Liver Pathology II.pdf

Liver Pathology II: Cirrhosis, Jaundice, Wilson’s Dz Liver Cirrhosis Live inflammation and damage causes liver to be fibrotic and develop scar tissue Most common risk factors: o Excessive alcohol consumption o Prolonged viral attack like HBV, HCV, HDV o Medications o Drugs o Fatty liver (NASH) Prese...

Liver Pathology II: Cirrhosis, Jaundice, Wilson’s Dz Liver Cirrhosis Live inflammation and damage causes liver to be fibrotic and develop scar tissue Most common risk factors: o Excessive alcohol consumption o Prolonged viral attack like HBV, HCV, HDV o Medications o Drugs o Fatty liver (NASH) Presence of: o Regenerative nodules (micro, macro) o Fibrotic tissue and collagen btwn nodules o Tissue is thick w lots of proteins that can lead to fibrotic or scar formation Considered end stage liver damage, not reversible HSC in healthy tissues: Store vitamin A Quiescent or Dormant mode Natural wound healing Cirrhosis Fibrotic Tissue Formation When injured fibrosis is mediated by special cells called hepatic stellate cells (HSC) HSC sit between the sinusoids and hepatocyte, known as the perisinusoidal space Stellate cells (perisinusoidal space) Injured tissues: merge sinusoid endothelial cells w o Hepatocyte secrete paracrine factors that activate the HSC (can lead to Vit A Deficiency) central vein § Once HSC are activated, they lose vitamin A § Proliferate and secrete TGF-β1à produce collagen (main ingredient of ECM, fibrosis and scar tissue) o As fibrotic tissue builds up it compress the central veins and sinusoids o Constant injury when HSC are activated ↑ collagen and other extracellular components that lead to fibrosis. Cirrhosis Complications (boards) Portal HTN o Sinusoids and portal vein become compressed, push on the fluid inside o Pressure start to build up à Intrasinusoidal or portal HTN Ascites o High portal vein pressure à fluid in blood vessels pushed into tissues and across tissues into large open spaces (peritoneal cavity) à excess peritoneal fluid leads to ascites o Congestive splenomegaly: Enlarged spleen due to all fluid and blood backing up from liver to spleen Esophageal Varices o To alleviate the increased pressure within the portal vein o Blood seeks alternative pathways to return to the systemic circulation o Collateral vessels form, attempting to bypass the obstructed flow within the liver. Portosystemic Shunt o Circulatory system divert blood away from the liver due to high liver pressure o Blood follows the path of least resistance shunting away from portal to systemic circulation (towards the heart) Hepatorenal Failure o Changes in portal flow trigger renal vasoconstriction o Low kidney blood flow à reduced filtration à kidney failure followed by liver failure Hepatic Encephalopathy o Low/loss of liver function à less detoxification à Toxins accumulate and gets into the brain à mental deficit Asterixis (ammonia leak) o Ammonia leaks from liver into circulation, reaches brain leading to tremoring or jerky hands when outstretched o More toxins build up à Coma Decrease Estrogen Metabolism o Liver metabolizes estrogen into inactive metabolites, by removing from blood and excreted o Liver damage à increased estrogen in blood can cause: § Gynecomastia (hormonal imbalance from high estrogen) § Spider angiomata (cluster of blood vessels) § Palmar erythema Jaundice: Increase CB and UB (from dead hepatocytes) Hypoalbuminemia Increase Liver Enzymes: ALT, AST, GGT, ALP Bleeding: Less clotting factor production Cirrhosis Symptoms Compensated (Early Stage) o Early with small amount of scarring and fibrosis o Liver can still function o Asymptomatic or non-specific symptoms: weight loss, weakness or fatigue Decompensated o Extensive fibrosis o Liver can’t function o All listed complications and symptoms Micro and macro nodules still present w surrounding collagen Cirrhosis Diagnosis and Treatment Diagnosis o Gold Standard = liver biopsy o Common lab findings: § Elevated serum bilirubin (C and UB) § Elevated liver enzymes (AST > ALT, ALP and GGP) § Thrombocytopenia (low platelet count) Treatment o Focus on underlying causes leading to cirrhosis o Liver scarring is irreversible o Prevent further dmg by treating underlying cause § Stop alcohol consumption (toxic and inflammatory) § Antiviral tx (HBV, HDV, HCV) o Advanced cirrhosis: liver transplant Jaundice Retention of bilirubin: causes yellow discoloration of skin, mucous membranes, eyes (conjunctiva over sclera) Bilirubin metabolism in normal conditions: CB gives color to urine o RBC are eaten by macrophages (120 days) o Hemoglobin breakdown to heme, globin UB is NOT water soluble, making it § Globin à amino aicds the only variant the kidneys can § Heme à Fe and protoporphyrin à UB filter out o Albumin binds to UB and takes it to hepatocytes o Uridine glucuronyl transferase (UGT) enzyme conjugates UB à CB o CB is secreted out in bile canaliculi (drain into bile ducts and sent to gall bladder for storage) o After a meal, bile with CB move through common bile duct to duodenum and is converted into urobilinogen. o Part of urobilinogen is then reduced to stercobilin (pigment of brown feces) o And other is recycled back, reabsorbed in the blood, sent to the kidneys for Urine excretion (yellowness of urine) Disrupted Bilirubin metabolism/liver damage: o Can’t conjugate bilirubinà release UB in circulation o Hepatocyte die à release their CB in circulation o Increase of UB, CB or both in blood o Deposits on eye and skin tissues àyellow color § Yellow Sclera is an early sign bc elastin protein has high affinity for bilirubin Normal total serum bilirubin level: 0.3-1.2 mg/dl Jaundice serum bilirubin levels > 2.0-2.5 mg/dl Jaundice: High UB Jaundice can be caused by increase UB or CB or both in the blood Disorders that cause increase UB: o Extravascular hemolytic anemia (RBCs broken down earlier than normal) o Ineffective hematopoiesis (blood cells incorrectly formed in marrow, macrophages break them down) o For both: RBCs broken down, cause high levels of UB § Hepatocytes can convert a limited amount of UB to CB per minute When more RBC are broken down: o Hepatocyte CANNOT conjugate all UB, so some UB stays in the blood o Liver max out, a lot of CB goes to the bile (increases risk of bilirubin gallstone) Once CB sent to duodenum: o Converted to urobilinogen o Some recycled back to blood and sent to kidneys (causes dark urine color) o UB deposits in different tissues of body Physiologic Jaundice of Newborns o Hepatocytes can’t conjugate enough UB to keep normal load § Newborn livers have a lower amount of UGT to convert UB o After birth: § UB high due to natural process of macrophages destroying fetal RBC o If UB too high: § Kernicterus (collect in brain’s basal ganglia) causes brain dmg/death o Treatment: Phototherapy § Light induces structural change in bilirubin § New shape more soluble, excretable § Effective and non-invasive method of tx Jaundice: High CB Dubin-Johnson o Autosomal recessive deficiency in MRP2 § CB buildup in hepatocytes § MRP3 dysregulated, moves into interstitial space opposed to bile canaliculus § ↑ CB in blood also excreted into urine causes dark urine and dark liver (Liver can still do UB à CB) Obstructive Jaundice o Blockage of bile flow § Gall stones, pancreatic carcinomas, cholangiocarcinoma, parasites o Bile made of CB § Blockage causes ↑ pressure in bile duct § Bile leaks thru tight junctions btwn hepatocytes § Bile acids, salts, cholesterol leak into blood o Complications: § Pruritis § Hypercholesterolemia § Xanthoma (fatty skin lesion) § Dark urine § Steatorrhea § Fat-Soluble vitamin deficiency o Tx § Surgery § Nutrient dense diet (high fiber) § Hydrate Jaundice: High UB and CB Viral Hepatitis (A, B, C, D, E) o ↑ CB and UB in blood o Damaged hepatocytes die off and cannot conjugate UB = ↑ UB o Damaged hepatocytes of bile ducts die letting CB leak out = ↑ CB (More CB excreted, darker urine) Wilson Dz Copper: Essential mineral that our body needs to get through our diet We take in about 1 to 2 mg per day from food o Body needs about 0.75 mg/day so that extra copper is excreted o Whole grains, beans, nuts, and potatoes o 90% copper is excreted into bile (fecal copper) and the other 10% is excreted in urine Wilson’s disease is an autosomal genetic defect o Characterized by accumulation of copper in various tissues (brain, liver, eyes, etc,.) o Free copper reacts w hydrogen peroxide in bodyà OH radical, ROS forms à Tissue dmg by free radical generation Hepatocyte play a major role in helping body shed excess copper o Copper from diet is metabolized in stomach, small intestine via enterocytes o Passed off into the portal vein to the liver o Once in the liver, sent to transport protein ATP7b o ATP7B Function: § Binds copper to apocelluloplasmin (copper carrying protein) in blood, responsible for carrying 95% of the copper in the blood — Once bound called ceruloplasmin, can hold 6 molecules of copper § Gather up the rest of the copper into vesicles to be exocytosed into the bile caniculi where it goes into the bile and is eventually excreted Wilson disease o Autosomal defect in the ATP7B transport protein o Copper build-up in hepatocyte makes free radicals o Hepatocytes injury/death = free copper to spill out in interstitial space, can access blood supply o Once in the blood, free copper circulate and deposited into different tissues, damaging them Tissues: o Liver § Early sign § Progress from acute hepatitis to cirrhosis and liver failure o Brain: § Basal ganglia: movement disorder like parkinsonism § Cerebral cortex: toxic to neurons è neuronal death and dementia o Descemet’s membrane of the cornea § Deposited in basement membrane of cornea § Kayser-Fleischer ring (green to brownish ring) Other complications: o Enlarged liver and spleen (hepatosplenomegaly) o Renal disease due to damage to the proximal tubule of the kidney o Hemolytic anemia due to the direct damage that circulating free copper causes to RBC Diagnosis o Decrease level of ceruloplasmin in the blood o High level of free copper in the blood and urine Treatment o Penicillamine (copper chelating agent) o Zinc and ammonium tetrathiomolybdate (Prevents copper reabsorption from urine) o Liver transplant (liver failure)