Autoimmune hepatitis

AUTOIMMUNE HEPATITIS

Autoimmune hepatitis is a liver disease of unknown aetiology characterised by
a strong association with other autoimmune diseases
high levels of serum immunoglobulins (hypergammaglobulinaemia) and autoantibodies in the serum.
It occurs most often in women, particularly in the second and third decades of life

Pathophysiology

Several subtypes depend on immunological markers:
Classical (type I) autoimmune hepatitis is characterised by a high frequency of other autoimmune disorders, such as Graves' disease. is associated with HLA-DR3 and DR4, particularly. These patients have high titres of antinuclear and anti-smooth muscle antibodies,

Type II autoimmune hepatitis is characterised by the presence of anti-LKM (liver-kidney microsomal) antibodies and lack of antinuclear and anti-smooth muscle antibodies. Anti-LKM antibodies recognise cytochrome P450-IID6, which is expressed on the hepatocyte membrane.

Type III autoimmune hepatitis is characterised by elevated serum immunoglobulin levels; the antibodies described above are absent, whilst antibodies against soluble liver antigen are present.

Associated diseases

Conditions associated with autoimmune hepatitis
Migrating polyarthritis
Urticarial rashes
Lymphadenopathy
Hashimoto's thyroiditis
Thyrotoxicosis
Myxoedema
Pleurisy
Coombs-positive haemolytic anaemia
Transient pulmonary infiltrates
Ulcerative colitis
Glomerulonephritis
Nephrotic syndrome


Clinical features
The onset is usually insidious, with fatigue, anorexia and jaundice.
Jaundice is mild to moderate or occasionally absent, but signs of chronic liver disease, especially spider naevi and hepatosplenomegaly, are usually present.
Some patients have CLD signs
In about one-quarter of patients the onset is acute, resembling viral hepatitis, but resolution does not occur..
Other features include fever, arthralgia
Amenorrhoea is the rule but general health may be good.
Some patients have a 'Cushingoid' face with acne, hirsutism and pink cutaneous striae, especially on the thighs and abdomen.
Approximately two-thirds of patients have associated autoimmune disease such as Hashimoto's thyroiditis, renal tubular acidosis and rheumatoid arthritis.

Investigations

Serological tests for autoantibodies are often positive
Antinuclear antibodies and anti-smooth muscle antibody .
Antimicrosomal antibodies (anti-LKM) occur particularly in children and adolescents.
Elevated levels of serum IgG immunoglobulins are invariable and are an important diagnostic feature.
liver biopsy should be performed. It typically shows interface hepatitis, with or without cirrhosis

Management

corticosteroids . Initially, prednisolone 40 mg/day is given orally; the dose is then gradually reduced as the patient and LFTs improve.
Maintenance therapy is required for at least 2 years after LFTs have returned to normal, and withdrawal of treatment should not be considered unless a liver biopsy is also normal.
Most individuals require long-term immunosuppression.
Azathioprine 1.0-1.5 mg/kg/day orally may allow the dose of prednisolone to be reduced . Azathioprine can also be used as the sole maintenance immunosuppressive agent.
Corticosteroids treat acute exacerbations but do not prevent cirrhosis; they are therefore less important in mild asymptomatic autoimmune hepatitis.
The disease is characterised by exacerbations and remissions, but most patients eventually develop cirrhosis and its complications.
Hepatocellular carcinoma is uncommon.
Approximately 50% of symptomatic patients will die of liver failure within 5 years if no treatment is given, but this falls to about 10% with therapy.


Primary biliary cirrhosis
Primary biliary cirrhosis (PBC) is a chronic, progressive cholestatic liver disease of unknown cause which predominantly affects middle-aged women.
The condition is strongly associated with the presence of antimitochondrial antibodies (AMA), which are diagnostic.
It is characterised by a granulomatous inflammation of the portal tracts, leading to progressive damage and eventually loss of the small and middle-sized bile ducts. This in turn leads to fibrosis and cirrhosis of the liver.
The condition typically presents with an insidious onset of itching and/or tiredness; it may also be found incidentally as the result of routine blood tests.

Epidemiology

The prevalence of PBC varies across the world.
It is relatively common in northern Europe and North America
There is a strong female to male predominance of 9:1; it is also more common amongst cigarette smokers.

Pathophysiology

The cause of PBC is unknown but immune mechanisms are clearly involved.
The condition is closely associated with other autoimmune non-hepatic diseases, such as thyroid disease
Antimitochondrial and antinuclear antibodies are found in the serum with
elevations in serum immunoglobulin levels, particularly IgM;
cellular immunity is impaired and abnormal cellular immune reactions have been described hypothesis remains unproven.
The primary pathological lesion is a chronic granulomatous inflammation which damages and destroys the interlobular bile ducts; progressive lymphocyte-mediated inflammatory damage causes fibrosis, which spreads from the portal tracts to the liver parenchyma and eventually leads to cirrhosis

Clinical features

Non-specific symptoms, such as lethargy and arthralgia, are common and may precede diagnosis for years.
Pruritus is the most common initial complaint, pointing to hepatobiliary disease, and may precede jaundice by months or years;
jaundice is rarely a presenting feature.
Although there may be right upper abdominal discomfort
Bone pain or fractures can rarely result from osteomalacia (fat-soluble vitamin malabsorption) or, more commonly, from osteoporosis (hepatic osteodystrophy).
considerable weight loss can occur as the disease progresses. Scratch marks may be found.


Clinical features
Jaundice is only prominent late in the disease and can become intense.
Xanthomatous deposits occur in a minority, especially around the eyes, in the hand creases and over the elbows, knees and buttocks.
Hepatomegaly is virtually constant, and splenomegaly becomes increasingly common as portal hypertension develops. Liver failure may supervene.
Associated Autoimmune and connective tissue diseases occur with increased frequency in PBC, particularly the sicca syndrome , systemic sclerosis, coeliac disease and thyroid diseases.
Hypothyroidism should always be considered in patients with fatigue

Diagnosis and investigations

The LFTs show a pattern of cholestasis .
Hypercholesterolaemia is common and worsens as disease progresses.
The antimitochondrial antibody is present in over 95% of patients, and when it is absent the diagnosis should not be made without obtaining histological evidence and considering cholangiography (MRCP or ERCP) to exclude other biliary disease.
Antinuclear and anti-smooth muscle antibodies are present in around 15% of patients; autoantibodies found in associated diseases may also be present.
Ultrasound examination shows no sign of biliary obstruction.
Liver biopsy is only necessary if there is diagnostic uncertainty.
The histological features of PBC correlate poorly with the clinical features; portal hypertension can develop before the histological onset of cirrhosis

Management

Asymptomatic patients require monitoring on a yearly basis to assess the onset of symptoms and associated disease.
Immunosuppressants such as corticosteroids, azathioprine, penicillamine and ciclosporin have all been tried in PBC, but none is effective and all may have serious adverse effects.
The hydrophilic bile acid, ursodeoxycholic acid (UDCA), improves bile flow, replaces toxic hydrophobic bile acids in the bile acid pool, and reduces apoptosis of the biliary epithelium.
Clinically, UDCA improves LFTs, may slow down histological progression and has few side-effects ; it is therefore widely used in the treatment of PBC at a dose of 13-15 mg/kg/day.
Liver transplantation should be considered once liver failure has developed


Management
Pruritus This is the main symptom requiring treatment.
The cause of itching is unknown but current research suggests that it is due to up-regulation of opioid receptors and increased levels of endogenous opioids.
It is best treated with the anion-binding resin colestyramine, which probably acts by binding potential pruritogens in the intestine and increasing their excretion in the stool. A dose of 4-16 g/day orally is used.
Colestyramine may bind other drugs in the gut (e.g. anticoagulants), which should therefore be taken 1 hour before the binding agent..
Alternative treatments include rifampicin 300 mg/day, naltrexone (an opioid antagonist) 25 mg/day initially increasing up to 300 mg/day,

Management

Fatigue affects about one-third of patients with PBC. The cause is unknown but it may reflect intracerebral changes due to cholestasis. Unfortunately, once depression and hypothyroidism have been excluded, there is no treatment.
Prolonged cholestasis is associated with steatorrhoea and malabsorption of fat-soluble vitamins, which should be replaced as necessary.
Coeliac disease should be excluded since its incidence is increased in PBC.
Bone disease Osteopenia and osteoporosis are common, and normal post-menopausal bone loss is accelerated. Baseline bone density should be measured and treatment started with replacement calcium and vitamin D3. Bisphosphonates should be used if there is evidence of osteoporosis.