Cholestasis is not considered to be a common feature of chronic viral hepatitis, although intrahepatic cholestasis might be an indicator of disease progression. A number of studies have been carried out to investigate clinical, laboratory and histological characteristics of cholestasis in chronic hepatitis B and C virus infections.
More than 350 million people worldwide are chronically infected with hepatitis B virus (HBV). The disease spectrum ranges from the ‘inactive’ carrier state to progressive chronic hepatitis, cirrhosis and hepatocellular carcinoma. The complex natural history of chronic HBV infection is diverse and variable. Three phases have been described: (i) immune-tolerant phase that mostly occurs after perinatal transmission with high levels of HBV replication, normal or minimally elevated aminotransferase levels and minimal histological evidence for disease, (ii) immune-active phase with high HBV-DNA levels, elevated or fluctuating aminotransferases, significant necroinflammation and progression of liver fibrosis and (iii) inactive HBV carrier state with HBV-DNA levels <2000 IU/mL, normal aminotransferases and minimal inflammation and fibrosis with a very low risk of progression to cirrhosis and development of hepatocellular carcinoma .
Most patients with mild-to-moderate chronic HBV infection are asymptomatic or have nonspecific symptoms such as fatigue. Pruritus occurs in 8% of patients in the inactive HBV carrier state, with laboratory and histological parameters being comparable to those without pruritus . In general, the onset of jaundice can be caused either by a severe progressive disease with the development of decompensated cirrhosis or a flare due to immune reactivation (Table 3). Various studies have reported jaundice in 8–48% of patients with HBV-related cirrhosis , with elevated levels of bilirubin, AP and γGT.
Table 3. Prevalence of jaundice and histological cholestasis in patients with chronic viral hepatitis in selected studies
|Author and year [reference]||Aetiology|| N ||Design||Jaundice (%)||Cholestasisa (%)||Moderate–severe cholestasis (%)||Cirrhosis (%)||Comments|
|Davies et al. (1991) ||HBV||27||Cross-sectional||22||22||22||9||Six of 27 patients with chronic HBV infection developed fibrosing cholestatic hepatitis after liver transplantation|
|Mason et al. (1993) ||HBV||14||Cross-sectional||NR||43||NR||≥ 7||Six of the 14 patients with HBV re-infection after liver transplantation developed fibrosing cholestatic hepatitis|
|Wong et al. (2011) ||HBV||36||Prospective||NR (bilirubin range 23–754 μM)||NR||NR||14||Despite initiation of entecavir treatment in patients with spontaneous severe acute exacerbation of chronic HBV, short-term mortality was 19%|
|Mori et al. (2012) ||HBV||37||Prospective||100||NR||NR||19||Patients with acute HBV exacerbation were followed, bilirubin levels > 5 mg/dL were determinants of hepatic failure|
|Tong et al. (1995) ||HCV||131||Prospective||1·5||NR||NR||51||Both of the two patients with jaundice had already developed cirrhosis|
|Chia et al. (1998) ||HCV||8||Retrospective||0||25||12·5||63||Eight of 151 screened HCV patients presented with severe pruritus and moderate-to-severe fibrosis or cirrhosis; in liver histology, features of chronic cholestasis were subtle compared with primary biliary cirrhosis patients|
|Kumar et al. (2001) ||HCV||6||Retrospective||0||33||NR||33||Of 620 screened patients with chronic HCV, only six presented with cholestatic features, mostly in advanced disease|
Intrahepatic cholestasis might also indicate severe HBV reactivation. Reactivation is characterised by a sudden increase in HBV replication in a patient with inactive or mildly active HBV infection , accompanied by a substantial elevation of aminotransferase activities. In more severe forms of HBV reactivation, bilirubin, AP and γGT levels may become elevated. In chronic HBe antigen-positive hepatitis B, elevated aminotransferases and cholestasis may denote hepatitis flares in the context of immunological reactivation, often followed by HBe antigen seroconversion to anti-HBe and accompanied by a decrease in HBV-DNA levels. Spontaneous reactivation may occur in patients with HBe antigen-negative hepatitis B, with typical flares preceded by an increase in HBV-DNA, followed by a rise of ALT levels. In severe forms, these flares can be icteric (resembling acute hepatitis), and it might often be difficult to differentiate a flare from acute hepatitis B . In most instances, in HBV carriers, reactivation is triggered by exposure to chemotherapy or immunosuppressive agents or spontaneously in women during pregnancy or after delivery . On rare occasions, immunosuppression may lead to reactivation in HBs antigen-negative individuals who still harbour replicative intermediates of HBV . Reactivation may also occur after withdrawal of antiviral therapy or the development of resistance to antiviral therapy, especially with lamivudine . In a study involving 100 Chinese patients, about half of those with HBV reactivation developed jaundice . Indeed, in a recent prospective study , serum bilirubin levels > 5 mg/dL (and prothrombin activity < 45%) were determinants of hepatic failure and liver-related death in jaundiced patients with acute exacerbation of chronic HBV infection. Despite the initiation of antiviral treatment with more potent nucleos(t)ide analogues, such as entecavir and tenofovir, severe acute exacerbations can be fatal . To avoid HBV reactivation, guidelines recommend pre-emptive therapy before immunosuppressive therapy or chemotherapy in HBV carriers and close monitoring in HBs antigen-negative patients with positive anti-HBc antibodies and undetectable HBV-DNA .
In the era before institution of universal hepatitis B immune globulin and antiviral medication for prophylaxis, re-infection of the graft after liver transplantation was almost universal resulting in significant reduction in graft survival and patient survival . About 20–40% of patients developed fibrosing cholestatic hepatitis, characterised by rapid development of severe jaundice, graft failure and death within a few months after development of recurrent HBV infection in the allograft [53, 54]. Cases of fibrosing cholestatic hepatitis B have also been reported in other transplant settings such as kidney, heart or bone marrow transplantation and after chemotherapy for leukaemia, lymphoma or small-cell lung cancer . Typical laboratory findings include increased serum bilirubin levels, mild-to-moderate elevation of aminotransaminases and prolonged prothrombin time. Severe periportal fibrosis, intrahepatic cholestasis with marked ductular reaction, widespread hepatocellular ballooning yet mild infiltration of inflammatory cells are the characteristic histopathological findings . In the absence of inflammation, the direct cytopathic effect of uncontrolled HBV replication may cause fibrosing cholestatic hepatitis in organ recipients without immune reconstitution , and while antiviral therapy can improve liver function, mortality is still high .
In summary, the occurrence of clinical or laboratory signs of intrahepatic cholestasis in patients with chronic hepatitis B mostly indicates severe progressive liver disease or an acute exacerbation of HBV infection.
Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease affecting approximately 180 million people worldwide. The natural history of chronic HCV infection is variable, with 15–30% of patients progressing to liver cirrhosis within three decades . Jaundice is rarely seen in chronic HCV infection and seldom in acute HCV infection now that blood transfusions are no longer a source of disease. In a study of 131 HCV patients , only two presented with jaundice, both of whom had already developed cirrhosis.
Characteristic but nonspecific findings in liver biopsies from patients with chronic HCV infection are portal lymphoid aggregates, mild steatosis and some inflammatory bile duct damage [59, 60]. Bile duct lesions are usually mild, with small- or medium-sized bile ducts affected, and bile duct loss is rarely seen . The high variability of bile duct injury in liver biopsies reported in previous studies, ranging from 8% to 91%, might be attributable to either the various comorbidities associated with high-risk individuals or differences in histopathological assessment and reporting bias of studies with smaller cohorts . In the study of Kaji et al. , advanced disease and a higher degree of necroinflammatory infiltrates, particularly in portal tracts, were associated with the presence of bile duct lesions. Cytopathic effects of HCV and immune-mediated mechanisms have been suggested to be causative for bile duct lesions, although the exact mechanisms have yet to be defined . The diagnostic value of bile duct lesions has been questioned by some authors, because biliary destruction is reportedly absent in liver biopsies from a large cohort of patients with chronic HCV infection .
Clinical or laboratory findings of cholestasis are uncommon in chronic HCV infection (Table 3). In a data set of 620 patients with hepatitis C, those with either AP > 400 U/L or AP > 250 U/L and pruritus were defined as presenting with cholestasis . Of the 32 patients identified meeting these criteria, 24 had to be excluded because of confounding factors such as heavy alcohol abuse and/or lack of liver histology. Four of the remaining six patients presented with pruritus, bile duct loss was observed in four patients, and most patients exhibited an advanced fibrosis stage in liver biopsy.
Giannini et al.  assessed whether the presence of bile duct lesions in liver biopsies from patients with chronic HCV infection is reflected by serum parameters. An association with γ-GT levels was found, but virological parameters such as HCV-RNA and HCV genotype were not implicated . In an earlier study, the same group found bile duct lesions more often in older patients with advanced disease and biochemical evidence of cholestasis . In contrast, γ-GT serum levels were not correlated with the presence of bile duct damage in 201 patients with chronic HCV infection , but increased γ-GT levels were associated with more advanced liver disease. Similarly, a significant association with increased γ-GT activities and hepatic fibrosis was reported from another study but no association with serum bile acid concentrations or with histological cholestasis scores was found . These studies suggest that increased γ-GT levels may reflect more advanced liver disease rather than intrahepatic cholestasis exclusively.
In a chart review of patients with chronic HCV infection, the typical symptom of cholestasis, pruritus, was observed in 5% of subjects . Serum bile acids were the only laboratory parameters that were significantly increased in pruritic patients compared with controls. Most pruritic patients had advanced liver disease accompanied by bile duct abnormalities. Similarly, in a series of eight patients with severe pruritus, moderate-to-severe fibrosis was present in all patients; liver histology showed subtle features of cholestasis, whereas biochemical markers of cholestasis were not strikingly elevated . In a prospective study, 20% of 119 patients with chronic HCV infection reported pruritus, but laboratory and histological parameters were similar to those without .
The number of HCV patients with cholestatic features described in the different studies is too small to draw general conclusions concerning the virological response to antiviral therapy. On the whole, the reduced reported rates were in the range expected for patients with advanced fibrosis. In part, it is possible that the lower response rates might be related to increased serum bile acid levels, which have been proposed as a predictive marker for failure to achieve sustained virological response to antiviral therapy . In vitro studies have demonstrated that bile acids may enhance replication of HCV genotype 1 via a pathway involving the transcription factor FXR , upregulate HCV replicon expression  and reduce the antiviral effect of interferon . Therefore, it has been suggested that FXR antagonists or bile acid sequestrants may be useful adjuncts to antiviral therapy in patients with increased serum bile acid levels .
The potential effect of bile acids on response rates to antiviral therapy is also indicated by studies involving genetic variants of hepatic bile acid transporters. A common variant (p.A444V) of the hepatocanalicular BSEP (ABCB11) is associated with significant reduction in response rates for patients infected with HCV genotypes 2 and 3 compared with wild-type carriers; a weaker association was found for genotype 1 . Consistent with these findings, two other studies [76, 77] showed that this variant was associated with HCV positivity in 206 and 649 patients, respectively. These data suggest that decreased BSEP expression in patients harbouring the p.A444V variant may lead to increased intracellular bile acid levels, which in turn may enhance viral replication via FXR. Furthermore, bile acids have been shown to reduce the activity of 2′,5′-oligoadenylate synthetase, a protein involved in the antiviral activity of interferon . Accordingly, there is a need to investigate whether bile acid levels and genetic variants of bile acid transporters also affect response rates in patients receiving antiviral triple therapy comprising peginterferon, ribavirin and direct antiviral agents, such as the protease inhibitors boceprevir or telaprevir.
A specific subtype of HCV infection with a progressive cholestatic course has been described in patients after liver transplantation [79-81]. This cholestatic HCV disease has also been noticed in some cases after renal, heart and bone marrow transplantation and outside the transplant setting in HCV/human immunodeficiency virus coinfection. In liver transplant recipients, recurrence of HCV in the hepatic allograft leads to cholestatic hepatitis with histological features of hepatocyte ballooning predominantly in the perivenular zone analogous to features observed in patients with fibrosing cholestatic hepatitis B. Typically, serum bilirubin levels, AP and γ-GT activities are increased, and serum HCV-RNA levels are very high. Independent predictors of cholestatic HCV disease are donor age, previous rejection and total bilirubin . Without treatment, progression to liver failure and graft loss is usually seen within 1 year after transplantation. Next to reduction in immunosuppressive medication, patients should be considered for antiviral therapy. First successful treatments with regimes including the recently introduced directly antiviral agents have been reported [83, 84].
In summary, cholestatic presentation is infrequently seen in chronic HCV infection. Most patients with cholestasis display advanced disease, present with pruritus, and show bile duct injury in the setting of advanced fibrosis.