Liver Diseases Student 2024 PDF

ESSENTIALS OF GASTROENTEROLOGY LIVER DISEASE KATHLEEN FISCHER, M.ED., PA-C  OBJECTIVES o Describe the functions of the liver o List the structures in the portal triad o Describe the anatomy and physiology of the hepatocyte o Discuss and describe the...

ESSENTIALS OF GASTROENTEROLOGY LIVER DISEASE KATHLEEN FISCHER, M.ED., PA-C  OBJECTIVES o Describe the functions of the liver o List the structures in the portal triad o Describe the anatomy and physiology of the hepatocyte o Discuss and describe the following with respect to their etiologies, epidemiology, clinical presentation, diagnostic test findings, treatments and prognoses: o Alcoholic Liver Disease o Nonalcoholic Fatty Liver Disease (NALD) o Drug-Induced Liver Injury (DILI) o Cirrhosis o Ischemic Hepatitis o Primary Biliary Cholangitis o Wilson’s Disease  FUNCTIONS OF THE LIVER o Liver is the most metabolically active organ in the body o Hepatocytes perform many metabolic functions: 1. Secretion of bile: Bile (salts) emulsifies fat Return back to liver via enterohepatic circulation 2. Metabolism and storage of carbohydrates: Converts excess glucose to glycogen for storage Converts glycogen back to glucose when needed for energy  FUNCTIONS OF THE LIVER 3. Metabolism of lipids: Converts carbohydrates and proteins (when in excess) into fats Oxidizes fatty acids Synthesizes: Cholesterol / Lipoproteins / Phospholipids 4. Metabolism of Proteins: Processes free amino acids – synthesized into new proteins (ie. Albumin) and enzymes Excess amino acids are converted to fat or broken down into urea and excreted  FUNCTIONS OF THE LIVER 5. Detoxification: removes toxins (ie. EtOH and drugs) and waste from blood Some medications taken orally are metabolized in liver (First pass affect) may be deactivated before affects take place - so other routes are necessary: IV, IM, inhaled as aerosol Some medications are Pro-Drugs and need to pass through liver to be converted to active drug 6. Storage for : Iron / Vitamins A, D, B12 / Glucose as Glycogen Blood flow: 2/3 of blood enters liver from portal vein 1/3 of blood enters liver from hepatic artery (regular circulatory system)  HEPATIC PORTAL SYSTEM Deviation from typical capillary / veinous mechanism: Capillary bed from systemic system drains into capillary bed in the liver (portal system) before going to heart Allows direct transportation of nutrients from GI tract (plus spleen and pancreas) to drain into portal vein which then goes to liver before the heart Allows for nutrients to be absorbed, toxins and pathogens to be processed in the liver Then enters circulation - draining into inferior vena cava then going to the heart https://socratic.org/questions/what-is-a-portal-system-what-is-the-purpose-of-the-hepatic-portal  LIVER TESTS (LIVER BIOCHEMICAL TESTS) o Liver enzymes: o ALT - Alanine Aminotransferase o AST – Aspartate Aminotransferase o Liver, heart, kidney, RBC o ALKP - Alkaline Phosphatase o Liver, bone, small intestine, WBC o GGT - Gamma-Glutamyl Transferase o Liver, biliary o Synthetic Function: o Albumin o INR - Coagulation factors o _____________ o Bilirubin – (after metabolized gives color to urine (yellow) and stool (brown) o Unconjugated (from hemolysis) goes to liver – conjugated by UGT – goes to GB stored as bile HEPATITIS A, B AND C (PRE-RECORDED)  Hepatitis A Hepatitis B Hepatitis C Transmission Fecal Oral Blood and bodily fluids Primarily blood RNA or DNA Single Stranded RNA Double stranded DNA Single stranded RNA Chronic Phase No Yes ~10% Yes ~80% Liver Function Test Markedly elevated ALT/AST Markedly elevated ALT/AST Waxing and waning ALT/AST Special Lab Test Active infection: Active infection: HBsAg, HCV RNA PCR, genotype and IgM anti-HAV AntiHBc IgM, HBeAg viral load Chronic infection: HBsAg, AntiHBc IgG, +/-HBeAg, +/- AntiHBe Treatment Self-limiting Acute HBV – self limiting. New treatment regimens – Vaccine available (2doses) Chronic HBV nucleoside and Glecaprevir&pibrentasvir OR nucleotide analogs Sofosbuvir&velpatasvir Vaccines available (3doses) depends on extend of disease – leading cause for liver transplantations, NO vaccine Copyrights apply ALCOHOL-ASSOCIATED LIVER DISEASE  ALCOHOL-ASSOCIATED LIVER DISEASE: EPIDEMIOLOGY o Liver disease that is caused by excess alcohol consumption o Most common precursor to cirrhosis in the US o 10-15% of people with alcoholic liver disease will progress to cirrhosis o Women are more susceptible than men to alcoholic liver disease and progression to cirrhosis o Associated with 4-5 times more hospitalizations and deaths than Hep C  ALCOHOL-ASSOCIATED LIVER DISEASE ETIOLOGY o Excess alcohol is considered: >50g daily o Men: >4 12oz beers, >3 shots (4oz) of hard liquor, or >3 glasses (15oz) of wine daily o Women: >2 12oz beers or >2 glasses (10oz) of wine daily More susceptible to alcoholic liver disease, even after adjustment for body size o Consumption of >50g of alcohol daily for >10 years develop cirrhosis of the liver o Risk increases in patients with obesity o Genetic factors play a role in susceptibility to and severity of liver disease Copyrights apply  ALCOHOL-ASSOCIATED LIVER DISEASE: ETIOLOGY o Alcohol (ethanol) absorption: o Readily absorbed in the stomach and also small intestine o Detoxified in the liver Hepatocytes become damaged when excess alcohol needs to be broken down Alcohol can not be stored – has to be broken down Excessive EtOH → fatty liver → hepatitis → cirrhosis  ALCOHOL-ASSOCIATED LIVER DISEASE: PATHOPHYSIOLOGY o Alcoholic liver disease: progression o Steatosis – fatty liver - early stage (reversible) o fat accumulates in the liver with no inflammation o Steatohepatitis – fat in liver with inflammation of hepatocytes Alcoholic Hepatitis Chronic inflammation leads to fibroblastic activity – fibrosis (reversible) Chronic fibrosis leads - collagen deposition (parenchymal necrosis) and regenerative nodules = cirrhosis (irreversible) Alcoholic Steatohepatitis Fibrosis from Collagen deposit Fatty liver (inflammation chronic and regen. nodules Steatosis from fat) inflammation Cirrhosis  ALCOHOL-ASSOCIATED LIVER DISEASE: CLINICAL PRESENTATION o Symptoms vary depending of stage of disease o Asymptomatic in early disease o Vague, non-specific symptoms: o Anorexia o Poor dietary intake leads to malnutrition o Nausea o Abdominal pain from o Hepatomegaly and/or Portal Hypertension Gastropathy  ALCOHOL-ASSOCIATED LIVER DISEASE: PHYSICAL EXAM Stigmata: Hepatomegaly / Splenomegaly Jaundice Ascites Palmer erythema Gynecomastia +/-Encephalopathy Mental status changes  ALCOHOL-ASSOCIATED LIVER DISEASE: PHYSICAL EXAM o Severe disease: o Spider angiomata o Face and/or chest o Dupytren’s contracture o Abdominal collaterals (caput medusa)  SCREENING TOOL AUDIT – C FOR ALCOHOL ABUSE/DEPENDENCE  ALCOHOL-ASSOCIATED LIVER DISEASE: DIAGNOSTIC STUDIES o Liver Test: o Elevated transaminases: AST greater than ALT (usually 2x higher) Elevated Bilirubin Elevated ALKP When elevated with GGT = liver disease / when elevated alone = bone disease Elevated GGT (non-specific) (not typically ordered) not a part of liver panel – needs to be ordered separately  ALCOHOL-ASSOCIATED LIVER DISEASE: DIAGNOSTIC STUDIES o Test to measure Synthetic Function of the Liver: o Prothrombin Time (PT)/ INR – prolonged (>6 sec above control OR >1.1) Decreased coagulation factors made in the liver due to disease o Albumin decreased: hypoalbuminemia Due to decreased liver synthesis of albumin  ALCOHOL-ASSOCIATED LIVER DISEASE: DIAGNOSTIC STUDIES o CBC: +/- leukocytosis +/- anemia (macrocytic) Thrombocytopenia (in about 10% of cases) Due to direct alcohol toxic effect on megakaryocytes and/or splenomegaly  ALCOHOL-ASSOCIATED LIVER DISEASE: DIAGNOSTIC STUDIES o Abdominal US: evaluate for Fatty liver – can detect moderate to severe steatosis Size Ascites Helps rule in or out biliary obstruction o CT with IV contrast or MRI: may be needed in certain cases to identify Dilated vessels (varices) Lesions or masses Involvement of the pancreas  ALCOHOL-ASSOCIATED LIVER DISEASE: DIAGNOSTIC STUDIES o Liver biopsy: may be needed if diagnosis is uncertain and to establish severity of disease o Evaluates for fatty infiltration (steatosis and steatohepatitis) o PMN infiltration in hepatic necrosis, Mallory bodies (alcoholic hyaline) o Metavir Scoring System assess extent of inflammation and fibrosis by histology o Inflammation Activity Grade: A0 – no activity / A1 – mild activity / A2 – moderate activity / A3 – severe activity Fibrosis Stage: F0 – no fibrosis / F1 – portal fibrosis without septa / F2 – portal fibrosis with few septa / F3 – numerous septa without cirrhosis / F4 - cirrhosis  ALCOHOL-ASSOCIATED LIVER DISEASE: DIFFERENTIAL DIAGNOSIS Cholecystitis Cholelithiasis Drug toxicity (DILI) Non-alcoholic Fatty Liver Disease (NASH)  ALCOHOL-ASSOCIATED LIVER DISEASE: TREATMENT o ABSTINCENE FROM ALCOHOL o Fatty liver is reversible with abstinence o Alcohol dependence: o Naltrexone (Vivitrol, Revia) 50mg PO qd OR Acamprosate (Campral) 666mg PO tid o Start after withdrawal symptoms have resolved o Nutritional support: carbohydrates and calories Supplementation replacement especially: Thiamine, folic acid, zinc o Counseling (either inpatient or outpatient) o Referral to substance abuse counseling clinic  ALCOHOL-ASSOCIATED LIVER DISEASE: TREATMENT o Severe alcoholic-hepatitis: patient with ascites, jaundice, encephalopathy Admit - CIWA –Ar (Clinical Institution Withdrawal Assessment for Alcohol – revised) Monitor for withdrawal symptoms (which can occur 6-18 hrs after last drink and last for 24-72hr) Shakiness, irritability, anxiety Fatigue Emotional changes, depression, bad dreams Delirium tremens (DTs) Hallucinations , seizures, tremors, arrhythmias Methylprednisolone may reduce short-term mortality in patient with alcohol-associated hepatitis and encephalopathy NONALCOHOLIC FATTY LIVER DISEASE (NAFLD)  NAFDL: EPIDEMIOLOGY o Group of conditions where an accumulation of excess fat in liver of people who drink little or no alcohol o Strongly associated with metabolic disfunction - Metabolic-associated Fatty Liver Disease (MAFLD) o Obesity and insulin resistance o Present in 37% of the population in the US o Even adolescents and young adults are affected o Frequency and severity > men than women until after menopause then it is equal o Increased risk for cardiovascular disease, chronic kidney disease and colorectal cancer  FATTY LIVER DISEASE AND NASH: ETIOLOGY o 2 types of NAFLD: o Fatty liver Disease: Most common form of NAFLD Non-serious condition does not cause inflammation Fat accumulates in the liver cells o Non-alcoholic steatohepatitis (NASH): (3-6% of US population) Fat accumulates in the liver is associated with inflammation and scarring Focal infiltration of PMN and Mallory hyaline (makes it look like alcoholic hepatitis) o NASH is a potentially serious condition that can lead to severe cirrhosis  NAFLD: ETIOLOGY o Many causes of NAFLD including: Obesity (40%) Diabetes mellitus Hypertriglyceridemia Hypercholesterolemia Medications including: corticosteroids (long-term use), amiodarone, diltiazem, methotrexate, tamoxifen, antiretroviral therapies Endocrine disorders: Cushings, hypopituitarism, polycystic ovary syndrome, hypothyroidism Risk increases in patients with psoriasis  NAFLD: CLINICAL PRESENTATION o Usually asymptomatic o May have mild RUQ pain o Hepatomegaly develops in 75% of patients o Stigmata of chronic liver disease - uncommon o Signs of portal hypertension indicate advanced liver fibrosis or cirrhosis  NAFLD: DIAGNOSTIC STUDIES o Liver Tests: o Mild elevation AST, and ALT (ratio AST:ALT >1) o Mild elevation ALKP o Viral hepatitis panel: negative Non-invasive assessment of fibrosis: FIB-4 score: based on age, platelet count AST and ALT levels BARD: based on BMI, AST/ALT ratio and DM NAFLD Fibrosis Score: based on age, hyperglycemia, BMI, platelet count, albumin and AST/ALT ratia  NAFLD: DIAGNOSTIC STUDIES o Liver biopsy: Diagnostic o Usually not recommended in asymptomatic patients NASH – biopsy evaluation of histologically show inflammation of hepatocytes PMN’s, Mallory hyalin = Steatohepatitis NAFDL spectrum: Fatty liver → isolated portal fibrosis →steatohepatitis → cirrhosis →increased risk of HCC  NAFLD: DIAGNOSTIC STUDIES Non-invasive scoring systems: to assess for fibrosis FIB-4 – based on age, platelet count, AST and ALT levels BARD score – based on BMI >28, AST/ALT ratio >0.8 and DM NAFLD Fibrosis Score – based on age, hyperglycemia, BMI, platelet count, albumin, AST/ALT ratio  NAFLD: TREATMENT o Multidisciplinary approach - lifestyle changes o Weight loss!! Loss of 5% body weight improves steatosis / >7% improves steatohepatitis / >10% improves fibrosis o Low fat diet and exercise (Ie. Mediterranean diet) o Discontinue: hepatotoxic medications or moderate alcohol consumption o Bariatric surgery if BMI >35 improves NASH in most cases o Liver transplantation if advanced cirrhosis (NASH 3 rd most common indication) o Monitor in 3-6 months with repeat LT’s o Various experimental therapies are being looked at DRUG INDUCED LIVER INJURY (DILI)  DRUG INDUCED LIVER INJURY (DILI): ETIOLOGY Can mimic viral hepatis, biliary tract obstruction and other liver diseases Can cause jaundice and liver injury Worse outcomes when there is pre-existing liver disease May need liver transplantation within 6 months ALWAYS keep on differential list and ALWAYS check patient medication list  DRUG INDUCED LIVER INJURY (DILI): ETIOLOGY Hepatoxic drugs include: (not a comprehensive list) Acetaminophen (especially with second agent alcohol) ALT/AST can be as high as 3,000IU/L Most common cause of acute liver failure – 45% of cases Antibiotics: Amoxicillin/Clavulanate, Nitrofurantoin (especially in elderly), Fluroquinolones, Oxacillin Antituberculosis drugs: Isoniazid (especially with second agent rifampin)  DRUG INDUCED LIVER INJURY (DILI): ETIOLOGY Antiepileptics: Carbamazepine, phenytoin Amiodarone, dapsone, diclofenac, chloramphenicol, duloxetine, methyldopa OTC herbal and dietary supplements Direct hepatotoxicity Dose-related (ie. Acetaminophen) Indirect hepatotoxicity Liver injury occurs when drug exacerbates pre-existing liver disease (ie. Immunosuppressive drugs cause flare of HBV)  DRUG INDUCED LIVER INJURY (DILI) Refer to GI Liver biopsy Discontinue offending agent CIRRHOSIS  CIRRHOSIS: EPIDEMIOLOGY o Result of chronic hepatocellular injury with inflammation o Eighth leading cause of death in the US o Approximately 49,500 deaths per year in US o Mexican American and black persons have higher frequency of cirrhosis o Hepatocellular injury due to increased fibroblastic activity  CIRRHOSIS: ETIOLOGY o Caused by: Alcohol abuse Infections; Viral hepatitis (B and C), Schistosomiasis Drug toxicity (ie. methotrexate, isoniazid, amiodarone) Metabolic: Obesity leading to NAFDL Autoimmune disease (autoimmune hepatitis AIH, PSC, PBC) Chronic biliary obstruction Inherited metabolic defects (hemochromatosis,Wilson disease, alpha1-antitrypson deficiency) Vascular disorders (Budd-Chiari syndrome)  CIRRHOSIS: PATHOPHYSIOLOGY o Fibrosis occurs due to prolonged inflammation o Thick fibrous connective tissue septa form o Fibrosis can be reversed if cause is removed o As total collagen content of parenchyma increases (3 to10-fold) leads to scarring of the cells o Regenerative nodules o Elastin formation o Marks the conversion to irreversible fibrosis = cirrhosis  CIRRHOSIS CLINICAL PRESENTATION o Cirrhosis progresses through 3 stages as the fibrous septa get thicker: 1. Compensated 2. Compensated with varices 3. Decompensated (ascites, variceal bleeding, encephalopathy, jaundice) o Symptoms result from: o Hepatocellular dysfunction o Portosystemic shunting o Portal Hypertension  CIRRHOSIS: CLINICAL PRESENTATION Compensated Cirrhosis: early stages may have no symptoms (vague) Fatigue Disruption in sleep Muscle cramps Weight loss Anorexia Nausea +/- vomiting  CIRRHOSIS: CLINICAL PRESENTATION o Compensated with varices: as disease progresses Varices form (90% of patients with cirrhosis) Jaundice (mild at first but increases as disease progresses) Spider nevi (telangiectasia) – usually upper half of body Palmer erythema – mottled redness of thenar and hypothenar eminences Dupuytren contractures Glossitis, cheilosis - from vitamin deficiencies Decreased libido Gynecomastia and ED in men Amenorrhea in women Muscle weakness / wasting  CIRRHOSIS: CLINICAL PRESENTATION o Decompensated Cirrhosis: Portal Hypertension can cause Abdominal pain from: Portal Hypertensive Gastropathy (increased pressure on gastric vessels) - can lead to UGIB RUQ pain - Hepatosplenomegaly (from stretching of capsule of the liver) Ascites (also pleural effusions, peripheral edema and ecchymosis – late findings) Esophageal varices bleeding – UGI bleed (also rectal varices and abdominal (caput medusa) Encephalopathy: liver fails to remove toxins from blood (ie. ammonia) toxins cross BBB Day night reversal Asterixis / Tremor Dysarthria / Delirium Ultimately coma and death  ANATOMY REVIEW: TO UNDERSTAND VARICES PORTAL VENOUS SYSTEM OR SYSTEMIC VENOUS SYSTEM HEPATIC PORTAL SYSTEM https://teachmeanatomy.info/abdomen/vasculature/venous-drainage/  VARICES: ESOPHAGEAL, ABDOMINAL, RECTAL o Normal hepatic portal venous pressure 10mmHg o Pressure gradient between portal vein and hepatic vein o Varices develop due to Portal Vein Hypertension (>12mmHg) o a less common cause of varices: hepatic vein thrombosis o Portal system and systemic (caval) systems meet in 3 locations: o Inferior (distal) esophagus: ↑ pressure causes esophageal varices o Round ligament of the liver: ↑ pressure causes varices of superficial veins of abdominal wall (caput medusa) o Superior rectum: ↑pressure causes rectal varices (different from hemorrhoids)  CIRRHOSIS: PHYSICAL EXAM Skin: Jaundice Spider telangiectasia (nevi) – face and chest Palmer erythema (mottled redness of thenar and hypothenar areas) Dupuytren contractures Abdomen: Hepatomegaly with firm sharp or nodular edge Splenomegaly Ascites Peripheral edema  CIRRHOSIS: DIAGNOSTIC STUDIES o CBC: Anemia: decreased HGB/HCT usually macrocytic Deficiency of B12 and Folate or decreased erythropoiesis RBC trapped by spleen (d/t splenomegaly) GI bleed (overt or occult) Thrombocytopenia: decreased platelets caused by: Alcohol suppression of production in the marrow (megakaryocytes) Folate deficiency Splenic sequestration of thrombocytes (d/t splenomegaly) WBC: may be low due to hypersplenism or high due to infection  CIRRHOSIS: DIAGNOSTIC STUDIES o LT’s: Elevated: AST/ ALT / ALKP Progressive elevation of bilirubin o Synthetic function tests: o Prothrombin Time/INR prolongation caused by: Decreased clotting factors produced by liver o Decreased albumin caused by: Inflammation of the liver cells → impaired breakdown of protein Hypoalbuminemia causes ascites - decreased colloidal osmotic pressure (pull) in vessels  CIRRHOSIS: DIAGNOSTIC STUDIES o Ultrasound: o Assesses liver size o Presence of nodules or lesions o Presence of Ascites o US with Doppler: assesses patency of splenic, hepatic, portal veins o Rule out Budd-Chiari syndrome – thrombosis of hepatic vein) o CT or MRI: assesses nodules o if suspicious for malignancy a liver biopsy (US guided) is needed o +/- EGD: confirms presence of: varices, gastropathy  CIRRHOSIS: DIAGNOSTIC STUDIES o Liver biopsy: diagnostic o Typically performed laparoscopically through abdomen o Transjugular approach if coagulopathy or ascites o Assesses: fibrosis / cirrhosis / NASH / fatty liver o Grade and Stage: (Metavir Score) o Grade 0-4: Inflammation o Stage 0-4: Fibrosis (Cirrhosis = 4/4)  CIRRHOSIS: DIAGNOSTIC STUDIES o Alternatives to liver biopsy: o FibroSure Test – looks at serum biomarkers for hepatic fibrosis o Hylauronic acid, amino-terminal propeptide of type III collagen, tissue inhibitor of matrix metalloproteinase 1 o Magnetic resonance elastography score o Prognostic scoring systems for cirrhosis: predicts risk of decompensation o Child-Pugh o MELD  CHILD-PUGH SCORE o Measures severity of chronic liver disease: risk of decompensation Ascites Encephalopathy: None: 1 point / grades I-II (or suppressed with medication): 2 point / grades III-IV (or refractory): 3 points Total bilirubin Serum albumin Prothrombin time (INR 2.3: 3 points) o The point scores are then added up and classified as: o Class A: 5-6 points o Class B: 7-9 points o Class C: 10-15 points CHILD - PUGH SCORE  MODEL FOR END-STAGE LIVER DISEASE MELD-NA SCORE o Measures mortality risk in end-stage liver disease and predict survival of complications (next 3 months) o Scoring system used for liver transplant candidates o Measures: Bilirubin measures how effectively the liver excretes bile INR (prothrombin time) the liver’s ability to make blood clotting factors Creatinine which measures kidney function (Impaired kidney function is often associated with severe liver disease.) Serum sodium o Score ranges from 6-40  MELD SCORE o Used for wait list for liver transplantation: higher the score the higher on wait list o Score >17 is required to be listed o Greater than or equal to 25 – highest on list o Survival rate in severe disease o 1.8 o Platelets if platelet count 1:40 in serum) Hallmark!! o Serum IgM elevated o Baseline Ultrasound o Liver biopsy is not needed for the diagnosis  PBC: DIFFERENTIAL DIAGNOSIS Chronic biliary obstruction Stone or stricture Carcinoma of bile ducts Primary Sclerosing Cholangitis Sarcoidosis Drug toxicity (ie. Chlorpromazine)  PBC: TREATMENT o Refer to GI: o Symptomatic treatments: o Pruritus: o Cholestyramine 4g in 8oz. water PO tid Refractory pruritus – Plasmapheresis (remove antibodies) o Daytime somnolence: Modafinil (Provigil) 100-200mg PO qd But poorly tolerated o Vitamin supplementation (especially A,D,K)  PBC: TREATMENT o Ursodeoxycholic Acid (Ursodiol) 13-15mg/kg PO qd – preferred medical treatment Slows progression of disease Improves long term survival Decreases risk of developing varices Decreases or delays need for transplantation Without liver transplantation – survival averages 7-10yrs from symptom onset WILSON’S DISEASE  WILSON’S DISEASE: ETIOLOGY AKA: hepatolenticular degeneration Rare autosomal recessive disorder Defect on chromosome 13 – copper transported adenosine triphosphatase Excessive deposition of copper in liver and brain Occurs in people between 3 and 55yo  WILSON’S DISEASE: CLINICAL PRESENTATION Presents as liver disease in adolescents (more common females) Young patients with hepatitis, splenomegaly with hypersplenism, Coombs-negative hemolytic anemia, portal HTN, psychiatric abnormalities Presents as neuropsychiatric disease (more common in males) Kaye-Fleischer rings around cornea Neurologic symptoms can include: Parkinsonism Ataxia Dysarthria Dysphagia Spasticity  WILSON’S DISEASE: DIAGNOSTIC STUDIES Increased urinary copper excretion Decreased serum ceruloplasmin Elevated copper levels Coombs negative hemolytic anemia If diagnosis unclear: Liver biopsy for quantitative copper measurement If done: MRI shows increased copper in basal ganglia, brainstem and cerebellum If available: molecular analysis of ATP7B pathogenic variant – diagnostic First degree relatives require screening with serum ceruloplasmin, Liver tests and slit lamp exams  WILSON’S DISEASE: TREATMENT Early removal of copper results in less hepatic and neurologic damage Dietary restriction of foods containing copper – shellfish, organ foods, nuts, mushrooms Chelating agents: Oral penicillamine enhances urinary excretion of copper Alternative if intolerant to penicillamine Trientime hydrochloride (increasingly becoming first-line) Oral zinc Oral pyridoxine (B6)