Liver Disease 2025 PDF

WE MAKE DOCTORS LIVER DISEASE Dra. Vera /Dr. Herrera/ Dra. Franco. Modified by: Dr. Rivera Ayala WE MAKE DOCTORS Objectives Apply knowledge of the cellular response to injury, the pathogenic mechanisms leading to disease and the biochemical alterations of hepatic function to explain the clini...

WE MAKE DOCTORS LIVER DISEASE Dra. Vera /Dr. Herrera/ Dra. Franco. Modified by: Dr. Rivera Ayala WE MAKE DOCTORS Objectives Apply knowledge of the cellular response to injury, the pathogenic mechanisms leading to disease and the biochemical alterations of hepatic function to explain the clinicopathologic features, prognosis, and treatment of disorders resulting from ethanol and other drugs and toxins Describe the clinicopathologic features of excessive ethanol ingestion, focusing on biochemical pathways and short- and long-term complications, and compare alcoholic with nonalcoholic fatty liver disease. Describe the clinicopathologic features of excessive acetaminophen ingestion focusing on biochemical pathways and short- and long-term complications.  LIVER Hepatic lobule: basic functional unit. Digestive function of the liver: production of bile Synthesis and endocrine secretion into the blood: Production and major plasma proteins Storage of vitamin A (in hepatic stellate cells), other fat-, soluble Gluconeogenesis vitamins Detoxification Removal of effete erythrocytes (by specialized macrophages, or Deamination - producing urea Kupffer cells) Storage of glucose and triglycerides Storage of iron in complexes with the protein ferritin. Citation: Chapter 16 Organs Associated with the Digestive Tract, Mescher AL. Junqueira's Basic Histology Text and Atlas, 16e; 2021. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=3047&sectionid=255122 004 Accessed: January 24, 2022 Copyright © 2022 McGraw-Hill Education. All rights reserved CLASSIC HEPATIC LOBULE Chapter 16 Organs Associated with the Digestive Tract, Mescher AL. Junqueira's Basic Histology Text and Atlas, 16e; 2021. Available at: https://accessmedicine.mhmedical.com/content.aspx?bookid=3047&sectionid=255122004 Accessed: January 24, 2022 Copyright © 2022 McGraw-Hill Education. All rights reserved  HEPATIC SINUSOIDS Venousandarterial blood mixesin the irregular hepatic sinusoids. – Anastomosing sinusoids have thin, discontinuous linings of fenestrated endothelial cells surrounded bysparsebasal lamina and reticular fibers. – Thediscontinuities and fenestrations allow plasma to fill anarrow perisinusoidal space(orspaceofDisse) Liver disease The liver is vulnerable to a wide variety of metabolic, toxic, microbial, circulatory, and neoplastic insults. Hepatic damage also occurs secondary to other diseases Functional reserve of the liver masks the possible damaged created to the parenchyma With the exception of acute liver failure, liver disease is an insidious process Test Category Serum Measurement a Hepatocyte integrity Cytosolic hepatocellular enzymes Serum aspartate aminotransferase (AST) Serum alanine aminotransferase (ALT) Serum lactate dehydrogenase (LDH) a Biliary excretory function Substances normally secreted in bile Serum bilirubin Total: unconjugated plus conjugated Direct: conjugated only Urine bilirubin Serum bile acids a Plasma membrane enzymes (from damage to bile canaliculus) Serum alkaline phosphatase Serum γ-glutamyl transpeptidase (GGT) Hepatocyte synthetic function Proteins secreted into the blood b Serum albumin b Coagulation factors Prothrombin time (PT) and partial thromboplastin time (PTT): fibrinogen, prothrombin, factors V, VII, IX, and X Hepatocyte metabolism a Serum ammonia b Aminopyrine breath test (hepatic demethylation)  MECHANISMS OF INJURY AND REPAIR INJURED HEPATOCYTES Steatosis Necrosis (fat) REVERSIBLE IRREVERSIBLE CHANGES CHANGES Apoptosis Cholestasis (bilirrubin) Ballooning Fibrosis (mallory hyaline) X steatohepatitis Edward C. Klatt. MD. Robbins and Cotran Atlas of Pathology. The liver chapter 8. 3rd edition. Elsevier  NECROSIS APOPTOSIS Defective membrane transporter: Ion Apoptotic cell death predominates in viral, inbalance with release of cytoplasmic autoimmune, and drug- and toxin-induced constituents, ion invalance, cell edema and reputure. hepatitides. Response to oxidative stress (pyknosis) Ischemic/hypoxic injury karyorrhexis) Associated to macrophage clusters In the more frequent settings in which Widespread death of hepatocytes -> confluent apoptotic hepatocytes are seen (e.g., acute necrosis. and chronic hepatitis), the term acidophil bodies is used, due to their deeply – Acute toxic or ischemic injuries eosinophilic staining characteristics – Severe chronic viral hepatitis – Autoimmune hepatitis Clusters of macrophages with PAS-positive intracellular material derived from necrotic Foci of lobular hepatitis in chronic hepatitis C show an hepatocytes. apoptotic hepatocyte (“acidophil body”; arrow ) and a focus of mononuclear infiltration surrounding a more darkly stained, injured hepatocyte (double arrows).  extracellular matrix (ECM) reactive oxygen species (ROS) SCAR FORMATION tumor necrosis factor alpha (TNF-α) The principal cell type involved in scar deposition in the liver is the hepatic stellate cell. If quiescent, the main function of stellate cells is lipid storage. Triggered by TNF-α, ECM, and ROS. Acute and chronic injury Highly fibrogenic myofibroblasts (ito cel) Diffuse scarring (cirrhosis) vascular compromiso→collapse of reticulin and collagen deposition Incomplete septal cirrhosis – Interruption of chronic injury- LIVER FAILURE 80% to 90% of functional capacity must be lost Most severe form of liver disease. ACUTE-ON- CHRONIC CHRONIC ACUTE sudden and massive After insidious, hepatic destruction progressive liver injury Edward C. Klatt. MD. Robbins and Cotran Atlas of Pathology. The liver chapter 8. 3rd edition. Elsevier Acute liver failure Massive hepatic necrosis, severe hepatic injury in a patient w/o preexisting liver disease. *Fulminant liver failure=massive hepatic necrosis” Main clinical characteristics: Elevated aminotransferases Encephalopathy Coagulation abnormalities Common causes in the Western world: Drugs, Toxins. 1. Acetaminophen toxicity (46%) 2. Indeterminate (14%) 3. Idiosyncratic drug reaction (12%) 4. Viral hepatitis (A, B) (10%) vs HepA and HepE in Asia  Acute liver failure JAUNDICE + HEPATIC ENCEPHALOPATHY + Elevated aminotransferases + Coagulation abnormalities Laboratory test abnormalities: – INR ≥1.5, Prolonged prothrombin Nonspecific symptoms: time (MUST) – Nausea, Vomiting – Elevated aminotransferase levels – Loss of apetite (ALT- AST: markedly elevated) – Right upper abdominal pain, – Elevated bilirubin level – Hepatomegaly – Low platelet count (≤150,000/mm3) - – Fever – Fatigue – Coluria, Acolia HEPATIC ENCEPHALOPATHY Often precipitated by an inciting event (e.g., GI bleeding, electrolyte abnormalities, infections, medications, dehydration) Wijdicks, E. F. M. (2016). Hepatic Encephalopathy. New England Journal of Medicine, 375(17), 1660–1670. doi:10.1056/nejmra1600561 HEPATIC ENCEPHALOPATHY Graphic 62922 Version 2.0 © 2022 UpToDate, Inc. and/or its affiliates. All Rights Reserved  ACUTE LIVER FAILURE Other laboratory findings : – Elevated serum Cr and blood urea – Elevated ammonia level nitrogen – Elevated lactate dehydrogenase (LDH) – Hypoglycemia level – Acidosis or alkalosis Acute kidney injury complicates acute liver failure 30 - 70 %. In patients who are improving, the bilirubin and prothrombin time/INR will decline, whereas in those with worsening liver failure, the bilirubin and prothrombin time/INR will continue to rise Complications –Metabolic derangements –Encephalopathy –Cerebral edema –Seizures –Renal failure  Acute Liver Faliure Imaging studies Treatment – Ultrasound with Doppler- preferred Treatment initial modality for the evaluation – Symptom management – Neuroimaging (head CT or MRI) – Preventing infections Cerebral edema – Providing sufficient calories and protein Decrease in size of ventricles – Correcting fluid and electrolyte imbalances flattening of cerebral convolutions attenuation of intensity of brain parenchyma In many cases, liver transplantation remains the only effective treatment. – Contrast Abdominal CT- Renal involvement by intravenous contrast. Heterogenous liver parenchyma- Abnormal. hepatomegaly, ascites, malignant infiltration, hepatic vein occlusion. CHRONIC LIVER FAILURE AND CIRRHOSIS Diffuse transformation of the liver into regenerative parenchymal nodules surrounded by fibrous bands and vascular (portosystemic) shunting. -Cirrhosis requires at least a decade to develop from chronic liver injury. -Small liver “bumpy” Leading causes: – Chronic hepatitis B – Chronic hepatitis C – Nonalcoholic fatty liver disease – Alcoholic liver disease  CIRRHOSIS A liver biopsy is required to definitively confirm the diagnosis of cirrhosis. Clinical, laboratory, and radiologic data strongly suggest the presence of cirrhosis a biopsy would not alter the patient's management. Although cirrhosis and chronic liver failure are often associated, they are not synonymous; not all cirrhosis leads inexorably to chronic liver failure, and not all end-stage chronic liver disease is cirrhotic Cirrhosis: parenchymal nodules surrounded by dense bands of fibrosis throughout the liver, capsule is a bumpy surface with depressed areas of scarring and bulging regenerative nodules. Clinical features persistent cholestasis can lead to pruritus (itching), Some patients may scratch their skin raw Impaired estrogen metabolism leads to hyperestrogenemia. Produces vascular changes that may lead to palmar erythema (a reflection of local vasodilation) and spider angiomas of the skin. Hypogonadism and gynecomastia. Micronodular cirrhosis Uniform nodules less than 3 mm in diameter Alcohol, hemochromatosis, hepatic, venous outflow obstruction, chronic biliary obstruction Macronodular cirrhosis Irregular nodules with a variation greater than 3 mm in diameter Hepatitis B and C, alpha-1 antitrypsin deficiency, and primary biliar cholangitis Mixed cirrhosis CIRRHOSIS CIRRHOSIS COMPLICATIONS- Portal Hypertension Risk factor + clinical manifestations of portal hypertension Hepatic Venous Pressure Gradient (HVPG) – Normal: 1-5mmHg – PORTAL HYPERTENSION: >6mmHg – Clinical significant: >10mmHg – Variceal bleeding: >12mmHg  PORTAL HYPERTENSION In cirrhosis with portal hypertension, there is depletion of vasodilators (predominantly NO) intrahepatically but an excess of NO extrahepatically in the splanchnic and systemic circulation, which lead to sinusoidal vasoconstriction and splanchnic (systemic) vasodilation. The collaterals also contribute to the hyperdynamic circulation by increasing the venous return to the heart AUTOIMMUNE HEPATITIS Chronic, progressive hepatitis with all the features of autoimmune diseases in general – Genetic predisposition – Other AID association – Autoantibodies – Response to immunosuppression Strong HLA-associations ✓ Viral infections or drug or toxin exposures  Epidemiology White northern europeans Type 1 Middle-aged to older Females (78%) individuals Antinuclear (ANA) Types 1 & 2 Anti–smooth muscle actin (SMA) Anti–soluble liver antigen/liver-pancreas Type 2 antigen (anti-sla/LP) Children and teenagers Anti-mitochondrial Anti–liver kidney microsome-1 (anti- (AMA) antibodies lkm-1) antibodies Directed against CYP2D6 Anti–liver cytosol-1 (ACL-1) antibodies.  Early phase of severe parenchymal destruction followed rapidly by scarring – Severe necroinflammatory activity – Plasma cell predominance – Hepatocyte “rosettes” Rapidly progressive or indolent – Very severe hepatocyte injury with widespread confluent necrosis, but little scarring: symptomatic acute hepatitis Clinical Gastroenterology and Hepatology. Vierling, John M... Published November 1, 2015. Volume 13, Issue 12. Pages 2088-2108. © 2015. DIAGNOSTIC CRITERIA Definite autoimmune hepatitis (AIH): P7 Probable AIH: P6 Adapted from Hennes EM, et al. Simplified criteria for the diagnosis of autoimmune hepatitis. Hepatology 48:169-176; 2008 DRUG AND TOXININDUCED LIVER INJURY Liver = drug metabolizing and detoxifying – Direct toxicity – Hepatic conversion of a xenobiotic to an active toxin Immune mechanisms temporal 1. Liver damage with drug or toxin exposure 2. Recovery upon removal of the inciting agent 3. Exclusion of other potential causes Classified as: -predictable (intrinsic) dose-dependent -unpredictable (idiosyncratic) – propensity to mount an immune – rate at which the agent can be metabolize  EPIDEMIOLOGY Global incidence of 1 to 14 per 100,000 Mild to very serious Alcohol Herbal remedies, dietary supplements, topical applications, environmental exposures ACETAMINOPHEN Most common cause of acute liver failure requiring transplantation in the United States Toxic metabolite produced by the cytochrome P-450 – Suicide attempts – Accidental overdoses Cytotoxicity is dependent on the cytochrome P-450 system ALCOHOLIC LIVER DISEASE Most common etiology of cirrhosis in the developed world In women after a shorter duration of drinking and with a lower daily alcohol intake than in men. Consumption of 80 g/day of alcohol is considered to be the threshold to develop alcoholic liver disease Excessive alcohol intake causes steatosis  SPECTRUM OF DISEASE Fat accumulation in liver cells, the earliest and most predictable response to alcohol ingestion: 90% of heavy drinkers Necro-inflammation and fibrosis (alcoholic hepatitis, or steatohepatitis): 10% to 35% Cirrhosis can develop within 5 years: 10%  1. Patients with severe disease have extremely high short- term mortality rates Alcoholic Hepatitis 2. They also can develop portal hypertension in the absence of cirrhosis 3. Is a well-documented precursor of cirrhosis, long-term risk 9 times higher than that for patients with fatty liver alone PATHOGENESIS Ethanol Metabolism and Toxic Metabolites 3 major systems in the liver: alcohol dehydrogenase (ADH), cytochrome P450 2E1 (CYP2E1), and, of least importance, catalase Low concentrations High concentrations  alter the cellular impair normal oxidation-reduction carbohydrate and (redox) state lipid metabolism aldehyde dehydrogenase ADH and CYP2E1 (ALDH) Ethanol acetaldehyde acetate highly reactive and impair form adducts with potentially toxic mitochondrial reactive residues on glutathione nausea, proteins or small transport headaches, molecules (e.g., cysteines) and flushing sensitize hepatocytes to TNF-mediated killing autoimmune-like manifestations CLINICAL FEATURES 1/3 of hospitalized patients with fatty liver have laboratory abnormalities Serum AST levels are almost always less than 300 to 500 U/L and typically are associated with trivial elevation of serum ALT levels, resulting in an AST/ALT ratio greater than 2. – A ratio greater than 2 is characteristic of alcoholic liver disease  Centrilobular and perivenular fatty infiltration Ballooning degeneration of hepatocytes, alcoholic hyaline (Mallory-Denk bodies) within damaged hepatocytes, and a surrounding infiltrate composed of polymorphonuclear leukocytes. Fibrosis/ Cirrhosis Cirrhosis typically is micronodular or Robbins and Cotran Pathologic Basis of Disease. Theise, Neil D.. Published January 1, 2015. Pages 821-881. © 2015. Figure 18-2 mixed micro- and macronodular NONALCOHOLIC FATTY LIVER DISEASE Hepatic steatosis (fatty liver) in individuals who do not consume alcohol Most common chronic liver disease in the US 3-5% Histologic hallmarks of NAFLD are most consistently associated with the metabolic syndrome PATHOGENESIS Risks factors = obesity Established insulin resistance and metabolic syndrome: – ↓Adiponectin – ↑Inflammatory cytokines such as tnf-α and IL-6 Hepatocyte apoptosis – Lipid peroxidation Diminished autophagy – Mitochondrial injury – Mallory-denk bodies Stellate cells activation – Deposition of scar tissue  PATHOGENESIS Sleisenger and Fordtran's Gastrointestinal and Liver Disease. Torres, Dawn M.; Harrison, Stephen A.. Published December 31, 2015. Pages 1428-1441.e5. © 2016. FIGURE 87-3 MORPHOLOGY > 5% Hepatocytes Droplets of fat NASH almost completely overlaps in its histologic features with alcoholic hepatitis Steatofibrosis -> cirrhosis Clinical features  Clinical history Robbins and Cotran Pathologic Basis of Disease. Theise, Neil D.. Published January 1, 2015. Pages 821-881. © 2015. Figure 18-23 HEMOCHROMATOSIS Caused by excessive iron absorption – Increased intestinal iron absorption that results in tissue iron deposition Liver and pancreas, followed by heart, joints, and endocrine organs Hereditary hemochromatosis Secondary hemochromatosis PATHOPHYSIOLOGY The pathophysiologic mechanisms of HH fall into the following 4 main categories: 1. Increased intestinal absorption of dietary iron 2. Decreased expression of the iron-regulatory hormone hepcidin 3. Altered function of HFE protein 4. Iron-induced tissue injury and fibrogenesis.  HEPCIDIN Iron-regulatory hormone – Absorption, mobilization, and storage – Expressed predominantly in hepatocytes – Binds to ferroportin: internalized and degraded, thus inhibiting iron export In all types of HH, iron overload results from impairment in the hepcidin regulatory pathway Sleisenger and Fordtran's Gastrointestinal and Liver Disease. Bacon, Bruce R.; Britton, Robert S.. Published December 31, 2015. Pages 1261-1269.e2. © 2016. FIGURE 75-1 IRON-INDUCED TISSUE INJURY AND FIBROSIS Liver damage that results from iron overload Advanced HH, hepatic fibrosis and cirrhosis – Iron-dependent lipid peroxidation and associated impairment of membrane-dependent functions of mitochondria, microsomes, and lysosomes. – Iron-induced lipid peroxidation causes hepatocellular injury or death – Kupffer cells produce profibrogenic cytokines CLINICAL FEATURES Most common are weakness and lethargy, arthralgias, abdominal pain, and loss of libido or potency in men Nonspecific right upper quadrant abdominal pain Hepatomegaly Abnormal skin pigmentation Complications of chronic liver disease Destruction of pancreatic islets, cardiac dysfunction (arrhythmias, cardiomyopathy), and atypical arthritis MORPHOLOGY Deposition of hemosiderin – Golden-yellow hemosiderin granules in the cytoplasm of periportal hepatocytes that stain with prussian blue Ferri's Clinical Advisor 2018. Ferri, Fred F., M.D... Published January 1, 2018. Pages 565-566.e1. © 2018. WILSON DISEASE Autosomal recessive disorder caused by mutation of the ATP7B gene, resulting in impaired copper excretion into bile and a failure to incorporate copper into ceruloplasmin Accumulation of toxic levels of copper in many tissues and organs, principally the liver, brain, and eye Copper Metabolism Sleisenger and Fordtran's Gastrointestinal and Liver Disease. Cox, Diane W.; Roberts, Eve A.. Published December 31, 2015. Pages 1270-1279.e2. © 2016. FIGUREs 76-1, 76-2 MOLECULAR PATHOGENESIS Gene mutated (ATP7B) The product, ATP7B (known as the Wilson ATPase ), is a membrane-bound P 1 - type ATPase The structure has 6 copper-binding units, a phosphorylation domain, an ATP-binding region, and 8 transmembrane domains Result in retention of copper in the liver  PATHOLOGY Earliest stages: – Steatosis, focal necrosis, glycogenated nuclei in hepatocytes, and sometimes apoptotic bodies Later stages: – Periportal fibrosis develops. Cirrhosis is usually macronodular. Changes in hepatocellular mitochondria – vary in size, and the numbers of dense bodies in mitochondria may be increased CLINICAL FEATURES Present clinically at any age Chronic or fulminant liver disease Progressive neurologic disorder without clinically prominent hepatic dysfunction Isolated acute hemolysis Psychiatric illness  DIAGNOSIS The biochemical diagnosis of Wilson disease is based on a decrease in serum ceruloplasmin, an increase in hepatic copper content (the most sensitive and accurate test), and increased urinary excretion of copper (the most specific screening test). Demonstration of Kayser-Fleischer rings Zakim and Boyer's Hepatology. Roberts, Eve A.; Loudianos, Georgios.. Published January 1, 2018. Pages 926-940.e4. © 2018. Bibliography: Robbins & Cotran Pathologic Basis of Disease, 10th Edition, Chapter 18, (823-879) Sections: 1) Chronic Liver Failure and Cirrhosis/Portal Hypertension, 2) Hepatitis B Virus, 3) Inherited Liver Disease WE MAKE DOCTORS Password: N-acetylcysteine