Evaluation of Abnormal Liver Chemistry Tests James Panetta, DO What are LFTs? Transaminases Alkaline phosphatase Bilirubin Gamma-glutamyl transpeptidase What are LFTs? 5 nucleosidase Lactate Dehydrogenase Albumin Prothrombin Time 1
Transaminases Transfer amino groups to form hepatic metabolites AST- oxaloacetate ALT- pyruvate Transaminases Released into blood from damaged hepatocytes ALT is more specific than AST AST also in cardiac/skeletal muscle, kidney, brain Isolated AST elevation suggests non-hepatic cause 2
Alkaline Phosphatase Hydrolase enzyme Catalyzes dephosphorylation from several types of molecules Works best in ph >7 Alkaline Phosphatase Canalicular membrane Elevated in bile duct obstruction Present in bone, placenta, intestine, kidney Elevated GGT can suggest hepatic origin Can also fractionate 3
Bilirubin From breakdown of heme in senescent RBCs Predominantly circulates in unconjugated form Conjugated form is water soluble Converted to urobilinogen in colon Bilirubin Usually reported at total bilirubin <1.1 mg/dl 70% unconjugated (indirect) Can fractionate Markers of Synthetic Function 4
Albumin True LFT Synthesized exclusively by the liver T 1/2 is 3 weeks Can decrease in other disease states Prothrombin Time The other true LFT More sensitive that albumin Vitamin K dependent Can be elevated in other disease states What is normal? Varies depending on lab Mean of the distribution +/- 2 standard deviations Includes 95% of healthy subjects 5
ALT/AST ULN variations Studies suggest >20 may be associated with morbidity and mortality Effect of lowering ULN Increased cost Unnecessary evaluations Decreasing blood donation pool What Causes Abnormal LFTs? 6
Causes of Elevated Transaminases Drug Induced Liver Disease Top of differential Any drug can cause abnormal LFTs Detailed history is key Empiric trials of drug discontinuation may be required livertox.nih.gov Hepatitis C Often have elevated AST & ALT Some do not Test all with risk factors CDC recommended testing baby boomers regardless of labs/risk factors 7
Hepatitis B 1.5 million Americans Vertical transmission common Efficient sexual transmission Test if persistent AST/ALT Surface antigen/antibody, total core antibody Non-alcoholic fatty liver NAFLD vs NASH No serologic test to tell the difference AST/ALT elevations usually mild Rarely above 300 No unique pattern Alcoholic Liver Disease Significant" weekly alcohol consumption Men 210 gm Women 140 gm Radiographically/histologically similar to NAFL 8
Alcoholic Liver Disease AST & ALT rarely above 300 Pattern: AST:ALT ratio 2:1 If 3:1, 96% have alcoholic liver disease GGT Look at MCV Autoimmune Hepatitis Generally more striking transaminase elevations TB/alk phos usually less/not elevated Occasionally has cholestatic pattern Autoimmune Hepatitis Numerous serologic markers to help make dx Look for other AI conditions IgG and autoantibodies Liver biopsy to confirm 9
Hemochromatosis Usually elevated transaminases Numerous associated conditions Ferritin/iron studies can help HFE testing -> biopsy Wilson s Disease Uncommon cause of elevated AST & ALT AR disorder of biliary copper excretion Usually young men Neurologic/psychiatric manifestations Check ceruloplasmin -> 24 hr urine copper, slit lamp, liver biopsy Alpha-1-Antitrypsin deficiency Uncommon cause of AST & ALT elevation, cirrhosis, HCC Also pulmonary manifestations Check A1AT levels and PI genotype PIZZ mutations most severe PIZM heterozygotes may also have liver disease 10
Other Causes of Elevated Transaminases Ischemic Hepatitis Congestive hepatopathy Budd Chiari syndrome Biliary obstruction Infection Other Causes of Elevated Transaminases Celiac disease Thyroid disease Pregnancy associated liver disease Acute fatty liver or pregnancy HELLP syndrome Non hepatic Causes of Elevated Alkaline Phosphatase 11
Drugs Again, top of differential Detailed history is key Empiric trials of drug discontinuation may be required livertox.nih.gov Primary Biliary Cholangitis Rare F>M Elevated alk phos +/- bilirubin AMA elevated in 95% Biopsy not routinely required Primary Sclerosing Cholangitis Uncommon chronic liver disease Immune mediated inflammation of bile ducts No serologic hallmarks Cholangiography shows multifocal strictures Liver biopsy not usually required 12
Other Causes of Cholestasis Extra hepatic Choledocholithiasis Tumors Ductal infections Other Causes of Cholestasis Intrahepatic Infiltrative diseases Metastatic disease Intrahepatic cholestasis of pregnancy Non-hepatic Initial Evaluation of LFT Elevation Look at pattern of abnormality Degree of abnormality (esp transaminases) Detailed H&P Consider repeating and/or performing clarifying test 13
Pattern Hepatocellular Injury AST/ALT Cholestatic Alkaline phosphatase/bilirubin Mixed Isolated hyperbilirubinemia R ratio ALT ALT ULN AP AP ULN R ratio > 5 hepatocellular injury < 2 cholestatic 2-5 Mixed 14
Degree of Transaminase Elevation Hepatocellular Borderline: <2X ULN Mild: 2-5X ULN Moderate: 5-15X ULN Severe: > 15X ULN Massive: > 10,000 IU Fulminant hepatic failure Fulminant hepatic failure Acute liver injury with severe impairment of synthetic function and hepatic encephalopathy in a patient without obvious previous liver disease Regardless of ALT level Requires immediate evaluation 15
Borderline/mild elevation Broad differential AST > ALT ALT > AST Borderline/mild elevation AST generally > ALT Medications Alcoholic liver disease Cirrhosis of any cause Congestive hepatopathy TPN Budd Chiari Borderline/mild elevation ALT generally > AST NAFLD Acute/chronic viral hepatitis Medications Hemochromatosis Autoimmune hepatitis Fatty liver of pregnancy/hellp syndrome 16
Borderline/mild elevation ALT generally > AST Wilson s disease Celiac Alpha-1-antitrypsine deficiency Acute biliary obstruction Liver trauma Acute viral hepatitis Moderate/Severe Elevation Ischemic hepatitis/shock liver Budd Chiari Toxins/medications HELLP Autoimmune hepatitis Wilson s disease Massive Elevation Ischemic (Shock liver) Drugs Viral 17
Non-hepatic Skeletal muscle damage Strenuous exercise Rhabdomyolysis Hemolysis Myocardial infarction Thyroid disease Borderline/mild elevation H&P Discontinue hepatotoxic medications Stop alcohol Assess for risk factors for fatty liver and viral hepatitis Borderline/mild elevation Repeat LFTs PT/INR CBC HBsAg, HBsAb, HBcAb, HCV Ab Iron panel Ultrasound Monitor 3-6 months 18
Borderline/mild elevation Persistent after 3-6 months ANA ASMA IgG A1AT phenotype Ceruloplasmin Consider liver biopsy Moderate Elevation H&P Stop hepatotoxic medications/alcohol Ultrasound CBC, CMP PT/INR Immediate referral to transplant center if FHF Moderate Elevation HAV IgM, HBsAg/Ab, HBcAb, HCV Iron panel Ceruloplasmin ANA, SMA, IgG Biopsy if stable/serologic evaluation negative 19
Severe/Massive H&P Stop hepatotoxic meds/alcohol CBC, CMP, acute viral panel PT/INR US to include Doppler Transplant center if FHF Severe/Massive ANA, ASMA, LKM, IgG EBV/CMV/HSV serologies Serum/urine toxicology Consider NAC If negative work up and stable, biopsy Cholestatic Liver Diseases Elevated alkaline phosphatase +/- increased TB Extra-hepatic Intra-hepatic Non-hepatic Isolated vs mixed 20
Isolated Alk Phos elevation H&P Check GGT If normal check for non-hepatobiliary causes Isolated Alk Phos Elevation GGT elevated Look for/stop hepatotoxic medications Ultrasound CBD dilated: MRCP/ERCP Not dilated: AMA, ANA, ASMA Mild elevation, observe 3-6 months If > 2X ULN consider biopsy H&P Alk Phos, Transaminases +/- Bilirubin Elevated No need for GGT Ultrasound Dilated CBD: ERCP/MRCP Non-dilated: AMA, ANA, ASMA AMA positive: PBC AMA negative: observe if mild; biopsy if marked, consider MRCP or EUS 21
Elevated Bilirubin H&P Fractionate bilirubin Indirect (unconjugated) Direct (conjugated) Indirect Hyperbilirubinemia Most likely Gilbert s Consider hemolysis Drugs Crigler-Najjar Indirect Hyperbilirubinemia H&P Review meds Evaluate for hemolysis Genetic testing for Gilbert s Rarely needs biopsy 22
Direct Hyperbilirubinemia Obstruction usually not isolated Drugs Cirrhosis TPN Dubin-Johnson Syndrome Rotor Syndrome Direct Hyperbilirubinemia H&P Review medications Ultrasound Dilated CBD: MRCP/ERCP/EUS Non dilated CBD: AMA, ANA, ASMA, consider biopsy Case Presentation 61 year old man admitted to ICU Sepsis from LLE cellulitis Noted to be jaundiced Denied prior history of liver disease 23
PMHx DM A-fib Dilated CM/CHF AICD GERD Gout Allergic rhinitis Testicular cancer Medications Carvedilol 12.5 mg bid Ferrous Sulfate 325 mg daily Furosemide 40 mg daily Glipizide 10 mg bid Lisinopril 10 mg daily Lyrica 50 mg daily Xarelto 20 mg daily Medications Fortesta 10mg patch daily Astepro 137 mcg nasal spray daily Flonase 50 mcg nasal spray daily Allopurinol 100 mg daily 24
SurHx BL orchiectomy Inguinal hernia repair AICD placement Physical Exam Temp 97, HR 83, R 22, BP 76/43 61 M, jaundiced, dyspneic HEENT: icteric CARD: Irregular PULM: Diminished, poor effort ABD: +BS, distended/dull, mild diffuse TTP EXT: Markedly edematous/erythematous LLE LABS WBC 29.3 Hgb 12.7 Plt 128 AST 137 ALT 73 AP 50 TB 9.5 PT/INR 21.7/2.1 25
Imaging US: ascites, GB wall thickening, coarse liver echotexture, CBD 4 mm HIDA: Poor uptake of tracer. GB filled after several hours. Small bowel never visualized MRCP: Nondiagnostic ECHO: EF 35% What is most likely cause of abnormal LFTs A) Acute alcoholic hepatitis B) Cholangitis C) Ischemia (shock liver) D) Hepatic congestion/chf E) Toxic/medications Summary Transaminase elevation guided by degree of elevation and presentation If mild AST/ALT elevation: stop hepatotoxic medications, alcohol consumption. Check for fatty liver, chronic HCV/HBV, hemochromatosis If negative, check for AIH, Wilson s, A1AT 26
Summary Higher AST/ALT elevations: Acute viral hepatitis panel Iron panel,ceruloplasmin, A1AT, AIH markers Refer if evidence of liver failure Summary Isolated alkaline phosphatase elevation Confirm with GGT or fractionated alk phos US Normal: Autoimmune markers, possible biopsy Dilated CBD: MRCP, ERCP, EUS Summary Elevated bilirubin Fractionate Indirect: Gilbert s likely, consider hemolysis Direct: Check US Dilated CBD: MRCP/ERCP Non-dilated CBD: Check AI markers 27
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