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.

TABLE 38.1 Non-viral causes of chronic hepatitis

Cause	Specific histology
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

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.

Drug-induced hepatitis

Drugs associated with inducing hepatitis are listed in Table 38.2. For more information on drug-induced hepatotoxicity, see Chapter 41.

TABLE 38.2 Drugs reported to cause chronic hepatitis

Cryptogenic hepatitis

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.

Inherited metabolic liver diseases

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.

CLINICAL FEATURES

General

Chronic non-viral hepatitis may present with asymptomatic liver function test abnormalities, non-specific symptoms or overt manifestations of liver failure.

Autoimmune hepatitis

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.

TABLE 38.3 Clinical features of severe autoimmune hepatitis

Clinical features at presentation	Frequency (%)
Symptoms
• Fatigue and loss of energy	85
• Dark urine and/or light stools	77
• Abdominal pain/discomfort	48
• Anorexia, nausea	30
• Pruritus	36
• Polymyalgias	30
• Diarrhoea	28
• Amenorrhoea (women)	89
• Cosmetic changes (facial rounding, hirsutism, acne)	19

Clinical signs • Hepatomegaly 78 • Spider naevi 58 • Palpable spleen 32–56 • Scleral icterus/jaundice 46 • Ascites 20 • Encephalopathy 16

Diagnostic approach

The key objectives in the assessment of chronic hepatitis are to establish:

• the cause

• degree of hepatic necroinflammation and fibrosis

• severity of chronic liver disease.

The diagnostic tests for chronic hepatitis are listed in Table 38.4.

TABLE 38.4 Diagnostic tests for viral and non-viral causes of chronic hepatitis

Cause	Diagnostic investigations
Viral
• Chronic hepatitis B	HBsAg, HBeAg, HBV DNA
• Chronic hepatitis C	Anti-HCV Ab, HCV RNA
• Chronic hepatitis D	Anti-HDV IgM, HDV RNA
Non-viral
• Autoimmune hepatitis	ANA, SMA, LKM-1; IgG or gammaglobulin level; HLA B8, Drw3, Drw4
• Wilson’s disease	Serum caeruloplasmin level, serum and urinary copper studies, hepatic copper concentration
• Alpha₁-antitrypsin deficiency	Serum alpha₁-antitrypsin level, protease inhibitor phenotype
• Drug-induced	Careful drug history
• Cryptogenic	Exclusion of above causes

Ab = anitbody; ANA = antinuclear antibodies; HBeAg = hepatitis B e antigen; HBsAg = hepatitis B surface antigen; HBV = hepatitis B virus; HCV = hepatitis C virus; HDV = hepatitis D virus; HLA = human leucocyte antigen; IgG = immunoglobulin G; LKM-1 = antibodies to liver-kidney microsome type 1; SMA = anti-smooth muscle antibody.

INVESTIGATIONS

Liver function tests

In AIH, serum levels of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) are elevated: serum aminotransferase levels reflect the severity of inflammatory activity and prognosis (Table 38.5). Most patients with AIH have serum AST levels <500 U/L at presentation. Serum alkaline phosphatase (ALP) levels are usually normal to less than 2-fold elevated. Hyperbilirubinaemia is common in severe AIH. A reduced serum albumin concentration and/or prolonged international normalised ratio (INR) indicate an advanced stage of liver disease.

TABLE 38.5 Markers of severity of inflammation in autoimmune hepatitis

Inflammatory activity
Severe	Mild–moderate
• AST ≥10-fold • AST ≥5-fold plus gammaglobulin ≥2-fold • Bridging necrosis • Confluent necrosis

• AST <10-fold

• Gammaglobulin <2-fold

• Periportal hepatitis

Serum globulins

Hypergammaglobulinaemia is present in more than 80% of cases of AIH and is a marker of disease severity (Table 38.5). A polyclonal increase in serum immunoglobulins is also common, particularly the IgG fraction. Elevated serum globulin concentrations are also a feature of most cases of cryptogenic hepatitis.

Grade	Necroinflammatory activity	Fibrosis
0	None or minimal	None
1	Portal inflammation; lobular inflammation with no necrosis	Expanded fibrotic portal tracts
2	Mild piecemeal necrosis; focal lobular necrosis	Periportal or portal-portal septa but intact architecture
3	Moderate piecemeal necrosis; severe focal cell damage in lobules	Fibrosis with architectural distortion
4	Severe piecemeal necrosis, bridging necrosis in lobules	Cirrhosis

TABLE 38.7 Scoring system for diagnosis of autoimmune hepatitis parameter

Autoimmune hepatitis parameter	Score
Gender
Female	+2
Male	0
Serum biochemistry
Ratio of elevation of serum alkaline phosphatase vs aminotransferase
>3.0	−2
1.5–3	0
<1.5	+2
Total serum globulin, gammaglobulin, or IgG times upper limit of normal
>2.0	+3
1.5–2.0	+2
1.0–1.5	+1
<1.0	0
Autoantibodies (titres by immunofluorescence)
ANA, SMA, LKM-1
>1:80	+3
1:80	+2
1:40	+1
<1:40	0
Antimitochondrial antibody
Positive	−4
Negative	0
Hepatitis viral markers
Negative	+3
Positive	−3
Other aetiological factors
History of drug usage
Yes	−4
No	+1
Alcohol usage
<25 g/day	+2
>60 g/day	−2
Genetic factors: HLA DR3 or DR4	+1
Other autoimmune diseases	+2

Response to therapy Complete response +2 Complete response with relapse +3 Liver histology Interface hepatitis +3 Predominant lymphoplasmacytic infiltrate +1 Rosetting of liver cells +1 None of the above −5 Biliary changes −3 Other changes −3 Seropositivity for other defined autoantibodies +2

ANA = antinuclear antibodies; HLA = human leucocyte antigen; LKM-1 = antibodies to liver-kidney microsome type 1; SMA = anti-smooth muscle antibody.

DIAGNOSIS

Autoimmune hepatitis

A diagnosis of AIH requires:

• exclusion of viral, alcohol, drug-related and hereditary liver diseases

• demonstrable hepatitis (predominantly raised AST and ALT)

• features of immune reactivity (autoantibodies, high globulin levels)

• compatible histology.

A scoring system that grades individual components of the syndrome may be applied to confirm the diagnosis (Table 38.7). Using this system, a definite diagnosis of AIH can be made with aggregate scores of >15 before treatment and >17 after treatment. Probable AIH corresponds to pre- and post-treatment scores of 10–15 and 12–17 respectively.

Other conditions

Cryptogenic hepatitis is a diagnosis of exclusion requiring negative viral and autoantibody markers in the absence of relevant drug or toxin exposure. Drug-induced chronic hepatitis requires a compatible drug-history and the exclusion of viral and other non-viral causes. Wilson’s disease is diagnosed on the basis of low serum caeruloplasmin levels, elevated 24-hour urinary copper and hepatic copper overload as demonstrated by staining and/or measurement of hepatic copper concentration.

TREATMENT

Autoimmune hepatitis

Treatment of AIH significantly improves life expectancy. Indications for treatment are sustained severe inflammation or persistent symptoms (e.g. fatigue, arthralgia) associated with mild–moderate disease. Treatment is not indicated in those with inactive cirrhosis, asymptomatic portal or mild interface hepatitis and those with decompensated liver disease.

Standard treatment regimens are prednisolone alone or prednisolone combined with azathioprine (Table 38.8). Prednisolone monotherapy is preferred in pregnancy and those with cytopenias or active malignancy.

TABLE 38.8 Treatment of autoimmune hepatitis

	Monotherapy regimen	Combination regimen
Induction
• Prednisolone	60 mg for 1 week, 40 mg for 1 week, 30 mg for 2 weeks; 15–20 mg for maintenance	30 mg for 1 week, 20 mg for 1 week, 15 mg for 2 weeks; 10 mg for maintenance
• Azathioprine	None	50–100 mg for maintenance
Upon remission^*
• Prednisolone	Taper by 2.5 mg every week	Taper by 2.5 mg every week
• Azathioprine	NA	Reduce by 25 mg every 3 weeks
Relapse
• Prednisolone	Same as induction schedule	Same as induction schedule
• Azathioprine	None	50–100 mg maintenance

* Treatment should be for 12–24 months and for at least 3–6 months after clinical and biochemical remission is achieved.

The goal of treatment is to induce remission as defined in Table 38.9. For both treatment schedules, remission rates are around 65% after 18 months’ therapy. Treatment should be continued for between 12 and 24 months and at least 3–6 months after clinical and biochemical remission is achieved. Prednisolone is then slowly withdrawn over 6 weeks with regular monitoring of liver function tests and globulin levels during follow-up. Relapse occurs within 6 months in up to 50% of cases. This rate is reduced to 20% if histologic remission is documented prior to drug withdrawal. Treatment of relapse is with the original treatment schedule.

TABLE 38.9 End points of treatment and appropriate management response

End point	Definition	Response
Remission	Asymptomatic and AST levels ≤2-fold times normal and/or normal liver or portal hepatitis or inactive cirrhosis on biopsy	Taper off prednisolone over 6–12 weeks and monitor
Incomplete response	No remission within 2 years of treatment	Continue drug(s) on lowest possible dose to keep AST ≤5-fold normal or achieve histologic remission
Treatment failure	Clinical and/or biochemical deterioration despite treatment compliance	Prednisolone 60 mg/day or prednisolone 30 mg/day plus azathioprine 150 mg/day for at least 1 month
Drug intolerance	Severe side effects of treatment: marked weight gain, psychosis, symptomatic osteoporosis, unstable diabetes (prednisolone); and/or severe cytopenia, fever, neoplasm, rash, nausea/vomiting (azathioprine)	Dose reduction by 50%; complete withdrawal if no improvement or toxicity severe

Other treatment end-points that may occur are an incomplete response, treatment failure and intolerance of drug therapy (Table 38.9). Patients with an incomplete response typically require long-term maintenance immunosuppressive therapy at the lowest possible dose to maintain AST levels <5-fold normal. Treatment failure occurs in 10%–15% of patients and requires a trial of high-dose corticosteroids or combination therapy in higher doses (Table 38.9). Liver transplantation should be considered in those who fail to respond and/or develop liver failure, or are fulminant cases. Therapeutic options for drug intolerance are dose reduction by 50% or withdrawal of the implicated drug and to use a higher dose of the tolerated agent. New therapies for difficult-to-treat patients include tacrolimus, cyclosporin A, mycophenolate mofetil, ursodeoxycholic acid and budesonide.