Abnormal Liver Chemistries Lauren Myers, MMsc. PA-C Oregon Health and Science University
Disclosure 1. The speaker/planner Lauren Myers, MMSc, PA-C have no relevant financial relationships to disclose 2. The speaker/planner Atif Zaman, MD MPH have no relevant financial relationships to disclose.
Objectives Basics of Liver Physiology/Abnormal LFT s Review the anatomy and function of the liver Interpret abnormal biochemical markers that may reflect liver disease Identify the warning signs of worsening liver disease
Liver Anatomy RadioGraphics. Sept 2002. 22(5) p 1063-1076
https://www.slideshare.net/dimitriskorkolis/liver-anatomy (5_2018)
http://histonano.com/books/junqueira (5_2018)
Liver Functions Metabolism of carbohydrates, fat and protein Synthesizes 90% of plasma proteins Metabolizes drugs and degrades toxins Maintains blood glucose Conversion ammonia to urea Stores and processes vitamins Regulates blood clotting Synthesizes non-essential amino acids
Liver Chemistries AST ALT Alkaline Phosphatase Total bilirubin Albumin INR Markers of liver inflammation Markers of liver function
Liver Chemistries AST ASpartate aminotransferase Aka Serum Glutamic-Oxaloacetic Transaminase (SGOT) ALT ALanine aminotransferase Aka Serum Glutamic-Pyruvic Transaminase (SGPT) ALT more specific marker of liver injury than AST AST and ALT are intra-cellular enzymes and when released in blood = hepatocytes are dying
Liver Chemistries Alkaline Phosphatase Present in liver, gut, bone, placenta AP physiologically higher in children due to rapid bone growth and pregnant women An isolated AP level should be confirmed for hepatic source by GGT (Gamma Glutyl Transferase) Liver AP is induced by elevated levels of bile acid (biliary obstruction/hepatocyte injury)
Alkaline Phosphatase HIGH Liver Cirrhosis Cholestasis Tumors Drugs Verapamil, phenytoin, erythromycin, allopurinol Bone Paget s Bone mets Mult myeloma Hypothyroidism Blood Leukemoid reactions P.vera Myelofibrosis LOW Children Achondroplasia Cretinism Pernicious anemia Aplastic anemia CML Magnesium deficiency Hypothyroidism Wilson s disease Osteoporosis Slide courtesy Michael Chang
Liver Chemistries Total Bilirubin Comprised of both Conjugated (direct) and Unconjugated (indirect) bilirubin Bilirubin is produced during the breakdown of hemoglobin Conjugation occurs in the hepatocyte Bilirubin rises due to over production (ie. hemolysis), under secretion (ie. biliary obstruction, liver injury, shunt), or impaired metabolism (ie. Gilbert s syndrome) Slide courtesy Michael Chang
Liver Chemistries Albumin Blood protein that is made in the liver Half life of endogenous albumin is 14-21 days (compared to T½ of infused albumin, which is ~8 hours) Production is inhibited by physiologic stress (surgery, infection, acute disease) Production is inhibited in advanced stages of chronic liver disease INR Reflects clotting cascade function of the extrinsic clotting pathway (factors II, V, VII, X) All extrinsic factors made by the liver Factors II, V, VII are also Vitamin K dependent Rise in INR reflects deficient production of at least one of the co-factors (in absence of vitamin K deficiency Factor VII has the shortest half life of all the cofactors (3 hrs), and is a reasonable measure of immediate liver function Slide courtesy Michael Chang
What are Normal Cutoffs? ALT >33 for men and ALT >25 are associated with increased liverrelated mortality Normal lab values defined as the mean value of a healthy population ± 2 standard deviations ALT levels are higher in males than females. AST and ALT ULN ranges can vary between different labs. Clinicians may rely on local lab ULN ranges for alkaline phosphatase and bilirubin. ALT 29-33 IU/l-MEN ALT 19-25 IU/l -WOMEN Kwo. Am Journal Gastro.2017
Patterns of Liver Chemistry Abnormalities Hepatocellular: ALT, AST Mixed Cholestatic: AP ± TB Slide courtesy Joseph Ahn
Common Diagnoses Hepatocellular: HBV HCV ETOH NAFLD Hemochromatosis Mixed Cholestatic: Biliary Disease Drug-Induced Liver Injury Slide courtesy Joseph Ahn
Gilbert s Syndrome Most common cause of elevated unconjugated bilirubin 3-7% of the U.S. population Genetic defect in UDP-glucuronyltranferase = decreased hepatic conjugation of bilirubin Almost never exceed 6mg/dL, usually < 3mg/dL Fasting and serious illness -> increase unconjugated bili by 2- or 3-fold Diagnosis in absence of hemolysis, medications, normal serum transferases and alk phos https://ghr.nlm.nih.gov/condition/gilbert-syndrome
ALT/AST <5x ULN ALT/AST 5-15x ULN ALT/AST >15x ULN ALT >10,000 IU/l Viral hepatitis Acute Hepatitis (A, B, C) Acetaminophen toxicity Alcoholic hepatitis Consider all Ischemic hepatopathy NAFLD Hemochromatosis Wilson s Alpha-1 Antitrypsin Deficiency Autoimmune Hepatitis Drug-induced-Liver-Injury
Things to consider Confirm abnormal liver chemistries Confirm an isolated AP for liver source by GGT Does the clinical history suggest a chronic liver illness? If so, does this person have cirrhosis? Is there any impairment in liver synthetic function? What is the degree of serum transferase elevation and or do you really need to worry about them clinically?
Case 1 43 yo M with psoriasis treated with ustekinumab who presents with several day history of arthralgias, fatigue and mild abdominal pain AST 1561, ALT 2089, AP 540, GGT 165, t bili 1.7
Case 1 AST or ALT more than x 10-20 ULN Should prompt more urgent evaluation Close follow up In association with elevated INR or Tbili, should prompt hospitalbased evaluation.
Case 2 58 yo M without known liver disease, recently treated for bronchitis with amoxicillin/clavulanate presents complaining of itching, nausea and yellow eyes AST: 171, ALT: 326, AP 255, t bili 6, INR 0.9
Case 2 Tbili > 2 in setting of new medications *Absence of Gilbert s Syndrome Hy s Law AST/ALT > x3 ULN Tbili > 2 (normal alk phos) Suggests significant Drug Induced Liver Disease (DILI) with a case fatality rate as high as 10% Slide courtesy Michael Chang
Case 3 18 yo F with depression comes into urgent care vomiting and drowsy. AST 7430, ALT 2557, AP 109, t bili 4.0, INR 6.9
Case 3 Constellation of elevated INR, Tbili, and encephalopathy*** Defines Acute Liver Failure Requires hospitalization *** in absence of cirrhosis/advanced liver disease
Case 4 42 yo M with a history of diarrhea, presents with itching, abdominal pain, fatigue, dark urine, feels feverish ALT 240, AP 340, t bili 6, INR 1.5
Case 4 Alk Phos > 200 with elevations in T bili and systemic symptoms (fevers, pain, etc) cholangitis Charcot s Triad Fever, RUQ pain, jaundice Reynold s Pentad 50% mortality Charcot + shock + confusion Slide courtesy Michael Chang