Liver pothology


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  • Like the pancreas, the liver, together with the gallbladder, is considered, also to be derived embryologically, as an outpocketing of the foregut.
  • Classical anatomic landmarks in the average 1400-1800 gram adult liver.
  • Relationship of the liver with neighboring organs
  • The liver is nothing more than an array of cells between the portal and caval venous systems. This shows the direction of flow. The liver gets about 80% of its blood supply fron the portal veins and 20% from the hepatic arterial system.
  • The IDEAL three-dimensional diagram.
  • The classical view of liver tissue from a liver biopsy, H&E stained.
  • What is the direction ov venous blood flow, portal to central, or vice versa?
  • The FIRST part of the lobule, i.e., portal triad is the FIRST to get blood flow, so it is also the FIRST to get the brunt of general toxic effects, and the LAST to get the brunt of ischemic effects.
  • The LAST part of the lobule, central vein, VICE VERSA!
  • The classical classification of diseases!
  • Heatocyte cytoplasm is “balooned”
  • Hepatocytes have “feathery” cytoplasm
  • Fat vacoules are small enough to lie completely WITHIN the hepatocte cytioplasm
  • Fat vacuoles are large enough to completely REPLACE the hepatocyte cytoplasm. Why is the differential diagnosis of MACRO vesicular steatosis the same as MICRO vesicular steatosis?
  • Of the three types of common golden pigment found in the body, 1) hemosiderin, 2) melanin, and 3) bile, only hemosiderin stains BLUE with the prussian blue stain. There are special stains to identify melanin and bile however.
  • Crucially important concept worth repeating. KNOW the difference between an acinus and a lobule.
  • The “hyalinized” appearing round structures are cells dying from a NORMAL replacement process called apoptosis.
  • Triads are involved with hepatitis earlier than general sinusoids. Why?
  • Cirrhosis is the natural END STAGE IRREVERSIBLE disease of ANYTHING which chronically damages the liver!!! Cirrhosis is the natural END STAGE IRREVERSIBLE disease of ANYTHING which chronically damages the liver!!! Cirrhosis is the natural END STAGE IRREVERSIBLE disease of ANYTHING which chronically damages the liver!!! Cirrhosis is the natural END STAGE IRREVERSIBLE disease of ANYTHING which chronically damages the liver!!!
  • Cirrhosis is the natural END STAGE IRREVERSIBLE disease of ANYTHING which chronically damages the liver!!! Cirrhosis is the natural END STAGE IRREVERSIBLE disease of ANYTHING which chronically damages the liver!!! Cirrhosis is the natural END STAGE IRREVERSIBLE disease of ANYTHING which chronically damages the liver!!! Cirrhosis is the natural END STAGE IRREVERSIBLE disease of ANYTHING which chronically damages the liver!!!
  • The hepatoma/cirrosis cycle: Hepatomas often, perhaps usually, arise in a cirrhosis background, and can be thought of as regenerating nodules that have lost growth control, ususlly NOT metastasizing, the hepatoma itself causing FURTHER functional liver disease.
  • Even a blind man would know this liver surface feels “smooth” which generally rules out cirrhosis or tumors even before slicing it for examination.
  • In a normal liver, ther is connective tissue ONLY in the small portal triad area.
  • Is this MACROnodfular or MICROdular cirrhosis?
  • Why are TRICHROME stains recommended for every liver biopsy?
  • Ther are twokinds of hepatic enzymes: INTRACELLULAR and MEMBRANE ASSOCIATED. This fact forms the basis for hepatic diagnostic enzymology.
  • Almost all primarilly INTRACELLULAR liver pathologies result in MEMBRANE elevations too, and VICE VERSA!
  • Sclera and conjunctiva are the best places to see early jaundice, palms too!
  • A normal liver should NOT have this much bile pigment, in fact bile pigment in a normal liver biopsy should be scarce!
  • Bile accumulations . Why does it look like a lot is BETWEEN hepatocytes in early stages?
  • “ swollen” liver?
  • The inflammation of hepatitis starts in the portal triad areas, with increasing severity it extends to the sinusoids.
  • “ Fulminant” hepatitis is associated with massive hepatic necrosis and often (usually) results in death.
  • It would be VERY nice to see Councilman bodies on a liver biopsy to enable the diagnosis of Hepatitis B. Unfortunately, you may not be lucky enough to find them. Does this remind you of the “apoptosis” image? Each “Councilman body” represents apoptotic death of a single liver cell.
  • Consequences of hepatitis B, surprisingly, most cases of Hepatitis B are SUB-clinical
  • Consequences of hepatitis C
  • Laboratory findings in hepatitis B, classical.
  • The MAIN differential of NON viral “hepatitis”: 1) TOXIC (alcohol the most common), 2) autoimmune, and 3) non-viral infectious!
  • Many of the classical liver toxins can produce a fairly predictable pattern of liver changes. BUT, they can also be quite UN-predictable and varied as well!
  • Alpha-1-antitrypsin PROTECTS tissues, especially lung, liver, from HARMFUL NATURAL PROTEASE. Lack of this enzyme, due to a genetic defect, would then be expected to cause destructive changes in these areas.
  • The liver can be thought of as being a “lymph” node for early metastases of any organ which has a portal circulation!
  • How would the blind man know this is metastatic cancer, rather than macronodular cirrhosis?
  • Individually, hepatoma “cells” usually very closely resemble normal hepatocytes!
  • Cholangiocarcinoma is ALWAYS confused with liver metastases. Why? What feature of this picture would NOT suggest metastases?
  • Common gallbladder “anomalies” are usually developmental.
  • Cholecystitis predisposes to cholelithiasis, and VICE VERSA!
  • Liver pothology

    2. 2.
    3. 3.
    4. 4.
    5. 5. DUCT SYSTEM
    6. 6.
    7. 7. The IDEAL three-dimensional diagram.
    8. 8. The classical view of liver tissue from a liver biopsy, H&E stained.
    10. 10. The FIRST part of the lobule, i.e., portal triad is the FIRST to get blood flow, so it is also the FIRST to get the brunt of general toxic effects, and the LAST to get the brunt of ischemic effects.
    11. 11. The LAST part of the lobule, central vein, VICE VERSA!
    12. 12. PATTERNS OF HEPATIC INJURY <ul><li>Degeneration: </li></ul><ul><ul><li>Balooning, “feathery” degeneration, fat, pigment </li></ul></ul><ul><li>Inflammation: Viral or Toxic </li></ul><ul><ul><li>Regeneration </li></ul></ul><ul><ul><li>Fibrosis </li></ul></ul><ul><li>Neoplasia: 99% metastatic, 1% primary </li></ul>
    15. 15. FATTY LIVER
    17. 17. MACROVESICULAR STEATOSIS Obesity Diabetes Toxic
    18. 18. “ Golden” pigment stained with Prussian Blue stain to make it blue. Hemosiderin? Bile? Melanin?
    19. 19.
    20. 20. APOPTOSIS
    21. 21. INFLAMMATION <ul><li>PORTAL TRIADS </li></ul><ul><li>(early) </li></ul><ul><li>SINUSOIDS </li></ul><ul><li>(more severe) </li></ul>
    22. 22. MILD TRIADITIS
    23. 23. More severe portal infiltrates with sinusoidal infiltrates also
    24. 24. Hepatic Regeneration <ul><li>The LIVER is classically cited as the most “REGENERATIVE” of all the organs! </li></ul>
    25. 25. FIBROSIS <ul><li>FIBROSIS is the end stage of MOST chronic liver diseases, and is ONE (of TWO) absolute criteria needed for the diagnosis of cirrhosis. </li></ul><ul><li>What is the other? </li></ul>
    26. 26. CIRRHOSIS <ul><li>PORTAL-to-PORTAL (bridging) FIBROSIS </li></ul><ul><li>The “normal” hexagonal “ARCHITECTURE” is replaced by NODULES </li></ul>
    27. 27. CIRRHOSIS <ul><li>Liver </li></ul><ul><li>Alcoholic </li></ul><ul><li>Biliary (Primary or Secondary) </li></ul><ul><li>Laennec’s </li></ul><ul><li>Advanced </li></ul><ul><li>Post-necrotic </li></ul><ul><li>Micronodular </li></ul><ul><li>Macronodular </li></ul>
    28. 28. ALL CIRRHOSIS IS: <ul><li>IRREVERSIBLE </li></ul><ul><li>The end stage of ALL chronic liver disease, often many years, often several months </li></ul><ul><li>Associated with a HUGE degree of nodular regeneration, and therefore represents a significant “risk” for primary liver neoplasm, i.e., “Hepatoma”, aka, Hepatocellular Carcinoma </li></ul>
    29. 29. BLIND MAN’s LIVER
    30. 30. Blind Man’s Diagnosis
    31. 31. N O FIBROUS TISSUE In a normal liver, ther is connective tissue ONLY in the small portal triad area.
    33. 33. TRICHROME
    36. 36. DEFINITIONS: <ul><li>CIRRHOSIS is the name of the disease as demonstrated by the anatomic changes </li></ul><ul><li>LIVER FAILURE is the series and sequence of abnormal pathophysiologic events </li></ul>
    37. 37.
    38. 38.
    40. 40. Common Clinical/Pathophysiological Events <ul><li>Portal Hypertension WHY? WHERE? </li></ul><ul><li>Ascites WHY? (Heart/Renal?) </li></ul><ul><li>Splenomegaly WHY? </li></ul><ul><li>Jaundice WHY? </li></ul><ul><li>“ Estrogenic” effects WHY? </li></ul><ul><li>Coagulopathies (II, VII, IX, X) WHY? </li></ul><ul><li>Encephalopathy WHY? </li></ul>
    41. 41. Hepatic Enzymology <ul><li>Transaminases (AST/ALT), aka (SGOT/SGPT), and LDH are “hepatic INTRACELLULAR ” enzymes, and are primarilly indicative of hepatocyte damage . </li></ul><ul><li>Alkaline Phosphatase (AlkPhos), Gamma-GTP (Gamma-glutamyl transpeptidase), and 5’-Nucleotidase (5’N) are MEMBRANE enzymes and are primarilly indicative of bile stasis/obstruction </li></ul>
    42. 42. Intracellular = DAMAGE AST/ALT/LDH Membrane = OBSTRUCTION AlkPhos/GGTP/5’N
    43. 43. JAUNDICE
    44. 44. Bilirubin: (0.3-1.2 mg/dl) UN-conjugated (indirect) Conjugated (direct)
    45. 45. JAUNDICE <ul><li>Hemolytic (UN-conjugated) </li></ul><ul><li>Obstructive (Conjugated ) </li></ul>
    46. 46. JAUNDICE <ul><li>Excessive production </li></ul><ul><li>Reduced hepatic uptake </li></ul><ul><li>Impaired Conjugation </li></ul><ul><li>Defective Transportation </li></ul>
    47. 47. Neonatal Jaundice <ul><li>Neonatal, genetic </li></ul><ul><ul><li>Gilbert Syndrome </li></ul></ul><ul><ul><li>Dubin-Johnson Syndrome </li></ul></ul><ul><li>Neonatal, NON-genetic </li></ul><ul><ul><li>MASSIVE differential diagnosis, i.e., everything </li></ul></ul>
    48. 48. CHOLESTASIS <ul><li>Def: Suppression of bile flow </li></ul><ul><li>Associated with membrane enzyme elevations, “primarily”, ie, AP/GGTP/5’N </li></ul><ul><li>Familial, drugs, but bottom line is OBSTRUCTION </li></ul>
    49. 49.
    50. 50. Bile accumulations
    51. 51. Bile “plugs”, Bile “lakes”
    52. 52. VIRAL HEPATITIS <ul><li>A, B, C, D, E </li></ul><ul><li>They all look the same, ranging from a few extra portal triad lymphocytes, to “FULMINANT” hepatitis </li></ul><ul><li>Associated with full recovery (usual), chronic progression over years leading to cirrhosis (not rare), risk of hepatoma (uncommon), or death (uncommon) </li></ul>
    53. 53. VIRAL HEPATITIS <ul><li>Jaundice, urine dark, stool chalky </li></ul><ul><li>Viral “prodrome” </li></ul><ul><li>Upper respiratory infection </li></ul><ul><li>All have multiple antigen (virus) and antibody (serology) serum tests </li></ul><ul><li>“ Councilman” bodies on biopsy are very very nice to find. Why? </li></ul>
    54. 54.
    55. 55. Chiefly Portal Inflammation
    57. 57. “ FULMINANT” Acute Viral Hepatitis
    58. 58. “ Councilman” Bodies……Diagnostic? Probably!
    59. 59. B
    60. 60. C LESS common than B (one fourth) LESS dangerous than B in the acute phase MORE likely to go chronic than B MORE closely linked with hepatoma than B
    61. 61.
    62. 62. NON-Viral hepatitides <ul><li>Staph aureus (toxic shock) </li></ul><ul><li>Gram-Negatives (cholangitis) </li></ul><ul><li>Parasitic: </li></ul><ul><ul><li>Malaria </li></ul></ul><ul><ul><li>Schistosomes </li></ul></ul><ul><ul><li>Liver flukes (Fasciola hepatica) </li></ul></ul><ul><li>Ameba (abscesses) </li></ul><ul><li>AUTOIMMUNE </li></ul><ul><li>ALCOHOLIC HEPATITIS </li></ul>
    63. 63. DRUGS/TOXINS <ul><li>Steatosis (ETOH) </li></ul><ul><li>Centrolobular necrosis (TYLENOL) </li></ul><ul><li>Diffuse (massive) necrosis </li></ul><ul><li>Hepatitis </li></ul><ul><li>Fibrosis/Cirrhosis (ETOH) </li></ul><ul><li>Granulomas </li></ul><ul><li>Cholestasis (BCPs, steroids) </li></ul>
    64. 64. “ Metabolic” Liver Disease <ul><li>Steatosis (i.e., “fat”, fatty change, fatty “metamorphosis”) </li></ul><ul><li>Hemochromatosis (vs. hemosiderosis) </li></ul><ul><ul><li>Hereditary (Primary) </li></ul></ul><ul><ul><li>Iron Overload (Secondary), e.g., hemolysis, increased Fe intake, chronic liver disease </li></ul></ul><ul><li>Wilson Disease (Toxic copper levels) </li></ul><ul><li>Alpha-1-antitrypsin ( NATURAL protease inhibitor) </li></ul><ul><li>Neonatal Cholestasis </li></ul>
    65. 65. PAS positive inclusions with alpha-1-antitrypsin deficiency
    67. 67. Points of Interest <ul><li>INTRA-hepatic vs. EXTRA-hepatic </li></ul><ul><li>PRIMARY biliary cirrhosis is a bona-fide AUTOIMMUNE disease of the INTRA-hepatic bile ducts </li></ul><ul><li>SECONDARY biliary cirrhosis is caused by chronic obstruction/inflammation/both of the intrahepatic bile ducts </li></ul><ul><li>CHOLANGITIS, or inflammation of the INTRA-hepatic bile ducts, is associated with chronic bacterial (often gram negative rods) infections, or Crohns/Ulcerative colitis (IBD) </li></ul>
    68. 68. CIRCULATORY Disorders
    69. 69. Points of Interest <ul><li>Infarcts are rare. WHY? </li></ul><ul><li>Passive congestion with “centrolobular” necrosis, is EXTREMELY COMMON in CHF, and a VERY COMMON cause of cirrhosis, i.e., “cardiac” cirrhosis </li></ul><ul><li>Various semi reliable clinical and anatomic findings are seen with disorders of: </li></ul><ul><ul><li>Portal Veins </li></ul></ul><ul><ul><li>Hepatic veins/IVC </li></ul></ul><ul><ul><li>Hepatic arteries </li></ul></ul>
    70. 70. MISC. <ul><li>Hepatic Diseases are seen often with </li></ul><ul><ul><li>Pregnancy </li></ul></ul><ul><ul><ul><li>PRE-Eclampsia/Eclampsia (HTN, proteinuria, edema, coagulopathies, DIC) </li></ul></ul></ul><ul><ul><ul><li>Fatty Liver </li></ul></ul></ul><ul><ul><ul><li>Cholestasis </li></ul></ul></ul><ul><ul><li>Transplant —Bone Marrow or other Organs </li></ul></ul><ul><ul><ul><li>Drug Toxicities </li></ul></ul></ul><ul><ul><ul><li>GVH </li></ul></ul></ul>
    71. 71. BENIGN LIVER TUMORS <ul><li>… ..are, in most cases, really regenerative nodules </li></ul><ul><li>Have been historically linked to BCPs </li></ul><ul><li>Can really be neoplasms of blood vessels also </li></ul>
    72. 72. MALIGNANT LIVER TUMORS <ul><li>99% are metastatic, i.e., SECONDARY, esp. from portal drained organs </li></ul><ul><li>Just about every malignancy will wind up eventually in the liver, like the lungs </li></ul><ul><li>PRIMARY liver malignancies, i.e., hepatomas, aka hepatocellular carcinomas, arise in the background of already very serious liver disease chronic hepatitis/cirrhosis, are slow growing, and do NOT metastasize readily </li></ul><ul><li>CHOLANGIOCARCINOMAS are malignancies if the INTRA-hepatic bile ducts and look MUCH more like adenocarcinomas than do hepatomas </li></ul>
    73. 73.
    78. 78.
    79. 79. MAIN CONSIDERATIONS <ul><li>Anomalies </li></ul><ul><li>Stones (Clolesterol/Bilirubin) </li></ul><ul><li>(Chole[docho]lithiasis) </li></ul><ul><li>Inflammation (Cholecystitis/Cholangitis) </li></ul><ul><li>Cysts </li></ul><ul><li>Neoplasms </li></ul>
    80. 80. Anomalies <ul><li>Congenitally absent Gallbladder </li></ul><ul><li>Duct Duplications </li></ul><ul><li>Bilobed Gallbladder </li></ul><ul><li>Phrygian Cap </li></ul><ul><li>Hypoplasia/Agenesis </li></ul>
    81. 81. Phrygian Cap
    82. 82. Cholelithiasis Factors <ul><li>Bile supersaturated with cholesterol </li></ul><ul><li>Hypomotility </li></ul><ul><li>Cholesterol “seeds” in bile, i.e., crystals </li></ul><ul><li>Excess mucous in gallbladder </li></ul>
    83. 83. Cholesterolosis of gallbladder mucosa
    84. 84. Cholesterolosis of gallbladder mucosa
    85. 85.
    86. 86.
    87. 87. Cholecystitis <ul><li>Acute: fever, leukocytosis, RUQ pain </li></ul><ul><li>Chronic: Subclinical or pain </li></ul><ul><li>Ultrasound can detect stones well </li></ul><ul><li>HIDA (biliary) nuclear study can help </li></ul><ul><li>Go hand in hand with stones in gallbladder or ducts </li></ul><ul><li>If surgery is required, most is laparoscopic </li></ul>
    88. 88. Choledochal Cysts <ul><li>Dilatations of the common bile duct usually in children. </li></ul>
    89. 89. Adenocarcinoma of the gallbladder
    90. 90. <ul><li>LIVER AND BILIARY TRACT </li></ul><ul><li>5 generalized disease patterns: </li></ul><ul><li>a) degeneration and intracellular accumulation </li></ul><ul><li>i) moderate swelling is reversible </li></ul><ul><li>ii) severe swelling (ballooning degeneration) </li></ul><ul><li>- “clumped” cytoplasmic organelles; large clear spaces </li></ul><ul><li>iii) Fe, Cu, fat accumulation </li></ul>
    91. 91. - “micro-” and “macro-” vesicular steatosis b) necrosis and apoptosis i) centrilobular necrosis c) inflammation i) hepatitis d) regeneration e) fibrosis i) irreversible damage ii) “scar” tissue is referred to as “cirrhosis”
    92. 92. <ul><li>Hepatic failure </li></ul><ul><li>a) functional capacity of 80-90% </li></ul><ul><li>b) 70-80% mortality without liver transplantation </li></ul><ul><li>c) massive hepatic necrosis </li></ul><ul><li>i) drugs, toxins </li></ul><ul><li>- acetominophen (~40%) </li></ul><ul><li>- halothane, anti-TB drugs, </li></ul><ul><li> CCl 4 , mushroom (Amanita phalloides) </li></ul><ul><li>ii) infections/inflammations </li></ul><ul><li>- HAV, HBV, unknown </li></ul>
    93. 93. d) chronic liver failure i) most common route - cirrhosis e) hepatic dysfunction without overt necrosis i) viable without normal function - Reye syndrome - tetracycline toxicity - acute steatosis of pregnancy
    94. 94. f) clinical: i) jaundice ii) hypoalbuminemia iii) impaired estrogen metabolism - hypogonadism - gynecomastia iv) MSOF susceptibility v) coagulopathy - II, VII, IX and X deficiency of clotting factors vi) death in weeks to months
    95. 95. vii) 2 grave complications: - hepatic encephalopathy neurotransmission disturbances of CNS and neuromuscular system. - hepatorenal syndrome severe renal failure without any intrinsic disorders. 1. Na + retention 2.  H 2 O excretion 3.  RBF 4.  GFR
    96. 96. <ul><li>Cirrhosis </li></ul><ul><li>a) main causes are ETOH and viral hepatitis (in Western World) </li></ul><ul><li>b) characteristics: </li></ul><ul><li>i) diffuse fibrosis </li></ul><ul><li>- “broad” linking scars </li></ul><ul><li>ii) parenchymal nodules </li></ul><ul><li>- balance between regeneration and scaring </li></ul><ul><li>iii) disruption of entire liver architecture </li></ul><ul><li>- revasculature (bypass) </li></ul>
    97. 97. c) cirrhosis essentially irreversible i) main pathogenic processes: - progressive fibrosis - vascular reorganization (blood shunted around parenchyma) ii) collagen deposits (via perisinusoidal satellite cells) - Types I and III d) may be clinically silent e) death: progressive liver failure, portal hypertension, CA
    98. 98.
    99. 99.
    100. 100. <ul><li>Portal Hypertension </li></ul><ul><li>a)  resistance to portal flow </li></ul><ul><li>i) prehepatic </li></ul><ul><li>- obstructive thrombosis </li></ul><ul><li>- stenosis </li></ul><ul><li>ii) intrahepatic </li></ul><ul><li>- cirrhosis (most causes of portal hypertension; compression of HV and  resistance from scaring) </li></ul><ul><li>iii) posthepatic </li></ul><ul><li>- right sided heart failure </li></ul>
    101. 101. b) clinical consequences i) ascites ii) portosystemic shunts iii) congestive splenomegaly iv) hepatic encephalopathy 1. ascites a) fluid accumulation of fluid in peritoneum b) Starling forces
    102. 102. 2. portosystemic shunts a) shunt flow where portal and systemic share common circulation i) rectum (hemorrhoids) ii) cardioesophageal junction - esophageal varices - massive hematemesis iii) periumbilical and abdominal collaterals - caput medusae
    103. 103. <ul><li>3. Splenomegaly </li></ul><ul><li>a) congestion </li></ul><ul><li>i) Starling forces </li></ul><ul><li>Jaundice </li></ul><ul><li>a) hepatic bile formation (bile salts) </li></ul><ul><li>i) emulsify dietary fats </li></ul><ul><li>ii) eliminate waste products </li></ul><ul><li>- primary bilirubin, cholesterol and xenobiotic elimination </li></ul>
    104. 104. b) bilirubin and bile formation i) bilirubin end product of heme degradation - senescent RBC’s - in spleen, liver and bone marrow - accounts for ~ 0.3 gm/day ii) most remainder of bilirubin - turnover of hepatic heme iii) heme  biliverdin (via heme oxidase)  bilirubin (via biliverdin reductase)
    105. 105. iv) bound to albumin (not soluble) - free may  in hemolytic diseases v) taken up by liver (carrier mediated), conjugated with glucuronic acid - H 2 O - secreted into bile - degraded by bacteria to urobilinogens - excreted in feces and urine - reab in ileum and colon
    106. 106.
    107. 107. <ul><li>Bile salts </li></ul><ul><li>a) major are cholic acid chenodeoxycholic acid </li></ul><ul><li>i) degrade lipids </li></ul><ul><li>Jaundice </li></ul><ul><li>a) both conjugated and unconjugated </li></ul><ul><li> may  systemically </li></ul><ul><li>i)  in tissues </li></ul><ul><li>- yellow color of skin </li></ul><ul><li>- or sclera (icterus) </li></ul><ul><li>b) unconjugated is insoluble, bound to albumin; not excreted in urine </li></ul>
    108. 108. i) small amount may diffuse into brain of infants  kernicterus -  in hemolytic diseases (erythroblastosis fetalis) c) conjugated is H 2 O soluble i) can be excreted in urine d) normal bilirubin = 0.3-1.2 mg/dl e) jaundice >2-2.5 mg/dl i) imbalance between production and clearance
    109. 109. 1. excess production 2. reduced hepatic uptake 3. impaired conjugation 4. decreased excretion 5. impaired bile flow f) 1-3 = unconjugated hyperbilirubinemia g) 4-5 = conjugated hyperbilirubinemia h) see table 18-3
    110. 110. <ul><li>specific types of jaundice </li></ul><ul><li>1) neonatal jaundice </li></ul><ul><li>i) conjugation/excretion develops ~ 2 weeks after birth </li></ul><ul><li>ii) almost all newborns develop neonatal jaundice or physiologic jaundice of the newborn </li></ul><ul><li>a) breast fed  jaundice </li></ul><ul><li>i) β -glucuronidase </li></ul><ul><li>- deconjugates bilirubin glucuronides in gut </li></ul>
    111. 111. 2) hereditary hyperbilirubinemia a) genetic deficiency of UGT1A1 i) Crigler-Nijar syndrome typeI - absent UGT1A1 - fatal ii) Crigler-Nijer syndrome typeII - reduced UGT1A1 - mild - may develop kernicterus iii) Gilbert syndrome - mild jaundice - innocuous
    112. 112. iv) Dubin-Johnson syndrome - excretion problem - conjugated bilirubin v) Rotor syndrome - decreased uptake and excretion vi) see table 18-4
    113. 113. <ul><li>Cholestasis </li></ul><ul><li>a) Cholestasis simply means failure of flow of bile. The cause of this failure can arise anywhere in the biliary system, from the liver cell down to the ampulla of Vater. For clinical purposes it is easiest to think of cholestasis as being either intra- or extrahepatic </li></ul><ul><li>b) may present with jaundice </li></ul><ul><li>c) pruritis common presenting sign </li></ul><ul><li>d) skin xanthomas  cholesterol </li></ul>
    114. 114. e) classic lab test is  Alk. Phos. i) detergent effects of retained bile salts. ii) must verify hepatic in nature - several isoforms iii) nutritional deficiencies of Vit A, D and K - malabsorption from gut f) extrahepatic (obstruction) i) surgery to correct g) intrahepatic not helped with surgery (see table 18-5)
    115. 115. <ul><li>Causes: (cholestasis) </li></ul><ul><li>a) intrahepatic </li></ul><ul><li>i) Common - Viral hepatitis - Drugs - Alcoholic hepatitis ± cirrhosis </li></ul><ul><li>b) extrahepatic </li></ul><ul><li>i) Common - Common bile duct stone(s) - Pancreatic/periampullary cancer </li></ul>
    116. 116. <ul><li>ALCOHOLIC LIVER DISEASE </li></ul><ul><li>Leading cause of liver disease in </li></ul><ul><li>Western World </li></ul><ul><li>a) ~ 14 million Americans categorized as alcohol abusers </li></ul><ul><li>i) 200,000 deaths/yr </li></ul><ul><li>3 overlapping forms of liver disease: </li></ul><ul><li>a) hepatic steatosis </li></ul><ul><li>b) alcoholic hepatitis </li></ul><ul><li>c) cirrhosis </li></ul>
    117. 117.
    118. 118. 1. hepatic steatosis a) moderate amounts of ETOH intake  small lipid droplets (microvesicular) b) chronic etoh intake  large lipid globules (macrovesicular) i) compressing and displacing nucleus to periphery of hepatocyte ii) initially centrilobular iii) may involve entire lobe of liver with progression
    119. 119. Alcoholic liver disease: macrovesicular steatosis, involving most regions of the hepatic lobule. The intracytoplasmic fat is seen as clear vacuoles. Some early fibrosis (stained blue) is present (Masson trichrome).
    120. 120. The cluster of inflammatory cells marks the site of a necrotic hepatocyte. A Mallory body is present in a second hepatocyte ( arrow ).
    121. 121. iv) fibrosis with chronic etoh use v) reversible changes with abstinence from etoh 2. alcoholic hepatitis a) swelling of hepatocytes i) single or scattered foci ii) swelling due to fat and H 2 O iii) mild hemosiderin deposits iv) Mallory inclusions - eosinophilic cytoplasm - not specific (also seen in Wilson disease, cholestasis
    122. 122. 3. alcoholic cirrhosis a) irreversible and final form of alcoholic liver disease b) nodule formation (micro and macro) c) fibrosis d) deranged vascular perfusion
    123. 123. The characteristic diffuse nodularity of the surface reflects the interplay between nodular regeneration and scarring. The greenish tint of some nodules is due to bile stasis.
    124. 124. The microscopic view shows nodules of varying sizes entrapped in blue-staining fibrous tissue.
    125. 125. <ul><li>Pathogenesis </li></ul><ul><li>a) 8 beers or 7 oz. 80 proof etoh/day </li></ul><ul><li>i) mild liver changes (reversible) </li></ul><ul><li>- fatty liver </li></ul><ul><li>b) 160 gms/day for 10-20 yrs </li></ul><ul><li>i) severe injury </li></ul><ul><li>c) ~ 15% of alcoholics develop cirrhosis </li></ul><ul><li>d) women more susceptible </li></ul><ul><li>e) cirrhosis may develop without </li></ul><ul><li> any injury such as steatosis or </li></ul><ul><li> alcoholic hepatitis ! </li></ul>
    126. 126. <ul><li>hepatocellular steatosis: </li></ul><ul><li>a) shift of fat metabolism from catabolism to fat biosynthesis </li></ul><ul><li>i) generates excess NADH + H </li></ul><ul><li>- alcohol dehydrogenase </li></ul><ul><li>- acetaldehyde dehydrogenase </li></ul><ul><li>b) impaired biosynthesis and secretion of lipoproteins </li></ul><ul><li>c) increased peripheral catabolism of fat </li></ul>
    127. 127. <ul><li>etoh-induced impaired metabolism of </li></ul><ul><li>methionine </li></ul><ul><li>a ) decreased intrahepatic glutathione </li></ul><ul><li>i) oxidative injury </li></ul><ul><li>induction of cytochrome P-450 </li></ul><ul><li>(CYP2E1) </li></ul><ul><li>a) toxic drug metabolites </li></ul><ul><li>i) e.g., acetaminophen </li></ul><ul><li>ii) O 2 free radicals </li></ul><ul><li>etoh directly affects microtubules and </li></ul><ul><li>mitochondria and membrane fluidity </li></ul><ul><li>acetaldehyde induces lipid peroxidation </li></ul>
    128. 128. <ul><li>etho major source of calories in </li></ul><ul><li>alcoholics </li></ul><ul><li>a) nutritional deficiencies </li></ul><ul><li>i) B12 and folate </li></ul><ul><li>etoh directly causes LPS release into </li></ul><ul><li>portal circulation </li></ul><ul><li>a) activates inflammation within liver </li></ul><ul><li>directly releases endothelins </li></ul><ul><li>a) potent vasoconstrictor </li></ul><ul><li>b) regional hepatic hypoxia </li></ul>
    129. 129. <ul><li>alcoholic liver disease: </li></ul><ul><li>a) chronic disease: </li></ul><ul><li>i) steatosis </li></ul><ul><li>- hepatomegaly with </li></ul><ul><li> increased bilirubin and </li></ul><ul><li> ALK phosphatase </li></ul><ul><li>ii) hepatitis </li></ul><ul><li>- acute change </li></ul><ul><li>- malaise, wt loss </li></ul><ul><li>iii) progressive fibrosis </li></ul>
    130. 130. iv) cirrhosis - distended abdomen - wasted extremities - caput medusae - LABS: ALK phos (variable) aminotransferase bilirubin hypoproteinemia (all) anemia v) vascular derangements
    131. 131. <ul><li>causes of death: </li></ul><ul><li>a) hepatic coma </li></ul><ul><li>b) massive GI hemorrhages </li></ul><ul><li>c) infection </li></ul><ul><li>d) hepatorenal syndrome </li></ul><ul><li>e) CA (3-6%) </li></ul>
    132. 132. <ul><li>METABOLIC LIVER DISEASE </li></ul><ul><li>nonalcoholic fatty liver disease and </li></ul><ul><li>steatohepatitis </li></ul><ul><li>a ) similar to alcoholic liver disease </li></ul><ul><li>i) occurs at lower alcohol consumption </li></ul><ul><li>b) associated with </li></ul><ul><li>i) obesity </li></ul><ul><li>ii) type 2 diabetes </li></ul><ul><li>c) is a Dx of exclusion </li></ul><ul><li>d) asymptomatic except for lab values (ALT, AST, etc.) </li></ul>
    133. 133. <ul><li>hemochromatosis </li></ul><ul><li>a) excessive accumulation of body iron. Deposited mainly in: </li></ul><ul><li>i) liver </li></ul><ul><li>ii) pancreas </li></ul><ul><li>b) results mainly from genetic defects causing: </li></ul><ul><li>i) excess iron absorption </li></ul><ul><li>ii) parenteral administration </li></ul><ul><li>- transfusions </li></ul><ul><li>c) hereditary hemochromatosis </li></ul><ul><li>i) homozygous recessive </li></ul>
    134. 134. <ul><li>d) acquired hemochromatosis </li></ul><ul><li>i) “secondary” hemochromatosis </li></ul><ul><li>ii) see table 18-9 </li></ul><ul><li>Total body iron </li></ul><ul><li>a) 2-6 gms (normal) </li></ul><ul><li>i) 0.5 gms in liver </li></ul><ul><li>- 98% in hepatocytes </li></ul><ul><li>b) hemochromatosis </li></ul><ul><li>i) > 50 gms </li></ul><ul><li>- > 33% stored in liver </li></ul>
    135. 135. <ul><li>clinical (hemochromatosis) </li></ul><ul><li>a) micronodular cirrhosis in all patients </li></ul><ul><li>b) diabetes mellitus in ~ 80% </li></ul><ul><li>c) skin pigmentation in ~ 80% </li></ul><ul><li>d) lifelong accumulation </li></ul><ul><li>i) appearing in 5 th to 6 th decades </li></ul><ul><li>e) hemochromatosis gene  6 (p21.3) </li></ul><ul><li>i) regulated dietary iron absorption </li></ul><ul><li>ii) causes 1gm/day accumulation </li></ul><ul><li>f) S&S after 20 gm accumulation </li></ul>
    136. 136. g) excess iron is directly toxic i) lipid peroxidation - via Fe-induced free radical ii) stimulation of collagen formation iii) O 2 free radicals and iron interact with DNA  lethal injury - predisposing to hepatocellular CA iv) removing excess iron is Tx in cells not irreversible damaged
    137. 137. h) most common 2 o hemochromatosis i) hemolytic anemias associated with ineffective erythropoiesis i) most common sites for hemosiderin deposition (decreasing order) i) liver ii) pancreas iii) myocardium iv) pituitary gland v) adrenals vi) thyroid, parathyroid vii) joints and skin
    138. 138. <ul><li>Wilson disease </li></ul><ul><li>a) accumulation of toxic levels of Cu ++ </li></ul><ul><li> in liver, brain and eye </li></ul><ul><li>b) 40-60% Cu ++ absorbed in stomach </li></ul><ul><li> and duodenum (~ 2-5 gms) </li></ul><ul><li>i) transported to liver on albumin </li></ul><ul><li>ii) resecreted into blood as ceruloplasmin (90-95% of plasma copper) </li></ul><ul><li>c) Cu ++ excreted in bile (after normal aging process of proteins - albumin) 40-150 mg total body Cu ++ </li></ul>
    139. 139. d) gene for Wilson disease  13 e) when excretion is defective i) Cu ++ spills over into blood -  urinary excretion ii) causes direct toxic effects - hemolysis - organ dysfunction f) rare before 6 yrs.
    140. 140. g) most common presentation i) acute/chronic liver disease ii) neuropsychiatric (behavioral) iii) Dx   urine Cu ++ ,  serum ceruloplasmin,  hepatic Cu ++ iv) plasma Cu ++ NOT useful !! v) “Kayser-Fleischner” rings - green to brown deposits in cornea h) D-penicillamine Tx (Cu ++ chelator)
    141. 141. <ul><li> - 1 antitrypsin deficiency </li></ul><ul><li>a) autosomal recessive </li></ul><ul><li>b) important protease inhibitor </li></ul><ul><li>i) primarily elastase, cathepsin G </li></ul><ul><li> and proteinase 3 </li></ul><ul><li>- released from neutrophils </li></ul><ul><li> during inflammation </li></ul><ul><li>c) formed on chromosome 14 </li></ul><ul><li>i) “Pi”  protein inhibitor </li></ul><ul><li>ii) most important variant is PiZZ </li></ul><ul><li>- only 10% of normal  - 1AT </li></ul>
    142. 142. d) Most commonly diagnosed genetic liver disease in infants and children e) clinical: i) neonatal hepatitis with cholestatic jaundice  10-20% ii) older children  hepatitis or cirrhosis iii) adults  emphysema
    143. 143. <ul><li>neonatal cholestasis </li></ul><ul><li>a) see table 18-10 </li></ul><ul><li>b) idiopathic neonatal hepatitis and </li></ul><ul><li> biliary atresia share similar clinical </li></ul><ul><li> S&S </li></ul><ul><li>i) need to Dx for adequate Tx </li></ul>
    144. 144. <ul><li>Intrahepatic biliary tract disease </li></ul><ul><li>1 o and 2 o biliary cirrhosis </li></ul><ul><li>1 o sclerosing cholangitis </li></ul><ul><li>see table 18-11 </li></ul><ul><li>1 o biliary cirrhosis </li></ul><ul><li>a) destruction of intrahepatic biliary tree </li></ul><ul><li>i) portal inflammation and scaring </li></ul><ul><li>ii) cirrhosis and liver failure </li></ul><ul><li>b) chronic, progressive and often fatal </li></ul>
    145. 145.
    146. 146. c) major features are: i) nonsuppurative inflammation ii) destruction of medium sized bile ducts d) mainly in middle aged women (6:1) i) peak between 40-50 yrs e) initial presentation is pruritis i) jaundice late in course ii) hepatomegaly is typical iii) xanthomas due to cholesterol f) antimitochondrial Ab in > 90% i) against PDH complex E 2 subunit
    147. 147. g) clinical: i) autoimmune disease ii) sicca complex - dry eyes and mouth iii) etiology remains unclear - lack of “trigger(s)” iv) causes of death: - liver failure  - portal hypertension and variceal bleeding - infection
    148. 148. <ul><li>2 o biliary cirrhosis </li></ul><ul><li>a) prolonged obstruction of extrahepatic bile tree </li></ul><ul><li>b) most common causes </li></ul><ul><li>i) cholelithiasis (gallstones) </li></ul><ul><li>ii) malignancies of biliary tree or head of pancreas </li></ul><ul><li>iii) strictures </li></ul><ul><li>- following previous surgery </li></ul><ul><li>c) obstructions in children </li></ul><ul><li>i) atresia </li></ul><ul><li>ii) cystic fibrosis and cyst </li></ul>
    149. 149. <ul><li>d) secondary inflammation can cause </li></ul><ul><li> periportal fibrosis  hepatic </li></ul><ul><li> scaring and nodule formation  </li></ul><ul><li> 2 o biliary cirrhosis </li></ul><ul><li>1 o sclerosing cholangitis </li></ul><ul><li>a) inflammation  </li></ul><ul><li>b) obliterative fibrosis </li></ul><ul><li>i) intra- and extrahepatic bile ducts </li></ul><ul><li>ii) dilation of preserved segments </li></ul>
    150. 150. c) 1 o seen in association with inflammatory bowel disease i) UC - ~75% coexistence ii) only ~4% of patients with UC have have coexistence of 1 o sclerosing cholangitis d) etiology unknown i) association with IBD e) liver transplant is Tx
    151. 151. <ul><li>Circulatory disorders </li></ul><ul><li>pre, intra and post hepatic circulatory </li></ul><ul><li>disorders </li></ul><ul><li>impaired blood flow into liver </li></ul><ul><li>1- hepatic artery </li></ul><ul><li> a) infarcts are rare ! Localized infarcts due to: </li></ul><ul><li>i) thrombosis </li></ul><ul><li>ii) compressive neoplasms </li></ul><ul><li>iii) emboli </li></ul><ul><li>iv) sepsis </li></ul>
    152. 152. b) loss of hepatic artery flow does not always cause infarct i) sufficient collaterals ii) exception is transplanted liver (thrombosis causes infarct) 2 – portal vein a) abdominal pain b) ascites c) similar to portal hypertension i) esophageal varices - prone to rupture
    153. 153. d) extrahepatic portal vein obstruction: i) Banti syndrome - neonatal umbilical sepsis - umbilical catheterization ii) peritonitis - pylephlebitis iii) thrombogenic disorders iv ) trauma v) pancreatitis - splenic vein thrombosis to portal vein
    154. 154. e) portal vein thrombus  NO infarct i) red-blue discolorization which is well demarcated - “ infarct of Zahn” ii) severe hepatocellular atrophy f) neoplastic obstruction 3 – intrahepatic a) most common cause is cirrhosis b) sickle cell disease c) DIC i) eclampsia of pregnancy d) obstructive neoplasms
    155. 155. e) passive congestion and centrilobular necrosis i) CHF (R-sided) - cardiac cirrhosis ii) CHF (L-sided) - ischemic damage - centrilobular necrosis - “nutmeg” liver f) peliosis hepatis i) 1 o sinusoidal dilation (rare) ii) usually exposure to anabolic steroids
    156. 156. 4 – hepatic vein obstruction a) single vein obstruction i) is silent b) 2 or more major hepatic veins (“ Budd-Chiari syndrome ”) i) hepatomegaly ii) pain iii) ascites iv)  intrahepatic BP
    157. 157. c) venous thrombosis associated with i) myeloproliferative disorders ii) inherited disorders of coagulation iii) PNH iv) hepatocellular CA d) BC pills and pregnancy i) with underlying thrombotic disorders e) if untreated  mortality is high f) veno-occlusive disease i) following bone marrow trans.
    158. 158. <ul><li>Hepatic Disease Associated With Pregnancy </li></ul><ul><li>Preeclampsia </li></ul><ul><li>a) ~ 10 % of pregnancies </li></ul><ul><li>i) hypertension </li></ul><ul><li>ii) proteinuria </li></ul><ul><li>iii) peripheral edema </li></ul><ul><li>iv) coagulopathy (DIC) </li></ul><ul><li>Eclampsia </li></ul><ul><li>a) same as preeclampsia with </li></ul><ul><li>i) seizures and hyperreflexia </li></ul>
    159. 159. <ul><li>Clinical ( HELLP syndrome) </li></ul><ul><li>a) hemolysis </li></ul><ul><li>b)  hepatic enzymes </li></ul><ul><li>c)  platelets </li></ul><ul><li>Acute Fatty Liver </li></ul><ul><li>a ) may be similar presentation to pre- or eclampsia </li></ul><ul><li>i) Tx is termination of pregnancy </li></ul><ul><li>b) fetus (rare) causing hepatic failure in mother </li></ul>
    160. 160. <ul><li>Neoplasms </li></ul><ul><li>Benign </li></ul><ul><li>a) cavernous hemangiomas </li></ul><ul><li>i) most common </li></ul><ul><li>- no percutaneous biopsy </li></ul><ul><li>- do not mistake for metastatic tumors </li></ul><ul><li>b) liver cell adenomas </li></ul><ul><li>i) develop from hepatocytes </li></ul><ul><li>ii) young women (BC pills) </li></ul>
    161. 161. <ul><li>Malignancies </li></ul><ul><li>a) most often metastatic site (lungs also !) </li></ul><ul><li>b) 1 o CA of liver are rare in USA and Western Europe </li></ul><ul><li>i) hepatoblastoma </li></ul><ul><li>- most common in children </li></ul><ul><li>ii) angiosarcoma </li></ul><ul><li>- same as in other parts </li></ul><ul><ul><ul><ul><ul><li>vinyl chloride, arsenic </li></ul></ul></ul></ul></ul><ul><li>c) most arise from hepatocytes </li></ul><ul><li>i) hepatocellular CA (HCC) </li></ul>
    162. 162. <ul><li>d) less common from bile duct </li></ul><ul><li>i) cholangiocarcinoma </li></ul><ul><li>Hepatocellular Carcinoma (HCC) </li></ul><ul><li>a) Asian (~ 75% of all HCC) </li></ul><ul><li>b) > 85% of HCC occur in countries with high rates of chronic HBV </li></ul><ul><li>c) when HBV is not prevalent, ~ 90 % of HCC occur in patients with cirrhosis </li></ul><ul><li>Pathogenesis: 3 main etiologies </li></ul><ul><li>1) viral (HBV, HCV); 2) chronic etoh; </li></ul><ul><li>3) food contamination (aflatoxins) </li></ul>
    163. 163. <ul><li>Clinical </li></ul><ul><li>a)   -fetoprotein in ~ 75% </li></ul><ul><li>b) palpable irregular mass </li></ul><ul><li>c) metastasis 1 st to lung then to other parts </li></ul><ul><li>d) death from: </li></ul><ul><li>i) cachexia </li></ul><ul><li>ii) variceal bleeding </li></ul><ul><li>iii) liver failure with coma </li></ul><ul><li>iv) rupture of tumor with fatal hemorrhage </li></ul>
    164. 164. <ul><li>Metastatic tumors </li></ul><ul><li>a) more common than 1 o tumors </li></ul><ul><li>i) multiple nodular metastases </li></ul><ul><li>ii) hepatomegaly </li></ul>