1% to 60.8 +/- 4.3% (P less than 0.05). The relative concentration of cholic and chenodeoxycholic acids in bile increased slightly but not significantly after surgery, while deoxycholate fell from 8.5 +/- 1.7% to 2.1 +/- 0.6%. CONCLUSIONS: (1) in cirrhosis the serum and biliary bile acid composition are markedly different, the cholic-chenodeoxycholic ratio being much lower in serum than in bile; (2) after portacaval anastomosis serum and biliary bile acid patterns tend to become similar; (3) percent biliary deoxycholate decreases significantly after surgery.

Sulfated bile acids in serum, bile, and urine of cirrhotic patients before and after portacaval anastomosis.

Sulfated and unsulfated bile acid composition was studied in serum and bile in 10 patients with alcoholic cirrhosis. Samples, collected before and 2 months after portacaval anastomosis, were analyzed using a gaschromatographic method. Mean total serum bile acid levels rose from 32.0 +/- 5.3 (SE) mumol/liter before to 87.4 +/- 13.3 mumol/liter after surgery (P less than 0.005). The increase in serum bile acid levels was significantly only with respect to the unsulfated fraction (22.7 +/- 3.0 mumol/liter to 67.6 +/- 8.1 mumol/liter, P less than 0.005). Thus the percent sulfation of total serum bile acid decreased from 24.6% to 19.2%. The sulfated bile acid fraction comprised mainly chenodeoxycholate both before and after surgery. Percent sulfation of individual bile acids was not modified after portacaval anastomosis. Bile acid sulfates were present in bile only in negligible amounts. The daily urinary excretion of bile acids, studied in 6 patients, increased significantly (P less than 0.05) after surgery, the increase being due only to the unsulfated compounds. Data from this study indicate that in cirrhotic patients no significant changes occur in serum with respect to sulfated bile acids after portacaval anastomosis, despite a definite increase in serum unsulfated bile acid levels. This is likely due to the lack of an efficient enterohepatic circulation of bile acid sulfates.