DISEASES OF INTRAHEPATIC BILE DUCTS

LARGE DUCT BILIARY OBSTRUCTION, PRIMARY BILIARY CIRRHOSIS, PRIMARY SCLEROSING

CHOLANGITIS

LARGE DUCT BILIARY OBSTRUCTION

• Usually extrahepatic, rarely intrahepatic at porta hepatis.• Causes - gallstones, tumours, strictures, biliary atresia.• Effects on the liver:- Acini - perivenular (zone 3) cholestasis.

Portal tracts - bile duct proliferation at margins of tracts. - neutrophil polymorph infiltrate. - oedema of connective tissue.Sometimes bile “infarcts” and bile lakes (duct rupture).

• Complications:- acute suppurative cholangitis (ascendingcholangitis). - liver abscesses if untreated. - secondary biliary cirrhosis if unrelieved.

• Clinical features of cholestatic jaundice.

PRIMARY BILIARY CIRRHOSIS

• A chronic cholestatic disease due to a non-suppurative destructive cholangitis of intrahepatic bile ducts, immune mediated.

• F:M as 10:1. Age range 20-80years, peak at 40-50.• May be associated with other autoimmune diseases.• Very insidious onset, may be asymptomatic for decades, pruritis,

fatigue, xanthelasmas, leading to frank cholestatic jaundice, cirrhosis.• 90-95% positive antimitochondrial antibodies (AMA) against E2 subunit

of pyruvate dehydrogenase complex inner mitochondrial membrane.• Characteristically a granulomatous destruction of bile ducts. Leads to

ductopenia. Copper accumulates in periportal hepatocytes due to chronic cholestasis. Chronic inflammation in portal tracts with interface hepatitis. Portal fibrosis progresses to cirrhosis.

• Liver biopsy used to confirm diagnosis and to stage the disease.

PRIMARY SCLEROSING CHOLANGITIS

• A chronic cholestatic disease due to a non-specific inflammatory fibrosis of bile ducts, intrahepatic and extrahepatic.

• M:F as 2:1. Affects mostly young men.• 70% have ulcerative colitis. Linkage with HLAB8, DR2, DR3. pANCA+• May be associated with other rare fibrosing conditions.• May be asymptomatic, pruritis and cholestatic jaundice and then

cirrhosis develop over many years.• Concentric fibrosis of bile ducts; may result in a scar at site of duct.

Leads to ductopenia. Copper accumulates in periportal hepatocytes. Usually scanty lymphocytic infiltrate. Portal fibrosis

progresses to cirrhosis. Liver biopsy used to confirm diagnosis and stage.

• 10% at risk of developing cholangiocarcinoma.

MISCELLANEOUS BILE DUCT DISEASES

• Acquired sclerosing cholangitis can occur in a number of conditions including AIDS.

• Bile duct injury can also occur with liver allografts, graft-versus-host-disease (GVHD), viral hepatitis, drugs, toxins, pyogenic infections, parasitic infestations and other rare conditions.

• Biliary atresia is among several neonatal and childhood disorders such as the fibropolycystic disorders which include congenital hepatic fibrosis and various cystic conditions.

VASCULAR DISORDERS

• Portal veins - agenesis or hypoplasia.- thrombosis of large and/or small veins.

- obliterative portal venopathy (various causes). Possible sequelae:- Zahn “infarcts”; non-cirrhotic portal hypertension.

• Hepatic veins - thrombosis of large veins, the Budd-Chiari syndrome. - occlusion of small veins, veno-occlusive disease.

• Sinusoids - dilatation. - peliosis hepatis.

• Arteries - atheroma, embolism, arteritis.

HEPATIC CONGESTION AND ISCHAEMIA

• Hepatic congestion - chronic passive venous congestion due to right heart failure. Congestion in perivenular (zone 3) with atrophy of liver cell plates and fatty change in other zones result in a characteristic appearance called “nutmeg liver.” In long-standing cases, perivenular fibrosis with venular to venular bridging fibrosis leads to “cardiac fibrosis” (not cirrhosis). - acute passive congestion with hypoperfusion due to co-existent left heart failure leads to a haemorrhagic necrosis.

• Hepatic ischaemia - shock causes confluent necrosis in zone 3 (“shock liver”); there may be a neutrophil polymorph response. - infarcts are rare due to the dual blood supply. - infarcts of cirrhotic nodules may occur.

PORTAL HYPERTENSION

• Portal hypertension - when venous blood pressure exceed 10mmHg.

Classification.• Pre-sinusoidal - portal vein thrombosis; other causes of obstruction.

- Schistosomiasis causes fibrous obliteration of intrahepatic veins (“pipestem liver”). The most common cause of portal hypertension worldwide.

- hepato-portal sclerosis (idiopathic portal hypertension) - congenital hepatic fibrosis.

• Sinusoidal - cirrhosis most common. Other causes rare.• Post-sinusoidal - hepatic vein obstruction.

- IVC obstruction. - constrictive pericarditis.

TUMOURS AND TUMOUR-LIKE LESIONS

• Benign epithelial tumours. Liver cell adenoma.Bile duct adenoma.

Bile duct cystadenoma. Biliary papillomatosis.

• Benign non-epithelial tumours. Haemangioma. Others are very rare.

• Malignant epithelial tumours.

Hepatocellular carcinoma.Hepatoblastoma.Cholangiocarcinoma.Bile duct cystadenocarcinoma.

• Malignant non-epithelial tumours.Angiosarcoma.Other sarcomas and other tumours are rare.

• Metastatic tumours.

Comments:- Haemangioma is the most common benign tumour. Metastatic carcinomas are the most common of the malignant tumours. Hepatocellular carcinoma is the most common of the primary ones.Hepatoblastoma is the most common liver tumour in young children.

HEPATOCELLULAR CARCINOMA

• 5% of all cancers in the world. The most common cancer in some areas.• Marked geographical distribution;85% occur where HBV is endemic.• Constant risk factors are male gender, age, cirrhosis which pre-exists in 85% in

Western world;absent in 50% in areas of high HBV incidence where it occurs in younger age group (20-40).

• Enviromental factors are HBV, HCV, aflatoxin (Aspergillus flavus) and other naturally occuring carcinogens.

• Inherited conditions, haemochromatosis, tyrosinemia.• Morphology - soft tumour - multiple nodules, solitary mass or diffuse. Propensity

for vascular invasion. Forms trabeculae of malignant hepatocytes but many patterns possible. May produce bile if well differentiated.

• Spread to regional lymph nodes, lungs and less often elsewhere.• Alpha-fetoprotein - raised plasma levels a useful but non-specific marker.• Extremely poor prognosis. (Better in sub-type fibrolamellar carcinoma).

BILE DUCT CARCINOMA (CHOLANGIOCARCINOMA)

• Less common than HCC but more evenly distributed worldwide.• A disease of older individuals; males and females affected equally.• Not associated with cirrhosis.• Highest incidence in S.E.Asia, associated with liver fluke infestation -

Clonorchis sinensis and Opisthorchis viverrini.• Other risk conditions include primary sclerosing cholangitis and

congenital anomalies of the biliary tree, eg Caoli’s disease and choledochal cysts. In most cases the cause is unknown.

• Morphology - firm white tumour - an adenocarcinoma, mucin production detectable.

• Spread to regional lymph nodes, lungs and elsewhere, and to peritoneum.

• Extremely poor prognosis.

ANGIOSARCOMA

• Rare, but the commonest liver sarcoma.• More common in males than in females.• Aetiological agents include thorium dioxide (Thorotrast), vinyl chloride,

arsenic, copper sulphate, anabolic and other steroids.• Morphology - spongy haemorrhagic nodules throughout the liver.

- characteristically, malignant endothelial cells grow on the surface of liver cell plates using them like a scaffold (tectorial growth).

• Spread to regional lymph nodes, spleen, lungs, bone, adrenals, brain.• Extremely poor prognosis.

METASTATIC TUMOURS

• Most common malignant liver tumour in the Western world.

• Metastases are present in the liver at autopsy in 40% of all patients with malignant neoplasms.

• The liver is an especially common site for secondary spread from the gastrointestinal tract, pancreaticobiliary tract, lung and breast.

• Morphology - single to innumerable deposits possible. Large deposits at the surface may show

“umbilification.”

TUMOUR-LIKE LESIONS

• Focal nodular hyperplasia.

• Nodular regenerative hyperplasia.

• Cysts - solitary, polycystic disease, hydatid cyst, choledochal cyst.

• Biliary hamartoma (von Meyenburg complex).

• Other exist.

THE LIVER IN SYSTEMIC DISEASE

• A wide variety of conditions can give rise to 3 morphological appearances - non-specific hepatitis, granulomatous inflammation and fatty change.

• Liver pathology may be associated with disease of other organs - gastrointestinal diseases (eg chronic inflammatory bowel disease), endocrine diseases (eg diabetes mellitus), haematological and lymphoproliferative diseases, rheumatoid arthritis, amyloidosis, nutritional diseases and many others. Liver biopsy is useful in the diagnosis of some such as sarcoidosis, metastatic disease.

• Some liver diseases in pregnancy and in childhood take special forms, eg pre-eclampsia, acute fatty liver of pregnancy, neonatal hepatitis.

• Liver transplantation may be complicated by acute or chronic rejection, amongst others. Liver biopsy forms part of the assessment.

• Bone marrow transplantation may be complicated by acute or chronic graft-versus-host disease. Liver biopsy is often performed.