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Primary Biliary Cirrhosis (PBC)

What is PBC?

PBC is a chronic cholestatic disease with a progressive course primarily affecting women (M: F 9:1). It is characterised by progressive destruction of the small and intrahepatic bile ducts, leading to fibrosis and cirrhosis. The aetiology of PBC is thought to be due to a combination of genetic predisposition and environmental
triggers.

Discuss the diagnosis of PBC?

The diagnosis of PBC can be established when 2 of the following 3 criteria are met:

  • Cholestatic liver tests based mainly on alkaline phosphatase elevation.
  • Presence of AMA.
  • Histologic evidence of nonsuppurative destructive cholangitis and destruction of interlobular bile ducts

Discuss the clinical manifestations of PBC?

Symptoms

  • Fatigue is the most common symptom in PBC. It does not correlate with the severity, histologic stage, or duration of PBC.
  • Pruritus can be local or diffuse, usually worse at night and is often exacerbated by contact with wool, other fabrics, heat, or pregnancy. Once pruritus occurs in PBC, it is unlikely to disappear completely without treatment until a patient develops cirrhosis and liver failure. The cause of pruritus in PBC is unknown.  The likely causes include accumulation of bile acids in the skin or it may be related to retention of opioid agonist substrates and up regulation of opioid receptors.
  • Sicca Syndrome (dry eyes and/or mouth) is common.
  • CREST syndrome is an uncommon association.

Signs
The physical examination is usually normal. Occasionally, xanthelasma and xanthoma are recognized. Clubbing may be present sometimes. Signs of portal hypertension may develop with progressive liver disease.

Discuss investigations for PBC?

Liver biochemistry- elevated AP (usually at least 3-4 times normal). Transaminases are only slightly elevated. Marked elevations of transaminases levels over 200-300U/l are distinctly unusual. Consider other or dual pathologies. Serum bilirubin rises as the disease progresses.
In patients without cirrhosis, the degree of elevation in alkaline phosphatase is
strongly related to the severity of ductopenia and inflammation; the increase in aminotransferase activity and IgG levels reflects mainly the degree of periportal and lobular necrosis and inflammation; hyperbilirubinemia reflects the severity of ductopenia and biliary piecemeal necrosis.

Serology- AMA is found in nearly 95% of patients with PBC. It is a highly disease-specific autoantibody and is found in less than 1% of normal controls. The presence or absence of antibody, rather than the titres of antibody level, is most important.
The targets of the disease-specific antimitochondrial response are all members of a family of enzymes, the 2-oxo-acid dehydrogenase complexes and include pyruvate
dehydrogenase complex (PDC-E2), branched chain 2-oxo-acid dehydrogenase complex and 2-oxo-glutaric acid dehydrogenase complex. In some AMA-negative patients, antibodies against the major M2 components (PDC-E2, 2-oxo-glutaric acid dehydrogenase complex) are present.

Immunoglobulin levels are increased (mainly IgM). As in other cholestatic diseases, serum cholesterol levels are often elevated

Discuss the role of liver biopsy?

With the high disease specificity of a positive AMA test, the role of liver biopsy to diagnose PBC is questionable. Liver biopsy may be needed in AMA-negative patients and to exclude other concomitant diseases such as AIH and NASH
Stage I is characterized by inflammation in the portal triad, focussed on bile duct
with or without florid bile duct lesions.
Stage II- inflammation extends into hepatic parenchyma
Stage III is characterized by a distortion of the hepatic architecture with numerous fibrous septa.
Stage IV- Cirrhosis

Discuss the role of imaging?

Imaging (USS/MRCP) of the liver and biliary tree is mandatory in all patients with biochemical evidence of cholestasis.

Discuss the management of PBC?

UDCA in a dose of 13-15 mg/kg/day is the only approved therapy. The drug is initiated gradually and generally given in two divided doses. UDCA has been shown to improve liver biochemistry, slows histologic progression, reduced need for liver transplantation and improved survival.
The drug is used for patients with any stage of PBC as long as their liver biochemistries are abnormal.  Loose stool is the only side effect.
UDCA therapy does not improve fatigue, pruritus, cholestasis associated bone disease, or autoimmune features found in association with PBC.

Discuss the management of symptoms of PBC?

Fatigue- there is no recommended therapy for the fatigue resulting from PBC. Other causes like anaemia, hypothyroidism, depression, and a sleep disorder should be excluded.
Pruritus- Bile acid sequestrants should be used as initial therapy for patients with PBC who have pruritus. The recommended dose of cholestyramine is 4 g per dose to a maximum of 16 g/day given 2-4 hours before or after UDCA. Cholestyramine is well tolerated, although some patients report bloating, constipation, and diarrhoea. Colestipol and colesevalam have not been evaluated in controlled studies to treat pruritus in cholestasis.
The following agents can be used for pruritus refractory to bile acid sequestrants:

  • Rifampicin 150-300 mg twice daily. It may cause hepatitis and hepatic failure, haemolysis, renal impairment, and alteration in drug metabolism. Thus rifampicin treatment needs regular follow-up of blood tests (FBC, Liver biochemistry)
  • Oral opiate antagonists such as naltrexone 50mg daily. The dose can be started at 12.5 mg every day and to be increased by a quarter every 3-7 days, until the pruritus is ameliorated (max dose 50 mgs a day). The limiting factor in the use of opiate antagonists is the opioid withdrawal-like reaction (abdominal pain, high blood pressure, tachycardia, goose bumps, nightmares, and depersonalization) that can occur with this type of medication.  Drug administration can be held or the dose kept constant if signs of an opiate withdrawal-like syndrome develop, because the reaction tends to subside spontaneously.
  • Sertraline (75-100 mg daily) can be tried when other measures fail

Discuss screening the family members for PBC?

Family members of patients with PBC are at increased risk of developing PBC, particularly among first degree female relatives including sisters and daughters.
Screening is usually done by measuring the serum alkaline phosphatase level and if elevated by assessing for AMA. The value of screening these individuals for PBC has not been established, however.

Discuss complications related to chronic cholestasis?

Osteopenia/Osteoporosis- The cause of osteoporosis in PBC is uncertain, but there is an accelerated bone loss. This is due to decreased formation rather than increased resorption. Baseline and regular screening every 2-3 years using bone mineral density testing is appropriate.
Hyperlipidemia- Serum lipids may be strikingly elevated in PBC. Levels of HDL cholesterol are disproportionately elevated compared to LDL cholesterol. This is of little consequence as retrospective studies suggest that there is no increased risk of cardiovascular disease in patients with PBC and hypercholesterolemia. However, in patients at high risk of cardiovascular disease, it may be appropriate to use cholesterol lowering drugs. (Statins are safe in PBC)
Vitamin Deficiency- PBC may have decreased bile acid secretion resulting in increased risk of lipid malabsorption and may cause deficiencies of fat soluble vitamins.

Discuss pregnancy and PBC?

Estrogens promote cholestasis, so oral contraceptive pills and oestrogen supplements may induce or worsen pruritus.
Similarly, during pregnancy itching may become severe even early on in the pregnancy and it may fail to resolve completely after delivery in patients with PBC.
As with all other women with cirrhosis who become pregnant, it is advisable to check for varices in the second trimester when the mother’s blood volume increases
markedly. Treatment with beta blockers is safe in pregnancy. A short second stage of labour is optimal as the Valsalva manoeuvre may precipitate variceal haemorrhage.

Discuss liver transplantation in PBC?
The outcome of liver transplantation for patients with PBC is more favourable than for nearly all other disease categories. AMA may persist or reappear but does not signal the recurrence of PBC.
Indications for transplant-

  • Serum bilirubin exceeds 8.5mg/dl (150 umol/l)
  • Evidence of decompensated liver disease.
  • Intractable symptoms like pruritus, incapacitating fatigue or severe osteoporosis.

Discuss the prognosis of asymptomatic patients with positive AMA and normal liver biochemistry?

It is believed that many of these patients may eventually develop abnormal liver tests and symptoms. In a small study, the median follow-up time from the first positive AMA test to persistently abnormal liver tests in this series was 6 years (range 1-19 years). It is estimated that 0.5% of the general population is AMA-positive, which means that fewer than 10% of patients with AMA will develop PBC.

Ref

  1. AASLD Practice Guidelines 2009

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