AA, PBC, PSC, AIH and tumours

Question 1

Alpha₁-antitrypsin

Answer 1

A glycoprotein in the family of serine protease inhibitors controlling inflammatory cascades that is synthesised in the liver.

A deficiency is the main genetic cause of liver disease in children. In adults deficiency causes emphysema, chronic liver disease and hepatocellular carcinoma.

Question 2

Alpha1-antitrypsin deficiency - genetics

Answer 2

Gene is found on chromosome 14 and the disorder is inherited in an autosomal recessive pattern.

Genetic variants are typed by electrophoretic mobility as medium – M (normal genotype), slow – S (60% production of α1-antitrypsin) or very slow – Z (15% production).

Genotypes – MZ and SZ patients are at low risk of developing liver disease but ZZ patients are likely to be symptomatic.

Question 3

AA deficiency - features and investigations

Answer 3

• Clinical features – dyspnoea from emphysema, cirrhosis, cholestatic jaundice (remits in adolescence).
• Investigations – serum α1-antitrypsin levels, liver biopsy, phenotyping, prenatal diagnosis by analysis of chronic villus samples obtained between 11-13 weeks gestation and lung function tests.

Question 4

AA deficiency - management and prognosis

Answer 4

• Management – mostly supportive for emphysema and liver complications. Can consider augmentation therapy with α1-antitrypsin pooled from human plasma if FEV – 120mg/kg can be given SC every 2 weeks but very expensive. Liver transplantation is treatment of choice for decompensated failure.
• Prognosis – emphysema is the main cause of death and liver disease in around 5%.

Question 5

Primary biliary cirrhosis - definition

Answer 5

Intralobular bile ducts are damaged by chronic granulomatous inflammation causing progressive cholestasis, cirrhosis and portal hypertension.

The cause is thought to be a combination of genetic predisposition and environmental factors e.g. an autoimmune response being triggered.

Epidemiology – PBC affects women and men in a ratio of 9:1 and the peak onset is 50 years of age.

Question 6

PBC - associations

Answer 6

Thyroid disease, rheumatoid arthritis, Sjogren’s syndrome, keratoconjuntivitis sicca, systemic sclerosis, renal tubular acidosis and membranous glomerulonephritis.

Question 7

PBC - features and signs

Answer 7

Clinical features – often asymptomatic and diagnosed after high alkaline phosphatase is found on routine liver function tests. Lethargy and pruritus occur and can precede jaundice by months to years.

Signs – jaundice, skin pigment, xantholasma, xanthomata, hepatomegaly and splenomegaly.

Question 8

PBC - complications

Answer 8

Malabsorption of fat soluble vitamins (A, D and K) due to cholestasis and decreased bilirubin in the gut lumen result in osteomalacia and coagulopathy.

Others include portal hypertension, ascites, varices, haemorrhage, hepatic encephalopathy and hepatic cell carcinoma.

Question 9

PBC - investigations

Answer 9

• LFTs – alkaline phosphatase and γ-glutamyl transpeptidase are significantly raised, ALT and AST are mildly raised and in late stages bilirubin and prothrombin time is raised and albumin is low.
• Antibodies – 98% are anti-mitochondrial antibody positive which is a highly specific test.
• Other bloods – immunoglobulin’s (especially IgM), TSH and cholesterol may all be raised.
• Liver biopsy – granulomas are found around the interlobular bile ducts progressing to cirrhosis.

Question 10

PBC - management

Answer 10

Symptomatic – give 4-8mg Colestyramine PO OD to treat pruritis (can also use naltrexone or rifampicin), 30mg Codeine phosphate PO TDS to treat diarrhoea and osteoporosis prevention.

Specific – fat soluble vitamin prophylaxis (A, D and K) and 10-15mg/kg Ursodeoxycholic acid PO in 2-3 divided doses (improves symptoms but unsure whether improves survival).

Liver transplantation – the last resort in patients with end-stage liver disease. Recurrence in the graft has been histologically estimated at 17% at around 5 years but graft failure is rare.

Question 11

PBC - prognosis

Answer 11

Once jaundice develops survival is <2 years – with transplantation survival is 55% at 2 years.

Question 12

Primary sclerosing cholangitis - definition

Answer 12

A disorder of unknown cause characterised by non-malignant, non-bacterial inflammation, fibrosis and strictures of the intra and extra-hepatic bile ducts.

It most commonly occurs in men especially in those who suffer from ulcerative colitis (also associated with Crohn’s disease and HIV).

Chronic biliary obstruction and secondary cirrhosis leads to liver failure and death over 10 years.

Question 13

PSC - features and complications

Answer 13

Clinical features – asymptomatic and a high alk phos found on routine LFTs or symptoms – jaundice, pruritus, abdominal pain, fatigue and signs – jaundice, hepatomegaly, portal hypertension fluctuate.

Complications – bacterial cholangitis, cholangiocarcinoma (in 20-30% so check LFTs, cancer markers (CA19-9) and do radiological follow up) and increased risk of developing colorectal malignancy.

Question 14

PSC - investigations

Answer 14

• Bloods – initially raised alkaline phosphatase followed by raised bilirubin, hyper-gammaglobulinaemia and may be positive for ANA, SMA and ANCA.
• ERCP (endoscopic retrograde cholangiopancreatography) – required to distinguish between small and large duct disease and shows multiple strictures of the biliary tree with a characteristic beaded appearance. MRCP –cost effective and more accurate in diagnosis.
• Liver biopsy – will show a fibrous obliterative cholangitis.

Question 15

PSC - management

Answer 15

There is no curative medical therapy and liver transplant is the only effective treatment.

• Drugs – give 4-8mg Colestyramine PO OD to treat pruritis (can also use naltrexone or rifampicin), Ursodeoxycholic acid to improve cholestasis and antibiotics for cholangitis.
• Endoscopic stenting – can help symptomatic dominant strictures of the biliary ducts.
• Ultrasound – yearly to detect cholangiocarcinoma – cholecystectomy is indicated for polyps.
• Liver transplantation – indicated in end stage liver disease however recurrence occurs in 30%.
• Colonoscopy screening – should be done yearly in ulcerative colitis due to risk of malignancy.

Question 16

Autoimmune hepatitis - definition

Answer 16

An inflammatory liver disease of unknown cause characterised by suppressor T cells defects and auto-antibodies directed against hepatocyte surface antigens.

AIH predominantly affects young and middle aged women.

There are 3 types of AIH distinguished by the presence of auto-antibodies.

Question 17

AIH - 3 types

Answer 17

• Type 1 – affects children or adults – 80% are anti-smooth muscle positive and 10% are anti-nuclear antibody positive. In addition there is hypergammaglobulinaemia – IgG.
• Type 2 – affects young women – anti-liver and anti-kidney microsomal type 1 antibodies.
• Type 3 – affects adults – antibodies against soluble liver antigen or liver pancreas antigen.

Question 18

AIH - associations

Answer 18

Pernicious anaemia, ulcerative colitis, glomerulonephritis, autoimmune thyroiditis, autoimmune haemolysis, diabetes mellitus and primary sclerosing cholangitis.

Question 19

AIH - clinical presentation

Answer 19

25% present with acute hepatitis and signs of autoimmune disease e.g. fever, malaise, urticarial rash, polyarthritis, pleurisy, pulmonary infiltration or glomerulonephritis.

The remainder present insidiously or are asymptomatic and are diagnosed incidentally with signs of chronic liver disease. Amenorrhoea is common and disease tends to attenuate during pregnancy.

Question 20

AIH - investigations

Answer 20

• Bloods – LFTs (AST, ALT, serum bilirubin and alkaline phosphatase are raised in most patients), hypergammaglobulinaemia (especially IgG), positive auto-antibodies (e.g. ANA, SMA or anti-soluble liver antigen). There will also be low RBCs, WBCs and platelets in hypersplenism.
• Liver biopsy – mononuclear infiltrate of portal areas with necrosis, fibrosis and cirrhosis.
• MRCP – can help to exclude PSC if alkaline phosphatase is disproportionally raised.

Question 21

AIH - management

Answer 21

• Immunosuppression – 30mg Prednisolone PO for 1 months and decrease by 5mg a month to maintenance dose of 5-10mg OD. Corticosteroids can sometimes be stopped after 2 years but 50-86% will have a reoccurrence. 50-100mg Azathioprine PO can be used as steroid sparing agent. Remission is achievable in 80% of patients within 3 years – 20 year survival rates >80%.
• Liver transplantation – indicated for decompensated cirrhosis or if there’s failure to respond to medical therapy however reoccurrence may occur.

Question 22

AIH - prognosis

Answer 22

Appears not to matter whether symptomatic or asymptomatic at presentation – 10 year survival is 80%. The presence of cirrhosis at presentation reduces 10 years survival to 62%.

Question 23

Liver tumours - types of tumours

Answer 23

They are commonly metastatic tumours (90%) usually from breast, bronchus or gastrointestinal tract.

Primary hepatic tumours are much less common (10%) and may be benign or malignant:

• Benign – cysts, haemangioma, adenoma, focal nodular hyperplasia, fibroma or leiomyoma.
• Malignant – HCC, cholangiocarcinoma, angio or fibro or leiomyo – sarcoma or hepatoblastoma.

Question 24

Liver tumours - symptoms and signs

Answer 24

• Symptoms – fever, malaise, anorexia, weight loss, right upper quadrant pain (due to stretching of liver capsule) but jaundice is late (except in cholangiocarcinoma). Benign tumours are often asymptomatic.
• Signs – hepatomegaly (smooth or hard and irregular in metastases, cirrhosis and HCC), signs of chronic liver disease, evidence of decompensation (e.g. jaundice and ascites) or a bruit over the liver (HCC).

Question 25

Liver tumours - investigations

Answer 25

• Bloods – FBC, clotting, LFTs, hepatitis serology and α-fetoprotein (raised in 50-80% of HCC).
• Imaging – US or CT to identify lesions and guide biopsies, MRI is better for distinguishing between benign and malignant and ERCP and biopsy for suspected cholangiocarcinoma.
• Liver biopsy – may achieve a histological diagnosis (beware of seeding along the biopsy tract).
• For metastases – CXR, mammography, endoscopy, colonoscopy, CT, MRI or marrow biopsy.

Question 26

Liver metastases

Answer 26

Signify advanced disease but treatment and prognosis vary with type and extent of primary. Chemotherapy may be effective e.g. in lymphoma or germ cell tumours or resection may be possible e.g. with small solitary metastases from colorectal carcinoma. Mean survival is

Question 27

HCC - definition and causes

Answer 27

A malignant tumour of hepatocytes accounting for 90% of primaries. More common in China and sub-Saharan Africa (40% of cancers) and less common in West (2% of cancers).

Causes – persistent HBV or HCV infection, cirrhosis, aflatoxin, parasites and anabolic steroids.

Question 28

HCC - management and prognosis

Answer 28

Management – resection of solitary tumours <3cm diameter improves survival rate although 50% will have a reoccurrence within 3 years. Chemotherapy, percutaneous ablation or tumour embolisation are alternatives. Liver transplantation increases survival rate to 70% at 5 years.

Prognosis – often <6 months with a 95% 5 year mortality rate so prevention is vital.

Question 29

HCC - prevention and screening

Answer 29

Prevention – ensure HBV vaccination, don’t reuse needles, screen blood products and reduce exposure to aflatoxins (anti-humidity measures e.g. sun-drying to decrease spread of common fungal contaminant in stored maize – most important for those with chronic HBV infection).

Screening – using ultrasound and α-fetoprotein levels impact on survival rates is unproven.

Question 30

Cholangiocarcinoma - definition and causes

Answer 30

Biliary tree malignancy accounts for 10% of 1°s – mean survival is 5 months.

Causes – flukes (in East), PSC, biliary cysts, biliary-enteric drainage surgery or N-nitroso toxins.

Question 31

Cholangiocarcinoma - presentation and management

Answer 31

• Clinical presentation – fever, abdo pain (± ascites), malaise and raised bilirubin and alk phos.
• Management – 70% are unsuitable for surgical resection and of those that are 76% reoccur. Surgery involves hepatectomy, extrahepatic bile duct excision and caudate lobe resection. Palliative stenting of an obstructed extrahepatic biliary tree can improve quality of life.

Question 32

Haemangiomas

Answer 32

The most common benign liver tumour that are often incidental findings on CT or ultrasound. They do not require any treatment and definitely should not be biopsied!

Question 33

Adenoma

Answer 33

Relatively common and associated with anabolic steroids, the oral contraceptive pill and pregnancy but only require treatment if symptomatic or >5cm in diameter.