Pathology Ch18 -- Liver and Gallbladder -- part pp821-830
The Liver and Bile Ducts
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Adult liver weighs 1400-1600g
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Blood flows from portal vein (60-70%) and hepatic artery (30-40%)
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Lobular model: o Liver divided into 1-2mm diameter lobules oriented around terminal tributaries of hepatic vein o Centrilobular = hepatocytes in the vicinity of the terminal vein o Periportal = hepatocytes near the portal tract o Hepatocytes organized into anastomosing sheets extending from portal tracts to terminal hepatic veins o Between the trabecular plates are vascular sinusoids, lined by fenesterated endothelial cells o Kupffer cells (phagocyte system) attached to luminal face of endothelial cells o Space of Disse beneath endothelial cells contain hepatic stellate cells o Bile canaliculi found between abutting hepatocytes > drain into canals of Hering > bile ductules > terminal bile duct
General Features of Liver Disease
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Tests for Liver Disease: o Hepatocyte integrity
 Cytosolic hepatocellular enzymes
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Serum aspartate aminotransferase (AST)
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Serum alanine aminotransferase (ALT)
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Serum lactate dehydrogenase (LDH) o Biliary excretory function
 Substances normally secreted in bile
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Serum bilirubin o Total: unconjugated and conjugated o Direct: conjugated
 Urine bilirubin
 Serum bile acids
 Plasma membrane enzymes (from damage to bile canaliculus)
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Serum alkaline phosphate
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Serum γ-glutamyl transpeptidase (GGT) o Hepatocyte synthetic function
 Proteins secreted into the blood
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Serum albumin
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Coagulation factors > PT/PTT
 Hepatocyte metabolism
 Serum ammonia
 Aminopyrine breath test (hepatic demehtylation)
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Mechanisms of Injury and Repair o Hepatocyte and Parenchymal Responses
 Reversible injury: steatosis (fat accumulation) and cholestasis (bilirubin accumulation)
 Necrosis: cell swells due to defective osmotic regulation > leak contents (marked by macrophage present)
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Confluent necrosis: widespread parenchymal loss, noted by severe zonal loss of hepatocytes o From acute toxic or ischemic injuries, or several vital or autoimmune hepatitis
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Bridging necrosis: necrotic zone links central vein to portal tract or bridges adjacent portal tracts
 Apoptosis: programmed death (due to caspase cascade) > hepatocyte shrinkage, nuclear chromatin condensation (pyknosis), fragmentation (karyorrhexis) and cellular fragmentation into apoptotic bodies
 Regeneration of lost hepatocytes via mitotic replication of adjacent hepatocytes
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Stem cell replenishment usually not a significant part of parenchymal repair o Scar Formation and Regression
 Hepatic stellate cells are principal cells of scar deposition
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Quiescent form: stores lipids (vitamin A)
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Acute or chronic injury > increased expression of platelet-derived growth factor receptor β
(PDGFR-β) + release of cytokines/chemokines from Kupffer cells/lymphocytes > activate stellate cells > converted into highly fibrogenic myofibroblasts o (1) Chronic inflammation, /w production of inflammatory cytokines
 TNF, lymphotoxin, IL-1 β, and lipid peroxidation products

o (2) Cytokine and chemokine productions by Kupffer cells, endothelial cells, hepatocytes, and bile duct endothelial cells
 Transforming growth factor β (TGF-β), metalloproteinase 2 (MMP-2), tissue inhibitors of metalloproteinases 1 and 2 (TIMP-1 and -2) o (3) Response to disruption of ECM o (4) Direct stimulation by toxins
 If chronic injury is interrupted > stellate cell activation ceases > scars broken down/reversed o Inflammation and Immunity
 Antigens are taken up by Kupffer cells and blood-derived dendritic cells > presented to lymphocytes
 Toll-like receptors detect host molecules and those derived from foreign invaders
 Leads to elaboration of proinflammatory cytokines > recruitment of inflammatory cells/hepatocyte injury/vascular disturbances/promote scarring
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Liver Failure (80-90% function lost) o Acute Liver Failure (aka fulmitant liver failure)
 Acute liver illness associated w/ encephalopathy and coagulopathy that occurs within 26 weeks of initial liver injury in absence of pre-existing liver disease
 Caused by massive hepatic necrosis, often induced by drugs or toxins
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Acetaminophen accounts for 50% of cases > liver failure occurs within a week of symptom onset
Remainder from hepatitis A/B > disease takes longer to progress
 Morphology:
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Broad regions of parenchymal loss surrounding islands of regenerating hepatocytes
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Livers are small and shrunken
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Poisoning of liver cells can occur w/o obvious cell death (ex. diffuse microvesicular steatosis)
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Immunodeficiency can lead to histological features specific to type of virus infection
 Clinical Course:
 Manifests w/ nausea, vomiting, jaundice > progresses to encephalopathy, coagulation disorders o Serum liver transaminaes are markedly elevated o Liver initially enlarged due to hepatocyte swelling, inflammatory infiltrates, and edema o Liver shrinks as parenchyma is destroyed
 Alterations of bile formation and flow can lead to jaundice/icterus
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Hepatic encephalopathy = disturbances in consciousness o Elevated ammonia in the blood/CNS > impaired neuronal function and cerebral edema o Asterixis = nonrhythmic, rapid extension-flexion movements of the head and extremities
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Coagulopathy due to failure to produce clotting factors (easy bruising is early sign)
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Portal hypertension due to diminished flow> ascites, esophageal varices, hepatic encephalopathy
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Hepatorenal syndrome = sodium retention, impaired water excretion, decreased renal perfusion and glomerular filtration rate (drop in urine output and elevated BUN/creatinine is early sign) o Chronic Liver Failure and Cirrhosis
 Leading cause of chronic liver failure is hepatitis B/C, non-alcoholic fatty liver disease, and alcoholic liver disease (due to cirrhosis)
 NOTE: cirrhosis not always linked w/ chronic liver failure and sometimes present w/o chronic failure
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Cryptogenic cirrhosis = cirrhosis when there is no clear cause
 Child-Pugh classification system of cirrhosis
 Class A = well compensated
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Class B = partially decompensated
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Class C = decompensated
 Morphology:
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Cirrhosis occurs diffusely throughout the liver, comprised of regenerative parenchymal modules surrounded by dense bands of scar and variable degrees of vascular shunting
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Specific presentation of cirrhosis linked to different types of diseases
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Ductular reactions increase w/ advancing stage of disease and are most prominent in cirrhosis
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Rarely, regression of fibrosis can occur in established cirrhosis > cirrhosis should not be automatically equated w/ end stage disease
 Clinical Features:
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40% of individuals w/ cirrhosis are asymptomatic until the most advanced stages
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Causes of death in chronic liver failure as same as acute liver failure, along w/ hepatocellular carcinoma in the context of cirrhosis

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Impaired estrogen metabolism > hyperestrogenemia in male patients > palmar erythema and spider angiomas (central, pulsating, dilated arteriole) o Can lead to hypogonadism and gynecomastia o Portal Hypertension
 Prehepatic
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Obstructive thrombosis of portal vein
 Structural abnormalities such as narrowing of the portal vein before it ramifies in the liver
 Intrahepatic
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Cirrhosis from any cause***
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Nodular regenerative hyperplasia
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Primary biliary cirrhosis
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Schistosomiasis
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Massive fatty change
 Diffuse, fibrosing granulomatous disease (sarcoid)
 Infiltrative malignancy, primary or metastatic
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Focal malignancy w/ invasion into portal vein (hepatocellular carcinoma)
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Amyloidosis
 Posthepatic
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Severe right-sided heart failure
Constrictive pericarditis
 Hepatic vein outflow obstruction
 Pathophysiology:
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Increased resistance at level of sinusoids is due to contraction of vascular SM and myofibroblasts
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Disruption of blood flow caused by scarring and formation of parenchymal nodules
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Increase in portal blood flow due to hyperdynamic circulation (spanchnic vasodilation)
 Clinical Consequences:
 Ascites o Accumulation of excess fluid in the peritoneal cavity o 85% caused by cirrhosis o Generally serous (<3 gm/dL protein) o Neutrophils suggest infection, blood suggests cancer o Pathogenesis mechanism:
 Sinusoidal hypertension = drives fluid into space of Disse > removed by hepatic lymphatics
 Percolation of hepatic lymph into the peritoneal cavity = high increase in hepatic lymph flow w/ cirrhosis exceeds thoracic duct capacity
 Splanchnic vasodilation and hyperdynamic circulation = increaes perfusion pressure of interstitial capillaries > extravasation of fluid into abdominal cavity
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Portosystemic venous shunts o Rise in portal system pressure > flow reversed from portal to systemic circulation o Venous bypasses develop wherever the systemic and portal circulation share common capillary beds o Common sites: rectum (hemorrhoids), esophagogastric junction (varices), retroperitoneum, falciform ligament of liver, abdominal wall (caput medusae) o Esophagogastric varices appear in 40% of individuals w/ advanced cirrhosis > can cause massive metatemesis and death within 1/2
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Congestive splenomegaly o May induce thrombocytopenia or pancytopenia
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Hepatopulmonary syndrome o Seen in 30% of cirrhosis + portal hypertension o Develop intrapulmonary vascular dilations > blood flows rapidly through vessels > inadequate time for oxygen diffusion > hypoxia/dyspnea
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Portopulmonary hypertension o Manifests as dyspnea on exertion and clubbing of the fingers
Acute-on-Chronic Liver Failure
 Some patients w/ stable but well-compensated advanced liver disease suddenly develop signs of acute liver failure