SEARCH RESULTS FOR: hepatic encephalopathy

Hepatic Encephalopathy: Pathogenesis and Clinical Findings

Hepatic Encephalopathy: Pathogenesis and Clinical Findings Nicholls Chan Doherty Cheng portal systemic bypass congenital bypasses liver surgery blood flow delivery of toxins severe liver damage cirrhosis, acute liver failure decreased hepatocellular function toxin metabolism disordered metabolism and protein synthesis muscle atrophy extra-hepatic ammonia removal electrolyte dysregulation conversion NH4+ NH3

Acute Liver Failure: Pathogenesis and clinical findings

Acute Liver Failure: Pathogenesis and clinical findings Authors: Juliette Hall Reviewers: Vina Fan, Ben Campbell, Mayur Brahmania* * MD at time of publication Acetaminophen Overdose Accumulation of toxic NAPQI (a metabolite of acetaminophen) NAPQI binds hepatocellular proteins (see Acetaminophen Overdose: pathogenesis and clinical findings slide) Drug-induced liver injury Metabolism of drugs by the liver can produce reactive drug metabolites Intracellular stress, mitochondrial injury, or immune response Viral Hepatitis (i.e. HAV, HBV, HEV, HSV) Acute infection or infection flare provokes an immune response against infected hepatocytes Autoimmune Hepatitis Autoimmune antibodies attack hepatocytes (see Auto-immune Hepatitis (AIH) slide) Ischemia (i.e. from shock) ↓ O2 delivery to the liver Hepatocellular hypoxia Wilson’s Disease Heritable mutation in the ATP7B gene ↓ Biliary excretion of copper Hepatic copper accumulation injures hepatocytes (see Wilson’s Disease slide) Accelerated rate of hepatocellular necrosis or apoptosis Hepatocyte death exceeds regeneration such that liver function is compromised within a short amount of time Acute Liver Failure An illness of <26 weeks duration in the absence of pre-existing cirrhosis, characterized by INR ≥1.5 and evidence of altered mentation (hepatic encephalopathy) Injured hepatocytes leak hepatic enzymes (AST, ALT, GGT) into circulation ↑ Liver enzymes Hepatocellular inflammation Stimulation of foregut autonomic nerves Right upper quadrant pain ↓ Toxin metabolism Toxins build up and activate microglial cells (brain macrophage) Oxidative stress and cerebral edema Hepatic encephalopathy Characteristic set of neuropsychiatric symptoms (see Hepatic Encephalopathy slide) ↓ Hepatocellular function and number ↓ Complement protein synthesis ↓ Ability to clear immune complexes and activate B cells Accumulation of pigmented bilirubin ↓ Synthesis of coagulation factors ↑ INR ↓ Conjugation of bilirubin by the liver and ↓ transport into bile for excretion ↑ Serum bilirubin Jaundice Infection Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published November 15, 2022 on www.thecalgaryguide.com

Cirrhosis

Cirrhosis: pathogenesis and complications Author: Chunpeng Nie Yan Yu Reviewers: Paul Ratti, Amy Maghera, Vina Fan, Ben Campbell, Sam Lee*, Mayur Brahmania* *MD at time of publication Chronic viral hepatitis (B, C, or D) Hepatitis D occurs with hepatitis B Alcohol related liver disease Non-alcoholic steatohepatitis Autoimmune: autoimmune hepatitis, primary biliary & sclerosing cholangitis Genetic: hemochromatosis, Wilson’s disease, α1- antitrypsin deficiency Toxic: drugs may rarely cause chronic liver disease or cirrhosis Severe or chronic hepatocyte injury overrides regenerative capacity → Fibrosis Cirrhosis Mild fibrosis may reverse with treatment of underlying cause Nodular/shrunken liver on ultrasound ↑ Liver stiffness on transient elastography Diffuse fibrosis with nodular regeneration on biopsy Fibrotic liver provides ↑ resistance to blood flow Portal hypertension Irreversible formation of fibrosis, within which hepatic cell regeneration is restricted to form nodules of poorly-functioning cells Inflammation → epigenetic changes, oncogene mutations Hepatocellular carcinoma ↑ Serum α-fetoprotein (sensitivity 50%, specificity 99%) Fibrosis disrupts normal function of hepatic lobules Hepatic insufficiency ↓ Liver synthetic function ↓ Thrombopoietin synthesis Thrombocytopenia ↓ Conjugation of bilirubin, ↓ secretion of bilirubin into bile ducts, and ↓ drainage of bilirubin into hepatic duct Accumulation of serum bilirubin >30 μmol/L Jaundice Scleral icterus, jaundiced frenulum ↑ Pressure in portal venous circulation Portosystemic shunts Increased flow to esophageal, rectal, and splenic veins Vascular stretch → endothelial vasodilator (e.g. NO) release Vasodilators enter systemic circulation Pulmonary vasodilation Blood cells in pulmonary vasculature have ↓ time for gas exchange Hepatopulmonary syndrome (rare) Dyspnea or hypoxemia, worsened when upright ↓ Synthesis of clotting factors (V, VII, IX, X, XI, XII, fibrinogen, prothrombin) and anticoagulant proteins (antithrombin, proteins C/S) Unpredictable imbalance of hemostatic and anticoagulant factors Elevated INR ± coagulopathy Impaired metabolism of waste products and toxins Toxins (mainly ammonia) accumulate and cross the blood- brain barrier Hepatic encephalopathy Day-night reversal, asterixis, delirium Varices (dilated veins in the esophagus, stomach, or rectum) Variceal bleed GI bleed and hypovolemia Backflow of blood into spleen Splenomegaly Enlarged spleen sequesters (traps) blood cells Cytopenias (eg. thrombocytopenia or anemia), petechiae, easy bruising ↓ Blood flow to kidneys, which sense ↓ effective blood volume Kidneys retain water and Na+ ↑ Hydrostatic pressure in splanchnic vessels ↓ Albumin synthesis ↓ Capillary oncotic pressure Net fluid flux out of vasculature into interstitial space Ascites (fluid in peritoneal cavity) Peripheral edema Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published August 7, 2022, updated November 6, 2022 on www.thecalgaryguide.com

Carbonic Anhydrase Inhibitor Diuretics

Carbonic Anhydrase Inhibitor Diuretics: Renal mechanism and side effects Authors: Stephanie Happ Reviewers: Matthew Hobart Raafi Ali Adam Bass* * MD at time of publication Carbonic Anhydrase Inhibitors (CAI) Inhibition of carbonic anhydrase on the apical surface of the brush border cells in the proximal convoluted tubule (PCT) Activation of the Renin- Angiotensin-Aldosterone Systemfromvolume depletion Activation of principle cell Epithelial sodium channels (ENaC) on principal cells of the CCD reabsorb ↑ Na+ and waste K+ ↓ K+ in serum Hypokalemia See Hypokalemia: Clinical Findings slide ↑ Na+ delivery to the cortical collecting duct (CCD) H2O follows Na+ into the CCD to maintain a balanced osmotic pressure ↑ H2O available for excretion Mild diuresis (increase in frequencyandvolumeof urine) ↓ Blood volume Hypotension ↓ Na+ and HCO3- reabsorption in the PCT ↑ HCO3- delivery to cortical collecting duct Urine alkalization (increased pH) Chronic urine alkalization ↓Solubilityof citrate ↓ Urinary citrate ↓ Citrate binding with Ca2+à↑ Ca2+ complexing with oxalate ↑ Spontaneous nucleation, growth and agglomeration of calcium oxalate crystals Formation of calcium oxalate renal calculi ↑ HCO3- is lost in the urine ↓ pH of the blood Type II Renal Tubular Acidosis See Type II/Proximal Renal Tubular Acidosis slide CAI prevents the up- regulationofglutamine transporters in the PCT Inability to correct the metabolic acidosis and impaired urinary NH3 excretion Hyperammonemia (↑ serum NH3 ) ↑ Risk of hepatic encephalopathy in individuals with cirrhosis Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published Feb 3, 2024 on www.thecalgaryguide.com Carbonic Anhydrase Inhibitor Diuretics: Renal Mechanism and Side Effects Carbonic Anhydrase Inhibitors (CAI) Inhibition of carbonic anhydrase on the apical surface of the brush border cells of the proximal convoluted tubule (PCT) Authors: Stephanie Happ Reviewers: Matt Hobart Name Name* * MD at time of publication ↓ Na+ and HCO3- reabsorption in the PCT ↑ Na+ delivery to the cortical collecting duct (CCD) H2O follows Na+ into the CCD to maintain a balanced osmotic pressure ↑ H O available for 2 excretion Mild diuresis ↓ Blood volume Hypotension ↑ HCO3- delivery to cortical collecting duct Epithelial sodium channels (ENaC) on principal cells of the CCD reabsorb ↑ Na+ ↑ Intracellular Na+ drives Na+/K+ ATPase activity on the principal cells (moving 2 K+ into cell and 3 Na+ out into the peritubular capillary) ↑ Intracellular K+ drives H+/K+ ATPase activity on the intercalated cells (moving 1 H+ into cell and 1 K+ out into the tubular filtrate) ↓ K+ in serum Hypokalemia See Hypokalemia: Clinical Findings slide Urine alkalization ↑ HCO3- is lost in the urine, leading to ↓ pH of the blood Renal Tubular Acidosis Type II See Type II/Proximal Renal Tubular Acidosis slide CAI inhibit the up-regulation of glutamine transporters in the PCT Inability to correct the metabolic acidosis and impaired urinary NH3 excretion Hyperammonemia ↑ Risk of hepatic encephalopathy in individuals with cirrhosis Chronic urine alkalization leads to marked ↓ in urinary citrate ↓ Ability of citrate to bind to Ca2+ and calcium oxalate stones ↓ Inhibition of spontaneous nucleation ↓ Prevention of growth and agglomeration of crystals Formation of calcium oxalate renal calculi Legend: Pathophysiology Mechanism Sign/Symptom/Lab Finding Complications Published MONTH, DAY, YEAR on www.thecalgaryguide.com