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Chronic hepatitis is a polyetiological diffuse inflammatory process in the liver that lasts for more than 6 months (Recommendations of the European (Rome, 1988) and World (Los Angeles, 1994) congresses of gastroenterologists). Unlike cirrhosis of the liver in chronic hepatitis does not violate the architectonics of the liver.
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 the level of aminotransferases. In some patients, the first manifestation of the disease is cirrhosis of the liver or its complications (for example, portal hypertension). A liver biopsy is necessary to confirm the diagnosis, classification and severity of the process.
Therapy is aimed at treating complications and the underlying cause (eg, glucocorticoids in autoimmune hepatitis, antiviral therapy for viral hepatitis). Liver transplantation, as a rule, is shown at the final stage of the disease development.
Chronic hepatitis is a widespread disease. According to the data of AF Bluger and N. Novitsky (1984), the prevalence of chronic hepatitis is 50-60 patients per 100 000 population.
What causes chronic hepatitis?
As a rule, hepatitis is defined as chronic with a duration of the disease for more than 6 months, although these time frames are conditional. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are the most frequent causes of chronic hepatitis; 5-10% of cases of HBV infection (with or without co-infection with hepatitis D virus) and approximately 75% of cases of HCV infection go to chronic form. Hepatitis A and E viruses do not cause chronic hepatitis. Although the mechanism of the development of the chronic process is not completely clarified, liver damage is mainly determined by the body's immune response to infection.
Many cases are idiopathic. In a high percentage of cases of idiopathic chronic hepatitis, it is possible to detect pronounced signs of immune hepatocellular injury (autoimmune hepatitis), including the presence of serological immune markers; association with histocompatibility antigens haplotypes characteristic of autoimmune diseases (eg, HLA-B1, HLA-B8, HLA-DR3, HLA-DR4); prevalence of T-lymphocytes and plasma cells in histological preparations of the affected areas of the liver; disorders of cellular immunity and immunoregulatory function in in vitro studies; association with other autoimmune diseases (eg, rheumatoid arthritis, autoimmune hemolytic anemia, proliferative glomerulonephritis), and a positive response to therapy with glucocorticoids or immunosuppressants. Sometimes chronic hepatitis has manifestations of both autoimmune hepatitis, and other chronic liver disorders (eg, primary biliary cirrhosis, chronic viral hepatitis). These states are called cross-over syndromes.
Many medications, including isoniazid, methyldopa, nitrofurans and sometimes paracetamol, can cause chronic hepatitis. The mechanism of hepatitis development depends on the drug and may include a modified immune response, the formation of cytotoxic intermediate metabolites or genetically caused metabolic disorders.
Other causes of chronic hepatitis include alcoholic hepatitis and non-alcoholic steatohepatitis. More rarely, the cause of chronic hepatitis is a deficiency of α 1 -antitrypsin or Wilson's disease.
Previously, chronic hepatitis was classified based on the histological pattern and chronic persistent hepatitis, chronic lobular and chronic active hepatitis were isolated. The latter classification takes into account the etiology, the intensity of inflammation and necrosis (severity), as well as the degree of fibrosis (stage), determined by histological examination. Inflammation and necrosis are potentially reversible; fibrosis is usually irreversible.
Symptoms of Chronic Hepatitis
Clinical manifestations are different. Approximately one-third of cases develop after acute hepatitis, but more often gradually. In many patients, the disease is asymptomatic, especially with chronic HCV infection. Often there are signs such as malaise, anorexia and fast fatigue, sometimes with subfebrile temperature and undefined discomfort in the upper abdomen. Jaundice is usually absent. Often, especially with HCV infection, the first clinical manifestations are signs of chronic liver disease (eg, splenomegaly, vascular spiders or asterisks, palmar erythema, pain in the right side ). In some patients with chronic hepatitis, cholestasis can develop. In the autoimmune process, especially in young women, the manifestation of the disease can involve virtually any body system and include signs such as acne, amenorrhea, arthralgia, ulcerative colitis, pulmonary fibrosis, thyroiditis, nephritis and hemolytic anemia.
Chronic HCV infection is sometimes accompanied by lichen planus (Wilson's lichen), skin-mucous vasculitis, glomerulonephritis, late cutaneous porphyria and, possibly, non-Hodgkin's B-cell lymphoma. Approximately 1% of patients develop cryoglobulinemia with fatigue, myalgia, arthralgia, neuropathy, glomerulonephritis and skin rash (hives, purpura, or leukocytoclastic vasculitis); more characteristic is asymptomatic cryoglobulinemia.
Diagnosis of chronic hepatitis
Diagnosis should be expected in patients with similar symptoms, with occasional detection of an increase in the level of aminotransferases and if there is an indication in the history of acute hepatitis. Functional hepatic tests (if not previously studied) are investigated, which should include the determination of the level of ALT and ACT, alkaline phosphatase and bilirubin in serum. An increase in the level of aminotransferase is the most characteristic laboratory evidence. Although enzyme levels may vary, they are typically 100-500 IU / L. ALT is usually higher than ACT. Aminotransferase levels in chronic hepatitis can be normal if the course of the disease is stable, especially with HCV infection.
Alkaline phosphatase is usually normal or slightly elevated, but sometimes it can be noticeably high. Bilirubin, as a rule, is within the norm with a mild course and no progression of the disease. However, changes in these laboratory tests are not specific and may be a consequence of other diseases, such as alcoholic liver disease, recurrence of acute viral hepatitis and primary biliary cirrhosis.
If the results of laboratory tests confirm the clinical manifestations of hepatitis, serological tests for viruses are performed to exclude HBV and HCV. If these studies do not confirm a viral etiology, further research is needed. Initially, studies include the determination of autoantibodies, immunoglobulins, and the level of a1-antitrypsin. Children and adolescents undergo a screening examination for Wilson's disease with the determination of the level of ceruloplasmin. The detected increases in serum immunoglobulins suggest chronic autoimmune hepatitis, but are not final. Autoimmune hepatitis is usually diagnosed by the presence of antinuclear antibodies (AHA) in titres more than 1:80 (in adults) or 1:20 (in children), anti-smooth muscle antibodies or antibodies to liver microsomes and kidney type 1 (anti-LKMI).
In contrast to acute hepatitis, a liver biopsy is necessary if there is a suspicion of chronic hepatitis. Certain cases of chronic hepatitis can be manifested only by insignificant hepatocellular necrosis and inflammatory cell infiltration, usually in the area of portal venules, with normal acinar architectonics and little fibrosis or no fibrosis at all. Such cases rarely appear clinically and, as a rule, do not transform into cirrhosis of the liver. In more severe cases, biopsy usually reveals periportal necrosis with mononuclear cell infiltration, accompanied by periportal fibrosis and proliferation of bile ducts of varying severity. Acinar architectonics can be deformed by zones of damage and fibrosis, sometimes obvious cirrhosis of the liver is combined with signs of ongoing hepatitis. A biopsy is also performed to assess the severity and stage of the disease.
In most cases, a specific cause of chronic hepatitis can not be established on the basis of a biopsy, although cases caused by HBV infection can be differentiated by the presence of hepatocytes such as "frosted glass" and special coloration of HBV components. Autoimmune hepatitis usually has more pronounced lymphocytic and plasma cell infiltration. Patients with histological but non-serological signs of chronic autoimmune hepatitis should be diagnosed with different variants of it; many of them can correspond to cross-over syndromes.
Serum albumin and albumin should be examined to assess the severity of the process; liver failure is characterized by a low level of albumin and prolonged PV. If symptoms or signs of cryoglobulinemia develop in chronic hepatitis, especially in chronic hepatitis C, cryoglobulin levels and rheumatoid factor should be investigated; high levels of rheumatoid factor and low levels of complement also suggest cryoglobulinemia.
Patients with chronic hepatitis B to exclude hepatocellular carcinoma should undergo an annual ultrasound and an analysis of the vagal a-fetoprotein, although opinions on the profitability of such tactics diverge. Patients with chronic hepatitis C should undergo a screening test for HCC only in the case of liver cirrhosis.
What tests are needed?
Treatment of chronic hepatitis
The goal of the treatment is to treat complications (eg, ascites, encephalopathy) and the underlying cause. Drugs that caused hepatitis should be abolished. Major diseases, such as Wilson's disease, are treatable. With chronic viral hepatitis B, contact prevention may be useful; Glucocorticoids and immunosuppressive drugs should be avoided, as they enhance the replication of viruses. Preventive measures for contacts in HCV infection are not required.
Treatment of autoimmune hepatitis
Glucocorticoids, in combination with azathioprine or without, increase the life expectancy of patients with autoimmune hepatitis. Prednisolone is usually given at a dose of 30-40 mg orally once a day, then the dose drops to the lowest, which maintains aminotransferases at normal or near normal levels. Some investigators prescribe in parallel azathioprine at 1-1.5 mg / kg orally 1 time in the fuzz; others add azathioprine only if a low dose of prednisolone does not support suppression. Most patients need long-term low-dose therapy. Liver transplantation is indicated only in the final stage of the disease.
Treatment of chronic hepatitis B
Treatment is indicated in HBeAg-positive patients with elevated levels of aminotransferases. Therapy is aimed at eliminating HBV DNA and converting the patient from HBeAg to anti-HBe; the disappearance of HBsAg from serum is observed in approximately 10% of patients. For treatment, use interferon (IFN, usually IFN-a 2b) or lamivudine.
Interferon is administered subcutaneously at a dose of 5 million IU daily or 10 million IU subcutaneously 3 times a week for 4 months. In approximately 40% of patients, this regimen eliminates HBV DNA and causes seroconversion to anti-HBe; a harbinger of a positive effect is usually a temporary increase in the levels of aminotransferases. Interferon is used in the form of injections and is often poorly tolerated. The first 1-2 doses cause flu-like syndrome. Later, interferon can cause fatigue, malaise, depression, bone marrow suppression and, in rare cases, bacterial infections or autoimmune disorders. In patients with progressive cirrhosis of the liver, interferon can accelerate the development of liver failure, therefore, CP is a contraindication to its use. Other contraindications include renal failure, immunosuppression, organ transplantation, cytopenia, and substance abuse. Patients with HBV infection and concomitant hepatitis D virus infection usually do not respond well to therapy. Unlike chronic hepatitis C, with chronic hepatitis B, the use of pegylated interferon has not been sufficiently studied, but the first reports seem promising.
As an alternative, lamivudine is administered per 100 mg orally once a day. Although lamivudine, unlike interferon, has a few undesirable effects, but at the same time requires long-term therapy, often for many years. Lamivudine reduces the level of HBV DNA and aminotransferase levels in almost all patients, but after discontinuation of the drug, relapse occurs before seroconversion with HBeAg to anti-HBeg. Seroconversion occurs in approximately 15-20% of patients after one year of treatment, which increases to approximately 40% after 3 years. The development of resistance to the drug is a frequent phenomenon in long-term treatment. Unlike interferon, lamivudine can be given to patients with progressive cirrhosis of the liver with HBV infection, since it does not provoke the development of hepatic insufficiency. The combination of interferon and lamivudine is no more successful than therapy with only one drug.
Adefovir (taken orally) is likely to become the standard drug for the treatment of chronic hepatitis B, but further research is needed. It is generally a safe drug, resistance rarely develops.
Liver transplantation should be considered only in the final stage of liver disease caused by HBV, but the infection aggressively attacks the transplant and the prognosis is less favorable than with liver transplantation performed on other indications. Long-term therapy with lamivudine after transplantation improves the outcome.
Treatment of chronic hepatitis C
In chronic hepatitis C, treatment is indicated if the levels of aminotransferases are increased, and the results of the biopsy demonstrate an active inflammatory process with the development of fibrosis. Therapy is aimed at elimination of HCV RNA (stable response), which is accompanied by a constant normalization of the level of aminotransferases and termination of the histological progression of the process.
The combined treatment with pegylated interferon-plus ribavirin gives the best results. The administration of pegylated interferon-2b at a dose of 1.5 μg / kg subcutaneously once a week and pegylated interferon-2a at a dose of 180 μg subcutaneously once a week gives comparable results. Ribavirin is usually given at a dose of 500-600 mg orally 2 times a day, although 400 mg twice a day may be sufficient for genotypes of viruses 2 and 3.
The genotype of HCV and the viral load are determined before the start of treatment, since the treatment regimen depends on this. Genotype 1 occurs most often and is relatively resistant to therapy. Combination therapy is prescribed for 1 year; a stable response is observed in approximately 45-50% of patients. The results are more favorable in patients at an early stage of the disease and less favorable with already developed cirrhosis of the liver. HCV viral load should be determined after 3 months; if the level of RNA does not decrease by this time, at least 2 log in comparison with the initial one, the treatment stops.
Less common genotypes 2 and 3 are easier to treat. Combination therapy is required only for 6 months and causes a full sustained response in approximately 75% of patients. Longer treatment does not improve results.
When using pegylated interferon, the same undesirable effects occur, as with the use of standard interferon, but they can be somewhat less severe. In some patients with severe adverse events, treatment should be discontinued. The drug should be administered with caution and should not be prescribed to patients with drug dependence or major psychiatric disorders. Ribavirin is usually well tolerated, but often causes hemolytic anemia; The dosage should be reduced if hemoglobin is reduced to less than 10 g / dl. Ribavirin is a teratogenic drug for both men and women; During the entire treatment period and 6 months after completion of the treatment, patients should apply reliable contraceptive measures. Patients with intolerance to ribavirin should be given pegylated interferon, but interferon monotherapy is not as effective as combined treatment. Monotherapy with ribavirin has no effect.
In most transplant centers for adult patients, the most frequent indication for liver transplantation is progressive liver cirrhosis as a result of HCV infection. Although HCV infection recurs in both grafts, the course of the infection is usually prolonged and long-term survival is relatively high.
More information of the treatment
Prognosis of chronic hepatitis
The forecast is very variable. Chronic hepatitis caused by drugs is often resolved completely after drug withdrawal. Without treatment, cases caused by HBV infection can be resolved (rarely), progress rapidly or slowly over a decade with transformation into cirrhosis of the liver. The resolution of the process often begins with transient weighting of the disease and leads to seroconversion of HBeAg to anti-HBe. With concomitant HDV infection, the most severe form of chronic hepatitis B appears; without treatment, cirrhosis develops in 70% of patients. Untreated chronic hepatitis C leads to the development of liver cirrhosis in 20-30% of patients, although this process can last for decades. Chronic autoimmune hepatitis usually gives in to therapy, but sometimes leads to progressive fibrosis and often to cirrhosis of the liver.
Chronic hepatitis B increases the risk of developing hepatocellular carcinoma; the risk also increases with chronic hepatitis C, but only in the case of cirrhosis.