pathology of liver diseases iv · 2019-11-15 · features of secondary biliary cirrhosis taken from...
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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 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
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 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
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 Before
Cirrhosis Develops
Periductal portal tract fibrosis, segmentalstenosis of extrahepatic and intrahepatic bile
ducts
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