Primary Biliary Cirrhosis

Question 1

Primary biliary cholangitis is a chronic, progressive autoimmune destruction of small intrahepatic bile ducts.

Leading to cholestasis, fibrosis, cirrhosis and liver failure.

Mainly affects women (9:1)
50-70 years old

Question 2

Describe the pathogenesis of PBC

Answer 2

1. Anti-mitochondrial antigens expressed on biliary epithelial cells
2. Anti-mitochondrial antibodies (AMA) as acquired molecular mimicry
   - Postulated from recurrent exposure to E. coli infections
   - T cell mediated autoimmune attack against biliary cells
3. Chronic non-suppurative destructive cholangitis
   - Necrotising inflammatory process of portal tracts - medium and small bile ducts infiltrated with lymphocytes
   - Duct destruction, fibrosis and bile stasis
4. Reduction of bile ducts and proliferation of smaller bile tubules
   - Increased fibrosis, expansion of periportal fibrosis to bridging fibrosis
5. Development of cirrhosis

Question 3

Clinical presentation of patients with PBC

Answer 3

1. Middle aged women (women > men 9:1)
2. Fatigue
3. Debilitating pruritus and jaundice
4. Hypercholesterolaemia
5. Liver disease occurs late
6. Concomitant overlapping autoimmune disease (eg: Sjogren with sicca syndrome)

Question 4

What are the autoimmune conditions associated with PBC?
What are the features to look out for?

Answer 4

1. Graves: goitre, eye signs, thyroid acropachy, pretibial myxedema, hypo/hyperthyroidism
2. Sjogren: dry mouth, dry eyes
3. RA: symmetrical deforming arthropathy, eye signs
4. Scleroderma: telangiectasia, tight shiny skin, sclerodactyly, calcinosis, dystrophic nails
5. Dermatomyositis: heliotrope rash, Gottron papules
6. Idiopathic ILD: bibasal crepitations
7. MG: myasthenic facies, psotsis, proximal weakness, fatigability
8. Vitiligo: hypopigmented patches
9. Atrophic gastritis: pallor, koilonychia, IDA

Question 5

What are the examination findings of primary biliary cirrhosis?
What are PBC specific features to look out for?

• Usually presentation as isolated hepatomegaly or chronic liver disease if unable to elicit additional features

Answer 5

Middle aged female
Pruritus, jaundice 
Hypercholesterolaemia
Hepatomegaly +/- splenomegaly
Cirrhosis features and complications
Metabolic bone disease
Proximal myopathy
Other autoimmune conditions 

Occurs in middle aged female (75-90%)

1. Fatigue
2. Hyperbilirubinaemia - jaundice, pruritus
3. Generalised hyperpigmentation, worse over araes of exfoliation and lichenification - melanin deposit
4. Clubbing
5. Hypercholesterolaemia - xanthalesma, tendon xanthomata
6. Coagulopathy - petechiae, ecchymoses
7. Altered sex hormones - spider naevi, loss of axillary hair
8. Hepatomegaly smooth and non-tender +/- hepatic venous hum
   8A. Splenomegaly and ascites in portal hypertension
9. Complications of cirrhosis - hepatic encephalopathy, portal hypertension

PBC specific features:
1. Metabolic bone disease - kyphosis, fractures, osteoporosis
2. Proximal myopathy/osteomalacia (proximal muscle wasting and weakness)
3. Autoimmune disease

Question 6

What are the definitive investigations for PBC?

Answer 6

1. Serum anti-mitochondrial antibodies - positive in 95%
   - 5% negative requiring PBC-specific autoantibodies (sp100, gp210)
2. HLA DR8
3. Blood tests
   A. LFT - cholestatic picture (high GGT, ALP, mild ALT, AST, hyperbilirubinaemia)
   - Some patients have AIH overlap ALT > 5x UL
   B. IgM - raised
   C. Lipid panel - hypercholesterolaemia
   D. FBC - mono-pancytopenia
4. Liver biopsy if required
   - Histology: portal tract granuloma, cirrhosis
5. US HBS, ERCP/MRCP to exclude extra-hepatic cholestasis (stones)

Question 7

Histological features of PBC (Ludwig and Scheuer Staging Systems)

Answer 7

Stage 1 (Portal stage / florid ductal lesion): inflammation confined to portal triads, bile duct damage

Stage 2 (Periportal stage): periportal inflammation and fibrosis with proliferation of bile ductules

Stage 3 (Septal stage / bridging fibrosis): fibrous septa linking portal tracts, architectural distortion

Stage 4 (Cirrhosis): established cirrhosis

Question 8

Which drugs can cause cholestasis?

Answer 8

1. Phenothiazines
2. Sulphonamides
3. Penicillins
4. Rifampicin
5. Macrolides
6. Carbamazepine
7. Androgenic steroids
8. Diclofenac

Question 9

What are the complications of PBC?

Answer 9

1. Malabsorption
2. Osteomalacia
3. Coagulopathy
4. Thromboembolism - anti-thrombin antibodies
5. Sicca syndrome (70%)
6. Cirrhosis, portal hypertension and complications
7. Hepatocellular carcinoma (20x risk)

Question 10

What is the management of primary biliary cirrhosis and its complications?

Answer 10

General
1. MDT - hepatobiliary, PT, OT, dietitian
2. Supplement of fat soluble vitamins - A, D, E, K

Management of co-morbids
1. Treatment of bone disease/osteoporosis (vitamin D, calcium, bisphosphonates)
2. Treatment of hypercholesterolaemia
3. Management of fatigue (manage co-existent anaemia and hypothyroidism)

Specific treatment for PBC
1. Ursodeoxycholic acid - improves liver biochemistry and slows disease progression
2. Management of pruritis (colestyramine, rifampicin, naltrexone)
- Anti-histamines do not work and may worsen encephalopathy
3. Liver transplant (bilirubin >50, refractory fatigue or pruritis)
- Graft recurrence: 15% at 3 years, 30% at 10 years