Primary biliary cirrhosis

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117 Primary biliary cirrhosis

Instruction

Examine this patient’s abdomen.

Salient features

History

• Pruritus: affecting half of affected patients, more common in men

• Fatigue: commonest symptom

• Lethargy and right upper quadrant-pain (in 25%)

• Symptoms of hepatic decompensation (in 20%): jaundice, ascites, variceal haemorrhage

• Steatorrhoea.

Examination

• Usually occurs in middle-aged women

• Generalized pigmentation

• Xanthelasma (may occur at any stage but more common in advanced disease)

• Scratch marks

• Hepatosplenomegaly (common in early stages).

Proceed as follows:

• Look for xanthomata over joints, skin folds and sites of trauma to the skin.

Remember: There may be clinical features of other autoimmune diseases such as rheumatoid arthritis, dry mouth of Sjögren syndrome, systemic sclerosis, CREST syndrome (p. 553), Hashimato’s thyroiditis, dermatomyositis.

• Check for proximal muscle weakness from osteomalacia.

• Examine for peripheral neuropathy.

• Tell the examiner that you would like to test for high serum levels of alkaline phosphatase and anti-mitochondrial antibodies (AMA; present in 95% of the patients, with the M2 antibody being more specific; it is almost always negative in extrahepatic obstruction).

Diagnosis

This middle-aged woman has generalized pigmentation, jaundice, xanthelasmata and pruritus with hepatosplenomegaly (lesions) caused by primary biliary cirrhosis (aetiology). She is in liver cell failure as evidenced by the hepatic flap (functional status).

Advanced-level questions

How does primary biliary cirrhosis present?

Classically, it presents with itching in a middle-aged woman. However, in 50% of cases there may be no liver symptoms. There are four phases.

Asymptomatic with normal liver tests. Antibodies to pyruvate dehydrogenase complex (AMA) is detectable and about three-quarters develop symptoms of primary biliary cirrhosis (PBC) in 2 years and 83% developed abnormal liver function tests at median period of 5 years from first detection of AMA (Lancet 1996;348:1399–1402). Most patients have liver histology compatible with, or diagnostic for, PBC. In one series, none had died from liver disease 12 years after AMA detection (J Hepatol 1994;20:707–13).

Symptomless with abnormal liver tests. Circulating AMA are present. More than 50% have established fibrosis at diagnosis. Up to 80% of patients develop symptoms or signs of PBC during the first 5 years of follow-up. The median time from diagnosis to death is 8–12 years.

Symptomatic. Lethargy and pruritus is prominent and time to death or transplantation is 5 to 10 years.

Decompensated primary biliary cirrhosis. Signs include ascites, variceal haemorrhage or jaundice. The mean time to death or transplantation is 3–5 years.

What diseases are associated with primary biliary cirrhosis?

• Common (up to 80%): Sicca syndrome (p. 794)

• Frequent (~20%): arthralgia, fibrosing alveolitis, Raynaud syndrome, sclerodactyly, thyroid disease

• Rare (<5%): Addison’s disease, glomerulonephritis, hypertrophic pulmonary osteoarthropathy, myasthenia gravis, SLE, thrombocytopenic purpura, vitiligo.

Is primary biliary cirrhosis associated with cancer?

It is estimated that patients with PBC have a 20-fold increased relative risk of developing hepatocellular carcinoma and increased risk of overall cancer (J Hepatol 1997(suppl 1):101).

How would you investigate this patient?

• Liver function tests are normal in the presymptomatic stage; characteristically cholestatic pattern (raised alkaline phosphatase, 5-nucleotidase and γ-glutamyltransferase) may be seen; serum aminotransferases may be slightly raised but rarely exceed five times the upper limit of normal. Serum bilirubin is normal initially but rises as diseases progresses. Once serum bilirubin is >170 µmol/l the estimated survival is <18 months (Gut 1979;20:137–140).

• Hepatic synthetic function is well preserved until late stages; a prolonged prothrombin time may indicate malabsorption of vitamin K in cholestasis.

• Serum lipids: hypercholesterolaemia is common, lipoprotein lp(a) is low, HDL cholesterol is increased in the early stages but falls as the disease progresses.

• Immunological tests: IgM and IgG are elevated; complement activation occurs although C3 levels are normal; several antibodies are elevated but antibodies to components of the nuclear pore complex and AMA are very closely elevated with PBC. AMA is found in 96% of patients with PBC but the E2 subtype is specific to PBC. Autoimmune cholangitis is a variant of PBC that has characteristic histological features of PBC but is negative for AMA in serum (Gut 1997;30:440–2). The AMA is directed against the mitochondrial pyrudvate dehydrogenase complex.

• Histology identifies non-suppurative destruction cholangitis or granulomatous cholangitis.

What are the stages of primary biliary cirrhosis?

Primary biliary cirrhosis is divided into four histologic stages:

1 Defined by the localization of inflammation to the portal triads.

2 The number of normal bile ducts is reduced and inflammation extends beyond the portal triads into the surrounding parenchyma.

3 Fibrous septa link adjacent portal triads.

4 End-stage liver disease, characterized by frank cirrhosis with regenerative nodules.

Is liver biopsy necessary to confirm the diagnosis?

Athough, liver biopsy is routinely used to confirm the diagnosis, the need for this procedure for either diagnosis or prognosis is questionable (Lancet 1997;350:875–9). The very close association between histology and E2 AMA in PBC means that liver histology is not required unless clinical and serological features are equivocal. The presence of cirrhosis is of very little value in determining the prognosis, and clinically significant portal hypertension (ascites, variceal haemorrhage) may occur during the early histological stages.

What is the mechanism for itching in these patients?

The itching used to be ascribed to retention of bile acids with cholestasis, but more recent work emphasized the importance of naturally occurring opioid tone, characterized by an increase in the concentration of endogenous opioid receptors and upregulation of opioid receptors (Gut 1996;38:644–5). These findings led to the use of opioid antagonists for treatment of pruritus.

What drugs have been used to control pruritus?

Colestyramine is first line; rifampin and ursodeoxycholic acid are second line and naloxone, nalmefene and propofol are third-line agents used to treat pruritus.

What drugs have been used to treat primary biliary cirrhosis?

Ursodeoxycholic acid, corticosteroids, ciclosporin, azathioprine, tacrolimus, methotrexate and colchicines.

What is the rationale behind bile salt therapy?

Hepatocytes affected by autoimmune processes are further injured by endogenous bile acids (such as chenodeoxycholic acid and cholic acid), which accumulate as a result of associated cholestasis. Partial replacement of water-soluble bile acids such as ursodeoxycholic acid may reduce pruritus and damage to the liver cell.

Is there a cure for primary biliary cirrhosis?

Liver transplantation is the only known cure. The 5-year survival following transplantation exceeds 80%. It is associated with a rapid resolution of lethargy and itching, and bone loss slows after the first year. Although the quality of life is not normal, it is usually excellent.

When is liver transplantation indicated?

Indications for liver transplantation are either symptoms (e.g. intractable pruritus, lethargy) or signs and symptoms of end-stage liver disease: increasing jaundice with serum bilirubin >170 µmol/l, estimated survival <1 year, intractable ascites, encephalopathy, fasting serum albumin (<30 g/l), progressive muscle loss, recurrent spontaneous bacterial peritonitis, increasing osteoporosis, hepatopulmonary syndrome, early incidental hepatocellular carcinoma and unacceptable quality of life.

What factors predict survival after transplantation?

• Serum urea and albumin

• Presence of ascites

• Child’s grade and United Network for Organ Sharing status (reflecting whether the patient is at home, general hospital bed or intensive care unit) (Hepatology 1997;25:672–7).

What do you understand by secondary biliary cirrhosis?

It occurs secondary to large duct obstruction and is usually caused by extrahepatic obstruction such as bile duct stricture, gallstones and sclerosing cholangitis.

Professor Peter Brunt, contemporary gastroenterologist and liver physician, Aberdeen Royal Infirmary, is also the personal physician to the Queen and is an astute clinician. He is the President of the Association of Physicians of Great Britain, a society founded by Osler.

Roger Williams, Professor at King’s College, London, and Sir Roy Calne, Professor of Surgery, Cambridge, pioneered liver transplantation in the UK.

Thomas E Starzl, surgeon, Pittsburgh, USA, is an internationally known pioneer in liver transplantation.

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