Viral hepatitis in great detail

Introduction

Viral hepatitis is a major clinical problem worldwide, particularly in developing countries, though no society is exempt. There are five major hepatitis viruses—A, B, C, D, and E. These have tropism for the liver, and the liver bears the brunt of the disease. Other viruses can infect the liver, but with many of these (e.g. Epstein–Barr virus, cytomegalovirus), hepatic involvement is merely one facet of a systemic infection, and the liver involvement is usually trivial, although occasionally it may dominate. Other hepatitis viruses are being described and their clinical relevance is under investigation. This chapter will describe the clinical and pathological consequences of viral hepatitis in general, identify virus-specific clinical patterns, and discuss the investigation, management, and prophylaxis of viral hepatitis.

Clinical outcome of hepatitis virus infection

The clinical picture in viral hepatitis depends on the severity of the inflammation induced in the liver, and on whether the virus is cleared from the liver or persists long-term. These in turn reflect characteristics both of the virus and of the host immune response, so the clinical patterns are very varied. They range from a short-lived episode that may not even be clinically apparent, to chronic infection leading to cirrhosis and predisposing to hepatocellular carcinoma.

Acute icteric hepatitis is the commonest clinically recognized consequence of infection with a hepatitis virus. It is generally a self-limited condition with a low mortality and complete recovery. Typically, after an initial prodrome lasting from several days to a couple of weeks, comprising malaise, anorexia, mild fever, and upper abdominal discomfort, the patient becomes jaundiced (icteric). The icteric period lasts for a few days to a few weeks, after which jaundice slowly subsides. Pruritus may occur, generally after the onset of jaundice. Development of ascites or oedema is uncommon but may occur in more severe cases. Return to normality after an attack of hepatitis may take several weeks to a few months and residual fatigue is common.

There are a number of variations on the clinical course of acute hepatitis:

• ◆ In anicteric hepatitis jaundice does not occur, and the episode is asymptomatic or dismissed as ‘flu-like’. This may in fact be a more frequent pattern than a clinically recognized episode, as evidenced by serological surveys for immunity to hepatitis viruses in populations.
• ◆ In cholestatic hepatitis, jaundice with pruritus, pale stools, and dark urine persists for up to 2 or 3 months before recovery.
• ◆ In relapsing hepatitis there is a transient worsening of jaundice after an initial improvement before recovery eventually occurs.
• ◆ Acute hepatitis is only rarely fatal. If it is, patients usually rapidly develop hepatic encephalopathy, and the timing of onset of this has been used to define subtypes of acute severe hepatitis.
• ◆ In ‘fulminant hepatitis’ encephalopathy develops within 2 weeks of jaundice.
• ◆ In ‘subfulminant hepatitis’ encephalopathy develops later.

Hepatitis A, B, C, and E can all initiate an acute self-limited hepatitis, although hepatitis C is particularly unlikely to give rise to the fulminant form. Only hepatitis B and C have the propensity to cause chronic viral hepatitis: this is generally an indolent disease, in which viral carriage in the liver persists over years or decades, with inflammation that varies in intensity. Hepatitis D, which coinfects patients infected with hepatitis B, can contribute to either acute or chronic inflammation.

Features of acute hepatitis caused by different viruses

Hepatitis A virus (HAV)

This causes acute self-limited hepatitis, but not chronic viral carriage or chronic liver disease. The RNA virus is acquired orally. The incubation period is between 2 and 6 weeks. Transmission generally follows the ingestion of food or water contaminated with faeces from an HAV-infected individual. Viral shedding in the faeces ceases at approximately the onset of clinical symptoms. Transmission may occur in epidemics, following floods, or after sewage contamination of shellfish beds. The disease is also endemic in all parts of the world. In developing countries, infection is frequent; there is serological evidence of past infection in up to 100% of 10-year-olds in some countries. In Western countries, evidence of prior infection varies, typically ranging from 5 to 40% dependent on age, social class, and other factors. Promiscuous homosexual males have a high incidence of infection. Very rarely, pooled blood products have transmitted the disease parenterally. Clinically the disease is often anicteric or mild, particularly in young children. About 10% of patients have a relapse before recovery. The mortality rate is low, about 0.3%. Deaths occur predominantly in older people, among whom mortality rates may exceed 2%, and pre-existing chronic viral hepatitis B or C may predispose to a fatal outcome. A rare sequel is aplastic anaemia some months after recovery from hepatitis.

Hepatitis B virus (HBV)

Hepatitis B viral infection was recognized by its parenteral transmission route, classically as serum- and then transfusion-associated hepatitis. The incubation period of this DNA virus varies from 4 to 24 weeks. In between 90 and 95% of adult cases the infection is self-limited and the HBV is cleared. In infants, clearance rates are as low as 5 to 10%. The incidence of acute hepatitis B varies widely, and is very high in east Asia and Africa. Transmission may be vertical—i.e. infection of a newborn or infant child usually by a chronically infected mother, either at the time of birth or during close family contact. Horizontal transmission routes include blood transfusion and blood products, the use of contaminated needles medically or by drug addicts, exposure in dialysis units, tattooing, and sexual contact. Promiscuous homosexuals and heterosexuals are at risk.

Anicteric attacks of acute HBV are common. If the acute infection is recognized clinically, in addition to the typical clinical features of any acute hepatitis, the preicteric prodrome may include prominent arthritis, fever, and an urticarial rash, due to immune complex deposition. Hepatitis B is fulminant in about 0.3% of cases, and both the strain of HBV and a very active host immune response may contribute. In the great majority of cases, in which HBV is cleared after acute infection, hepatitis B surface antigen (HBsAg) disappears from the blood within weeks to a few months. Failure to clear within 6 months defines ‘chronic carriage’.

Hepatitis C virus (HCV)

This was recognized as a cause of transfusion-associated hepatitis. The incubation period ranges from 2 to 26 weeks, usually between 5 and 12 weeks. Apart from blood transfusion and blood product administration, drug addiction and renal dialysis are strong epidemiological associations. Sexual transmission and horizontal transmission are uncommon, but not unknown. Fulminant hepatitis due to HCV is rare. Indeed, the initial acute episode is most often subclinical, but after acquiring the infection about 70% of individuals fail to clear the virus. HCV infection is therefore usually not recognized until the chronic phase.

Hepatitis D virus (HDV)

The unique position of hepatitis D virus, an RNA virus ‘parasitic’ on HBV, is discussed in Chapter 7.5.21. If HBV and HDV coinfect simultaneously, either unremarkable acute hepatitis, or on occasion fulminant disease, result. If HBV is cleared, HDV must be so also. Acute HDV infection can superinfect a chronic HBV carrier, and result in worsening of liver function, particularly if the HBV has previously caused significant liver disease. In such a carrier, the superinfection with HDV may be transient, or chronic hepatitis D carriage may persist. Both coinfection and superinfection are recognized initiators of fulminant hepatitis. In Westernized countries, intravenous drug abuse is a prominent epidemiological association, but all parenteral modes demonstrated by HBV occur, including sexual transmission. The southern Mediterranean, eastern Asia, and South America are areas of high or moderate incidence.

Hepatitis E virus (HEV)

Like HAV, this enterally acquired RNA virus causes acute hepatitis without chronic carriage. Most major epidemics of acute hepatitis in the Indian subcontinent and east Asia are due to HEV. Such epidemics affect adults as well as children, indicating that immunity in those areas is not regularly acquired in childhood. Flooding and sewage contamination often precede epidemics. The incubation period is about 6 weeks, and faecal excretion of the virus may persist for nearly 2 months after the onset of hepatitis. A striking feature of HEV infection, and the main clinical difference from HAV, is the propensity to induce fulminant hepatitis if acquired during mid-trimester pregnancy, and mortality rates of 10 to 40% are recorded amongst pregnant women. In Western countires, HEV cases may be imported, or be a zoonosis from infected pigs.

Other hepatotrophic viruses

Other hepatotrophic viruses remain to be described, in particular to explain non-A/B/C/D/E fulminant and transfusion hepatitis. Although the hepatitis G virus and transfusion-transmitted virus (TTV) have been well characterized, they do not appear to give rise to significant disease.

Clinical examination

Jaundice and right upper quadrant abdominal tenderness characterize acute hepatitis. Skin manifestations include spider naevi (which often disappear after recovery), scratch marks in the pruritic phase, and rarely a vasculitic or urticarial rash. Mild hepatomegaly is common, but a rapid shrinkage in hepatic size may occur in severe or fulminant hepatitis. Splenomegaly is uncommon, and suggests alternative viral causes such as Epstein–Barr virus or cytomegalovirus, or pre-existing liver disease. Marked nausea and persistent vomiting indicate a severe hepatitis and increase the chance of developing hypoglycaemia. Stools become pale and urine darkens as jaundice is established. Ascites and peripheral oedema may occur in prolonged or severe episodes. The most significant clinical indicator of deterioration is the development of hepatic encephalopathy, indicating the onset of hepatic failure. In fulminant viral hepatitis deterioration can be very rapid, and indeed rarely encephalopathy may occur before obvious jaundice has had time to develop.

Laboratory investigations

Virological investigations depend on serological testing as outlined in the table below. The initial ‘screen’ for the cause of suspected acute viral hepatitis is for anti-HAV IgM antibodies, for HBsAg, and for anti-HCV antibodies.

Typically, hepatocellular enzyme levels in blood (AST, aspartate aminotransferase; ALT, alanine aminotransferase) are prominently raised at the time of the onset of symptoms, often more than 10-fold above normal, whilst the serum alkaline phosphatase level is only slightly increased, less than 2.5-fold As an episode evolves, transaminase levels fall and alkaline phosphatase may rise, notably if there is prolonged intrahepatic cholestasis. Urinary analysis shows excess urobilinogen in early and late phases of an episode, with excess bilirubin at the height of jaundice. The severity of the attack is best reflected in the synthetic parameters of albumin and clotting factors: in particular, progressive prolongation of the prothrombin time mirrors the onset of liver failure. A low factor V (<c.30% of normal) level has been used as an indicator of irreversible failure.

Hepatic imaging techniques such as ultrasonography contribute to diagnosis primarily by excluding other causes. Patients with uncomplicated hepatitis do not require a liver biopsy, but hepatic histology is very helpful if there is diagnostic uncertainty or an unusual course in severity or duration. In such cases, biopsy may require correction of clotting factors and use of the transjugular route or ‘plugged’ biopsy techniques.

Differential diagnosis

Drug-induced jaundice is the most common differential diagnosis, and its course may be very similar. Drug history and drug screening should particularly enquire about the use of acetaminophen and nonsteroidal anti-inflammatory drugs. Other potential drugs and toxins include halothane, antituberculous drugs, carbon tetrachloride, and mushroom poisoning. Alcoholic hepatitis often presents with less marked elevations of serum transaminases and a high circulating leucocyte count. About one-third of patients with autoimmune hepatitis present with a clinical picture of acute hepatitis. Autoantibody testing is generally helpful: the majority of patients with autoimmune disease having high levels of circulating autoantibodies. However, there are often low- or moderate-titre antinuclear and anti-smooth muscle antibodies in uncomplicated viral hepatitis. Similarly, there may be some increase of immunoglobulin levels in acute hepatitis, though not the doubling characteristic of autoimmune hepatitis. Although uncommon, acute Wilson’s disease is an important diagnosis to make, because of the high incidence of acute liver failure and the rapid necessity for transplantation. ‘Surgical’ obstructive jaundice tends not to raise transaminase levels markedly, but serum alkaline phosphatase levels are high. Obstruction is generally confirmed by imaging techniques, notably ultrasound. Individual causes may be suspected from features in the history such as nausea and biliary colic in cholelithiasis, and painless jaundice without systemic upset in an elderly patient with pancreatic cancer. Pregnancy-associated syndromes—acute fatty liver and HELLP (haemolysis, elevated liver function tests, low platelets)—are in fact less common in pregnancy than acute hepatitis. Occasionally ischaemia, generally after profound hypotension over many hours, and rapidly progressive malignant infiltration may mimic acute viral hepatitis.

Table 2  Serological tests used in the assessment of acute hepatitis

Test	Interpretation	Timing in relation to jaundice
HAVAg	Not tested in routine practice	Disappears at time of onset
HAVAb-IgM	Acute or recent infection	From onset for approximately 4 months
HAVAb-IgG	Acute, recent, or past infection	Persists till old age
HBeAg	Viral protein in blood	Cleared by 6 months in >90% of cases; persistence beyond 6 months confirms chronicity
HBsAb	Viral clearance occurring	Few weeks after jaundice—persists lifelong
HBeAg	Infectious phase, high-titre HBV DNA	Cleared by 1 month in >90% of cases
HBeAb	Immune response to infectious virus indicates that the virus will be cleared	Appears as HbeAg cleared
HBcAb-IgM	Acute infection	Present at onset, persists for c. 4 months
HBcAb-IgG	Acute, recent, or past infection	Persists for 2–5 years if virus cleared
HBV-DNA	Infectious virus in blood	Cleared in 2 months in >90% of cases
HCV-RNA	Active viral replication	Present at onset
HCVAb	Acute, recent, or past infection	May not appear until a few weeks after onset
HDVAg	Presence of viral protein in blood	Present at onset
HDVAb-IgM	Acute or chronic infection	Present at onset, persists in chronic carriage
HEVAb-IgM	Acute or recent infection	From onset for 4–6 months
HEVAb-IgG	Acute, recent, or past infection	From onset for several years

Ab, antibody; Ag, antigen; HBs, hepatitis B surface; HBc, hepatitis B core.

Management

Uncomplicated cases of hepatitis recover spontaneously. Classical studies in military personnel demonstrated no benefit from bed rest, though whether the same applies to older people is unknown. In any case malaise and nausea often enforce rest. Clinicians must be alert to signs of impending liver failure and ensure that hypoglycaemia is avoided, if necessary by parenteral administration of glucose. No diets are of established benefit, but dietary fat is often poorly tolerated. There is no rationale for protein restriction unless evidence of hepatic encephalopathy has emerged. Alcohol and potentially hepatotoxic drugs should be withdrawn. Troublesome pruritus can be treated with colestyramine, which is preferable to antihistamines because of their potential hepatotoxicity. There is no proven therapy to enhance recovery. Corticosteroids do not speed recovery or improve survival, although they do lower serum bilirubin levels. In hepatitis B, and particularly hepatitis C, the use of interferon has been advocated to enhance the chance of elimination of the virus. There is little evidence of its efficacy with HBV. Hepatitis C is rarely recognized during the stage of acute infection, but if it is, the use of interferon-α is associated with a very high rate of clearance of HCV (>95% with 6 months therapy) and thus should be used in patients with acute infection who have not cleared the virus within 12 weeks.In fulminant hepatic failure, which in the setting of viral hepatitis carries a mortality risk of 80%, patients should, if possible, undergo orthotopic liver transplantation. Criteria for listing differ in different centres, but include a marked abnormality of clotting parameters (e.g. prolongation of the prothrombin time to >50 s or a factor V level <20–30%) and the development of significant encephalopathy. Patients awaiting transplantation require glucose supplementation, full intensive care monitoring, and prophylaxis of infection. Some patients require renal support, such as haemofiltration, and ventilation. Some units invasively monitor intracerebral pressure, which may rise dangerously, so that cerebral oedema may be treated with intravenous mannitol or other manoeuvres.

Prevention of viral hepatitis

Sanitation and hygiene reduce the frequency of the enteric-borne infections HAV and HEV. Passive protection against hepatitis A (to close family contacts) and hepatitis B (after exposure to risk factors such as sexual contact with an individual incubating acute hepatitis B, or a needlestick injury) are available using gammaglobulin preparations (standard preparations for protection against HAV, specific high-titre preparations for HBV). Active immunization to HAV, using formalin-inactivated viral preparations, provides a high level of protective immunity within a few days—suitable, for example, for use prior to travel from Western countries to highly endemic areas, and also advisable in patients with established chronic liver disease, particularly chronic viral hepatitis. Active immunization to HBV is discussed below, which also protects against HDV. Vaccines are not yet available for HCV or HEV.

Features of chronic viral hepatitis caused by different viruses

Chronic hepatitis B

Up to 10% of adults and more than 90% of infants become chronic B carriers after infection, defined by the persistence of HBsAg in the blood for more than 6 months. Subsequently, a low proportion of patients will clear the virus spontaneously each year, but most are infected long-term. Failure to clear the virus is more common in neonates or those infected as infants, in males, and those with natural or iatrogenic immunosuppression. Carriage rates in the population vary widely geographically, and are notably high in east Asia and southern Africa (10–20%), and low in northern Europe and North America (<1%).

The consequences of long-term carriage are varied, reflecting the strength of the immune response mounted by the host, the duration of infection, and alteration in the mechanisms of viral replication with time. Viral mutation may also contribute to modulation of the host response and viral replication. During the early years, the ‘replicative’ phase, HBeAg (hepatitis B e antigen)-expressing virus replicates independently of the host chromosomes, resulting in the production of fully infectious viral particles in the blood with high levels of HBV DNA. See table below. 

The early replicative phase is associated with a state of relative immune tolerance by the host, and may be very prolonged if infection is acquired as an infant. In the later replicative phase there is expression of immune responses associated with inflammation. Thereafter, HBeAg expression is often lost, HBeAb is expressed (‘seroconversion’), and HBsAg production may be driven by viral sequences integrated into the genome (integrative phase). In many patients this is associated with low or undetectable levels of HBV DNA in the blood, but in others HBV DNA levels may rise, particularly if HBV mutants not expressing HBeAg emerge.

Chronic hepatitis B infection is associated with a spectrum of histological damage and clinical manifestations. The inflammatory response to the virus may sometimes be so slight that the histological appearances of the liver are virtually normal, with the exception of evidence of virally infected hepatocytes seen as ‘ground-glass’ cells on routine eosin staining or by histochemistry. More commonly, the immune response is adequate to inflame the liver but inadequate to clear the virus. The resulting chronic inflammation may be confined to the portal tracts, with a chronic lymphocytic infiltration, associated to varying extent with periportal and/or lobular inflammation, a tendency to develop fibrosis spreading from the portal tracts, and in some cases eventually cirrhosis. These appearances can be categorized in terms of inflammatory activity and fibrosis (see table below). In general, the replicative phase of HBV infection with HBeAg-positivity, particularly in its later phase, is associated with more marked inflammation than the subsequent HBeAb-positive stage.

Table 4  Grading of chronic hepatitis

Grade	Activity	Staging
I	Minimal inflammation in portal tracts; scanty piecemeal necrosis; no lobular necrosis	Mild fibrous expansion of portal tracts
II	Mild portal inflammation; piecemeal necrosis; scanty lobular necrosis	Periportal fibrosis, only fine strands of fibrosis into parenchyma
III	Moderate portal inflammation; piecemeal necrosis; lobular necrosis	Bridging of fibrosis with confluent portal tracts or portocentral vein bridging
IV	Marked portal inflammation; prominent piecemeal necrosis; lobular necrosis including confluent bridging necrosis between portal tracts	Cirrhosis–bridging fibrosis and nodular regeneration

Chronic hepatitis B infection may be clinically silent for years, or give rise only to nonspecific symptoms of fatigue. The condition may be recognized on screening (e.g. during pregnancy) or the investigation of coincidentally detected abnormal liver function tests. Some patients present with nonspecific indications of chronic liver disease (malaise or hepatomegaly), or at a late stage with a complication of established cirrhosis. Episodes of enhanced inflammation (‘flares’) may give rise to transient worsening of liver function tests, particularly transaminase elevations and jaundice at any stage of the disease; precipitating events may include a reduction of prior immunosuppression, or the time of conversion from HBeAg- to HBeAb-positivity. Usually the progression to cirrhosis takes many years, but the rate varies. The incidence of hepatocellular cancer in chronic hepatitis B is high, probably increased 100-fold over noninfected controls. Most, but not all, patients with hepatocellular cancer will have cirrhosis.

Chronic HBV infection may also give rise to a number of extrahepatic manifestations. These include membranous glomerulonephritis, polyarteritis nodosa, and cryoglobulinaemia.

After establishing the diagnosis of chronic HBV infection, it is necessary to define the virological status of the patient with respect to infectivity and viral replication, and the hepatic status with respect to the presence of inflammation and liver damage. Interpretation of viral status may be complicated by the emergence of viral mutants, particularly the ‘precore’ mutant that results in absent HBeAg expression, but which, none the less, is associated with active inflammation and circulating HBV DNA levels.

Treatment

The general measures relevant to chronic liver disease of any aetiology are discussed elsewhere.

With respect to HBV infection, the prospects for inducing viral clearance in an individual patient are relatively low, but the viral load, infectivity, and intensity of hepatic inflammation can often be reduced. The two current approaches are the use of α-interferons, which combine immunomodulatory and antiviral properties, and the use of inhibitors of viral replication, nucleotide and nucleoside analogues.

Patient selection is important. Those with active inflammation, viral replication independent of host DNA, but low levels of HBV DNA have the greatest potential to benefit. Most such patients will have circulating HBeAg present. Whilst some patients will clear HBsAg from the blood in response to treatment, loss of HBeAg is a more common event. In the absence of elevated transaminases the response to treatment is very poor.

α-Interferons (IFN-α) act predominantly by enhancing T-cell-mediated viral clearance, by processes including the enhancement of hepatocyte class I HLA expression. Treatment involves parenteral IFN-α—best administered weekly in pegylated form (long-acting, conjugated to polyethylene glycol) for 6 to 12 months. If viral clearance or HBeAg to HBeAb conversion occurs, there is generally an inflammatory flare during the second or third month. Side effects include malaise, fever (particularly in the first weeks of treatment), anaemia, alopecia, and depression. HBeAg to HBeAb conversion or loss of HBV DNA occurs in 30 to 40% of cases, HBsAg clearance in about 10%. Women, those with a shorter duration of carriage, Westerners, and those without an additional immunosuppressed background (such as HIV infection) respond more favourably. Relapse after the clearance or sustained loss of HBV replication is rare (5–10%). Successful treatment slows histological progression and reduces liver-related mortality (including hepatocellular cancer).

Nucleoside and nucleotide analogues can inhibit viral reverse transcriptase and inhibit replication, and have the advantage of oral bioavailablity. They have the disadvantage of a tendency to induce viral mutation, and their effect is suppressive rather than curative, so once treatment has been initiated logic suggests long-term therapy is indicated, particularly as occasionally cessation of therapy can be followed by a disease flare. The first drug in use, lamivudine (100 mg daily), markedly reduced HBV DNA during treatment, lead to HBeAg to HBeAb conversion in one-third of patients after 12 months, and reduced serological and histological parameters of inflammation. Loss of HBsAg was infrequent. However, lamivudine-esistant strains predictably emerged at the rate of around 20% of treated patients per year, so after 3 to 4 years most patients carried viruses with mutations in the DNA polymerase (YMDD mutants). Newer agents used in combination (adefovir 10 mg daily plus lamivudine) and more powerful single agents (e.g. tenofovir 245 mg daily, entecavir 0.5–1mg daily) have much lesser tendencies to induce mutations. Monitoring of HBV DNA levels is now a key part of effective management of antiviral therapy. A particular use of antivirals is prior to chemotherapy or immunosupression in chronic carriers.

Prevention of hepatitis B

Active immunization for the prevention of HBV infection initially involved a vaccine derived from viral proteins in infected blood, but now uses recombinant HBsAg proteins. Vaccination strategies range from universal vaccination in infancy to the vaccination of only high-risk individuals. In areas of high carriage in east Asia, universal vaccine programmes have already reduced the national incidence of infection, carriage, and hepatocellular cancer. Conventional three-dose immunization in adults leads to protective immunity, as judged by anti-HBsAg, in 90% of individuals.

Passive immunization with anti-HBsAg hyperimmune globulin provides rapid protection after exposure (e.g. after needlestick injury). A combination of passive and active immunization is recommended immediately after birth for children born to infected mothers. In some infants, chronic infection with a mutant ‘escape’ virus has subsequently occurred.

Chronic hepatitis C

Around 70% of patients who become infected with HCV fail to clear the virus and become chronic carriers. In the majority of cases the initial presentation will have been asymptomatic, and HCV infection is generally recognized in the chronic phase. An asymptomatic indolent necroinflammatory response to the persistent virus in the liver tends to persist long term, and often, but not inevitably, leads to cirrhosis after 15 to 25 years and predispose to hepatocellular cancer thereafter.

Mechanisms of transmission and prevalence rates vary geographically from around 0.5% in the United Kingdom to greater than 20% in some parts of Asia, perhaps 2 to 2.5% of the world’s population. In Western countries, blood transfusion and treatment of clotting disorders with plasma concentrates (prior to the early 1990s) and intravenous drug abuse constitute the main routes of transmission. Medical use of unsterilized needles, including in vaccination programmes, tattooing, dentistry, and communal shaving practices, may all contribute worldwide. Vertical transmission is uncommon and has been estimated at around 3%. Sexual transmission is low (<5% in stable heterosexual relationships).

As with HBV, the severity of liver damage reflects host–virus responses. Severe inflammation is less common if the virus is acquired in childhood and progression to cirrhosis less frequent and probably slower. HBV coinfection and alcoholism worsen disease and increase the likelihood and rate of developing cirrhosis. The histological response of the liver shows a similar variety of response to that seen in HBV infection, from minimal to severe portal inflammation, periportal hepatocyte necrosis, and progressive fibrosis leading to cirrhosis. The presence of lymphoid follicles in portal tracts and parenchymal steatosis are characteristic of the response to HCV.

Patients may be diagnosed coincidentally during the investigation of fatigue or abnormal liver function tests, or with manifestations of chronic liver disease. In addition, there are a variety of extrahepatic manifestations thought to reflect either antigen–antibody complex formation or the induction of crossreacting autoimmunity. These include a vasculitic rash associated with cryoglobulinaemia (type 2, polyclonal immunoglobulin plus rheumatoid factor), glomerulonephritis, abnormal thyroid function, thrombocytopenia, and porphyria cutanea tarda. As in HBV, assessment of a patient with HCV involves both the virological and the hepatic status.

The initial screening test for HCV is detection of circulating anti-HCV antibody. If present, confirmation is required using polymerase chain reaction (PCR) for viral RNA. Viral genotyping (types 1–6) is important as response to treatment varies between genotypes, and quantitative PCR is valuable in judging treatment response.

The severity of inflammation in the liver is poorly judged from routine liver function tests such as aminotransferase level measurements. Histological assessment may reveal both significant inflammation and progressive fibrosis despite normal serum enzyme levels.

Treatment of chronic HCV

The main aim of treatment in chronic HCV infection is to clear the virus, which has been established to be associated with a reduction in necroinflammation and slowing in the rate of accumulation of fibrosis in the liver. There is general agreement that patients with the full spectrum from mild to severe precirrhotic disease as judged by activity grading, and with well-compensated cirrhosis, should be considered for treatment, but in decompensated cirrhosis current treatment may induce deterioration.

Treatment results have improved markedly over the last decade, with the introduction of combination therapy with IFN-α2a and IFN-α2b plus ribavirin, and the use of pegylated interferon preparations. Successful treatment produces a sustained virological response, which combines end-of-treatment suppression of viral RNA with persistent negativity 6 months after cessation of treatment. Sustained virological response rates to IFN-α of as low as 10 to 12% reported in the 1990s have been transformed by the coadministration of ribavirin (ineffective alone) and the longer-acting pegylated interferons. Genotypes 2 and 3 respond well to 6 months treatment with IFN-α (pegylated, weekly) plus ribavirin orally, with clearance rates of around 80%. For genotypes 1 and 4, treatment for 12 months is recommended, and clearance rates are 40 to 50%. Older people respond less well. Interferon dosage varies with the preparation, and both IFN-α2a and IFN-α2b are effective; dosage may require to be decreased in response to lowering of platelet and white cell counts. Ribavirin dose varies between 800 and 1200 mg/day; the drug is teratogenic and can induce haemolysis. Use of serial and quantitative RNA analysis can define nonresponders to IFN-α plus ribavirin—in whom therapy can be abandoned after 3 months—and also identify rapid responders who may have sustained remission with shorter duration therapy.

IFN-a regimens have side-effects as discussed under HBV treatment, and in particular may induce thyroiditis and some other auto-immune phenomena. Thrombocytopenia, leucopenian, and anaemia may limit the ability to sustain IFN therapy, though the use of growth factors for this may help. Ribavirin induces cough, rash, dyspnoea, and insomnia in about 25% of patients, and there is predictably a dose-dependent haemolytic anaemia. The drug is contraindicated in renal failure as it accumulates and then causes severe haemolysis. Both pregnancy and fathering children need to be avoided whilst taking ribavirin. The full role of interferon therapy in established cirrhosis, and possible long-term benefits (less fibrosis, lower incidence of hepatocellular cancer) in patients in whom viral clearance is not been achieved, are currently under investigation; in decompensated cirrhosis, however, it is contraindicated. The next few years are likely to see the emergence into clinical practice of other antiviral strategies currently under clinical trial, such as the use of HCV protease and polymerase inhibitors, analogous to those use for the treatment of HIV. Genetic approaches such as the initiation of expression of inhibitors of RNA expression (RNAis) may also enter the clinical arena.

Treatment of HIV–HCV coinfected patients is a growing practice; there is a greater risk of metabolic complications of highly active retroviral therapy and of decompensation in cirrhosis.

Prevention of hepatitis C

There is no vaccine available for HCV; the major difficulty is the rapid evolution of changes in the composition of the HCV structural proteins as the virus mutates rapidly and many quasi-species develop. Passive immunization with gammaglobulin containing antibodies to HCV is not protective. For similar reasons, patients successfully treated with a sustained virological response do remain susceptible to re-infection.

Chronic hepatitis D

Chronic HDV generally follows superinfection of a chronic HBV carrier in whom ample HBsAg to permit HDV encapsulation is already present. The spectrum of chronic liver disease associated with the double chronic infection is as variable as with HBV alone. Overall, however, the liver tends to be more severely affected, and in 10 to 15% of chronic carriers there may be a rapid (1–2 year) evolution to cirrhosis. HDV acts to suppress HBV infection, so that markers of HBV activity, such as HBV DNA, in the serum may become suppressed. Many patients with HDV may therefore be HBeAb positive.

The treatment of HDV mirrors that for HBV. Prolonged courses of IFN-α (≥6 months) may transiently clear HDV in some patients in whom HBsAg persists. In general, HBsAg clearance is required to cause sustained HDV clearance.

Liver transplantation for viral hepatitis

Liver transplantation is indicated both in fulminant hepatic failure due to acute hepatitis and in advanced chronic hepatitis with cirrhosis. Recurrence of viral hepatitis after transplantation is a major concern. The use of hyperimmune globulin, interferon, and nucleoside analogues allows control in HBV, but severe recurrence remains a significant problem after transplantation for HCV.