Overview of Liver Tests. You Ordered It...Now What? Evaluation of Abnormal Liver Tests. Patterns of Abnormal Liver tests.

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1 Overview of Liver Tests You Ordered It...Now What? The Liver Panel : AST, ALT, alk phos, GGT, total bilirubin, albumin, sometimes GGT and direct bilirubin The True Liver Function Tests: Albumin, bilirubin, prothrombin time/inr Others (clotting factors, lactate, cholesterol) Barry Schlansky, MD MPH Assistant Professor of Medicine Division of Gastroenterology & Hepatology Oregon Health and Science University Ammonia is a poor test of liver function and poorly correlates with hepatic encephalopathy 2 Patterns of Abnormal Liver tests Hepatocellular AST/ALT >>> bili, alk phos Cholestatic Bili, alk phos >>> AST, ALT Mixed Bili, alk phos ~ AST, ALT Viral hepatitis (A, B, C, D, E) Obstruction (gallstones, tumors) Alcoholic hepatitis Nonalcoholic steatohepatitis Primary biliary cholangitis Vascular / congestion Autoimmune hepatitis Primary sclerosing cholangitis Drug induced liver injury Liver Macro-Anatomy Three Lobes (left, right, and caudate) Dual Blood Supply: Portal vein 75% blood, 50% O 2 Hepatic artery 25% blood, 50% O 2 The portal vein drains the esophagus, stomach, spleen, and intestines into the liver Hemochromatosis Infiltration (cancer, sarcoid, TB) Wilson s disease Vascular / congestion Liver Micro-Anatomy Alpha-1-antitrypsin deficiency Celiac disease Vascular / congestion Drug induced liver injury Drug induced liver injury 3 Lobule = anatomic unit of the liver Six portal triads surrounding cords of hepatocytes with a central vein Portal triad = portal venule, hepatic arteriole, and bile ductule Arterial and venous blood mix in the hepatic sinusoids, flows to central vein Separate system of bile canaliculi drain bile in the opposite direction to the bile ductule AST and ALT Alkaline Phosphatase ASpartate and ALanine aminotransferase AKA SGOT and SGPT Intracellular hepatocyte enzymes involved in gluconeogenesis Leak out in times of injury, measured in the serum AST also in myocardium, skeletal muscle, brain, stomach, kidney, pancreas, spleen, lung, and erythrocytes (90% of serum AST is from the liver) ALT is predominately hepatic (minute amounts in kidney and muscle) (~100% of serum ALT is from the liver) Commonly abnormal a 2002 study found elevated ALT levels in 8.9% of the U.S. population Likely higher with stricter ULN (<30 in men, <20 in women) Enzyme in hepatocyte membrane lining the bile canaliculi Localized in liver > bone > intestine; also produced by the placenta Fluctuates with age: A liver origin for an elevated alk phos can be confirmed by testing the GGT or 5 -nucleotidase, or it can be fractionated Isolated liver alk phos elevations can occur with infiltrative liver diseases (lymphoma, sarcoidosis, TB), PBC/PSC, and certain drugs (phenytoin) 6

2 Bilirubin Most (~80%) bilirubin is a product of heme degradation Unconjugated (indirect) bilirubin released into the blood bound to albumin Hepatocyte ER conjugates bilirubin to its direct form Direct bilirubin excreted into the bile (rate-limiting) Elevated bilirubin may reflect over-production (hemolysis rarely >5 mg/dl), impaired conjugation (Gilbert s syndrome rarely >3 mg/dl), impaired secretion by hepatocytes (liver injury/failure), or blockage of bile flow (biliary obstruction) Over-production and impaired conjugation cause predominately indirect hyperbilirubinemia Impaired secretion or blockage cause mixed or direct 7 hyperbilirubinemia The True Liver Function Tests Albumin Plasma protein synthesized by the liver (t 1/2 =14-21 days) Levels <3.5 mg/dl suggest chronic/advanced liver disease Non-specific Production inhibited by inflammation, infection, protein malnutrition, and alcohol abuse Prothrombin time/inr Liver synthesizes extrinsic pathway clotting factors (I, II, V, VII, IX, X, XII, and XIII) and some vwf Many are vitamin K-dependent and are reduced in both liver disease and vitamin K deficiency INR is one of the most sensitive measures of acute liver failure (with presence of encephalopathy) Does not represent bleeding risk in liver disease autoanticoagulation is not a real thing 8 Many things cause a one-time elevation of liver tests Except for viral hepatitis serologies in high-risk patients, mild liver test elevations should be monitored for 3-6 months before a full lab work-up for etiology is performed Normal = 2 SD above and below the mean in a young, healthy population Thus, 2.5% of normal, healthy people will have an abnormal test Do they have a condition where an high test is normal? (alk phos in pregnancy, AST in a marathon runner, INR in a coumadin user) 9 10 Duration of elevation, symptoms (pruritus, fatigue, pain, arthralgias/myalgias, fever, weight loss, urine/stool changes) Medications (including OTC/supplements, dose changes, duration of exposure) PMH Personal or family history of autoimmune disease 11 Social history is crucial! How much do you drink? (be specific!) Recent travel or immigrant? Prior blood transfusions before 1991, tattoos, hemodialysis? Healthcare worker with prior needlestick? Prior injection or intranasal drug use, even once? Mushroom ingestion? High-risk sexual behavior? (MSM, multiple partners, unprotected sex) 12

3 Stigmata of chronic liver disease (Spider telangiectasias, firm liver edge, splenomegaly, ascites, edema, caput medusae, temporal wasting, palmar erythema, jaundice/icterus, asterixis) Most of the time, history + exam will provide the likely cause of the abnormal liver tests 5. Stop all alcohol, any unnecessary medications associated with liver injury, and all herbal/dietary supplements Elevated AST/ALT 5. Stop all alcohol, any unnecessary medications associated with liver injury, and all herbal/dietary supplements 6. Elevated AST/ALT Initial Work-Up: HCV-Ab (reflex RNA if +), HBsAg, HBcAb-IgM/IgG, HAV- IgM/IgG, HBsAb, ferritin and % transferrin saturation if negative, monitor for 3-6 months Elevated AST/ALT 5. Stop all alcohol, any unnecessary medications associated with liver injury, and all herbal/dietary supplements 6. Elevated AST/ALT Initial Work-Up Initial work-up negative and AST/ALT remain elevated RUQ ultrasound with Dopplers, ANA, antismooth muscle, SPEP, 1AT level, anti-ttg, TSH, ceruloplasmin (if age <50) Elevated Bilirubin or Alk Phos 5. Stop all alcohol, any unnecessary medications associated with liver injury, and all herbal/dietary supplements 6. Elevated Bilirubin / Alk Phos Initial Work-Up: CMP, CBC, INR, and RUQ ultrasound with Dopplers Elevated Bilirubin or Alk Phos 5. Stop all alcohol, any unnecessary medications associated with liver injury, and all herbal/dietary supplements 6. Elevated Bilirubin / Alk Phos Initial Work-Up: CMP, CBC, INR, and RUQ ultrasound with Dopplers Evidence of biliary obstruction: CT or MRI-MRCP, ERCP, EUS-FNA, tumor markers if mass present No evidence of biliary obstruction: AMA, IgG4, CT or MRI-MRCP possible ERCP or liver biopsy 17 18

4 When to Worry! 1. Severe Hepatocellular Injury: AST/ALT >15x ULN (~400) 1. Severe Drug-Induced Liver Injury: AST/ALT >3x and bilirubin >2x ULN with normal alk phos Hy s Law predicts liver failure with a 10% case fatality rate 1. Hepatic Synthetic Dysfunction: Acutely elevated liver tests (AST/ALT, bili, alk phos) with associated increases in the INR (>1.5) or development of hepatic encephalopathy in a patient without known cirrhosis Acute Liver Failure warrants urgent hospitalization Cases 1. Acute Cholangitis: Elevated bilirubin and alk phos with associated RUQ abdominal pain and fever (Charcot s triad) Reynold s pentad = Charcot s + shock + confusion 50% mortality Case #1 48 year-old man with abnormal liver tests at annual physical No significant past medical history No medications Tried IV drugs one time in college Normal physical exam AST 62, ALT 88, Alk Phos 75, total bili 0.7, INR 1.0, albumin 4.1 Normal abdominal ultrasound Case #1 48 year-old man with abnormal liver tests at annual physical No significant past medical history No medications Tried IV drugs one time in college Normal physical exam AST 62, ALT 88, Alk Phos 75, total bili 0.7, INR 1.0, albumin 4.1 Normal abdominal ultrasound HCV-Ab+ What now? Case #1 48 year-old man with abnormal liver tests at annual physical No significant past medical history No medications Tried IV drugs one time in college Normal physical exam AST 62, ALT 88, Alk Phos 75, total bili 0.7, INR 1.0, albumin 4.1 Normal abdominal ultrasound Case #1: Hepatitis C HCV-Ab positivity indicates active infection or prior exposure with immune clearance (~25%) False positives with rheumatologic disease False negatives in immunosuppressed patients HCV-Ab seroconverts ~8-16 weeks after exposure (can test HCV RNA if HCV-Ab negative with acute liver test elevation) HCV RNA detectable ~2 weeks after exposure, level does not correlated with severity of liver disease HCV-Ab+ What now? HCV RNA, HCV genotype, HBsAg, HBcAb, HBsAb, HIV Hepatitis A and B vaccinations, Hepatology referral 23 24

5 Case #2 45 year-old male Somalian immigrant with abnormal liver tests at routine physical PMH: hyperlipidemia No medications or prior alcohol or drug use Born in Somalia, emigrated to U.S. in 1990 Father died from liver cancer but otherwise no known history of viral hepatitis Normal physical exam AST 50, ALT 60, Alk Phos 70, total bili 0.5, INR 0.8, albumin 3.9 Abdominal ultrasound 3-cm liver mass Case #2 HBsAg positive HBsAb negative Total HBcAb positive (HBcAb-IgM negative) Further testing: HBV DNA 100 million IU/mL, HBeAg+, HBeAb-, AFP 954 liver protocol CT with 3-cm right lobe hepatocellular carcinoma What now? Case #2: Hepatitis B Global Distribution of Hepatitis B HBsAg positive HBsAb negative Total HBcAb positive (HBcAb-IgM negative) Further testing: HBV DNA 100 million IU/mL, HBeAg+, HBeAb-, AFP 954 liver protocol CT with 3-cm hepatocellular carcinoma Diagnosis Chronic Hepatitis B (likely vertically transmitted) million chronic carriers worldwide Ninth leading cause of death worldwide Nearly 75% of HBV chronic carriers are Asian High risk of liver cancer in Sub-Saharan African patients HBsAg Prevalence (%) 8: High 2-7: Intermediate <2: Low 28 Interpretation of Hepatitis B Serology Interpretation of Hepatitis B Serology HBsAg HBsAb HBcAb HBV DNA Interpretation (IgM) + Acute Hepatitis B Infection (IgG) + Chronic Hepatitis B Infection Vaccinated for Hepatitis B - +/- + - Past Exposure to Hepatitis B 29 HBsAg HBsAb HBcAb HBV DNA Interpretation (IgM) + Acute Hepatitis B Infection (IgG) + Chronic Hepatitis B Infection Vaccinated for Hepatitis B - +/- + - Past Exposure to Hepatitis B HBeAg and HBeAb are only applicable to patients with chronic hepatitis B infection Chronic active infection = elevated ALT and HBV DNA, needs antiviral treatment Chronic inactive (carriers) = normal ALT and low level HBV DNA, needs active surveillance for HBV flares (conversion to active) HBeAg can be negative in active infection (precore mutation), treated similarly to HBeAg+ chronic active hepatitis B 30

6 Case #3 19 year-old healthy female college student with several days of fatigue, jaundice, and mild pruritus No alcohol or drug use, no medications No high-risk behavior, sick contacts, or travel Recent ear infection treated with Augmentin Exam icterus, jaundice, otherwise normal AST 180, ALT 290, Alk Phos 248, total bili 8.5, INR 0.9, albumin 4.4 Negative viral serologies Abdominal ultrasound normal Case #3: Drug-Induced Liver Injury Liver tests normalized over 8 weeks after stopping Augmentin #1 cause of DILI in the U.S. is acetaminophen As little as 2-3 gm/d can cause toxicity with alcohol / fasting What is the diagnosis? Case #3: Drug-Induced Liver Injury Liver tests normalized over 8 weeks after stopping Augmentin #1 cause of DILI in the U.S. is acetaminophen As little as 2-3 gm/d can cause toxicity with alcohol / fasting 33 Top Ten Prescription Causes of DILI (NIH DILI Network) Rank Agent Percent 1 Amoxicillin/clavulanic acid 12% 2 Isoniazid 7% 3 Nitrofurantoin 6% 4 TMP-SMX 4% 5 Minocycline 4% 6 Cefazolin 3% 7 Azithromycin 2% 8 Ciprofloxacin 2% 9 Diclofenac 2% 10 Levofloxacin 2% All of the top 20 drugs for DILI were approved before Case #4 56 year-old woman with several months of fatigue, myalgias No alcohol or drug use, no medications PMH type 1 diabetes, Hashimoto s thyroiditis Exam scleral icterus, otherwise normal AST 350, ALT 400, alk phos 205, total bili 2.5, INR 1.0, albumin 3.4 Negative viral serologies Abdominal ultrasound with mild hepatomegaly Case #4 ANA 1:640, ASMA 1:380, SPEP with elevated IgG level Diagnosis Autoimmune Hepatitis (probable) What is the leading diagnosis? What additional labs? 35 36

7 Case #4: Autoimmune Hepatitis ANA 1:640, ASMA 1:380, SPEP with elevated IgG level Diagnosis Autoimmune Hepatitis (probable) Biopsy required interface hepatitis with plasma cells Middle-aged woman, non-drinker, without viral hepatitis Symptoms Fatigue, arthralgias/myalgias, jaundice Often history of other autoimmune disease Increased AST/ALT (can be >1,000), often elevated bilirubin, elevated ANA, ASMA (F-actin), and IgG Prompt response to steroids, followed by long-term steroid-sparing immune suppression (azathioprine) Case #5 60 year-old obese man with new-onset diabetes found to have elevated liver tests PMH: DM2, osteoarthritis, HTN No family history of liver disease Drinks 4 beers/day, no prior drug use Exam normal AST 75, ALT 65, alk phos 122, total bili 0.5, INR 0.8, albumin 4.4 Negative viral serologies Normal ultrasound What other lab testing? Case #5 Ferritin 610, transferrin sat 78% HFE testing C282Y homozygote Diagnosis Iron Overload Syndrome Hemochromatosis vs. Alcohol vs. NASH or All Three? Case #5: Iron Overload Ferritin 610, transferrin sat 78% HFE testing C282Y homozygote Diagnosis Iron Overload Syndrome Hemochromatosis vs. Alcohol vs. NASH or All Three? Things to keep in mind: 1. Hemochromatosis = 0.5% of Caucasians (rare other races) 2. Test HFE only if elevated iron tests or in family members 3. C282Y/C282Y penetrance in men = 24-43% (women lower) 4. Hemochromatosis is not the most common cause of an elevated ferritin level in the primary care setting! Case #5: Iron Overload The Hemochromatosis and Iron Overload Screening (HEIRS) study (2011) tested iron studies and HFE in 44,892 Caucasian primary care patients Elevated ferritin in 19% of men (>300), 9% of women (>200) Most with ferritin <1,000 did not have iron overload HFE genotypes Inflammation, NASH, and alcohol use are more common causes Men Women Alcoholic Liver Disease Occurs in 25% of heavy drinkers Liberal hepatology definition 21/wk in men, 14/wk women Multiple phenotypes: 1. Alcoholic fatty liver (liver tests may be normal) 2. Alcoholic steatohepatitis and cirrhosis (mimics NASH) 3. Alcoholic hepatitis (40% 90-day mortality if severe) AST > ALT (but always <500) Cirrhosis can occur despite normal liver tests 41 42

8 Case #6 47 year-old Caucasian woman with several months of pruritus and fatigue PMH: osteoporosis, dyslipidemia No family history of liver disease No alcohol or drug use history Exam skin excoriations AST 110, ALT 130, alk phos 450, total bili 1.4, INR 0.9, albumin 4.2 Negative viral serologies Ultrasound with heterogenerous appearing liver Case #6 AMA+ 1:360, ANA+ 1:80, ASMA-, IgG normal Diagnosis Primary Biliary Cholangitis What other lab testing? Case #6: Primary Biliary Cholangitis AMA+ 1:360, ANA+ 1:80, ASMA-, IgG normal Diagnosis Primary Biliary Cholangitis Name changed from Primary Biliary Cirrhosis in 2015 Autoimmune destruction of intrahepatic bile ducts AMA 95% specific for diagnosis (ANA+ in 60%) Biopsy is not required for diagnosis Middle-aged women (9:1 F:M) Fatigue, pruritus, elevated cholesterol, osteoporosis, xanthomas, fat-soluble vitamin deficiencies (A, D, E, K) Ursodiol improves liver tests and delays progression to cirrhosis 45 Case #7 32 year-old Caucasian man with history of ulcerative colitis presents with fevers, abdominal pain, and jaundice Exam jaundice, RUQ TTP AST 120, ALT 130, alk phos 380, total bili 4.4, INR 0.9, albumin 4.2 Ultrasound with heterogenerous appearing liver without biliary dilation What test would confirm the diagnosis? What cancer is the patient at risk for? 46 Case #7 Case #7: PSC ERCP with diffuse beading of intra- and extrahepatic bile ducts, stones/pus removed with balloon sweeping Diagnosis Acute Cholangitis with underlying Primary Sclerosing Cholangitis ERCP with diffuse beading of intra- and extrahepatic bile ducts, stones/pus removed with balloon sweeping Diagnosis Acute Cholangitis with underlying Primary Sclerosing Cholangitis MRCP >> ERCP for diagnosis (in absence of cholangitis) Typically diagnosed in young men, >80% have UC PSC + UC is associated with a high colon cancer risk Colonoscopy at PSC diagnosis and annually thereafter Most will need transplant within 10 years of diagnosis Increased risk of cholangiocarcinoma Screening annual MRCP and CA19-9 levels 47 48

9 Case #8 68 year-old Hispanic woman with elevated liver tests at routine physical PMH DM2, HTN, dyslipidemia, OSA Meds metformin, HCTZ, atorvastatin FHx of DM2 and CAD, no liver disease Exam with acanthosis nigricans, morbid obesity AST 115, ALT 130, alk phos 80, total bili 0.5, INR 0.7, albumin 4.3 Ultrasound with increased liver echogenicity Case #8: Nonalcoholic Steatohepatitis Non-alcoholic fatty liver disease (NAFLD) encompasses: 1. Isolated fatty liver 40% U.S. prevalence, 80% of diabetics, no increased risk of liver mortality/cirrhosis 2. NASH - ~5% U.S. prevalence, associated with risk of cirrhosis What is the diagnosis? Case #8: Nonalcoholic Steatohepatitis Non-alcoholic fatty liver disease (NAFLD) encompasses: 1. Isolated fatty liver 40% U.S. prevalence, 80% of diabetics, no increased risk of liver mortality/cirrhosis 2. NASH - ~5% U.S. prevalence, associated with risk of cirrhosis Diagnosis of exclusion, liver biopsy is controversial Rising incidence will eclipse HCV as the #1 indication for liver transplantation and #2 cause of cirrhosis Treatment: Weight loss (10%), aerobic exercise, Heart Healthy diet, and excellent control of risk factors (DM, HTN, HLD, OSA, PCOS) Statins are OK to use! Vitamin E improves histology but controversial (CV and prostate cancer risk), contraindicated with DM or cirrhosis Questions? Or please schlansk@ohsu.edu