Pathology of Liver Diseases IV · 2019-11-15 · Features of Secondary Biliary Cirrhosis Taken from Robbins Basic Pathology, 7th Edition, Table 16-9 Etiology Extra-hepatic bile duct

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.


• 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


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 serum

alkaline phosphatase, bile acids, cholesterol

Important PathologicFindings Before

Cirrhosis Develops

Prominent bile stasis in bile ducts, bile ductproliferation with surrounding neutrophils,

portal tract edema

Secondary Biliary Cirrhosis


From Sherlock, Fig. 257, reticulin stain


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 Cirrhosis

Etiology Possibly autoimmune; associated with other autoimmune conditions

Gender 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


Primary Biliary Cirrhosis

From Sherlock and Summerfield, Fig. 12


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


• 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




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 Before

Cirrhosis Develops

Periductal portal tract fibrosis, segmentalstenosis of extrahepatic and intrahepatic bile

ducts


Pericholangitis in Ulcerative

Colitis


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


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.


• 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


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




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




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


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Pathology of Liver Diseases IV · 2019-11-15 · Features of Secondary Biliary Cirrhosis Taken from Robbins Basic Pathology, 7th Edition, Table 16-9 Etiology Extra-hepatic bile duct