Natural history of hepatitis C virus infection: from chronic hepatitis to cirrhosis, to hepatocellular carcinoma

Hepatitis C is a heterogeneous disease and is responsible for considerable mortality and morbidity. The hepatitis C virus (HCV) infects nearly 170 million people world-wide. More than 80% of infected individuals develop chronic infection; the remaining 10-20% develop spontaneous clearance with natural immunity. Acute hepatitis is icteric in only 20% of patients and is rarely severe. The majority of patients who develop chronic HCV infection are asymptomatic; but 60-80% develop chronic hepatitis as indicated by elevated alanine aminotransferase (ALT), around 30% maintain persistently normal ALT levels despite having detectable HCV-RNA in serum. One-third of chronically infected patients develop progressive liver injury, fibrosis and cirrhosis over a period of 20-30 years. The relationship between virus load, HCV genotype, quasi-species variability and progression of liver disease is controversial. Acquired infection after age 40, male sex, excessive alcohol-consumption, hepatitis B virus (HBV) or HIV co-infection, steatosis, and immunosuppressed state have been identified as co-factors associated with progression of fibrosis and development of cirrhosis. In patients with cirrhosis, the incidence of hepatocellular carcinoma is 2-5% per year. At present, HCV-related end-stage cirrhosis is the first cause of liver transplantation.     

Hepatitis G infection and therapeutic response to interferon in HCV-related chronic liver disease.

Circulating HGV-RNA was determined in 117 patients with HCV-related chronic liver disease and in 200 healthy blood donors. The patients, aged 50.8+/-13.8 years, were classified as chronic hepatitis (CH; n = 82), liver cirrhosis (n = 25) and hepatocellular carcinoma (HCC; n = 10). HGV-RNA was detected in 5 (4.3%) patients, all with CH and in 10 (5%) of blood donors. The majority of all groups (52% to 70%) were infected with HCV genotype II/1b, including 4/5 patients with HGV co-infection. Of 5 patients with HGV co-infection, 4 were positive for anti-HBs and anti-HBc and none exhibited jaundice. A 24-week course of interferon treatment with 12-month follow-up was achieved in 27 patients with chronic active hepatitis, including 3 with HGV co-infection. Of these, 55.6% responded to the therapy, but only 6/27 (22.2%) patients were sustained responders. The majority of sustained responders were HCV genotype III/2a (4/6) while genotype II/1b was found in the majority of patients with relapse (7/9) and non-responders (9/12). At the 48- month follow up, 2/6 sustained responders (one with HGV co-infection) became HCV RNA positive. These results show that the prevalence of HGV infection in HCV-related chronic liver disease is low, as in the general population, and is found in younger patients with chronic hepatitis. HGV coinfection does not interfere with clinical severity, disease progression or response to interferon in patients with HCV-related chronic liver disease. The favorable factors ofinterferon treatment for HCV infection are young age, low HCV-RNA levels and HCV genotype III/2a.     

Hepatitis C: the clinical spectrum of the disease

The hepatitis C virus (HCV) infects nearly 170 million people worldwide and is responsible for approximately 20% of cases of acute hepatitis and 70% of cases of chronic hepatitis. Acute hepatitis is icteric in only 20% of patients and is rarely severe. Eighty-five percent of infected patients develop chronic infection which is generally asymptomatic, resulting in most cases in fortuitous diagnosis, which may be made at a late stage. Twenty-five percent of the HCV chronic carriers have persistently normal serum alanine aminotransferase (ALT) levels despite having detectable HCV RNA in serum; 75% have elevated ALT levels. The former patients usually have mild histologic lesions, probably with a good long-term prognosis. In the latter patients, a liver biopsy is the most accurate way to distinguish patients with mild chronic hepatitis from those with moderate or severe chronic hepatitis. While most patients with mild chronic hepatitis have a slowly progressive liver disease, the patients with moderate or severe chronic hepatitis may develop cirrhosis within a few years. In patients with HCV-related cirrhosis, the incidence of hepatocellular carcinoma is 2-5% per year. At presently, HCV-related end-stage cirrhosis is the first cause of liver transplantation.     

慢性丙型肝炎、肝硬化、肝癌患者血清IL-17、IL-6和维生素D水平变化及其临床意义

目的探讨慢性丙型肝炎、丙肝肝硬化、丙肝相关肝癌患者血清IL-17、IL-6和维生素D[25-OH-D和1,25(OH)2D]水平的变化及其临床意义。方法酶联免疫法(ELISA)测定54例慢性丙型肝炎、47例丙肝肝硬化和32例丙肝相关肝癌患者的血清IL-17、IL-6和维生素D水平,并检测患者HCV-RNA滴度、AFP水平,并与50名健康对照者比较。结果与对照组相比,各组患者的血清IL-17、IL-6、HCV-RNA滴度和AFP水平显著增加,而维生素D水平显著降低;三组患者相比,血清IL-17、IL-6、HCV-RNA滴度和AFP水平随着病情的发展逐渐升高(肝癌组肝硬化组慢性丙型肝炎组),而维生素D水平随着病情的发展逐渐降低(肝癌组肝硬化组慢性丙型肝炎组);IL-17与HCV-RNA滴度、AFP和IL-6呈明显正相关,而与维生素D呈明显负相关,IL-6也与HCVRNA滴度、AFP呈明显正相关,而与维生素D呈明显负相关。结论血清IL-17、IL-6和维生素D可能与HCV活跃程度有关,并在HCV感染后引起肝脏损伤、肝硬化、肝癌的发生发展过程中起重要作用。同时,IL-17、IL-6和维生素D的检测可能作为肝脏损伤程度新的标志物及AFP等经典标志物在肝癌诊断中的补充。     

The influence of human immunodeficiency virus coinfection on chronic hepatitis C in injection drug users: a long-term retrospective cohort study.

In this study we analyzed the influence of human immunodeficiency virus (HIV) infection on the course of chronic hepatitis C through multivariate analysis including age, alcohol consumption, immune status, and hepatitis C virus (HCV)-related virologic factors. Eighty HIV-positive and 80 HIV-negative injection drug users included between 1980 and 1995 were matched according to age, gender, and duration of HCV infection and followed-up during 52 months. The progression to cirrhosis was the primary outcome measure. The impact of HIV on HCV-RNA load, histologic activity index, response to interferon therapy, and liver-related death was also considered. In HIV-positive patients, chronic hepatitis C was characterized by higher serum HCV-RNA levels (P =.012), higher total Knodell score (P =.011), and poorer sustained response to interferon therapy (P =.009). High serum HCV-RNA level was associated with low CD4-lymphocyte count (P =.001). Necroinflamatory score was higher in HIV-positive patients (P =.023) independently of the CD4-lymphocyte count, whereas increased fibrosis was related to decreased CD4-lymphocyte count (P =.011). The progression to cirrhosis was accelerated in HIV-positive patients with low CD4 cell count (RR = 4.06, P =.024) and in interferon-untreated patients (RR = 4.76, P =.001), independently of age at HCV infection (P =.001). Cirrhosis caused death in 5 HIV-positive patients. The risk of death related to cirrhosis was increased in heavy drinkers (RR = 10.8, P =.001) and in HIV-positive patients with CD4 cell count less than 200/mm(3) (RR = 11.9, P =.007). In this retrospective cohort study, HIV coinfection worsened the outcome of chronic hepatitis C, increasing both serum HCV-RNA level and liver damage and decreasing sustained response to interferon therapy. Age and alcohol were cofactors associated with cirrhosis and mortality. Interferon therapy had a protective effect against HCV-related cirrhosis no matter what the patient's HIV status was.     

Influence of Helicobacter pylori infection on iron accumulation in hepatitis C.

GOAL: Iron may play a role in the pathogenesis of chronic hepatitis C. Helicobacter pylori (Hp) infection was recently associated with iron-deficiency anemia. We examined the influence of Hp infection on hepatic iron accumulation in hepatitis C. METHODS: Ninety-five hepatitis C virus (HCV)-RNA-positive patients, including 60 chronic hepatitis, 17 cirrhosis and 18 hepatocellular carcinoma as well as 95 age- and sex-matched normal subjects without HCV infection as control, were studied. Liver biopsies were also obtained from 44 HCV-infected patients. Serum Hp antibodies were measured by an enzyme-linked immunosorbent assay and clinical data, including iron parameters and histological findings, were compared between Hp-positive and -negative HCV-infected patients. RESULTS: The percentage of serum Hp antibodies was lower in HCV-infected patients than in controls (52/95 (54.7%) vs. 68/95 (71.6%); P<0.05). HCV-infected patients had higher serum ferritin levels than controls (120 [2.8-1700] vs. 58 [2.2-420] ng/ml; P<0.0001). In HCV-infected patients, the serum ferritin levels (medians and [ranges]) in Hp-positive patients were significantly lower than those of Hp-negative patients (99 [8.5-770] vs. 150 [2.8-1700] ng/ml; P<0.05). The grades of hepatic iron deposit in Hp-positive patients were significantly lower than those in Hp-negative patients (P<0.01). CONCLUSIONS: Hp infection may at least partly affect hepatic iron accumulation in HCV-related liver diseases.     

Occurrence of HCC in asymptomatic HCV-related chronic hepatitis

Patients with persistently normal ALT affected with HCV-related chronic hepatitis exist. The natural history of liver disease in these patients was demonstrated to be very slow and progression to cirrhosis likely absent. The case we report describes the occurrence of hepatocellular carcinoma (HCC) in a patient with persistently normal ALT affected with mild chronic hepatitis. This observation suggests that asymptomatic carriers of HCV may develop HCC that is not related to underlying liver cirrhosis.     

Circulating soluble-CD30 (sCD30) in patients with HCV-related chronic hepatitis and in patients with alcoholic liver disease

BACKGROUND/AIMS: Serum sCD30 (soluble CD30) is a marker of cells producing Th2-type (T-helper-2-type) cytokines. High levels of sCD30 have been found in the active phase of HBV infection. The Th2-type cytokine profile has been documented in alcoholic liver diseases, which have particularly high IgE and IgA serum levels. The aims were: 1) to evaluate sCD30 levels in patients with (a) alcoholic liver diseases and (b) HCV-related chronic hepatitis before and after interferon treatment; 2) to correlate sCD30 concentrations with IgE and IgA serum levels. METHODOLOGY: Serum samples from 34 HCV-related chronic hepatitis patients, before and after interferon treatment, and 17 alcoholic liver disease patients were tested for sCD30 using the ELISA method (Dako, CD30-Ki-1 Antigen, Denmark). RESULTS: Significantly higher levels of sCD30 were found in alcoholic liver disease than in HCV-related chronic hepatitis patients (73.3 +/- 120 vs. 27.5 +/- 44 U/mL, P < 0.05). Alcoholic liver disease patients also exhibited significantly higher levels of IgA than HCV-related chronic hepatitis patients (P < 0.0001). No correlation was found between sCD30 and serum IgA or IgE or response to interferon. CONCLUSIONS: Th2 cells are strongly expanded in alcoholic liver diseases, though the particular immunoglobulin profile observed in this condition has yet to be explained. Th2 function also plays a crucial part in chronic HCV infection, but seems unrelated to interferon response.     

Increased frequency of interferon-gamma-producing peripheral blood CD4+ T cells in chronic hepatitis C virus infection

OBJECTIVES: To determine the profile of cytokine secretion by CD4+ T helper (Th) cells in chronic hepatitis C virus (HCV) infection, we used flow cytometry to determine the percentage of interferon (IFN)-gamma and interleukin (IL)-4 producing cells from CD4+ T lymphocytes in peripheral blood obtained from patients chronically infected with HCV. METHODS: Peripheral blood mononuclear cells isolated from 89 HCV infected subjects (22 asymptomatic carriers, 56 patients with chronic hepatitis, and 11 patients with liver cirrhosis) and 24 healthy controls were stained with surface CD4 and intracellular IFN-gamma and IL-4. Serum soluble IL-2 receptor (sIL-2R) levels were analyzed by ELISA. RESULTS: The frequency of IFN-gamma producing CD4+ cells in asymptomatic HCV carriers, patients with chronic hepatitis, and patients with liver cirrhosis were significantly higher than those of healthy controls (p<0.01, respectively). In contrast, the percentages of IL-4-producing CD4+ cells were very low, and there were no significant correlations with disease progression. A significant elevation in serum sIL-2R levels was found in chronic HCV infection compared to healthy controls, and serum sIL-2R levels significantly correlated with the frequency of IFN-gamma-producing cells. CONCLUSIONS: In HCV infected subjects, both serum sIL-2R and IFN-gamma are increased in chronic HCV infection no matter the stage of disease, meaning they are no different in asymptomatic carriers, patients with chronic hepatitis, and patients with liver cirrhosis, and that Th1 cytokine or Th1 cells may participate in the pathogenesis of liver damage in chronic HCV infection.     

Hepatitis C virus in the setting of HIV or hepatitis B virus coinfection

Because of shared routes of transmission, coinfection with hepatitis C virus (HCV) or hepatitis B virus (HBV), or both, is common among HIV-infected persons, affecting approximately 15 to 30% and 10 to 15% of patients, respectively. Advances in antiretroviral therapy have improved the life expectancy of patients infected with HIV, and, as a consequence, HCV-related liver disease has emerged as a significant comorbid disease among such patients. Concurrent HIV infection may be associated with higher serum HCV RNA levels, accelerated progression of hepatic fibrosis, increased risk of end-stage liver disease, hepatocellular carcinoma and death among persons coinfected with hepatitis C. Similarly, coinfection with HCV and HBV may lead to more severe liver disease and greater risk of hepatocellular carcinoma (HCC) than does HCV infection alone. Although definitive randomized controlled trials are not yet completed, current guidelines recommend the use of pegylated interferon alfa plus ribavirin for the treatment of chronic HCV in eligible HIV-infected persons. Conversely, the optimal treatment of chronic HCV in persons with chronic HBV infection has not been defined but may include pegylated interferon alfa plus ribavirin, with or without additional antiviral agents, such as lamivudine or adefovir, or both.     

Management of Hepatitis C Post-liver Transplantation: a Comprehensive Review

Infection with hepatitis C virus (HCV) is a common cause of chronic liver disease, and HCV-related cirrhosis and hepatocellular carcinoma are the leading causes for liver transplantation in the Western world. Recurrent infection of the transplanted liver allograft is universal in patients with detectable HCV viremia at the time of transplant and can cause a spectrum of disease, ranging from asymptomatic chronic infection to an aggressive fibrosing cholestatic hepatitis. Recurrent HCV is more aggressive in the post-transplant population and is a leading cause of allograft loss, morbidity, and mortality. Historically, treatment of recurrent HCV has been limited by low rates of treatment success and high side effect profiles. Over the past few years, promising new therapies have emerged for the treatment of HCV that have high rates of sustained virological response without the need for interferon based regimens. In addition to being highly effective, these treatments have higher rates of adherence and a lower side effect profile. The purpose of this review is to summarize current therapies in recurrent HCV infection, to review the recent advances in therapy, and to highlight areas of ongoing research.     

Three patients treated with sofosbuvir plus ledipasvir for recurrent hepatitis C after liver transplantation

We previously reported results of interferon (IFN)-free daclatasvir and asunaprevir for the treatment of recurrent hepatitis C virus (HCV) genotype 1 infection after liver transplantation (LT). Here we report three patients who achieved viral response with no effect on the blood concentrations of immunosuppressive agents following sofosbuvir plus ledipasvir treatment. The first patient was a 68-year-old female with HCV-related liver cirrhosis who failed to respond to pegylated-IFN and ribavirin (PEG-IFN/RBV) after living donor LT. She had been treated with 50 mg/day of cyclosporine. The second was a 63-year-old male with HCV-related liver cirrhosis and hepatocellular carcinoma who failed to respond to PEG-IFN/RBV after living donor LT. He had been treated with 50 mg/day of cyclosporine. The third was a 63-year-old female with HCV-related liver cirrhosis. She had been treated with tacrolimus. High alanine aminotransferase levels persisted after LT. Liver biopsy examination revealed active hepatitis or chronic rejection. Therefore, sofosbuvir plus ledipasvir therapy was started. However, the combination treatment was stopped at 4 weeks due to development of interstitial pneumonia. Serum HCV RNA became negative at the time treatment was discontinued and remained negative 12 weeks after cessation of therapy in all three cases. Sofosbuvir plus ledipasvir treatment showed a remarkable viral response with little effect on blood levels of immunosuppressive agents for recurrent HCV genotype 1 infection after LT.     

Long-term treatment of chronic hepatitis C with ursodeoxycholic acid: influence of HCV genotypes and severity of liver disease.

AIMS/BACKGROUND: Current therapy for chronic hepatitis C virus (HCV) infection is based on the administration of interferon alpha (IFN) alone or in combination with other anti-viral agents. However, such therapy is effective in only a minority of selected patients. Long-term ursodeoxycholic acid (UDCA) treatment has been reported to improve liver function and structure especially in cholestatic disorders. We investigated the effect of long-term UDCA treatment on liver function in respect to the severity of chronic liver disease and HCV genotypes. METHODS: Forty-five patients with non-cholestatic laparoscopy-biopsy proven HCV-associated chronic hepatitis (n=16) or cirrhosis (n=29) who had not responded to, or were unsuitable for IFN, were randomly assigned to receive UDCA (600 mg/day; n=23) or no therapy (n=22) for 12 months. At entry, all patients were evaluated by means of conventional and quantitative liver function tests (LFTs), including galactose elimination capacity and antipyrine clearance, HCV antibodies, HCV-RNA and HCV genotypes. LFTs were measured at 6 and at 12 months, whereas HCV-RNA was determined again after treatment. RESULTS: Baseline characteristics were comparable in the two study groups. Long-term UDCA therapy was well tolerated. Based on the analysis of variance, there was a significant decrease in serum transaminase, LDH and GGT levels in UDCA treated patients. By contrast, the activities of these enzymes increased in untreated patients, with AST levels reaching statistical significance only. Statistical analysis also showed that the improvement in biochemical markers was more pronounced in UDCA treated patients with liver cirrhosis than in those with chronic hepatitis but was similar in patients with HCV genotype 1b and non-1b. However, HCV-RNA was positive in all patients after treatment. Quantitative LFTs remained, on average, stable over the 12 months of the trial in all groups. CONCLUSIONS: Long-term UDCA treatment is well tolerated in patients with HCV-associated chronic liver disease. The effect appears to be greater in cirrhotics than in patients with chronic hepatitis but is independent of HCV genotypes. Thus, long-term UDCA treatment, despite the absence of an anti-viral effect, seems beneficial in reducing disease activity in patients with chronic hepatitis or cirrhosis who are unsuitable for IFN therapy.     

Genetics and hepatitis C treatment: towards a personalized treatment?

Chronic HCV (hepatitis C virus) infection is an important cause of liver cirrhosis and hepatocellular carcinoma worldwide. HCV-related cirrhosis is the main indication for liver transplantation in our geographical area. Thus, treatment of this disease represents an important economical burden for the Health Care System. Current treatment of hepatitis C consists of pegylated interferon and ribavirin: only half of the patients achieve a sustained virological response after treatment. Factors related to the virus and the host influence response to treatment. Polymorphisms near the gene IL28B (encoding interferon-λ-3) have been recently identified as strong predictors of spontaneous HCV clearance in acute infection and of response to antiviral treatment in chronic hepatitis C. The aim of this article is to review the genetic studies that have emerged during the last months and its clinical implications, as well as to emphasize how Genetics is gaining importance in the management of liver diseases.     

Mutations in the NS5A gene predict response to interferon therapy in Japanese patients with chronic hepatitis C and cirrhosis.

The virus genotype, serum HCV-RNA level and liver histology are reported to be important factors in the response to interferon therapy. Recent studies have revealed that HCV NS5A 2209-2248 amino acid changes affect the response to interferon therapy of genotype 1b chronic hepatitis C. In contrast, some studies done in western countries have reported no such correlation. In the present study, interferon therapy was given to 58 Japanese patients, including 15 liver cirrhosis patients. NS5A 2209-2248 changes, the serum HCV level, ALT level, age and histology were examined in relation to the interferon effect. Twenty-four of the 58 patients (41%) showed a sustained virological response to the therapy. The responses to interferon therapy were significantly correlated with NS5A 2209-2248 changes (p < 0.0001), the HCV-RNA level (p < 0.0001) and histology (p < 0.0060). Among 15 liver cirrhosis patients, 3 of 6 mutant type patients showed a sustained virological response; 5 intermediate and 4 with wild type virus infected patients showed no responses. In conclusion, NS5A 2209-2248 changes may be a useful predictive marker of response to interferon therapy in addition to the serum HCV RNA level even in histologically advanced patients.     

Liver transplantation for acute or chronic liver failure by hepatitis non-A, non-B and hepatitis C viral infections: a postoperative follow-up.

Orthotopic liver transplantation (OLT) was performed for liver failure related to hepatitis non-A, non-B (HNANB) or hepatitis C (HCV) infections in 12 patients. Of those, 8 patients had chronic and 4 acute hepatic failure. To determine the incidence of recurrent infection, the clinical course, histological findings and serological HCV markers (HCV-RNA and detection of anti HCV antibodies, respectively) were comparatively studied in these patients. Recurrent infection was apparent in 5 of 6 patients transplanted for liver cirrhosis attributable to chronic HCV infection and with HCV-RNA detectable in serum. The clinical course of infection after OLT varied considerably. Chronic active hepatitis, progressing to liver cirrhosis 13 months postoperatively and an acute hepatitis, resolving spontaneously were seen in one case each. Recurrent infection led to chronic persistent hepatitis in the remainder. None of the patients with acute liver failure experienced recurrent infection. HCV-RNA was detectable in all the patients after OLT, with HCV-RNA present pretransplant, however the presence of HCV-RNA in serum was not necessarily associated with clinical illness.     

Relationship of the genomic complexity of hepatitis C virus with liver disease severity and response to interferon in patients with chronic HCV genotype 1b infection [correction of interferon

In patients with chronic hepatitis C, the influence of the genetic heterogeneity of the hepatitis C virus (HCV) on the progression of liver disease and on the responsiveness to interferon therapy is a matter of controversy. In this study we evaluated the genetic complexity of HCV by single-strand conformation polymorphism (SSCP) analysis of amplicons from the hypervariable region 1 (HVR1) in 168 patients with chronic genotype 1b HCV infection, of whom 122 received a single course of interferon therapy (3 MU, three times weekly for 6 months). No correlation was observed between the degree of genetic complexity of HCV (indicated by the number of bands in the SSCP assay) and patient age, serum alanine aminotransferase activity, or serum HCV-RNA concentration, measured by competitive polymerase chain reaction. HCV genomic complexity was not related to gender nor to the presumed source of infection. The number of SSCP bands detected in serum samples from patients with chronic hepatitis, either mild (8.1 +/- 3.9), moderate (8.0 +/- 3.3), or severe (9.2 +/- 3.3), and in patients with liver cirrhosis, either compensated (8.0 +/- 2.9), decompensated (6.3 +/- 2.9), or with superimposed hepatocellular carcinoma (9.5 +/- 2.9), was similar. The number of SSCP bands detected in patients with sustained response (7.5 +/- 3. 9), transient response (8.3 +/- 2.9), or no response (8.2 +/- 3.6) to interferon administration was similar as well. These observations suggest that the genetic complexity of hypervariable region (HVR1) of HCV, as estimated by SSCP analysis, is not related to the severity of liver injury nor to the type of response to interferon therapy. Thus, information offered by SSCP analysis of HVR1 of HCV in chronic HCV genotype 1b infection does not appear to be useful in the clinical management of these patients. (HEPATOLOGY 1999;29:897-903.)     

Interferon beta prevents recurrence of hepatocellular carcinoma after complete resection or ablation of the primary tumor-A prospective randomized study of hepatitis C virus-related liver cancer

Because hepatocellular carcinoma often recurs after surgical resection or ethanol injection therapy, we conducted a prospective randomized controlled trial of interferon (IFN) in patients with chronic liver disease caused by hepatitis C virus (HCV). Twenty eligible patients with cirrhosis were randomized into two groups: 10 patients treated with 6 million units of natural IFN-beta twice a week for 36 months and 10 patients without IFN therapy. One patient within the treatment group discontinued interferon therapy after 19 months of treatment because of a mild degree of retinopathy. None of the patients in either group lost HCV-RNA until the end of the observation. Although 7 (70.0%) of 10 patients in the nontreatment group showed tumor recurrence, only 1 (10.0%) of 10 patients with IFN therapy developed tumor recurrence during a median observation period of 25.0 months. Cumulative recurrence rates of the treated and untreated groups were 0% and 62.5% at the end of the first year, and 0% and 100% at the second year, respectively (log-rank test, P =.0004). In conclusion, intermittent administration of IFN suppressed tumor recurrence after treatment with surgery or ethanol injection in patients with HCV-related chronic liver disease.