Digestive Pathology Lecture 6 - School of Medicine · –Hemochromatosis 12. Intrahepatic biliary...

Digestive Pathology Lecture 6

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The liver III

11. Inborn errors of metabolism

– Wilson disease

– Alpha1-antitrypsin deficiency

– Hemochromatosis12. Intrahepatic biliary tract diseases

13. Circulatory disorders

14. Hepatic disease in pregnancy

15. Nodular hyperplasias

16. Benign neoplasms

17. Malignant neoplasms

Wilson disease (hepatolenticular degeneration)

Autosomal recessive

Progressive copper accumulation

Oxidative injury Commonly manifest in late adolescence Hepatic manifestations

– Chronic hepatitis, cirrhosis– Massive necrosis, fulminant failure

Wilson disease: Chronic hepatitis, copper stains

Wilson’s disease, glycogenated nuclei

Glycogenated nuclei are a common but nonspecific finding in Wilson’s diseaseGastrointestinal and Liver Pathology. C. Iacobuzio-Donahue

Wilson disease: Mallory bodies

Numerous Mallory bodies (arrowheads)Scheuer’s Liver Biopsy Interpretation

Wilson, cirrhosis, acute failure

Cirrhotic nodules (N) are surrounded by inflamed fibrous septa Scheuer’s Liver Biopsy Interpretation

Wilson disease: chronic hepatitis, cirrhosis


Neurologic manifestations– Injury of basal ganglia– Incoordination, dystonia

• muscle spasms/cramps, involuntary twisting, jerking, speech and gait disturbances

– Psychiatric disorders• Depression, bipolar disorder, psychosis

Wilson disease: basal ganglia degeneration, atrophy, cavitation


Hematologic manifestations– Hemolytic anemia

Ophthalmologic manifestations– Kayser-Fleischer rings (corneal limbus)

Kayser-Fleischer ring

D. Huster. Wilson disease. Research Clinical Gastroenterology Volume 24, Issue 5 2010 531 - 539

Kayser-Fleischer ring, slit lamp

Wilson disease

In hepatocytes copper is:

– Transported into the golgi apparatus where it is incorporated into apo-ceruloplasmin to form ceruloplasmin which is SECRETED into circulation (90-95% of plasma copper)

– Transported into bile (canaliculi) to be EXCRETED

ATP7B gene codes for a copper-transporting ATPase required for both functions

Defect in the ATP7B gene interferes with both secretion and excretion

ATP7B-mediated copper export in the hepatocyte

Copper entrance: copper transporter CTR1. Copper is delivered to ATP7B in the golgi apparatus by the copper chaperone ATOX1. In the golgi apparatus copper is incorporated in various cuproenzymes including ceruloplasmin. When copper levels rise, ATP7B redistributes to a vesicular compartment and participates in copper excretion in the bile via an unknown mechanism that probably involves COMMD1

Wilson disease

Diagnosis– LOW serum ceruloplasmin

– HIGH non-ceruloplasmin serum copper

– HIGH urinary copper

– HIGH hepatic copper

– Ophthalmologic evaluation

– Genetic testing is now available• Sequencing of the ATP7B gene, more than 500

different mutations identified

Alpha1-antitrypsin deficiency

Autosomal recessive disorder with codominant expression

The most common genetic cause of liver disease in children

The most common genetic cause of emphysema in adults

Alpha1-antitrypsin deficiency A1AT is a serine protease inhibitor (Pi, SERPINA1)

– Inhibition of neutrophil elastase and other proteases

SERPINA1 gene, has more than 100 allelic variants

Each gene allele provides half of the enzyme level

The normal gene product is PiM

Most common deficiency alleles are:

– PiS (50-60% enzyme levels)

– PiZ (10-20% enzyme levels)

Most common carrier genotypes: PiMS, PiMZ

Most common deficiency genotypes: PiSS, PiSZ, PiZZ

Alpha-1-antitrypsin deficiency

A single amino acid substitution

Alpha-1 antitrypsin abnormally folded

Cannot move from ER

Form large aggregates that resist normal degradation including autophagy

Appear as PAS-positive cytoplasmic globes

Alpha1-antitrypsin deficiency, biopsy, PAS stain


Defective degradation of the misfolded protein appears to induce apoptosis, inflammation

Only 10% of PiZZ individuals develop clinical disease

Other genetic/environmental factors must play a role


Liver manifestations

– Neonatal (giant cell) hepatitis

– Chronic hepatitis (adolescents)

– Cirrhosis (adults)

– Hepatocellular carcinoma

Lung manifestations:

– Emphysema


Diagnosis

– Serum levels of A1AT, used for screening

– Protein electrophoresis (phenotype)

– DNA analysis (genotype)

– Liver biopsy

Underdiagnosed

– PiZZ, present in 1/1800 live births

Hemochromatosis

Iron metabolism Absorbed in duodenum and proximal jejunum

No natural mechanism of excretion

Amount absorbed must balance out losses: epithelial exfoliation, minor hemorrhages, menstruation

Ferroportin, an iron channel, controls the release of iron into the circulation from: enterocytes, macrophages, hepatocytes

Hepcidin, produced in the liver, binds ferroportin which is then internalized and degraded preventing the release of iron

Hepcidin, ferroportin

Low iron, low hepcidin: ferroportin exports iron into the circulation

High iron, high hepcidin: hepcidin binds to ferroportin inducing its internalization and degradation; iron remains in the cells

Iron transport and storage Iron is transported in blood by TRANSFERRIN

Iron is stored as:– FERRITIN (circulation, readily available)

– HEMOSIDERIN (macrophages, tissues, poorly available)

Dietary Iron

Enterocyte

Hemoglobin

SpleenRES

Ferritin

Hemosiderin

Bone Marrow

Blood Losses

EpithelialShed

Transferrin

Hemosiderosis, hemochromatosis

HEMOSIDEROSIS: generic term, excessive accumulation of iron

HEMOCHROMATOSIS: the disease state caused by the generation of free radicals and oxidative injury

Hemochromatosis Secondary, acquired

– Ineffective erythropoiesis (the most common cause)

• Thalassemia

• Sideroblastic anemia

• Pyruvate kinase deficiency

• Other

– Parenteral administration• Transfusions, injections

– Increased oral intake• Bantu siderosis

Primary, hereditary– Excessive intestinal iron absorption

Hereditary hemochromatosis Adult form Autosomal recessive Mutations in proteins that regulate hepcidin

synthesis in response to iron levels– HFE (the most common)– Transferrin receptor 2 (TfR-2)– Hemojuvelin (HJV)

These mutations result in:– Lower hepcidin levels– Greater ferroportin levels– Greater transport of iron into the circulation

Hereditary hemochromatosis HFE mutations cause most cases of adult

hemochromatosis Two mutations: C282Y, H63D, account for

more than 90% of HH cases C282Y is the most common Common among whites (Northern European)

– Homozygotes, 1 of every 200– Heterozygotes, 1 of every 8 (accumulate less iron)

Hereditary hemochromatosis Men predominate 5:1

Occurs earlier in men (40’s) than in women (50’s)

Classic triad:– Cirrhosis (micronodular)

– Diabetes mellitus (pancreatic fibrosis, atrophy)

– Bronze skin pigmentation

Other manifestations:– Joint pain (arthropathy), the most common presenting

complaint, may precipitate pseudogout

– Cardiomyopathy: arrhythmia, heart failure

– Thyroid and adrenal insufficiency

– Hypogonadism: impotence, amenorrhea, early menopause

Hemochromatosis, bronze skin pigmentation

Hemochromatosis, liver, pancreas, lymph nodes

HemochromatosisA, Hereditary hemochromatosis, iron accumulates in hepatocytes before spilling over to Kupffer cells. Accumulation in periportal hepatocytes in early stages of the disease, becomes panlobular later on. B, Prussian blue stain. C,Secondary hemochromatosis, heavy iron deposition may be seen in Kupffer cells (arrow). Gastrointestinal and liver pathology. C. Iacobuzio-Donahue

Hemochromatosis

Diagnosis

– Elevated serum iron

– Increased transferrin saturation

– Elevated serum ferritin

– Increased iron concentration in liver

– Genetic analysis (HFE gene)

Hepatocellular carcinoma 200-fold risk

The liver III11. Inborn errors of metabolism

12. Intrahepatic biliary tract diseases

– Congenital abnormalities

– Primary and secondary biliary cirrhosis

– Primary sclerosing cholangitis13. Circulatory disorders

11. Hepatic disease in pregnancy




Congenital Abnormalities of the Intrahepatic Biliary Tree

von Meyenburg’s complexes (bile duct micro-hamartomas)

von Meyenburg’s complexes, MRI

Polycystic liver diseaseAutosomal DOMINANT polycystic (kidney) disease

Congenital hepatic fibrosis, broad fibrous septa Autosomal recessive polycystic (kidney) disease

Caroli diseaseSegmental cystic dilatation of bile ducts

RadioGraphics, 2006, 26:715-731

Caroli disease, cystically dilated bile ducts

Caroli’s disease, bile duct dilatation, cholangitis

Caroli disease and congenital hepatic fibrosis

Primary Biliary Cirrhosis Autoimmune

– Destruction of small and medium-size intrahepatic bile ducts

– Chronic hepatitis

– Biliary cirrhosis

Antimitochondrial antibodies– E2 component of pyruvate dehydrogenase

Association with other autoimmune conditions

Female predominance > 6:1

Peak incidence, 40-50 years

Family and geographic clustering

Symptoms: those associated with cholestasis and portal hypertension

Small and medium size ducts infiltrated by lymphocytes

Ducts, granulomatous inflammation

Primary biliary cirrhosis, jigsaw puzzle pattern

Biliary cirrhosis, micronodular, green

Secondary biliary cirrhosis

In adults:

– Choledocholithiasis

– Malignant neoplasms (head of the pancreas, biliary tree)

– Biliary strictures from surgical procedures

In children:

– Biliary atresia

– Choledochal cysts

– Cystic fibrosis

Primary Sclerosing Cholangitis Immune-mediated SEGMENTAL inflammation, fibrosis

and obliteration of LARGE intrahepatic and extrahepatic bile ducts, and pancreatic ducts

Males predominate 2:1

Third through fifth decades of life

Ulcerative colitis, 70% of patients

p-ANCA antibodies

Toxins released by inflamed gut may cause injury in the biliary tree

T cells and antibodies cross-reactivity between intestinal or bacterial antigens and bile ducts

Genetic predisposition

Primary sclerosing cholangitis, onion-skin fibrosis

Primary sclerosing cholangitis, fibrous obliteration

PSC, gross fibrosis of intrahepatic bile ducts

Primary sclerosing cholangitis, chain of lakes

Primary Sclerosing Cholangitis Inflammation (cholangitis) and stone

formation (hepatolithiasis) in dilated ducts

May involve gallbladder (cholecystitis) and pancreatic ducts (pancreatitis)

Risk for cholangiocarcinoma

Many progress to cirrhosis and liver failure and need liver transplantation

May recur after transplantation




– Passive congestion

– Infarcts

– Portal hypertension

– Budd-Chiari syndrome

– Veno-occlusive disease14. Hepatic disease in pregnancy




Nutmeg liver, passive congestion

Passive congestion, histology

Hemorrhagic necrosis, cardiac sclerosis

Hepatic artery obstruction, infarcts

Liver infarcts are rare

Double blood supply

– Hepatic artery 30 -40%

– Portal vein 60 -70%

Interruption of the main hepatic artery can be tolerated

– Except in transplanted liver: thrombosis of the hepatic artery a major cause of graft loss

Liver infarcts, shock, gross

Infarct of Zahn

Thrombosis of a portal vein radicle

Results in:

– Ischemia

– Dilatation and congestion of sinusoids

– Flattening of the surrounding hepatocytes

– No necrosis (pseudoinfarct)

Grossly visible as sharply demarcated area of congestion

Infarct of Zahn, gross

Posthepatic– Right-sided heart failure

– Hepatic veins thrombosis• Budd-Chiari syndrome

Intrahepatic– Cirrhosis (the most common cause)

– Nodular regenerative hyperplasia

– Sinusoidal obstruction syndrome

Prehepatic– Portal vein obstruction

• Pylephlebitis (portal thrombophlebitis)

Portal Hypertension, causes:

Portosystemic shunts, manifestations

Coronary VeinsEsophageal Varices

Splenic veinSplenomegaly

Inferior Mesenteric VeinHemorrhoids

Umbilical VeinCaput Medusae

Ascites

Caput medusae

Budd-Chiari syndrome Thrombosis of 2 or more major hepatic veins

Massive enlargement of the liver

Severe portal hypertension

Severe ascites

Etiology:– Hypercoagulable states

• Pregnancy, oral contraceptives

• Postoperative, postpartum states

• Deficiencies in antithrombin III, protein S or protein C

• Polycythemia vera, sickle cell disease


– Idiopathic, 10%

Budd-Chiari, hepatic vein thrombosis

Budd-Chiari, centrizonal congestion/necrosis

Sinusoidal obstruction syndrome

Also called veno-occlusive disease– Toxic damage of sinusoidal endothelial cells

– Desquamation, embolization into the terminal hepatic venules

– Extravasation of red blood cells

– Marked centrizonal congestion, necrosis, fibrosis

Etiology:– Acute: After bone marrow transplantation

– Subacute or chronic: Chemotherapy, herbal remedies (Jamaican bush tea, pyrrolizidine alkaloids found in many plants)

Veno-occlusive disease, centrizonal congestion/necrosis




14. Liver disease in pregnancy– Preeclampsia-Eclampsia

– Acute fatty liver of pregnancy

– Intrahepatic cholestasis of pregnancy




Preeclampsia-Eclampsia

Hypertension, proteinuria, edema, coagulation disorders

Hyperreflexia, seizures

HELLP syndrome

– Hemolysis, elevated liver enzymes, low platelets

Unknown etiology

Periportal fibrin deposits

Periportal coagulative necrosis

Parenchymal hemorrhage and infarcts

Subcapsular hematoma, catastrophic rupture

Eclampsia, periportal fibrin deposits, necrosis

Eclampsia, subcapsular hematoma, CT scan

Eclampsia, subcapsular hematoma

Acute Fatty Liver of Pregnancy

Third trimester

Jaundice

Acute liver failure

Microvesicular steatosis

Parental/fetal defect in mitochondrial oxidation of long-chain fatty acids that accumulate and cause liver toxicity

20-40% coexistent preeclampsia

Acute fatty liver, microvesicular steatosis

Intrahepatic Cholestasis of Pregnancy

Conjugated hyperbilirubinemia, < 5 mg/dl Pruritus and jaundice Third trimester More common in multiple pregnancies,

Scandinavia, Chile Resolve rapidly after delivery, may recur Increased incidence of fetal distress,

stillbirths, prematurity Pathogenesis not entirely clear:

– Estrogen/progesterone inhibit bile secretion– Mutation in genes encoding biliary transport

proteins

Intrahepatic cholestasis of pregnancy




14. Liver disease in pregnancy


– Focal nodular hyperplasia

– Nodular regenerative hyperplasia16. Benign neoplasms


Focal nodular hyperplasiaHyperplastic nodule with central stellate scar

Focal nodular hyperplasiaFibrous scar with misshaped vessels and bile ducts, hyperplastic lobular parenchyma

Robbins, Cotran

Focal nodular hyperplasia

Hyperplastic response to focal increased blood flood (vascular malformations)

More common in females

Questionable association with oral contraceptives

Nodular regenerative hyperplasiaRegenerative nodules, absence of fibrosis

Nodular regenerative hyperplasia, reticulumNodules surrounded by rims of compressed cords

Nodular regenerative hyperplasia

May be subclinical, no liver dysfunction

Presents with portal hypertension

Uncertain etiology

Associated with : toxic/drug vascular injury, autoimmune, infectious, hematologic/thrombotic conditions.

Obstructive vasculopathy with global decrease of the (low-pressure) venous portal blood supply and compensatory increase of the (high pressure) arterial blood supply







– Hemangiomas

– Adenomas17. Malignant neoplasms

Cavernous hemangiomas

The most common liver neoplasm

Red-blue soft nodules

Usually less than 2 cm

Often directly beneath the capsule

Significance:

– Mistaken for metastatic tumors

– Percutaneous biopsies may cause profuse bleeding

Cavernous hemangiomas

Hepatic adenoma Well-demarcated proliferation of hepatocytes

– No bile ducts

Often subcapsular

Young women

Related to the use of oral contraceptives and anabolic steroids

May regress on discontinuance

Significance:– Mistaken for hepatocellular carcinoma

– Rupture, bleeding

– May undergo malignant transformation

Hepatic adenoma

Adenoma subtypes

HNF1α mutation, fatty, almost no malignant transformation

β-catenin mutation, cytologic atypia, highest-risk for malignant transformation

Inflammatory, associated with non-alcoholic fatty liver disease, small risk of malignant transformation








– Hepatoblastoma

– Angiosarcoma


– Cholangiocarcinoma

– Metastases

Hepatoblastoma

Infants

More common in boys

Immature hepatocytes

Some have mesenchymal elements (cartilage, bone, striated muscle)

Survival has improved

Only chance for cure: total resection

Hepatoblastoma, fetal-like or embryonic-like hepatocytes

Odze & Goldblum Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas

Hepatoblastoma, bone (osteoid) and undifferentiated mesenchyme

Odze & Goldblum Surgical Pathology of the GI Tract, Liver, Biliary Tract and Pancreas

Angiosarcoma

Exposure to

– Poly-vinyl chloride (PVC) industry

– Arsenic

– Thorotrast

The latency period several decades

Highly aggressive, metastasize widely

Angiosarcoma

Liver carcinomas, mayor types

Hepatocellular carcinoma (hepatoma)

– 90% of all primary cancers

Cholangiocarcinoma

Mixed forms

Liver and intrahepatic bile duct cancer incidence rates

Hepatocellular carcinoma

Uncommon in the US

Cirrhosis present in > 85%

Male predominance 3:1

Rare before age 60


HBV endemic regions

20-40% of all cancers

Vertical transmission (200-fold risk)

Cirrhosis may not be present

Male predominance 8:1

Younger age (20-40 years)

Risk factors

Cirrhosis

HBV

HCV

Alcohol, NASH

Primary hemochromatosis, A1AT deficiency, Wilson disease

Hereditary tyrosinemia (40%)

Aflatoxins– Food spoilage molds (Aspergillus flavus)

– Activated in hepatocytes


Background cirrhosis and chronic hepatitis

May be preceded by hepatocellular dysplasia

Unifocal, multifocal or diffusely infiltrative

Strong propensity for vascular invasion

– Extensive intrahepatic metastases

– Extension to portal vein, inferior vena cava

– Hematogenous metastases to other organs tend to occur late

Poor prognosis

Elevated alpha-fetoprotein, 60-75%

Fibrolamellar carcinoma

Young adults (20 to 40 years of age)

Equal male and female incidence

No association with underlying liver disease or cirrhosis

No elevation of alpha-fetoprotein

Better prognosis, 76% alive at 5 years

Fibrolamellar carcinoma, fibrous bands, tumoral

cells with abundant eosinophilic cytoplasm

Cholangiocarcinomas

Resemble adenocarcinomas arising in the pancreas

Characteristically desmoplastic (fibrous)

Not commonly associated with cirrhosis

Preceded by biliary intraepithelial neoplasia

Usually detected late

Death within 6 months

Cholangiocarcinoma

Cholangiocarcinoma, risk factors

Primary sclerosing cholangitis

Congenital hepatic fibrosis

Caroli disease

Choledochal cysts

Hepatolithiasis, liver flukes

Thorotrast

HCV

Metastatic tumors Far more common than primary neoplasia Most common:

– Breast– Lung– Colon– Pancreas

Multiple implants– Cannon balls with central necrosis

Striking hepatomegaly Nodularity palpable on the free edge Extensive involvement may be silent

Metastatic tumors

Digestive Pathology Lecture 6 - School of Medicine · –Hemochromatosis 12. Intrahepatic biliary...

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