SALIENT FEATURES

History

· Pruritus (affecting half the patients) - more common in men.

· Fatigue (commonest symptom).

· Lethargy and pain in the right upper quadrant (in a quarter of the patients).

· Symptoms of hepatic decompensation (jaundice, ascites, variceal haemorrhage) in a fifth of patients.

· Steatorrhoea.

EXAMINATION

· Usually occurs in middle-aged women.

· Clubbing.

· Generalized pigmentation.

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

· lcterus.

· 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 that there may be clinical features of other autoimmune diseases such as rheumatoid arthritis, dry mouth of

Sj6gren's syndrome, systemic sclerosis, CREST syndrome (see p. 506), Hashimoto's thyroiditis, dermatomyositis.

· Check for proximal muscle weakness due to osteomalacia.

· Examine for peripheral neuropathy.

· Tell the examiner that you would like to test for high serum levels of alkaline phosphatase and antimitochondrial antibodies

(present in 95% of the patients, with the M2 antibody being more specific; it is almost always negative in extra-hepatic

obstruction).

DIAGNOSIS

This middle-aged woman has generalized pigmentation, jaundice, xanthelasmata and pruritus with hepatosplenomegaly (lesions)

due to 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 4

phases:

1. Asymptomutic with normal liver tests'

Antibodies to pyruvate dehydrogenase complex (antimitochondrial antibodies, AMA) are detectable. Approximately three quarters of

these patients develop symptoms of PBC in 2 years; 83% developed abnormal liver function tests at a median period of 5 years from

first detection of AMA (Lancet 1996; 348: 1399402). Most patients have liver histology compatible with or diagnostic of PBC. In one

series none had died from liver disease 12 years after AMA detection (d Hepatol 1994; 20:707-13).

2. Symptomless with abnormal liver tests

Circulating AMA are present. More than half 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.

3. Symptomatic

Lethargy and pruritus are prominent, and time to death or transplantation is 5-10 years.

4. Decompensated primary biliary cirrhosis

Signs include ascites, variceal haemorrhage and 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. 339).

· Frequent (-20%): arthralgia, fibrosing alveolitis, Raynaud's syndrome, sclerodactyly, thyroid disease.

· Rare (<5%): Addison's disease, glomerulonephritis, hypertrophic pulmonary osteoarthropathy, myasthenia gravis, systemic

lupus erythematosus, thrombo-cytopenic purpura, vitiligo.

Is primary biliary cirrhosis associated with cancer?

It is estimated that these patients have a 20-fold increased relative risk of developing hepatocellular carcinoma and increased risk of

cancer overall (Hepatology 1997: 26:113842).

How would you investigate this patient?

Liver function tests

Normal in presymptomatic stage , characteristically cholestatic pattern (raised alkaline phosphatase, 5-nucleotidase and y-glutamyl

transpeptidase); serum amino-transferases may be slightly raised but rarely exceed 5 times the upper limit of normal. Serum bilirubin

is normal initially but rises as disease progresses. Once serum bilirubin exceeds 170 [tmol/1, the estimated survival is less than 18

months (Gut1979; 20: 137-40).

Hepatic synthetic function

Well preserved until late stages; a prolonged prothrombin time may indicate mai-absorption of vitamin K due to cholestasis.

Serum !ipids

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 lgG are elevated; complement activation 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 which has characteristic histological features of

PBC but is negative for AMA in serum (Gut 1997; 30: 44042). The AMA are directed against the mitochondrial pyruvate

dehydrogenase complex.

Histology

Non-suppurative destructive cholangitis or granulomatous cholangitis.

Is liver biopsy necessary to confirm the diagnosis?

Although 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 equi-vocal. 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 recent work has emphasized the importance of

naturally occurring opioid tone charac-terized by an increase in the concentration of endogenous opioid receptors and upregulation

of opioid receptors (Gut 1996; 38: 644-5). These findings have led to the use of opioid antagonists for treatment of pruritus.

What drugs have been used to control pruritus?

Colestyramine is first line, rifampicin 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 this condition?

Ursodeoxycholic acid, corticosteroids, ciclosporin, azathioprine, tacrolimus, methotrexate, 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 due to 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. Five-year survival following trans-plantation 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 gmol/1, estimated survival less than one year, intractable ascites,

encephalopathy, fasting serum albumin <30 g/l, progressive muscle loss, recurrent spontaneous bacterial peritonitis, increasing

osteoporosis, hepato-pulmonary 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, in a general hospital bed or intensive care unit) are predictors of survival after transplantation (Hepatology 1997;

25: 672-7).

What do you understand by secondary biliary cirrhosis?

It is that which occurs secondary to large duct obstruction and is usually due to extrahepatic obstruction such as bile duct stricture,

gallstones or 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

Osier.

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 I transplantation.