Chapter 38 CHRONIC NON-VIRAL HEPATITIS
Chronic non-viral hepatitis is a clinicopathological liver syndrome due to causes other than chronic viral infection. The most common causes are autoimmune hepatitis, cryptogenic hepatitis and drug or toxin-induced hepatitis. Symptoms are typically non-specific and include fatigue, malaise and right upper quadrant discomfort. Signs of chronic liver disease, hepatosplenomegaly and portal hypertension may be present. The most important histologic feature is interface hepatitis with piecemeal necrosis in the periportal region. Autoimmune hepatitis is the most important differential diagnosis.
Chronic non-viral hepatitis is a disease of the liver characterised by chronic inflammation and liver cell necrosis, that is due to non-viral causes and which persists without improvement for at least 6 months. However, in autoimmune hepatitis, the 6- month requirement is no longer required to establish chronicity as the condition may present acutely. Also, drug or toxin-induced liver disease is sometimes considered a chronic disease when the duration of liver inflammation extends beyond 3 months.
The causes of non-viral chronic hepatitis are listed in Table 38.1. The principal cause is autoimmune hepatitis. Less common causes include drug-induced hepatitis and cryptogenic hepatitis. The hereditary metabolic liver diseases, Wilson’s disease and alpha1-antitrypsin deficiency, may also cause a chronic hepatitis-like picture. Diseases mimicking chronic hepatitis include non-alcoholic steatohepatitis, sclerosing cholangitis and primary biliary cirrhosis.
|Autoimmune hepatitis||Interface and lobular hepatitis, plasma cell and lymphocytic infiltrate, rosette formation, bridging and confluent necrosis|
|Drugs and toxins||Similar to chronic viral hepatitis; may be autoimmune hepatitis-like; ± eosinophils; ± granulomas|
|Cryptogenic||Similar to autoimmune hepatitis|
|Wilson’s disease||Copper deposits|
|Alpha1-antitrypsin deficiency||Eosinophilic globules in periportal zones|
Autoimmune hepatitis (AIH) accounts for about 20% of cases of chronic hepatitis. The disease has a female preponderance, affects all ages and has a worldwide distribution. There is a genetic association with the human leucocyte antigens B8, DR3 and DR4. The cause of AIH is unknown. Autoantibodies including antinuclear antibody (ANA) and anti-smooth muscle antibody (SMA) are very common but not specific for the disease or of pathogenetic significance. At least two types of AIH are recognised.
Type 1 AIH is the most common form representing 80% of cases. It is characterised by the presence of ANA and/or SMA and hypergammaglobulinaemia. The peak incidence occurs between the ages of 16 and 30 years, with 70% being females younger than 40 years. Around 30%–50% of patients have concurrent immune diseases including ulcerative colitis, autoimmune thyroiditis and synovitis. The clinical course is often indolent. Symptoms may start abruptly in 40% of patients, but an acute fulminant presentation occurs rarely. Cirrhosis may be present at diagnosis in 25% of cases.
Type 2 AIH is a rare disorder that predominantly affects children aged between 2 and 14 years. It is characterised by the presence of antibodies to liver-kidney microsome type 1 (anti-LKM-1). The target autoantigen is the drug metabolising enzyme, cytochrome mono-oxygenase P450 IID6 (CYP2D6). Extrahepatic immune diseases occur more commonly than in type 1 AIH. There is an association with autoimmune polyglandular syndrome type 1. The clinical course is more aggressive than type 1 AIH with a higher frequency of progression to cirrhosis.
Around 10%–20% of patients with chronic hepatitis have no definable cause and are classified as cryptogenic hepatitis. It is a diagnosis of exclusion. It may be due to an unknown virus, burnt-out non-alcoholic steatohepatitis or an autoimmune process. The condition may clinically resemble type 1 AIH in age and sex distribution, necroinflammatory activity, HLA status and response to therapy.
Wilson’s disease may cause chronic hepatitis in about 5%–30% of patients. Liver inflammation typically manifests in older children, and adults under the age of 35 years. Chronic hepatitis is an uncommon manifestation of alpha1-antitrypsin deficiency. It occurs in both children and adults and is usually mild. Globular eosinophilic deposits in the cytoplasm of hepatocytes on haematoxylin and eosin (H&E) or periodic acid-Schiff (PAS) staining after diastase are characteristic of the disease.
The clinical features of severe AIH are shown in Table 38.3. An acute onset is observed in about 25% of patients. Fulminant hepatitis occurs rarely. Common extrahepatic associations are autoimmune thyroid disease, ulcerative colitis and synovitis.
|Clinical features at presentation||Frequency (%)|
|• Fatigue and loss of energy||85|
|• Dark urine and/or light stools||77|
|• Abdominal pain/discomfort||48|
|• Anorexia, nausea||30|
|• Amenorrhoea (women)||89|
|• Cosmetic changes (facial rounding, hirsutism, acne)||19|
|• Spider naevi||58|
|• Palpable spleen||32–56|
|• Scleral icterus/jaundice||46|