Liver Pathophysiology PDF

Liver Pathophysiology Grace L. Guo, MBBS, PhD, FAASLD Telephone: 848-445-8186 e-mail: [email protected] Macrostructure of Liver • Liver is the largest visceral organ in the body • Right lobe is the largest lobe • 75 to 85% of blood supply is from portal vein The Liver • Liver Functions – –...

Liver Pathophysiology Grace L. Guo, MBBS, PhD, FAASLD Telephone: 848-445-8186 e-mail: [email protected] Macrostructure of Liver • Liver is the largest visceral organ in the body • Right lobe is the largest lobe • 75 to 85% of blood supply is from portal vein The Liver • Liver Functions – – – – – – Metabolic Storage Excretory/Secretory Protective Circulatory Coagulation Metabolic Functions • • • • • • • • Carbohydrate Metabolism • Gluconeogenesis • Glycogenolysis and glycogenesis Synthesis of fatty acids, lipoproteins, cholesterol Ketogenesis (breakdown of fatty acids to keytones) Protein Metabolism Synthesis of plasma proteins (albumin, globulin, fibrinogen) Urea Synthesis (ammonia to urea) Hormone Metabolism Red blood cell production (in fetal livers during the first trimester of pregnancy) Storage Functions • Glycogen • Vitamins –A, D, E, K (lipid soluble) –B12 (water soluble) • Iron • Copper Excretory/Secretory Functions • Bile –Water –Cholesterol –Bile pigments (bilirubin and biliverdin) –Anions of the bile acids –Phospholipids (mainly lecithin) –Bicarbonate and other ions • Insulin-like Growth Factor 1 (IGF-1) • Most blood proteins • Cholesterol, fatty acids Protective Function • Purification, transformation, and clearance –Endogenous (hormones, ammonia etc.) –Exogenous drugs and chemicals • Kupffer cells (residential macrophages) –Bacteria and other foreign materials from the (portal) blood Circulatory Function • Antechamber of the heart –Collecting portal blood from the GI tract Coagulation • Production of coagulation factors –Fibrinogen I –Prothrombin II –Factors (V, VII, IX, X, XI) –Protein C –Protein S –Antithrombin Liver Enzymes—Indicators of Liver Function • Transaminases (from damaged/dead hepatocytes) –Aspartate aminotransferase (AST or SGOT) –Alanine aminotransferase (ALT or SGPT) • Cholestatic Enzymes (from injured biliary epithelial cells) –Alkaline phosphotase (ALP) –Gamma-glutamyl transferase (GGT) Microstructure of Liver Hepatic Lobule Liver Pathology Histopathologic Illustration of Acute & Chronic Hepatitis Acute Liver Injury Viral Hepatitis • • HAV & HEV: direct disruption of hepatocytes HBV and HCV: immunoattack of hepatocytes – HCV: ~75% asymptomatic Drug-induced Liver Injury (DILI) • • High incidence 10% adverse drug reactions: DILI Hepatocellular (Tylenol) Cholestatic (methyl testosterone) and s g u l p Bile g change erin h t a fe Most common drugs for DILI 1. 2. 3. 4. 5. Amoxicillin/clavulanate Diclofenac Azathiopurin Infliximab Nitrofurantoin Ce nt r ne al lo cro bu sis lar • • Chronic Liver Injury -hepatitis, fibrosis, cirrhosis, HCC Etiology • Hepatitis • • Iron overload Copper overload: Wilson’s disease (hepatolenticular degeneration) Alpha1-antitrypsin deficiency Autoimmune • • – Viral – Alcohol – Drugs – Autoimmune – Obesity – PSC-progressing sclerosing cholangitis – PBC-progressing biliary cholangitis ASH and NASH/MASH Steatosis + inflammation + Hepatocyte ballooning • • ASH: alcoholic steatohepatitis MASH: metabolic dysfunction associated steatohepatitis (NASH: non-alcoholic steatohepatitis) Kong and Guo, 2008 MASH/NASH + ASH • Macrovesicular Steatosis + inflammation • Ballooned hepatocytes that also contain Mallory-Denk bodies • Infiltration of both lymphocytes and Kupffer cells • perivenular/pericellular ("chicken wire") fibrosis Epidemiology • Fatty liver diseases is the most common cause of abnormal liver enzyme tests – Lean NASH • Liver steatosis affects 30-40% population in developed countries – Fibrosis, cirrhosis, hepatocellular carcinoma • Affects 2-3% of children (35-50% of obese children) N. American Incidence of MASLD (metabolic dysfunction associated liver disease)--NAFLD and NASH +/- Fibrosis • Fatty liver diseases is the most common cause of abnormal liver enzyme tests • Liver steatosis affects 30-40% population in developed countries – Fibrosis, cirrhosis, hepatocellular carcinoma% of children (35-50% of obese children) • Affects 2-3% of children (35-50% of obese children) • N. American prevalence of NASH + fibrosis – 2.1% • US Census Estimated Population in July 2017 - 325,719,178 Number of individuals in US with or will have NASH + fibrosis : 7,078,411 Hepatology. 64(1):73-84. UNOS -Organ Procurement and Transplantation Network Database N. American Incidence of NAFLD and NASH +/- Fibrosis • NAFLD (by ultrasonography) – 25.2% • NASH among NAFLD patients – 21% • NASH patients who experience fibrosis (global) - 41% # Patients Added to Liver Tx Waiting List NASH Hepatitis C Virus 2017 2016 2015 2014 2013 2012 2011 2010 2009 2008 2,134 1,937 1,602 1,398 1,294 1,039 1,016 944 765 652 1,728 2,000 2,374 2,862 3,022 3,094 3,111 3,124 3,030 2,965 Hepatology. 64(1):73-84. UNOS -Organ Procurement and Transplantation Network Database Global MASLD/NAFLD Prevalence Nature Reviews Gastroenterology & Hepatology. 15: 11–20. Molecular Mechanism of MASH/NASH Two-hit (multi-hit) theory • First hit: fat accumulation in the liver – Obesity – Long-term fasting • Additional/parallel hit: injury leads to inflammation – Drugs – Pathogens – Leaky gut (LPS) – Genetic abnormalities (PTEN, FXR or other deficiency) – Oxidative stress ASH Pathophysiology Pathophysiology involves • Hepatic fat storage • Inflammation: increased hepatic uptake of gut-derived endotoxins triggering Kupffer cell activation and release of proinflammatory factors • Oxidation: induction of cytochrome P4502E1 producing toxic acetaldehyde and reactive oxygen species • ER stress: ethanol-mediated endoplasmic reticulum (ER) stress, protein mis-folding Mechanism of ALD--Inflammation • Activation of innate immunity • Increase pro-inflammatory cytokine production in all cells in the liver • Increase adaptive immunity Liver Fibrosis • Persistent HSC activation • Fibrosis potentially irreversible • ↓ Hepatic blood flow • Numerous sequelae • No therapeutic agents • Requires liver transplantation Cirrhosis induced by MASH/NASH Some of the histologic features of NASH—such as steatosis, ballooned hepatocytes, and lobular inflammation—may no longer exist ("burnt out" NASH), although the characteristic perivenular/pericellular fibrosis may still be present Liver Cysts Cyst: closed sac filled with liquid or other tissues • Simple cysts • Hydatid cysts: due to the parasite Echinococcus granulosus • Choledochal cysts: congenital, dilation of bile duct, common in east Asia Cholangiopathies Intrahepatic Bile Duct Primary Biliary Cholangitis (PBC) • T-cell mediated apoptotic destruction of biliary epithelial cells • Middle aged females • 4 histologic stages • Florid duct lesion • Ductular proliferation • Fibrotic septa • Cirrhosis Primary Sclerosing Cholangitis (PSC) • Inflammation, progressive fibrosis and destruction of bile duct • 10-30 yrs old males • Duct affected: all ducts • Often associated with IBD (UC) • Histology: Onion skin fibrosis, Inflammatory infiltrate is typically mild and limited to biliary epithelium and portal tracts Gall Bladder Pathology Congenital Gall Bladder Pathology Most severe case: Biliary atresia: biliary tree fails to develop; toxins involved—isoflavonid—biliatresone from plants: Dysphania genus, tight junction disruption This 3 month old child died with extrahepatic biliary atresia, a disease in which there is inflammation with stricture of hepatic or common bile ducts. This leads to marked cholestasis with intrahepatic bile duct proliferation, fibrosis, and cirrhosis. This liver was rock hard. The dark green color comes from formalin acting on bile pigments in the liver from marked cholestasis, turning bilrubin to biliverdin. Diseases of Gall Bladder • • • • Cholelithiasis (gallstone)-focus of this lecture Carcinoma of the bile duct Carcinoma of the gall bladder Biliary obstruction Gallstone Disease Risk Factors for Gallstone Disease • • • • • Female Forties Fat Fertile FXR mutation? Liver tumors 2019: What’s next for liver cancer research? https://www.youtube.com/watch?v=Ah7dF20upJY Liver tumors • Benign tumors – Liver cell adenoma – Angioma – Bile duct hamartoma – Focal nodular hyperplasia Liver tumors Malignant – Primary • Liver cell carcinoma (hepatocellular carcinoma-HCC) • Cholangiocarcinoma (adenocarcinoma of bile ducts) • Angiosarcoma (malignant neoplasm of vascular endothelium) • Hepatoblastoma (primary liver tumor in childhood) – Secondary: metastases from the GI, lung and breast cancers Molecular Mechanisms of Hepatocellular Carcinoma-Heterogenic Hepatology Volume 48, Issue 6, pages 2047-2063, 14 AUG 2008 DOI: 10.1002/hep.22580 http://onlinelibrary.wiley.com/doi/10.1002/hep.22580/full#fig1 HCC • Well differentiated: tumor cells resemble hepatocytes, form trabeculae, cords and nests, and may contain bile pigment in cytoplasm. • Poorly differentiated: malignant epithelial cells are discohensive, pleomorphic anaplastic, and giant HCC ~25% patients never develop cirrhosis Cholangiocarcinoma---Malignant Tumors in the Bile Duct