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  • 1. Diseases of the Liver Fe A. Bartolome, M.D. FPASMAP Department of Pathology
  • 2.
    • Functions of the Liver
      • processing of dietary amino acids, carbohydrates, lipids and vitamins
      • removal of microbes and toxins in splanchnic blood
      • synthesis of plasma proteins
      • detoxification and excretion into bile of endogenous waste products & pollutant xenobiotics
  • 3.  
  • 4. Patterns of Hepatic Injury Degeneration & Intracellular Accumulation
    • Degeneration
    • mild to moderate  hepatocyte swelling  reversible
    • severe damage  ballooning degeneration  irregularly clumped organelles and large clear spaces
    • Accumulations in Viable Hepatocytes
    • iron and copper
    • triglyceride fat deposits  STEATOSIS
      • microvesicular – multiple, tiny (e.g. acute fatty liver of pregnancy, alcoholic fatty liver
      • macrovesicular – single large deposit displacing the nucleus (e.g. obesity, diabetes, alcoholism)
  • 5.  
  • 6. Macrovesicular steatosis Iron stain using the Prussian Blue Reaction (x400). Hemosiderin granules stain as dark blue, coarse granules.
  • 7. Patterns of Hepatic Injury Necrosis and Apoptosis
    • Types:
      • Ischemic coagulative necrosis – “mummified” liver cells with lysed nuclei
      • Apoptotic cell death – shrunken, pyknotic & intensely eosinophilic cells with fragmented nuclei
      • Lytic necrosis – outcome of ballooning degeneration  (+) shards of cellular debris
      • Liquefactive necrosis - abscesses
  • 8. Necrosis (left lower) is around the centrilobular area. The periportal area is viable.
  • 9. Ischemia of centrilobular area resulting in coagulative necrosis of hepatic cords. (Preservation of cellular contour with disappearance of nucleus) Some viable hepatocytes with nucleus are seen in the upper middle and upper right areas.
  • 10. Bridging confluent lytic necrosis in severe chronic viral hepatitis B. Inflamed portal tract ‘bridged’ through area of necrosis with centrilobular area (lower left). The upper right part corresponds to an area of extensive lytic necrosis.
  • 11. Patterns of Hepatic Injury Necrosis and Apoptosis
    • Distribution:
      • Centrilobular – most common; immediately around terminal hepatic vein
      • Mid-zonal and periportal – rare
    • Degree of involvement:
      • Focal or spotty – limited to scattered cells within hepatic lobules
      • Interface hepatitis – between periportal parenchyma & inflamed portal tracts
      • Bridging necrosis – span adjacent lobules
      • Submassive necrosis – entire lobules
      • Massive – most of the liver
  • 12. Interface hepatitis
  • 13. Patterns of Hepatic Injury Inflammation
    • Hepatitis
    • Influx of acute and chronic inflammatory cells
    Regeneration
    • Occurs in all but the most fulminant hepatic diseases
    • Features:
      • Mitosis
      • Thickening of hepatic cords
      • Disorganization of parenchymal structure
  • 14.  
  • 15. Patterns of Hepatic Injury Fibrosis
    • Consequence of inflammation or direct toxic insult to liver
    • Irreversible
    • May eventually subdivide liver into nodules of proliferating hepatocytes surrounded by scar tissue  CIRRHOSIS
  • 16.  
  • 17. Hepatic Failure
    • Most severe clinical consequence of liver disease
    • May be:
      • result of sudden and massive hepatic destruction
      • end-point of progressive chronic liver disease
    • 80% - 90% loss of hepatic functional capacity
  • 18. Hepatic Failure
    • Morphologic alterations causing liver failure:
      • Massive hepatic necrosis
      • Mechanisms:
        • (i) direct damage to hepatocytes
        • (ii) immune-mediated hepatocyte destruction
      • a. drug or toxin-induced
      • b. infection – viral hepatitis except hep. C
      • Chronic liver disease – most common cause
      • Hepatic dysfunction without over necrosis – e.g. Reye’s syndrome, tetracycline toxicity, acute fatty liver of pregnancy
  • 19. Hepatic Failure
    • Clinical Features:
      • Jaundice
      • Hypoalbuminemia  peripheral edema
      • Hyperammonemia  cerebral dysfunction
      • Fetor hepaticus  “musty” or “sweet & sour” body odor due to mercaptan formation by action of GI bacteria on methionine (sulfur-containing)
      • Impaired estrogen metabolism  hyperestrogenemia
      • (a) palmar erythema – 2 o to local vasodilatation
      • (b) spider angiomas – central, pulsing, dilated arteriole from which small vessels radiate
      • (c) hypogonadism & gynecomastia in males
  • 20.  
  • 21. Hepatic Failure
    • Clinical Features:
      • Multi-organ system failure
        • respiratory failure with pneumonia, sepsis + renal failure  cause of death
      • Coagulopathy
        • impaired synthesis of factors II, VII, IX and X  (+) bleeding tendency
  • 22. Hepatic Failure
    • Complications:
      • Hepatic encephalopathy
        • associated with increased blood ammonia levels
        • reversible if underlying hepatic condition can be corrected
        • features:
        • (a) change in consciousness
        • (b) fluctuating neurologic signs – rigidity, hyperreflexia, asterixis
  • 23. Hepatic Failure
    • Complications:
      • Hepatorenal syndrome
        • renal failure in patients with chronic liver disease
        • main renal functional abnormalities:
        • (a) sodium retention
        • (b) impaired free water excretion
        • (c) decreased renal perfusion
        • (d) decreased GFR
  • 24. Hepatic Failure
    • Complications:
      • Hepatorenal syndrome
        • decreased urine output with rising BUN & creatinine
        • ability to concentrate urine retained  hyperosmolar urine without proteins; abnormal sediments; dec. Na +
  • 25. Cirrhosis
    • Most common cause is alcoholic liver disease
    • Key features:
      • The parenchymal injury & consequent fibrosis are diffuse .
      • The nodularity is part of the diagnosis  reflects balance between regeneration and scarring.
      • Vascular architecture is re-organized by the parenchymal damage and scarring  formation of abnormal interconnections
  • 26.
    • Pathogenesis:
    • Progressive fibrosis & re-organization of vascular micro-architecture of liver
    Collagen deposition (types I & III) in the lobule Loss of fenestration of sinusoidal endothelial cells New vascular channels in the septae Create delicate or broad septal tracts Impaired hepatocellular protein secretion (albumin, clotting factors, lipoproteins) Shunting of blood around the parenchyma
  • 27.
    • Main characteristics
      • Bridging fibrous septae
        • link portal tracts with one another & portal tracts with terminal hepatic vein
      • Parenchymal nodules
        • contain proliferating hepatocytes encircled by fibrosis
        • micronodules - < 3 mm diameter
        • macronodules - > 3 mm to several cm
      • Disruption of architecture of entire liver
  • 28.
    • Complications associated with cirrhosis:
      • Hepatic failure
        • Multiple coagulation defects
        • Hypoalbuminemia due to decreased albumin synthesis  pitting edema and ascites
        • Hepatic encephalopathy
        • Increased serum ammonia due to defective urea cycle
  • 29.
    • Complications associated with cirrhosis:
      • Portal hypertension
        • Ascites
        • Congestive splenomegaly
        • Esophageal varices
        • Hemorrhoids, periumbilical collateral circulation
  • 30. Cirrhosis
    • Complications associated with cirrhosis:
      • Hepatorenal syndrome due to decreased renal blood flow
      • Hyperestrinism in males
        • Gynecomastia
        • Spider angiomas
        • Female distribution of hair
  • 31.
    • Criteria for Diagnosis: liver biopsy or at least three of the following:
      • Hyperglobulinemia, esp. with hypoalbuminemia
      • Low protein (<2.5 g/dL) ascites
      • Evidence of hypersplenism (usu. Thrombocytopenia, often with leukopenia)
      • Evidence of portal hypertension (e.g. varices)
      • Characteristic “corkscrew” hepatic arterioles on celiac arteriography
      • Shunting of blood
  • 32. Bridging fibrous septae Nodules
  • 33.  
  • 34. Alcoholic Liver Disease
    • Hepatic Steatosis
      • Alcoholic fatty liver
      • Moderate alcohol intake  microvesicular
      • Chronic alcohol intake  macrovesicular
      • Enlarged, soft, yellow, greasy liver
      • Completely reversible
  • 35. Alcoholic Liver Disease
    • Alcoholic Hepatitis
      • Characteristics:
        • Hepatocyte swelling & necrosis  ballooning due to accumulation of fat, water & proteins
        • Mallory bodies – eosinophilic cytoplasmic inclusions in degenerating hepatocytes
        • Neutrophilic reaction – accumulate around degenerating hepatocytes (“satellitosis”)
        • Fibrosis – (+) activation of sinusoidal stellate cells & portal tract fibroblasts
  • 36. Histological features of alcoholic hepatitis. (A) Low- power view demonstrating the cardinal features of steatosis, fibrosis, inflammation, and hepatocellular injury.
  • 37. Histological features of alcoholic hepatitis. (B) (Black arrows) Mallory bodies are irregular eosinophilic cytoplasmic structures with a rope-like appearance. (Open arrow) Ballooning degeneration of hepatocytes.
  • 38. Histological features of alcoholic hepatitis. (c) (Open arrow) Pericellular fibrosis, also termed 'chicken-wire' fibrosis surrounds individual degenerate hepatocytes; (Black arrow) Perivenular fibrosis extends from the central vein.
  • 39. Histological features of alcoholic hepatitis. (d) The unit lesion (also termed satellitosis) comprises a degenerating hepatocyte with (arrow) a surrounding cuff of neutrophils. Marked steatosis is also evident.
  • 40. Alcoholic Liver Disease
    • Alcoholic cirrhosis
      • Final, irreversible; 10 – 15% of alcoholics
      • Micronodular with scattered larger nodules  “ hobnail ” appearance of liver surface
      • Broad expanses of tough, pale scar tissue due to ischemic necrosis & fibrous obliteration of nodules  Laennec cirrhosis
  • 41.  
  • 42. Alcoholic Liver Disease
    • Short-term ingestion of up to 80 gm of alcohol (~8 beers) over one to several days  FATTY LIVER
    • Daily intake of 160 gms or more for 10-20 years  SEVERE INJURY
  • 43. Alcoholic Liver Disease
    • Alcohol Effects
      • Alcohol through action of alcohol DH & acetaldehyde DH  excess NADH + H +  increased lipid biosynthesis
      • Impaired assembly & secretion of lipoproteins + increased peripheral fat catabolism  fatty liver
      • Impaired hepatic methionine catabolism  dec. intrahepatic glutathione (GSH) levels  inc. sensitivity to oxidative injury
  • 44. Alcoholic Liver Disease
    • Alcohol Effects
      • Induction of cytochrome P 450
      • (a) CYP2E1  inc. alcohol catabolism in ER & inc. conversion of other drugs to toxic metabolites
      • (b) production of reactive O 2 species  damage membrane  hepatocellular dysfunction
      • Impaired microtubular and mitochondrial function
      • Alcohol  acetaldehyde  (+) lipid peroxidation  disrupt cytoskeletal and membrane function
  • 45. Alcoholic Liver Disease
    • Alcohol Effects
      • Become a major caloric source  displace other nutrients  (+) malnutrition and vitamin deficiencies
      • Lead to chronic gastritis, intestinal mucosal damage and pancreatitis  impaired digestive function
      • Induce release of bacterial endotoxin into portal circulation from gut  (+) liver inflammation
      • Induce release of endothelins from sinusoidal endothelial cells  (+) vasoconstriction & contraction of stellate cells  dec. hepatic sinusoidal perfusion  regional hypoxia
  • 46.  
  • 47. Gynecomastia due to alcoholic cirrhosis A 32 year old male patient with normal secondary sex characteristics, no testicular mass, no hystory of drug ingestion, no other endocrine abnormalities and a normal neurological examination. Nevertheless, he had a history of more than 15 years of large amounts of alcohol intake and a liver biopsy confirm alcoholic cirrhosis (Laennec's Cirrhosis).
  • 48. Alcoholic Liver Disease
    • Cause of death:
      • Hepatic coma
      • Massive gastrointestinal hemorrhage
      • Intercurrent infection
      • Hepatorenal syndrome following alcoholic hepatitis
      • Hepatocellular carcinoma
  • 49. Portal Hypertension
    • Causes:
    • A. Pre-hepatic
        • Obstructive thrombosis
        • Narrowing of portal vein prior to ramification within the liver
      • B. Intrahepatic
        • Cirrhosis – most common
        • Schistosomiasis
        • Massive fatty change
        • Diffuse fibrosing granulomatous disease (TB)
        • Diseases affecting portal microcirculation
  • 50. Portal Hypertension
    • Causes:
    • C. Post-hepatic
        • Severe right-sided heart failure
        • Constrictive pericarditis
        • Hepatic vein outflow obstruction
  • 51. Portal Hypertension
    • Clinical consequences:
    • Ascites
      • collection of fluid in peritoneal cavity
      • clinically detectable: at least 500 ml.
      • contents: < 3 gm/dL of protein (albumin), glucose, Na + , K + , mesothelial cells, mononuclear wbc
  • 52. Portal Hypertension
    • Clinical consequences:
    • Ascites
      • Pathogenesis:
        • Sinusoidal HPN  drive fluid into space of Disse  removed by lymphatics
        • Percolation of hepatic lymph into peritoneal cavity  hepatic lymph flow in cirrhosis = 20 L/day
        • Intestinal fluid leakage
        • Renal retention of Na + & H 2 O due to 2 O hyperaldosteronism  activation of RAAS
  • 53.  
  • 54. Portal Hypertension
    • Clinical consequences:
    • Porto-systemic Shunts
    Inc. portal system pressure Development of by-passes Systemic & portal circulation share common capillary beds Veins around & within rectum Cardio-esophageal junction Periumbilical & abdominal wall hemorrhoids Esophageal varices Caput medusae
  • 55. Photograph shows a caput medusae accentuated by a large amount of ascites in a patient being prepared for liver transplantation. An extensive plexus of veins is seen emanating from the umbilical region and radiating across the anterior abdominal wall.
  • 56. Portal Hypertension
    • Clinical consequences:
    • Splenomegaly
      • secondary to long-standing congestion
      • lead to hypersplenism
      • Hepatic encephalopathy
  • 57. Jaundice and Cholestasis JAUNDICE
    • retention of bilirubin
    • functions of bile:
      • Emulsification of fat
      • Elimination of systemic waste products
    • Rate of bilirubin production = rate of hepatic uptake, conjugation and biliary excretion
  • 58.  
  • 59.  
  • 60. Crigler-Najjar Syndrome
    • Hereditary glucuronyl transferase deficiency
    • Rare familial autosomal recessive disease
    • Due to marked deficiency (type II) or absence (type I) of glucuronyl transferase
    • Type I should always be ruled out when persistent unconjugated bilirubin levels of 20 mg/dL are seen after 1 week of age without obvious hemolysis and especially after breast-milk jaundice has been ruled out.
  • 61. Gilbert’s Disease
    • Chronic, benign, intermittent, familial (AD), non-hemolytic unconjugated hyperbilirubinemia with evanescent increases of B1
    • Due to defective transport and conjugation of B1
    • Jaundice accentuated by pregnancy, fever, exercise, and various drugs including alcohol and birth control pills
  • 62. Dubin-Johnson Syndrome
    • Sprinz-Nelson Syndrome
    • Due to defective transport of bilirubin-glucuronide through hepatocytes into canaliculi
    • Characterized by mild, recurrent jaundice
    • Hepatomegaly and RUQ pain may be present
    • Jaundice may be produced by estrogens, birth control pills, or last trimester of pregnancy
    • May resemble mild viral hepatitis
  • 63. Differential Diagnosis of Hereditary Jaundice with Normal Liver Chemistries & No Signs or Symptoms of Liver Disease Unconjugated Hyperbilirubinemia Crigler-Najjar Syndrome Gilbert’s Type I Type II Incidence Inheritance mode Serum bilirubin usual total (mg/dL) Defect Age at onset of jaundice <7% of pop’n Very rare Uncommon AD AR AD <3; < 6 >20 <20 Mostly B1; inc. All indirect All indirect with fasting Hepatic UDP-glucuronyl transferase activity Decreased Absent Marked dec. Adolescence Infancy Childhood, adolescence
  • 64. Differential Diagnosis of Hereditary Jaundice with Normal Liver Chemistries & No Signs or Symptoms of Liver Disease Unconjugated Hyperbilirubinemia Crigler-Najjar Syndrome Gilbert’s Type I Type II Usual clinical features Liver biopsy Treatment Appear in early Jaundice, Asymptomatic adulthood; kernicterus in jaundice, often 1 st re- infants, kernicterus cognized w/ young adults rare fasting Normal Normal Normal Not needed Liver transplant Phenobarbital
  • 65. Differential Diagnosis of Hereditary Jaundice with Normal Liver Chemistries & No Signs or Symptoms of Liver Disease Conjugated Hyperbilirubinemia Dubin-Johnson Rotor’s Syndrome Incidence Inheritance mode Serum bilirubin usual total (mg/dL) Defect Urine total coproporphyrin Age at onset of jaundice Usual clinical features Oral cholecystogram Liver biopsy Treatment Uncommon AR 2-7; < 25 Direct ~ 60% Impaired biliary excretion Normal Childhood, adolescence Asymptomatic jaundice in young adults GB not visualized Charac. pigment Not needed Rare AR 2-7; < 20 Direct ~ 60% Impaired biliary excretion Increased Adolescence, early adulthood Asymptomatic jaundice Normal No pigment None
  • 66. Comparison of Jaundice (Cholestatic & Hepatocelllular) *Serum bilirubin > 10 mg/dL is rarely seen with CBD stone and usually indicates carcinoma. Hepatocellular Cholestasis Infiltration Disease example Acute viral hep. CBD stone Metastatic tumor Serum bilirubin (mg/dL) 4 – 8 6 – 20* Usually <4, often normal AST, ALT (U/mL) Markedly inc., often 500-1,000 May be sl. Inc., < 200 May be slightly inc., < 100 Serum ALP 1-2x normal 3-5x normal 2-4x normal PT Inc. in severe disease Inc. in chronic cases Normal Response to parenteral vit. K No Yes
  • 67. Liver Function Tests: Normal Values & Changes Tests Normal Values Hepatocellular Jaundice Uncomplicated Obstructive Jaundice Bilirubin Direct Indirect 0.1-0.3 mg/dL 0.2-0.7 mg/dL Increased Increased Increased Increased Urine bilirubin None Increased Increased Serum albumin/ total protein Alb, 3.5-5.5 g/dL Tot, 6.5-8.4 g/dL Albumin decreased Unchanged Alk phos 30-115 IU/L Increased (+) Increased (++++) Prothrombin time INR of 1.0-1.4; 10% inc. after vit K in 24 hrs No response to parenteral vit. K; prolonged Prolonged but responds to parenteral vit. K ALT, AST ALT: 5-35 IU/L AST: 5-40 IU/L Inc. in hepato- cellular damage, viral hepatitis Minimally increased
  • 68. Cholestasis
    • retention of bilirubin and other solutes eliminated in bile
    • Causes:
      • Hepatocellular dysfunction
      • Intrahepatic
        • Blockage of intrahepatic bile ducts
        • Drugs (oral contraceptives, anabolic steroids)
      • Extrahepatic
        • Blockage of CBD
        • Gallstone, primary sclerosing cholangitis, extrahepatic biliary atresia, CA of head of pancreas
  • 69. Cholestasis
    • Extrahepatic Biliary Atresia
      • Cause of jaundice in the newborn
      • Inflammatory destruction of all or part of the extrahepatic bile ducts
      • Bile duct proliferation in the triads
      • Common indication for liver transplantation in a child
  • 70. Cholestasis
    • Primary Sclerosing Pericholangitis
      • Obliterative fibrosis of intrahepatic and extrahepatic bile ducts
      • Male dominant
      • Associated with ulcerative colitis
      • Jaundice, cirrhosis + increased incidence of cholangiocarcinoma
  • 71.  
  • 72. “ Onion-skinning” around bile duct
  • 73. Cholestasis
    • Features:
      • Jaundice with pruritus – deposition of bile acids and bile salts in skin
      • Malabsorption – bile salts do not enter S.I.
      • Skin xanthomas – due to hyperlipidemia & impaired excretion of cholesterol
      • Inc. serum alk. phos. – released due to detergent action of retained bile salts on hepatocyte membrane
      • Deficiency of fat soluble vitamins (A, D or K)
  • 74. Skin xanthomas
  • 75. Cholestasis
    • Morphology:
      • Accumulation of bile pigment within the hepatic parenchyma  distention of bile ducts and ductules
      • Bile stasis  induce proliferation of duct epithelial cells  ductal proliferation
      • Portal tract edema & periductal neutrophilic infiltrates
      • Prolonged cholestasis  focal detergent dissolution of hepatocytes  bile lakes with cellular debris & pigments
      • Portal tract fibrosis
  • 76.  
  • 77. Infectious Disorders
    • Viral hepatitis
    • Miliary tuberculosis
    • Malaria
    • Staphylococcal bacteremia  2 0 to TSS
    • Salmonellosis  typhoid fever
    • Candida
    • Parasitic & helminthic infection
  • 78. Viral Hepatitis
    • Hepatotropic viruses
      • Hepatitis viruses
      • Epstein-Barr virus
      • Cytomegalovirus
      • Yellow fever
      • Children & immunocompromised  rubella, adenovirus, herpesvirus, enterovirus, CMV
  • 79. Hepatitis Viruses
    • Small, non-enveloped, ssRNA
    • Picornavirus genus Hepatovirus
    • Serology:
    Hepatitis A
  • 80.
    • Hepadnaviridae
    • present in all physiologic and pathologic body fluids  blood & body fluids the primary vehicle for transmission
    • Incubation period: 4 – 26 weeks
    • MOT:
      • Transfusion
      • Blood products
      • Dialysis
      • Needle stick accidents among health care workers
      • IV drug abuse
      • Sexual contact
      • Vertical transmission – lead to carrier state for life
    Hepatitis B
  • 81.
    • Protein sequences encoded by HBV genome
      • HBcAg – nucleocapsid “core” protein; remains in hepatocytes for assembly of complete virion
      • HBeAg – secreted into blood
      • HBsAg – envelope glycoprotein
      • DNA polymerase – with reverse transcriptase activity
      • HBx protein – necessary for virus replication  acts as transcriptional activator of viral genes; play a role in development of HCC in HBV-infected patients
    Hepatitis B
  • 82.
    • Spectrum of illness
      • Acute infection with resolution
      • Chronic hepatitis  cirrhosis  HCC or carrier
      • Fulminant hepatitis with massive liver necrosis
      • Backdrop of hepatitis D infection
    Hepatitis B
  • 83.  
  • 84.
    • Carrier state – (+) HBsAg in serum for 6 months or longer after initial detection
    • Serology:
    Hepatitis B
  • 85. Hepatitis B: Common Serologic Patterns HBsAg HBsAb HBeAg HBeAb HBcAb (TOTAL) HBcAb-IgM Interpretation + -- -- -- -- -- Late incubation or early acute HBV + -- + -- -- -- Early acute HBV; highly infectious + -- + -- + + Acute HBV -- -- -- -- + + Serologic window -- -- -- + + + Convalescence + -- + + + -- Chronic infection (chronic carrier) -- + -- -- -- -- Old previous HBV with recovery and immunity OR vaccination OR passive transfer of antibody
  • 86. Hepatitis B: Serologic Tests of Candidate for HBV Vaccine Test HBsAg HBsAb HBcAb Interpretation Follow-up + -- -- Acute HBV infection Repeat serology for resolution or chronicity -- -- + Acute HBV or carrier Previous HBV infection; vaccinate -- + + Immune; previous HBV infection or vaccination None + -- + Previous HBV infection; may not be immune Vaccinate -- -- -- Not immune Vaccinate
  • 87.
    • Most common chronic blood-borne infection  accounts for 50% of all patients with chronic liver disease in the US
    • Flaviviridae family, genus Hepacivirus
    • HCV RNA polymerase with poor fidelity  inherently unstable  (+) genomic instability & antigenic variability within one individual  evade IFN-mediated anti-viral response  repeated bouts of hepatic damage
    Hepatitis C
  • 88.
    • Persistent infection and chronic hepatitis are the hallmarks of HCV infection
    • MOT: 1. inoculations
    • 2. blood transfusions
    • 3. hemodialysis
    • 4. sexual transmission
    • 5. perinatal
    Hepatitis C
  • 89. Hepatitis C
    • potential outcomes:
    Stable cirrhosis Death
  • 90. Hepatitis C
    • serology:
  • 91. Hepatitis D
    • hepatitis delta virus
    • replication defective  cause infection only when encapsulated by HBsAg
    • co-infection vs. superinfection
  • 92. Hepatitis D
  • 93. Comparison of Types of HDV Infections Coinfection Superinfection HBV infection Acute Chronic HDV infection Acute Acute to chronic Chronicity rate < 5% > 75% Serology HBsAg HBcAb-IgM Anti-HDV-total Anti-HDV-IgM HDAg + + Negative or low Transient + Transient + Usu. persistent Negative + Transient Usu. persistent Liver HDAg Transient + Usu. persistent
  • 94. Hepatitis G
    • Flavivirus similar to HCV
    • MOT:
      • Contaminated blood or blood products
      • Sexual contact
    • 75% cleared from plasma; 25% chronic
    • Site of replication: mononuclear cells  not hepatotropic  no increase in serum transaminases
    • No pathologic effect
    • Commonly co-infects patients with HIV  protects against HIV disease
  • 95. Hepatitis
    • Clinicopathologic Syndromes:
      • Acute asymptomatic infection with recovery
        • Minimal serum transaminase elevation
        • Common in HCV-infected patients
      • Acute symptomatic infection with recovery
        • 4 phases:
        • (a) Incubation period
        • (b) Pre-icteric phase – non-specific S/Sx
        • (c) Icteric phase – conjugated hyper- bilirubinemia
        • (d) Convalescence
  • 96. Hepatitis
    • Clinicopathologic Syndromes:
      • Chronic hepatitis
        • Asymptomatic, biochemical or serologic evidence of continuing or relapsing hepatic disease for more than 6 months, with histologically documented inflammation and necrosis
  • 97. Hepatitis
    • Clinicopathologic Syndromes:
      • Fulminant hepatic failure
        • Hepatic insufficiency progresses from onset of symptoms to hepatic encephalopathy within 2 – 3 wks
        • Extrahepatic complications
        • (a) coagulopathy & bleeding
        • (b) cardiac instability
        • (c) renal failure
        • (d) ARDS
        • (e) electrolyte & acid imbalance
        • (f) sepsis
  • 98. Hepatitis
    • Morphology:
    • Acute Hepatitis
    • Ballooning degeneration  ground- glass hepatocytes
    • Periportal necrosis with inflammatory infiltrates
    • Lobular disarray
    • 2 patterns of hepatocyte death:
      • cytolysis 2 0 to rupture of cell membrane
      • apoptosis due to anti-viral cytotoxic T cells
    • severe acute hepatitis  (+) bridging necrosis
  • 99. Also known as acidophilic bodies, apoptotic bodies, or Councilman bodies (arrows), these intensely eosinophilic dead hepatocytes are engulfed by Kupffer cells and digested. 
  • 100. Hepatitis
    • Morphology:
    • Chronic Hepatitis
    • periportal lymphoid aggregates
    • Periportal necrosis & fibrosis
    • Bridging necrosis & fibrosis
    • Hallmark of irreversible liver damage is deposition of fibrous tissue
  • 101.  
  • 102. Metabolic Disorders
    • Non-alcoholic Fatty Liver Disease
    • (NAFL)
      • Occurs in patients who are not heavy drinkers
      • Strong association with obesity, dyslipidemia and insulin resistance, and overt type 2 DM
      • Presents only with elevated serum amino- transferases and/or GGT
      • (+) accumulation of triglycerides within hepatocytes
      • Progress to non-alcoholic steatohepatitis (NASH)  CIRRHOSIS
  • 103.  
  • 104. Metabolic Disorders
    • Hemochromatosis
      • Excessive accumulation of body iron  deposit in parenchymal organs (e.g. liver and pancreas)
      • May be secondary to a genetic defect (increased absorption) OR a consequence of parenteral administration of iron
      • Over 1/3 of iron accumulated stored in the liver
      • Increased risk of hepatocellular carcinoma
  • 105. Metabolic Disorders
    • Hemochromatosis
      • Hereditary hemochromatosis
        • Mutations involving hereditary hemochromatosis gene HFE
        • Unrestricted re-absorption of iron in the small intestines
      • Secondary or acquired  hemosiderosis
        • Causes: multiple blood transfusions, alcohol abuse
  • 106. Metabolic Disorders
    • Hemochromatosis
      • Features:
        • Fully developed cases with micronodular cirrhosis (all patients), type I DM, and skin pigmentation
        • Destruction of exocrine pancreas  malabsorption
        • Males predominate due to delayed iron accumulation in women
  • 107. Metabolic Disorders
    • Hemochromatosis
      • Morphology:
        • Hemosiderin deposition in liver, pancreas, myocardium, pituitary gland, adrenal gland, thyroid & parathyroid glands, joints, and skin  stain with Prussian blue
        • Liver cirrhosis
        • Pancreatic fibrosis
  • 108. Metabolic Disorders
    • Hemochromatosis
      • Classic clinical triad:
        • Pigment cirrhosis with hepatomegaly
        • Skin pigmentation – increased melanin production
        • Diabetes mellitus – destruction of β -islet cells
      • Death due to cirrhosis or cardiac disease
      • Risk for development of hepatocellular CA 200-fold greater
  • 109.  
  • 110. Metabolic Disorders
    • Wilson’s Disease (Hepatolenticular degeneration)
      • Copper accumulation particularly in liver, brain, and eye (demonstrated by rhodamine stain for copper)
      • Due to mutation of Wilson’s disease gene ( ATP7B ) on chr. 13  decreased synthesis of ceruloplasmin  defective biliary excretion of copper
  • 111. Metabolic Disorders
    • Wilson’s Disease
      • Morphology:
        • Fatty change  acute hepatitis  chronic hepatitis  cirrhosis
          • Massive liver necrosis a rare manifestation
        • Brain – atrophy or cavitation of basal ganglia, particularly in putamen (movement disorder)
        • Eye lesions – Kayser-Fleischer rings in Descemet’s membrane
  • 112.  
  • 113.  
  • 114. Metabolic Disorders
    • Wilson’s Disease
      • Diagnosis:
        • Decreased serum ceruloplasmin
        • Increased hepatic copper content (>250 ug/gram dry weight)
        • Increased urinary copper excretion
      • Treatment: copper chelation therapy with D-penicillamine
  • 115. Metabolic Disorders
    • Α 1-Antitrypsin deficiency
      • Autosomal dominant  normal genotype is PiMM  most common abnormal allele is Z
      • PiZZ variant with decreased AAT in serum  cause liver damage
        • Mutant protein cannot be secreted into blood
  • 116. Metabolic Disorders
    • Α 1-Antitrypsin deficiency
    • Clinical Findings:
      • Children
        • Neonatal hepatitis with intrahepatic cholestasis
        • Most common cause of cirrhosis in children
        • Increased risk for hepatocellular carcinoma
      • Young adults with panacinar emphysema
  • 117. Circulatory Disorders
    • Pre-hepatic Obstruction to Blood Flow
      • Obstruction of blood flow to the liver (i.e., hepatic artery and portal vein)
    • Hepatic artery thrombosis with infarction
      • Causes: liver transplant rejection or vasculitis due to polyarteritis nodosa
    • Portal vein thrombosis
      • Causes: pylephlebitis (inflammation of portal vein, usually due to acute AP), polycythemia vera, hepatocellular CA (invasion of portal vein)
  • 118. Circulatory Disorders
    • Intrahepatic Obstruction to Blood Flow
      • Obstruction to sinusoidal blood flow
      • Causes:
        • cirrhosis
        • centrilobular hemorrhagic necrosis
        • peliosis hepatis
        • sickle cell disease
  • 119. Circulatory Disorders
    • Intrahepatic Obstruction to Blood Flow
    • Centrilobular hemorrhagic necrosis
      • Most often due to left-sided HF and right-sided HF
      • LHF  decreased cardiac output  hypoperfusion of liver  ischemic necrosis of hepatocytes around central vein
      • RHF  back-up of systemic venous blood into central veins and sinusoids
  • 120. Circulatory Disorders
    • Intrahepatic Obstruction to Blood Flow
    • Centrilobular hemorrhagic necrosis
      • Enlarged liver with mottled red appearance (“nutmeg” liver)  congestion of central veins and sinusoids)
  • 121. Circulatory Disorders
    • Intrahepatic Obstruction to Blood Flow
    • Peliosis hepatis
      • Sinusoidal dilatation due to blood
      • Causes: anabolic steroids; Bartonella henselae
  • 122. Circulatory Disorders
    • Post-hepatic Obstruction to Blood Flow
      • Obstruction of blood flow out of the liver (e.g., hepatic vein)
      • Causes:
        • Hepatic vein thrombosis (Budd-Chiari syndrome)
        • Veno-occlusive disease
  • 123. Circulatory Disorders
    • Post-hepatic Obstruction to Blood Flow
    • Budd-Chiari Syndrome
      • Thrombosis of the major hepatic vein causing extreme blood retention in the liver
      • Causes:
        • Polycythemia vera – most common
        • Oral contraceptive pills
        • Hepatocellular carcinoma invasion of hepatic vein
  • 124.  
  • 125. Circulatory Disorders
    • Post-hepatic Obstruction to Blood Flow
    • Budd-Chiari Syndrome
      • Clinical:
        • Enlarged, painful liver
        • Portal hypertension, ascites, splenomegaly
        • High mortality rate
      • Laboratory: increased transaminases, increased PT
  • 126. Liver Abscess
    • common in developing countries
    • usually pyogenic  multiple, small abscesses ( E. coli, P. vulgaris, Enterobacter aerogenes, anaerobes )
    • parasitic – usually solitary  amebic & echinococcal
  • 127. Liver Abscess
    • Reach liver via:
      • Portal vein
      • Arterial supply
      • Ascending infection in biliary tract  ascending cholangitis
      • Direct invasion from nearby source
      • Penetrating injury
    • Clinical: RUQ pain, fever, tender hepatomegaly
  • 128. Liver Abscess
    • Abnormalities of liver function tests:
      • Dec. serum albumin (50%); inc. serum globulin
      • Inc. serum ALP (75%)
      • Inc. serum bilirubin (20-25%)  >10 mg/dL usually indicates pyogenic rather than amebic origin  poorer prognosis because of greater tissue destruction
    • Inc. wbc (70%)
    • Anemia (60%)
    • Laboratory findings due to complications: R pleural effusion (20%), subphrenic abscess, pneumonia, empyema, bronchopleural fistula
  • 129. Amebic liver abscess Amebic liver abscess with perforation of abscess through abdominal wall
  • 130. Pyogenic liver abscess
  • 131. Drug & Toxin-Induced Hepatic Disease
    • Mechanism of injury:
      • Direct toxicity
      • Hepatic conversion of a xenobiotic to an actual toxin
      • Immune mechanisms  drug or metabolite acts as hapten
    • Types of injury:
      • Hepatocyte necrosis
      • Cholestasis
      • Insidious liver dysfunction
    • Reye syndrome – children given ASA; extensive accumulation of fat droplets within hepatocytes (microvesicular steatosis)
  • 132.
    • Reye syndrome
      • Usually in children < 4 years of age
      • Often follows a chickenpox or influenza infection
      • Mitochondrial damage (? virus, salicylates)
        • Disruption of urea cycle  increased serum ammonia
        • Defective beta-oxidation of fatty acids
    Drug & Toxin-Induced Hepatic Disease
  • 133.
    • Reye syndrome
      • Microvesicular steatosis (? Salicylate effect)
      • Clinical findings:
        • Encephalopathy
        • Hepatomegaly  liver failure
      • Laboratory findings:
        • Transaminasemia
        • Normal to slight inc. total bilirubin
        • Increased serum ammonia
    Drug & Toxin-Induced Hepatic Disease
  • 134. Hepatic Disease Associated with Pregnancy
    • Pre-eclampsia
      • Hypertension, proteinuria, dependent pitting edema in the third trimester
      • HELLP syndrome  hemolytic anemia with schistocytes, elevated liver enzymes, low platelet (due to DIC)
      • Morphology:
        • fibrin deposition in periportal sinusoids
        • hemorrhage into space of Disse
        • periportal hepatocellular coagulative necrosis
  • 135. Congested liver of HELLP syndrome
  • 136. Hepatic Disease Associated with Pregnancy
    • Acute fatty liver of pregnancy (AFLP)
      • sub-clinical hepatic dysfunction to hepatic failure, coma and death
      • Abnormality in beta-oxidation of fatty acids
      • 3 rd trimester; with multiple metabolic defects
      • diagnosis depends on:
        • high index of suspicion
        • characteristic microvesicular steatosis demonstrated on frozen tissue sections OR with stain (oil red-O or Sudan black)
      • Treatment: termination of pregnancy
  • 137. Acute fatty liver of pregnancy: lobular parenchyma characterized by microvesicular steatosis and a small number of lymphocytes. (H&E)
  • 138. Hepatic Disease Associated with Pregnancy
    • Intrahepatic cholestasis of pregnancy
      • Characteristics:
        • onset of pruritus in 3 rd trimester
        • darkening of urine with occ. light stools
        • jaundice – conjugated hyperbilirubinemia
      • Mechanism: altered hormonal state + biliary secretion defects  cholestasis
      • Increased incidence of fetal distress, stillbirth and prematurity
  • 139. Nodules & Tumors Nodular Hyperplasia
    • non-cirrhotic liver nodules
    • types:
      • Focal nodular hyperplasia
        • spontaneous mass lesion; female preponderance
        • Morphology:
          • central stellate scar with large arterial vessels exhibiting fibromuscular hyperplasia  (+) narrowed lumen
          • Intense lymphocytic infiltration
          • bile duct proliferation
  • 140. Focal Nodular Hyperplasia: Subcapsular solid mass with central scar, composed  of the normal components of liver lobule
  • 141. Central portion of nodular hyperplasia showing the interphase between the fibrous scar and the hepatocytic nodules.
  • 142. Nodules & Tumors Nodular Hyperplasia
    • Nodular regenerative hyperplasia
      • (+) development of portal HPN
      • Associated with conditions affecting intrahepatic blood flow  renal transplant, BM transplant, vasculitic conditions
      • Morphology: plump hepatocytes surrounded by atrophic cells; no fibrosis
  • 143. Nodular Regenerative Hyperplasia: non-cirrhotic non-neoplastic nodular transformation of the liver parenchyma.
  • 144. Nodules & Tumors Benign Neoplasms
    • Cavernous hemangioma
      • Most common; blood vessel tumor
      • Soft nodules < 2 cm diameter immediately beneath the capsule
      • Clinical significance: mistaken for metastatic tumors  blind percutaneous biopsies not done
  • 145. Cavernous Hemangioma Normal liver Hemangioma
  • 146. Nodules & Tumors Benign Neoplasms
    • Liver cell adenomas
    • Cell of origin: hepatocytes
    • Young women on oral contraceptives  regress on discontinuance of use
    • Clinical significance:
      • Present as intrahepatic mass  mistaken for HCC
      • If subcapsular  (+) rupture  intraperitoneal hemorrhage
      • May harbor HCC – rare
    • Morphology: cords of hepatocytes with clear cytoplasm (w/ glycogen), absent portal tracts & prominent arterial vessels and draining veins
  • 147. The hepatic adenoma is composed of cells that closely resemble normal hepatocytes with disorganized hepatocyte cords and does not contain a normal lobular architecture. At the upper right is a well-circumscribed neoplasm that is arising in liver. This is an hepatic adenoma. Normal liver Adenoma
  • 148. Nodules & Tumors Malignant Tumors
      • Primary tumors uncommon  often involved in metastatic spread
    • Hepatoblastoma
    • rare; most common liver tumor of young children
    • fatal if not resected
    • (+) activation of Wnt/ β -catenin signaling pathway  stabilize mutations of β -catenin
  • 149. Hepatoblastoma Hepatoblastoma found to be invading the inferior vena cava at the time of surgical exploration.
  • 150.  
  • 151. Nodules & Tumors Malignant Tumors
    • Angiosarcoma
    • rare; malignant endothelial neoplasm
    • associated with exposure to vinyl chloride, arsenic or Thorotrast
    • highly aggressive, metastatic, fatal
  • 152. Angiosarcoma: Section of liver, showing multiple hemorrhagic tumor deposits.
  • 153. Nodules & Tumors
    • Cholangiocarcinoma
    • malignancy of intrahepatic biliary tract
    • risk factors:
      • Primary sclerosing cholangitis
      • Congenital fibropolycystic diseases of biliary system
      • Previous exposure to Thorotrast
      • Chronic liver fluke infection (O. sinensis)
    • Morphology: resemble sclerosing adenocarcinoma  well-defined glandular & tubular structures separated by dense collagenous stroma
  • 154. Intrahepatic cholangiocarcinomas are classified as either peripheral or hilar. The hilar variety are located in the hepatic hilum region and appear as discrete masses.
  • 155. Peripheral cholangiocarcinoma is the most common and develops in the interlobular ducts of the liver, where the interlobular bile duct branches within the portal triads. They may be a single or multiple masses.
  • 156. Nodules & Tumors
    • Hepatocellular Carcinoma
    • male preponderance; 20 – 40 y/o
    • Risk factors:
      • Viral infection – chronic HBV & HCV infection  no cirrhosis
      • Chronic alcoholism – (+) cirrhosis
      • Food contaminants – aflatoxin from Aspergillus flavus  bind covalently with cellular DNA  (+) p53 mutation
    • >85% occur in countries with high rates of chronic HBV and HCV infections
  • 157. Hepatocellular Carcinoma
    • Morphology:
      • Gross
        • Unifocal large mass
        • Multifocal
        • Diffusely infiltrative
  • 158. Hepatocellular Carcinoma
    • Morphology:
      • Microscopic:
        • Well differentiated  trabecular pattern or acinar, pseudoglandular pattern
        • Poorly differentiated  pleiomorphic with anaplastic giant cells
    bile
  • 159. Hepatocellular Carcinoma
    • Clinical features:
        • upper abdominal pain or fullness
        • malaise, fatigue, weight loss
        • hepatomegaly with irregularity or nodularity
    • Laboratory:
        • increased tumor markers – serum AFP and serum CEA  not conclusive  false (+) in non-neoplastic conditions (e.g. cirrhosis, chronic hepatitis, massive liver necrosis, fetal neural defects such as anencephaly)
  • 160. Liver Function Tests
    • ALBUMIN
      • Main constituent of total protein
      • Normal: 3.5 – 5.0 g/dL
      • Decreased in:
        • Chronic liver disease (e.g., cirrhosis)
        • Nephrotic syndrome
        • Poor nutritional state or states of protein catabolism
      • Not a useful marker of synthetic liver function
  • 161. Liver Function Tests
    • ALANINE TRANSAMINASE (ALT)
      • Serum Glutamic Pyruvate Transaminase (SGPT) or alanine aminotransaminase
      • Present in hepatocytes; cytosolic enzyme
      • Normal: 5 – 35 IU/L
      • Dramatic increase in: acute liver damage such as viral hepatitis or paracetamol overdose
      • Elevations measured in multiples of the upper limit of normal (ULN)
  • 162. Liver Function Tests
    • ASPARTATE TRANSAMINASE (AST)
      • Serum Glutamic Oxaloacetic Transaminase (SGOT) or aspartate aminotransaminase
      • Mitochondrial
      • Also associated with liver parenchymal cells
      • Normal: 5 – 40 IU/L
      • Dramatic increase in: acute liver damage
      • Also present in rbc, cardiac & skeletal muscles
  • 163. Liver Function Tests
    • Aminotransferases are most helpful in differentiating hepatocellular injury from cholestasis --
      • Persistent high serum levels > 400 U/L favor generalized hepatocellular injury (e.g. acute hepatitis)
      • Values < 400 U/L favor cholestasis and may also be seen in mild hepatocellular injuries from viruses, drugs, alcohol, cirrhosis and primary or metastatic neoplasms
  • 164. Liver Function Tests
    • ALKALINE PHOSPHATASE
      • Enzyme in the cells lining the biliary ducts of the liver
      • Normal: 40 – 200 IU/L (15-20 y/o); 35 – 125 IU/L (20-100 y/o)
      • Elevation > 4x the normal  cholestasis of either intrahepatic or extrahepatic cause
      • Dramatic increase in: large bile duct obstruction, intrahepatic cholestasis or infiltrative diseases of the liver
      • Also present in bone and placental tissue  higher in growing children
  • 165. Liver Function Tests
    • TOTAL BILIRUBIN (N = 0.3-1.0 mg/dL or 5-17  mol)
      • Causes of elevated levels:
        • Prehepatic – increased bilirubin production (e.g. hemolytic anemias, internal hemorrhage)
        • Hepatic – deficiencies in bilirubin metabolism (e.g. dec. uptake, impaired conjugation, dec. secretion of bilirubin)
        • Posthepatic – obstruction of bile ducts, either within the liver or outside the liver
      • Diagnosis narrowed down by looking at levels of direct bilirubin
  • 166. Liver Function Tests
    • DIRECT BILIRUBIN (N = 0 – 0.3 mg/dL or 5  mol)
      • If direct bilirubin is normal  problem is excess unconjugated bilirubin  location of problem is upstream of bilirubin excretion  suspect hemolysis, viral hepatitis or cirrhosis
      • If direct bilirubin is elevated  liver conjugating normally but unable to excrete  suspect bile duct obstruction by gallstones or cancer
  • 167. Liver Function Tests
    • DIRECT BILIRUBIN (N = 0 – 0.3 mg/dL or 5  mol)
      • If indirect fraction > 85% of the total  hemolysis or another cause of unconjugated hyper-bilirubinemia
      • Elevated B2 in the absence of other liver chemistry test abnormalities  hereditary disorder of hepatic secretion of bilirubin into the canaliculus (e.g. Dubin Johnson or Rotor’s)
  • 168. Liver Function Tests
    • GAMMA GLUTAMYL TRANSPEPTIDASE (GGT)
      • Normal: 10 – 48 IU/L
      • Like ALP, can be found in canalicular membranes
      • More sensitive marker for cholestatic damage than ALP
      • May be elevated with even minor, sub-clinical levels of liver dysfunction
      • Elevated in alcohol toxicity (acute and chronic)
  • 169. Other Tests Commonly Requested
    • 5’ Nucleotidase (5’ NTD)
      • Specific for cholestasis or damage to the intra- or extrahepatic biliary system
      • Used as substitute for GGT for ascertaining whether an elevated ALP is of biliary or extra-biliary origin
  • 170. Other Tests Commonly Requested
    • Coagulation Tests (e.g. INR)
      • International Normalized Ratio
      • Measures the speed of a particular pathway of coagulation, comparing it to the normal
      • If increased  blood is taking longer to clot
      • Will only be increased if the liver is so damaged that synthesis of vitamin K-dependent coagulation factors has been impaired
      • Not a sensitive measure of liver function
  • 171. Other Tests Commonly Requested
    • Serum Glucose (BG, Glu)
      • Liver’s ability to produce glucose is usually the last function to be lost in the setting of fulminant liver damage
    • Lactate Dehydrogenase (LDH)
      • Found in many body tissues, including the liver
      • Elevated levels may indicate liver damage
  • 172.  
  • 173. Patterns of Liver Chemistry Test Abnormalities Pattern Bilirubin Alkaline phosphatase Amino- transferase Albumin Prothrombin time Hemolysis Inc. (usu. B1) Normal Normal Normal Normal Acute hepatocellular +/- inc. (B1 and B2) Normal or < 3x normal Usu. >400 (ALT>AST) Normal Normal Chronic hepatocellular +/- inc. (B1 and B2) Normal or < 3x normal Usu. <300 U/L May be dec. Often prolonged; doesn’t correct with vit. K Cholestasis Usually inc. (B1 and B2) > 4x normal Usually < 300 U/L Usually normal Normal; corrects with vit. K if prolonged Infiltrative Usually normal > 4x normal; inc. GGT < 300 U/L Usually normal Normal
  • 174.