Pathology of Liver Diseases IV

METABOLIC AND INHERITED LIVER DISEASE (CONTINUED)INTRA-HEPATIC BILIARY DISORDERS

CIRCULATORY DISORDERS, AND NEOPLASIA

Alpha-1-Antitrypsin Deficiency• Over 75 alleles of the alpha-1-antitrypsin gene have been

identified. Most contain conservative changes from the most common PiM allele. Several have lower serum concentrations or activity.

• In patients who are homozygotes for the PiZ allele (PiZZ) mutant proteins accumulate in dilated ER cisternae. They can be visualized as eosinophilic, PAS+ small cytoplasmic globules. Incidence of PiZZ genotype is ~ 1:1800 making it the most commonly diagnosed hepatic disorder of neonates and children.

• Only a 10-15% of patients with the PiZZ genotype develop liver disease. Pulmonary manifestations are much more common.

Alpha-1-Antitrypsin Deficiency

• Neonatal hepatitis– Cholestasis,

hepatocellular necrosis, mononuclear cell infiltrate, PAS+ cytoplasmic granules

– Resolves in 80% of cases– Remainder develop

cirrhosis and liver failure• May present as chronic

hepatitis or cirrhosis in adolescent or adult

• Increased risk of hepatocellular carcinoma

From Robbins Pathologic Basis of Disease, 8th Edition, Fig. 18-28

Alpha-1-Antitrypsin Deficiency

From Sherlock and Summerfield, Fig. 351From Robbins Basic Pathology, 8th Edition, Fig. 16-22

Cystic Fibrosis

• Pulmonary and pancreatic symptoms usually predominate

• Mucous plugs in biliary tree produce obstruction• A cause of fatal hepatic failure in infancy• 10% of patients reaching age 25 develop cirrhosis

– Pathology resembles biliary cirrhosis secondary to extrahepatic obstruction, although the severity of the lesions varies from one part of the liver to the other

Cystic Fibrosis

From Sherlock and Summerfield, Fig. 380

Reye’s Syndrome

• Children under age 4, 3-5 days after viral illness• Weak association with salicylates• Vomiting, irritability, lethargy, hepatomegaly• Elevated ammonia levels and signs of hepatic

failure (25% of patients)• Pathology

– Fatty change– Cerebral edema– Mitochondrial damage

INTRA-HEPATIC BILIARY DISORDERS

Biliary Cirrhosis

• Inflammation and destruction of bile ducts• Portal-portal bridging fibrosis• Three different disorders

– Secondary Biliary Cirrhosis due to extra-hepatic obstruction

– Primary Biliary Cirrhosis– Sclerosing Cholangitis

• All have signs and symptoms of biliary tract obstruction

From Kumar, Cotran, Robbins, 5th Ed. Fig. 16-24A

Features of Secondary Biliary Cirrhosis

Taken from Robbins Basic Pathology, 7th Edition, Table 16-9

Etiology Extra-hepatic bile duct obstruction:Biliary atresia, gallstones, stricture, carcinomaof the head of the pancreas

Gender Predilection None

Symptoms & Signs Pruritis, jaundice, malaise, dark urine, lightstools, hepatosplenomegaly

Laboratory Findings Conjugated hyperbilirubinemia, elevated serumalkaline phosphatase, bile acids, cholesterol

Important PathologicFindings BeforeCirrhosis Develops

Prominent bile stasis in bile ducts, bile ductproliferation with surrounding neutrophils,portal tract edema

Secondary Biliary Cirrhosis

Secondary Biliary Cirrhosis

From Sherlock, Fig. 257, reticulin stain

Secondary Biliary Cirrhosis

From Rubin and Farber, Fig. 14-41 From Sherlock and Summerfield, Fig. 260

From Kumar, Cotran, Robbins, 5th Ed. Fig. 16-24B

Features of Primary Biliary CirrhosisEtiology Possibly autoimmune; associated with other

autoimmune conditionsGender Predilection Female-to-Male 10:1

Symptoms & Signs Pruritis, jaundice, malaise, dark urine, light stools, hepatosplenomegaly, insidious onset

Laboratory Findings Conjugated hyperbilirubinemia, elevated serum alkaline phosphatase, bile acids, cholesterol, elevated IgM and presence of autoantibodies, especially against mitochondrial pyruvate dehydrogenase

Important Pathologic Findings Before Cirrhosis Develops

Dense lymphocytic infiltrate in portal tracts with granulomatous destruction of bile ducts

Taken from Robbins Basic Pathology, 7th Edition, Table 16-9

Primary Biliary Cirrhosis

From Sherlock and Summerfield, Fig. 12

Primary Biliary Cirrhosis

From Robbins Basic Pathology, 8th Edition, Figure 16-23

Primary Biliary Cirrhosis• The florid ductal lesion

– Chronic inflammatory lesions, including granulomatous inflammation, resulting in destruction of the ducts. Bile duct epithelium becomes irregular and hyperplastic

• Cellular proliferation with periportal inflammation– Scars replace ducts destroyed by inflammation. Some

periportal inflammation persists and spills into lobules. Bile ductules proliferate

• Scarring, with bridging necrosis and septal fibrosis• Cirrhosis

– Fine nodularity and dark green coloration due to bile staining– May be difficult to distinguish from secondary biliary

cirrhosis

Primary Biliary Cirrhosis

From Sherlock and Summerfield, Fig. 249

Primary Biliary Cirrhosis

From Robbins and Cotran, Pathologic Basis of Disease, 9th Edition, Fig. 18-35

From Kumar, Cotran, Robbins, 5th Ed. Fig. 16-24B

Features of Primary Sclerosing Cholangitis

Etiology Unknown, possibly autoimmune, 50-70% ofcases associated with inflammatory boweldisease

Gender Predilection Female-to-male 1:2

Symptoms & Signs Pruritis, jaundice, malaise, dark urine, lightstools, hepatosplenomegaly, insidious onset

Laboratory Findings Conjugated hyperbilirubinemia, elevated serumalkaline phosphatase, bile acids,cholesterol,elevated serum IgM, hypergammablobulinemia

Important PathologicFindings BeforeCirrhosis Develops

Periductal portal tract fibrosis, segmentalstenosis of extrahepatic and intrahepatic bileducts

Taken from Robbins Basic Pathology, 7th Edition, Table 16-9

Pericholangitis in Ulcerative Colitis

From Sherlock and Summerfield, Fig. 218

Sclerosing Cholangitis

From Robbins and Cotran 9th ed., Fig. 18-39

Circulatory Disorders of the Liver

Taken from Robbins and Cotran, 9th Edition, Figure 18-43

Impaired Blood Flow into the Liver

• Portal vein obstruction– Peritonitis with phlebitis– Lymphoma or carcinoma

in porta hepatis– Pancreatitis with splenic

vein thrombosis– Post-abodominal surgery

• Hepatic arterial inflow– Embolism– Neoplasms– Arteritis, autoimmune or

septicFrom Robbins, 6th ed., Fig. 19-33

Impaired Intrahepatic Blood Flow

• Cirrhosis• Sickle cell disease• DIC

– Eclampsia• Passive congestion

From Kumar, Cotran, Robbins, Figure 16-25

Impaired Intrahepatic Blood Flow• Acute and chronic passive

congestion– Congestion of central sinusoids

with necrosis of centrilobular hepatocytes

– Fibrous strands envelop terminal venules and radiate from centilobular zones towards portal zones and adjacent central veins

– Regenerative nodules and complete fibrous septae are absent

From Robbins and Cotran, 9th Edition, Fig. 18-48

Hepatic Vein Outflow Obstruction

• Budd-Chiari Syndrome– Uncommon– Thrombosis of major

hepatic veins– Associated with

polycythemia vera, tumors, abcesses, oral contraceptives, pregnancy, and trauma

– 30% of cases are idiopathic– Relatively rapid onset of

portal hypertension, esophageal varices

From Robbins Basic Pathology, 8th Edition, Fig. 16-29

Hepatic Vein Outflow Obstruction

• Sinusoidal obstruction syndrome (Hepatic Veno-occlusive Disease)– Uncommon– More insidious onset than

Budd-Chiari– Associated with anti-neoplastic

agents, radiation, GVH disease– 25% of allogeneic bone marrow

transplants with mortality ~30%– Obliteration of central vein by

fibrosis with surrounding hemosiderin

From Robbins Basic Pathology, 8th Edition, Fig. 16-30

Benign Hyperplasias

• Focal Nodular Hyperplasia– Nodular mass several cm

in diameter– Characteristic central

scar with radiating fibrous septae

– Absence of normal lobular architecture, numerous tortuous bile ducts, and chronic inflammation

From Rubin and Farber, Fig. 14-59

From Robbins and Cotran, 9th ed, Fig 18-51A

Benign Hyperplasias

• Nodular Regenerative Hyperplasia– The entire liver consists of small hyperplastic

nodules without fibrosis– Plates of hepatocytes only two or three cells thick

compress the surrounding parenchyma– Can cause portal hypertension– Etiology unknown

Benign Neoplastic Lesions-Hepatocellular Adenoma

• Hepatocellular Adenoma– Linked to oral

contraceptives– Solitary, sharply

demarcated masses several cm in diameter

– Normal appearing hepatocytes

– Lobular architecture is absent, no central veins or portal tracts

– Bleeding into peritoneal cavity

From Robbins and Cotran 9th ed., Fig 18-53

Benign Neoplastic Lesions-Hepatocellular Adenoma

• Hepatic Adenoma– Can be classified into three types

• Mutations in HNF-1alpha – present in about 60% of the cases –these tumors are often are fatty in appearance because LFABP downstream of HNF-1alpha is absent in the tumor (this change is diagnostic) –there is no risk of malignancy

• Mutations in beta-catenin-present in about 15% of tumors-these tumors often show areas of dysplasia or regions with hepatocellular carcinoma- mutations result in nuclear translocation of beta-catenin and cells stain diffusely for glutamine synthetase

• Inflammatory hepatocellular adenomas-these tumors overexpress C-reactive protein and other acute phase reactants- contain mononuclear inflammatory cells and areas of fibrotic stroma

Benign Neoplastic Lesions

• Hemangioma– Most common benign

hepatic tumor– Well circumscribed

lesions consisting of endothelial cell lined vascular spaces

• Cysts– Cuboidal to columnar

epithelium lined simple hepatic cysts

– Multiple cysts can be indicative of adult polycystic kidney disease

Malignant Neoplastic Lesions

• Metastatic carcinoma– The most common

malignant tumor in the liver• GI tract• Breast• Lung• Pancreas• Malignant melanoma

– Most patients die within a year

From Rubin and Farber, Fig. 14-62

Hepatocellular Carcinoma• World–wide the third most common

cause of cancer deaths with ~700,000 deaths in 2008.

• In high incidence regions is associated with HBV infection

• Uncommon in the industrialized West but common in sub-Saharan Africa, S.E. Asia, and Japan

• In the western world, most cases (~75-90%) are in cirrhotic livers secondary to alcohol abuse or chronic hepatitis C virus infection. In Asia almost 50% of the cases are in non-cirrhotic livers.

Hepatocellular Carcinoma• p53 mutations in 60% of cases, particularly

at codon 249• Beta-catenin mutations in 40% of cases• Aflatoxin, a food contaminant, produces

the same p53 mutation in the laboratory. May act synergistically with injury due to hepatitis

• Regenerating hepatic stem cells (AKA oval cells or bipolar cells) are likely key players

• Circulating alpha-fetoprotein is a screening test, picks up ~50% of tumors

• Prognosis is poor, most patients die within 12 months of diagnosis

• Vascular invasion and intrahepatic metastases are common at diagnosis

From Cotran, Kumar, and Collins, Fig. 19-10

Hepatocellular Carcinoma

From Scientific American, April 1991

• HBV and hepatocellular carcinoma• Integrated HBV X gene is found in

most HCCs associated with HBV• Enhances HBV transcription and

replication• Stimulates cell proliferation, blocks

p53-mediated apoptosis, activates other pathways

• Transcriptional regulator of host genes

– Tumor suppressors (particularly p53) are down-regulated

– Cell cycle regulators

HCC-Precursor Lesions

From Robbins and Cotran 9th ed, Table 18-12From Robbins and Cotran 9th ed, Fig.18-57

Hepatocellular Carcinoma

From Rubin and Farber, Fig. 14-60

Hepatocellular Carcinoma

Kumar, Cotran, Robbins Figs 16-29 and 16-30

Hepatocellular Carcinoma

From Sherlock and Summerfield, Fig. 471

Hepatocellular Carcinoma

From Robbins, 5th Ed., Fig. 18-40

• Fibro-lamellar variant– Markedly better prognosis,

60% 5 year survival– Arises in otherwise healthy

young adults– Usually amenable to

surgical resection

Cholangiocarcinoma• Arise from biliary epithelium• Tumors can arise anywhere in the biliary

tree, from large intrahepatic bile ducts to the smallest ductule

• Small cuboidal cells arranged in ductular configurations, usually with a substantial fibrous stroma

• Can present with symptoms of obstructive jaundice or non-specific symptoms (weight loss, anorexia, pain, ascites)

• Prognosis is poor• Risk factors are exposure to Thorotrast,

sclerosing cholangitis, fibrocystic disease of the biliary tract

• Molecular changes associated with cholangiocarcinoma include overexpression of Erb-2 and c-met tyrosine kinase receptors and COX-2, and mutations in p16 tumor suppressor

From Robbins Basic Pathology, 8th Ed. Fig. 16-60

Hemangiosarcoma

• Malignant endothelial cells

• Associated with exposure to thorium dioxide, vinyl chloride, or inorganic arsenic

• Prognosis poor, majority of patients are dead within 12 months of diagnosis

From Sherlock and Summerfield, Fig. 490