Digestive Pathology Lecture 4

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LSUHSC-New Orleans, 2015

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The liver 01

1. Functional reserve

– Liver function tests2. Anatomic considerations

3. Patterns of injury

4. Cirrhosis

5. Liver failure

6. Hyperbilirubinemias, cholestasis

1. Liver functional reserve

Functional reserve: 80% to 90%

– Many disease processes remain subclinical

Functions

– Metabolism of nutrients

– Serum protein synthesis

– Detoxification

– Bile excretion

Liver function tests Serum proteins

Total, albumin

Coagulation factorsProthrombin time/int. normalized ratio(PT/INR),

Partial thromboplastin time (PTT)

AminotransferasesAspartate (AST), alanine (ALT)

Biliary canaliculi enzymes– Alkaline phosphatase (ALP)

– Gamma-glutamyl transferase (GGT)

Bilirubin

The liver 011. Functional reserve

2. Anatomic considerations3. Patterns of injury

4. Cirrhosis

5. Liver failure

6. Hyperbilirubinemias, cholestasis

Hepatomegaly

“Enlargement of the liver”

– Normal adult weight:

• 1,400-1,600 gm

– Normal (percussion, palpatory) span:

• 6-12 cm in the midclavicular line

• 4-8 cm in the midsternal line

– In a normal adult, the liver should not protrude 2 cm or more below the costal margin

Liver span, percussion examination

Hepatomegaly

Two models of the hepatic microarchitecture

Acinus, divided

into zones 1, 2 and

3, with three

adjacent lobules.

P, portal tracts,

contain bile ducts,

arterioles and

venules. E,

efferent vein

(central vein or

terminal hepatic

venule).

Scheuer’s Liver Biopsy

Interpretation

Acinar zones, gradients of metabolic activity

Central veins (terminal hepatic venules), trichrome

Portal triad, limiting plate, trichrome

Polyploidy (arrow) binucleation (arrow head)

Hepatic cords (sheets, plates), reticulin

Sinusoids, fenestrated, no adventitia

Sinusoids, space of Disse, endothelial cells (Ec), Kupffer cells (Kc), perisinusoidal stellate cells (Psc), canaliculi (bc)

Kupffer cells, PAS

Perisinusoidal stellate cells (Ito cells), osmium tretroxide

Canaliculi, tight junctions

Canaliculi, canals of Hering, ductules (cholangioles), bile ducts

The liver 011. Functional reserve

2. Anatomic considerations

3. Patterns of injury4. Cirrhosis

5. Liver failure

6. Hyperbilirubinemias, cholestasis

Ballooning

Ballooning and Mallory bodies

Mallory bodies, satellitosis

Foamy (feathery) degeneration

Steatosis, macrovesicular

Steatosis, microvesicular (nuclei centrally placed)

Fatty liver, foie gras

Focal lytic necrosis (drop out)

Apoptosis, apoptotic body

Apoptosis, Councilman body

Piecemeal necrosis (interface hepatitis)

Bridging necrosis, central-portal

Submassive necrosis

Massive necrosis

Ductular Proliferation/

reaction

Absence of fibrosis (trichrome stain)

Fibrosis, portal (trichrome stain)

Fibrosis, periportal (trichrome stain)

Fibrosis, bridging

Cirrhosis (trichrome stain)

The liver 011. Functional reserve

2. Anatomic considerations

3. Patterns of injury

4. Cirrhosis5. Hyperbilirubinemias, cholestasis

6. Liver failure

Cirrhosis

A diffuse process characterized by:

– Fibrosis (broad bridging fibrous septa)

– Structurally abnormal, regenerative parenchymal nodules

– i.e., scarring and regeneration affecting the entire liver

Cirrhosis, macronodular

Cirrhosis, micronodular

Cirrhosis, pathogenesis Inflammation

Hepatocyte injury and regeneration

Transformation of stellate cells into myofibroblasts-like cells

Deposition of collagen in the space of Disse

Loss of sinusoidal fenestrations

Bridging fibrosis

Impaired exchange of nutrients, waste products

Impaired secretion of proteins

Vascular shunting (bypass through new vascular channels)

Cirrhosis, etiology– Alcoholic steatohepatitis

– Non-alcoholic steatohepatitis

– Viral• In the US mostly hepatitis C

• Worldwide mostly hepatitis B

– Primary biliary cirrhosis

– Autoimmune hepatitis

– Inherited disorders:• Primary hemochromatosis

• Wilson disease

• Alpha-1-antitrypsin deficiency

– Cryptogenic

Cirrhosis, outcome

May remain asymptomatic

– Functional reserve: 80% to 90%

“Constitutional” symptoms: anorexia, fatigue, weight loss

Portal hypertension

Overt liver failure

Hepatocellular carcinoma

Child-Pugh score

Used to assess the prognosis of cirrhosis

– Total bilirubin

– Albumin

– Prothrombin time/INR

– Ascites

– Encephalopathy

The liver 011. Functional reserve

2. Anatomic considerations

3. Patterns of injury

4. Cirrhosis

5. Liver failure6. Hyperbilirubinemias, cholestasis

Liver failure, etiology Massive necrosis (acute, fulminant, failure)

– Acetaminophen

– Other drugs/toxins

– Hepatitis (viral hepatitis A and B, autoimmune hepatitis)

Dysfunction without overt necrosis– Acute fatty liver (microvesicular steatosis)

• Reye syndrome

• Acute fatty liver of pregnancy

Decompensation of chronic liver disease– Chronic hepatitis and cirrhosis

• Alcoholic and non-alcoholic steatohepatitis, Hep C or B

Liver failure, manifestations

Jaundice

Liver may shrink

Hypoalbuminemia

– Peripheral edema

– Ascites

Coagulopathy

Hyperestrogenemia

Palmar erythema

Spider angiomas

Gynecomastia

Liver failure, manifestations

Fetor hepaticus, accumulation of mercaptans (derived from methionine)

Hyperammonemia, hepatic encephalopathy

– Abnormal neurotransmission, brain edema

– Confusion, stupor, coma

– Rigidity, hyperreflexia, asterixis *

Liver failure, manifestations Cirrhosis and portal hypertension cause visceral

vasodilation, decrease vascular resistance

Initially compensated by increase in cardiac output

Disease progression causes decompensation

Two complications with high mortality:

– Renal failure (hepatorenal syndrome)

• Renal underperfusion

– Respiratory failure (hepatopulmonary syndrome)

• Ventilation-perfusion mismatch

The liver 011. Functional reserve

2. Anatomic considerations

3. Patterns of injury

4. Cirrhosis

5. Liver failure

6. Hyperbilirubinemias, cholestasis

– Bilirubin metabolism

– Unconjugated hyperbilirubinemia

– Conjugated hyperbilirubinemia

– Cholestasis

Bilirubin metabolism

– Bilirubin is derived from the prosthetic group heme• Hemoglobin

– Normal destruction of old erythrocytes by mononuclear phagocytic system, spleen

– Pathologic destruction of newly formed erythrocytes in the bone marrow(ineffective erythropoiesis: thalassemia, sideroblastic anemia, megaloblastic anemia)

• Other hemoproteins– Cytochromes, mostly in the liver

Unconjugated (indirect) bilirubin

Water-insoluble

– Tightly bound to albumin

– Not excreted in urine

– Potentially toxic

Hepatocyte carrier-mediated uptake

Conjugation: UDP-glucuronosyl transferase (UGT)

Conjugated (direct) bilirubin

Water-soluble

– Loosely bound to albumin

– Non-toxic

– Excreted in urine

– Actively excreted into the bile canaliculi

Bilirubin diglucuronide

BacterialGlucuronidases

Urobilinogens

Urobilinogens

Urine

Feces, 80%Stercobilinogen

Stercobilin

Bilirubin

Bilirubin

– Unconjugated (indirect) bilirubin

• Water-insoluble

• Tightly bound to albumin

• Not excreted in urine

• Potentially toxic

– Conjugated (direct) bilirubin

• Water-soluble

• Loosely bound to albumin

• Excreted in urine

• Not toxic

Jaundice, skin (bilirubin > 2.0-2.5 mg/dL)

Jaundice, sclera (icterus)

Unconjugated (indirect) hyperbilirubinemia

– Excessive bilirubin production• Internal bleeding

• Hemolytic anemias

– Reduced uptake into the hepatocytes• Drugs

• Hepatocyte injury

– Impaired conjugation within the hepatocytes

• Hepatocyte injury

• Hereditary hyperbilirubinemia

• Physiologic jaundice of the newborn

Erythroblastosis fetalis

Hemolytic anemia of newborn– Rh-negative mother, antibodies to Rh-

positive fetal blood

Marked neonatal unconjugatedhyperbilirubinemia

Injury of basal ganglia, pons, cerebellum (kernicterus)– Lethargy, death

– Cerebral palsy, mental retardation, hearing loss

Kernicterus (“kern” German for “core”)

Neonatal jaundice (physiologic jaundice of the newborn)

Transient, mild unconjugatedhyperbilirubinemia

Immature conjugation of bilirubin

Jaundice in:• 60% of term infants

• 80% of prematures

– Visible, 2nd to 3rd day

– Disappears, 5th to 7th day

Neonatal jaundice (physiologic jaundice of the newborn)

Breast-fed infants greater frequency• Maternal milk inhibition of UGT

• Beta-glucuronidases in maternal milk

– Deconjugate bilirubin in the intestine

– Deconjugated bilirubin is readily reabsorbed (increased enterohepatic circulation)

• Neonates lack intestinal bacteria that normally catabolize bilirubin into urobilinogens, stercobilinogen, stercobilin, making more bilirubin available for reabsorption

Unconjugated hereditary hyperbilirubinemias

Impaired conjugation (UGT defect)

Crigler-Najjar type I• UGT is completely absent

• Fatal without liver transplantation

Crigler-Najjar type II• Markedly reduced UGT activity

• Nonfatal but risk of kernicterus

Gilbert syndrome• Reduced UGT activity (about 30% of normal levels)

• Common (6% of the population)

• Mild hyperbilirubinemia with fasting, stress

Conjugated (direct) hyperbilirubinemia

– Decreased hepatocellular excretion

• Hepatocellular injury

• Hereditary hyperbilirubinemia

– Cholestasis (arrest in the flow of bile)

Conjugated hereditary hyperbilirubinemias

Impaired bilirubin excretion

Jaundice, clinically inconsequential

Rotor syndrome

– Liver is not pigmented

Dubin-Johnson syndrome

– Liver is darkly pigmented (defect in a canalicular multi-specific organic anion transport protein –Mrp2, polymers of epinephrine accumulate)

Dubin-Johnson

Cholestasis

Arrest in the flow of bile

Retention of bilirubin, bile acids and other solutes

Primary bile acids

Bile acids

– Amphipathic, emulsify lipids, form micelles

– Role in

• Excretion of lipids from the liver

• Absorption of lipids from the intestine

– 95% are actively reabsorbed in the terminal ileum

– Reexcreted in the bile (enterohepatic circulation)

Bile salts, micelles

Bile Acids

Feces, 5%

Reabsorbed, 95%

Systemic circulation, 5%

Cholestasis, manifestations Conjugated hyperbilirubinemia

Elevated bile acids

Hypercholesterolemia

Elevated ALP, GGT

Malabsorption, fat-soluble vitamins (A, D, E and K)– Bleeding diathesis: impaired synthesis of vitamin-

K-dependent coagulation factors II, VII, IX and X

Steatorrhea, fat in feces

Acholia, pale stools

Palmar xanthomas

Xanthelasma palpebrarum

Chronic cholestasis, pruritus, xanthomas

Intracellular cholestasis

Canalicular cholestasis

Bile lakes

Cholestasis, foamy (feathery) degeneration

Ductular proliferation

Biliary cirrhosis

Biliary cirrhosis

Cholestasis

Major causes:

– Obstructive

• Choledocholithiasis

• Cholangitis

• Primary biliary cirrhosis

• Primary sclerosing cholangitis

– Hepatocellular

• Drug-related

• Hepatitis

• Hereditary

Neonatal cholestasis Prolonged conjugated hyperbilirubinemia

Obstructive– Extrahepatic biliary atresia

– Choledochal cyst

Hepatocellular (neonatal hepatitis)– Congenital metabolic disorders

• Alpha-1-antitrypsin deficiency

• Tyrosinemia, Niemann-Pick, galactosemia…

– Infections• Cytomegalovirus, HIV, hepatitis viruses, bacteria…

– Endocrine disorders, toxins, drugs

– Idiopathic, 10-20% of cases

Neonatal cholestasis (obstructive)Bile ductular proliferation and portal fibrosis

Neonatal (giant cell) hepatitisPanlobular giant cell transformation of hepatocytes

Neonatal (giant cell) hepatitis