Chronic hepatitis

Chronic hepatitis is a polyetiological diffuse inflammatory process in the liver, lasting more than 6 months (Recommendations of the European (Rome, 1988) and World (Los Angeles, 1994) Congresses of Gastroenterologists). Unlike liver cirrhosis, chronic hepatitis does not disrupt the liver architecture.

The main causes are viral hepatitis B or C, autoimmune processes (autoimmune hepatitis) and drugs. Many patients have no history of acute hepatitis, and the first sign of chronic hepatitis is an asymptomatic increase in aminotransferase levels. In some patients, the first manifestation of the disease is liver cirrhosis or its complications (eg, portal hypertension). Liver biopsy is necessary to confirm the diagnosis, classify and determine the severity of the process.

Therapy is aimed at treating complications and the underlying cause (e.g. glucocorticoids for autoimmune hepatitis, antiviral therapy for viral hepatitis). Liver transplantation is usually indicated at the final stage of the disease.

Chronic hepatitis is a widespread disease. According to A. F. Bluger and N. Novitsky (1984), the prevalence of chronic hepatitis is 50-60 patients per 100,000 population.

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What causes chronic hepatitis?

Chronic hepatitis is generally defined as a disease lasting more than 6 months, although this time frame is arbitrary. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the most common causes of chronic hepatitis; 5-10% of HBV infections (with or without hepatitis D coinfection) and approximately 75% of HCV infections become chronic. Hepatitis A and E viruses do not cause chronic hepatitis. Although the mechanism for the development of chronicity is not fully understood, liver damage is determined primarily by the body's immune response to infection.

Many cases are idiopathic. A high percentage of cases of idiopathic chronic hepatitis have prominent features of immune hepatocellular injury (autoimmune hepatitis), including the presence of serologic immune markers; association with histocompatibility antigen haplotypes characteristic of autoimmune diseases (eg, HLA-B1, HLA-B8, HLA-DR3, HLA-DR4); predominance of T lymphocytes and plasma cells in histologic preparations of liver lesions; impaired cellular immunity and immunoregulatory function in vitro studies; association with other autoimmune diseases (eg, rheumatoid arthritis, autoimmune hemolytic anemia, proliferative glomerulonephritis) and a positive response to glucocorticoid or immunosuppressant therapy. Sometimes chronic hepatitis has manifestations of both autoimmune hepatitis and another chronic liver disorder (eg, primary biliary cirrhosis, chronic viral hepatitis). These conditions are called overlap syndromes.

Many drugs, including isoniazid, methyldopa, nitrofurans, and sometimes paracetamol, can cause chronic hepatitis. The mechanism of hepatitis depends on the drug and may involve an altered immune response, the formation of cytotoxic intermediates, or genetically determined metabolic disorders.

Other causes of chronic hepatitis include alcoholic hepatitis and nonalcoholic steatohepatitis. Less commonly, chronic hepatitis is caused by alpha ₁ -antitrypsin deficiency or Wilson's disease.

Previously, chronic hepatitis was classified based on histological features and included chronic persistent hepatitis, chronic lobular hepatitis, and chronic active hepatitis. The latter classification takes into account the etiology, intensity of inflammation and necrosis (severity), and degree of fibrosis (stage), determined by histological examination. Inflammation and necrosis are potentially reversible; fibrosis is usually irreversible.

Causes of chronic hepatitis

Symptoms of chronic hepatitis

The clinical manifestations are variable. In about one third of cases they develop after acute hepatitis, but most often gradually. Many patients are asymptomatic, especially in chronic HCV infection. Signs such as malaise, anorexia, and fatigue often appear, sometimes with low-grade fever and vague discomfort in the upper abdomen. Jaundice is usually absent. Often, especially in HCV infection, the first clinical manifestations are signs of chronic liver disease (eg, splenomegaly, vascular spiders or stars, palmar erythema, pain in the right side ). Some patients with chronic hepatitis may develop cholestasis. In the autoimmune process, especially in young women, disease manifestations may involve virtually any body system and include such features as acne, amenorrhea, arthralgia, ulcerative colitis, pulmonary fibrosis, thyroiditis, nephritis, and hemolytic anemia.

Chronic HCV infection is sometimes associated with lichen planus (Wilson's lichen), mucocutaneous vasculitis, glomerulonephritis, porphyria cutanea tarda, and possibly non-Hodgkin's B-cell lymphoma. About 1% of patients develop cryoglobulinemia with fatigue, myalgias, arthralgias, neuropathy, glomerulonephritis, and rashes (urticaria, purpura, or leukocytoclastic vasculitis); asymptomatic cryoglobulinemia is more common.

Diagnosis of chronic hepatitis

The diagnosis should be considered in patients with similar symptoms, incidental findings of elevated aminotransferases, and a history of acute hepatitis. Liver function tests (if not previously done) should include serum ALT and AST, alkaline phosphatase, and bilirubin. Elevated aminotransferases are the most characteristic laboratory finding. Although enzyme levels may vary, they are usually 100–500 IU/L. ALT is usually higher than AST. Aminotransferase levels may be normal in chronic hepatitis if the disease is stable, especially in HCV infection.

Alkaline phosphatase is usually normal or slightly elevated, but may occasionally be markedly elevated. Bilirubin is usually normal in mild cases and without progression of the disease. However, changes in these laboratory tests are not specific and may be due to other diseases, such as alcoholic liver disease, recurrent acute viral hepatitis, and primary biliary cirrhosis.

If laboratory test results confirm clinical manifestations of hepatitis, serologic tests for viruses are performed to exclude HBV and HCV. If these tests do not confirm a viral etiology, further testing is necessary. Initial tests include determination of autoantibodies, immunoglobulins, and alpha1-antitrypsin levels. Children and adolescents are screened for Wilson's disease with determination of ceruloplasmin levels. Elevated serum immunoglobulins suggest chronic autoimmune hepatitis, but are not definitive. Autoimmune hepatitis is usually diagnosed by the presence of antinuclear antibodies (ANA) in titers greater than 1:80 (in adults) or 1:20 (in children), anti-smooth muscle antibodies, or liver and kidney microsome type 1 antibodies (anti-LKMI).

In contrast to acute hepatitis, liver biopsy is necessary when chronic hepatitis is suspected. Certain cases of chronic hepatitis may present only with mild hepatocellular necrosis and inflammatory cell infiltration, usually in the area of the portal venules, with normal acinar architecture and little or no fibrosis. Such cases are rarely clinically evident and usually do not progress to cirrhosis. In more severe cases, biopsy usually reveals periportal necrosis with mononuclear cell infiltration, accompanied by periportal fibrosis and bile duct proliferation of varying severity. The acinar architecture may be distorted by areas of injury and fibrosis, and sometimes overt cirrhosis is associated with features of ongoing hepatitis. Biopsy is also performed to assess the severity and stage of the disease.

In most cases, a specific cause of chronic hepatitis cannot be identified by biopsy, although cases due to HBV infection can be differentiated by the presence of ground-glass hepatocytes and specific staining of HBV components. Autoimmune hepatitis usually has more prominent lymphocytic and plasma cell infiltration. Patients with histologic but not serologic evidence of chronic autoimmune hepatitis should be evaluated for its various variants; many of these may correspond to overlap syndromes.

Serum albumin and PT should be measured to assess the severity of the process; low albumin and prolonged PT are characteristic of liver failure. If symptoms or signs of cryoglobulinemia develop in chronic hepatitis, especially in chronic hepatitis C, cryoglobulin levels and rheumatoid factor should be measured; high rheumatoid factor levels and low complement levels also suggest cryoglobulinemia.

Patients with chronic hepatitis B should undergo annual ultrasound and serum alpha-fetoprotein testing to exclude hepatocellular carcinoma, although the cost-effectiveness of this approach is controversial. Patients with chronic hepatitis C should be screened for HCC only if cirrhosis develops.

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Treatment of chronic hepatitis

The goal of treatment is to treat complications (eg, ascites, encephalopathy) and the underlying cause. Drugs that may be causing the hepatitis should be discontinued. Underlying diseases such as Wilson's disease should be treated. In chronic viral hepatitis B, contact prophylaxis may be helpful; glucocorticoids and immunosuppressive drugs should be avoided because they enhance viral replication. Contact prophylaxis is not required for HCV infection.

Treatment of autoimmune hepatitis

Glucocorticoids, with or without azathioprine, prolong survival in patients with autoimmune hepatitis. Prednisolone is usually given at a dose of 30–40 mg orally once daily, then tapered to the lowest dose that maintains aminotransferases at normal or near-normal levels. Some investigators coadminister azathioprine at 1–1.5 mg/kg orally once daily; others add azathioprine only if low-dose prednisolone does not maintain suppression. Most patients require long-term low-dose therapy. Liver transplantation is indicated only in the final stages of the disease.

Treatment of chronic hepatitis B

Treatment is indicated in HBeAg-positive patients with elevated aminotransferase levels. Therapy is aimed at eliminating HBV DNA and converting the patient from HBeAg to anti-HBe; loss of serum HBsAg occurs in approximately 10% of patients. Interferon (IFN, usually IFN-a 2b) or lamivudine are used for treatment.

Interferon is administered subcutaneously at a dose of 5 million IU daily or 10 million IU subcutaneously three times a week for 4 months. In approximately 40% of patients, this regimen eliminates HBV DNA and induces seroconversion to anti-HBe; a positive effect is usually heralded by a transient increase in aminotransferase levels. Interferon is given by injection and is often poorly tolerated. The first 1-2 doses cause a flu-like syndrome. Later, interferon may cause fatigue, malaise, depression, bone marrow suppression, and, rarely, bacterial infections or autoimmune disorders. In patients with advanced cirrhosis, interferon may accelerate the development of liver failure, so cirrhosis is a contraindication to its use. Other contraindications include renal failure, immunosuppression, organ transplantation, cytopenias, and substance abuse. Patients with HBV infection and co-infection with hepatitis D virus are usually poorly responsive to therapy. Unlike chronic hepatitis C, the use of pegylated interferon in chronic hepatitis B has not been well studied, but early reports appear encouraging.

Alternatively, lamivudine 100 mg orally once daily is given. Although lamivudine, unlike interferon, has few side effects, it also requires long-term therapy, often for many years. Lamivudine reduces HBV DNA and aminotransferase levels in almost all patients, but relapse occurs after stopping the drug before seroconversion from HBeAg to anti-HBeg. Seroconversion occurs in approximately 15-20% of patients after one year of treatment, increasing to approximately 40% after 3 years. The development of resistance to the drug is common with long-term treatment. Unlike interferon, lamivudine can be given to patients with advanced cirrhosis due to HBV infection, as it does not provoke the development of liver failure. The combination of interferon and lamivudine does not appear to be more successful than therapy with either drug alone.

Adefovir (taken orally) is likely to become the standard drug for treating chronic hepatitis B, but more research is needed. It is generally safe, and resistance rarely develops.

Liver transplantation should be considered only in the final stages of HBV-induced liver disease, but the infection attacks the graft aggressively and the prognosis is less favorable than with liver transplantation performed for other indications. Long-term lamivudine therapy after transplantation improves outcome.

Treatment of chronic hepatitis C

In chronic hepatitis C, treatment is indicated if aminotransferase levels are elevated and biopsy results demonstrate an active inflammatory process with the development of fibrosis. Therapy is aimed at eliminating HCV RNA (sustained response), which is accompanied by constant normalization of aminotransferase levels and cessation of histological progression of the process.

Combination therapy with pegylated interferon plus ribavirin gives better results. Pegylated interferon-2b at a dose of 1.5 mcg/kg subcutaneously once a week and pegylated interferon-2a at a dose of 180 mcg subcutaneously once a week give comparable results. Ribavirin is usually given at a dose of 500-600 mg orally twice a day, although a dose of 400 mg twice a day may be sufficient for genotypes 2 and 3 of the virus.

HCV genotype and viral load are determined before treatment, as they influence the treatment regimen. Genotype 1 is the most common and relatively resistant to therapy. Combination therapy is given for 1 year; sustained response is observed in approximately 45-50% of patients. Outcomes are more favorable in patients with early disease and less favorable in those with advanced cirrhosis. HCV viral load should be determined after 3 months; if RNA levels have not decreased by at least 2 logs compared with baseline, treatment is stopped.

Less common genotypes 2 and 3 are easier to treat. Combination therapy is required for only 6 months and produces a complete, sustained response in approximately 75% of patients. Longer treatment does not improve outcomes.

With pegylated interferon, adverse effects are similar to those with standard interferon, but they may be somewhat less severe. In some patients with severe adverse effects, treatment should be discontinued. The drug should be used with caution and should not be used in patients with drug dependence or major psychiatric disorders. Ribavirin is generally well tolerated but frequently causes hemolytic anemia; the dosage should be reduced if hemoglobin falls to less than 10 g/dL. Ribavirin is teratogenic in both men and women; patients should use effective contraception during treatment and for 6 months after completion of treatment. Patients intolerant to ribavirin should be given pegylated interferon, but interferon monotherapy is not as effective as combination therapy. Ribavirin monotherapy has no effect.

In most transplant centers, the most common indication for liver transplantation in adult patients is progressive cirrhosis due to HCV infection. Although HCV infection recurs in the graft, the course of the infection is usually protracted and long-term survival is relatively high.

Prognosis of chronic hepatitis

Prognosis is highly variable. Drug-induced chronic hepatitis often resolves completely after drug withdrawal. Untreated cases due to HBV infection may resolve (rarely), progress rapidly, or progress slowly over a decade to cirrhosis. Resolution often begins with a transient worsening of the disease and results in seroconversion of HBeAg to anti-HBe. Concomitant HDV infection results in the most severe form of chronic hepatitis B; without treatment, cirrhosis develops in 70% of patients. Untreated chronic hepatitis C progresses to cirrhosis in 20–30% of patients, although this process may take decades. Chronic autoimmune hepatitis is usually treatable but occasionally leads to progressive fibrosis and often cirrhosis.

Chronic hepatitis B increases the risk of developing hepatocellular carcinoma; the risk also increases with chronic hepatitis C, but only if cirrhosis of the liver develops.