Approach to Abnormal LFT’s By William E. Stevens, MD

Approach to Abnormal LFT’s The biochemical LFT’s AST, ALT, ALK PHOS, BILI GGT, 5’NT, LDH ALB, P.T. Abnormal LFT syndromes Severe vs. mild elevations Acute vs. chronic elevations Hepatitic vs. cholestatic pattern

The Aminotransferases: Aspartate aminotransferase (AST) Alanine aminotransferase (ALT) Participate in gluconeogenesis; catalyzing transfer of amino groups to a~ketoglutarate AST found in liver, heart and skeletal muscle, brain, kidney, pancreas, lungs, WBC’s, and RBC’s ALT found primarily in liver Elevations occur due to hepatocyte membrane damage Almost all hepatobiliary diseases to some degree cause elevation The higher the AST:ALT ratio, the more specific for ETOH related liver disease AST:ALT >2:1 is 90% specific for ETOH injury AST:ALT >3:1 is 97% specific for ETOH injury

Alkaline Phosphatase Ubiquitous isoenzyme family found in liver, bone, placenta, kidney intestine, WBC’s Slight elevations can occur normally in blood type O and B, after fatty meals, and increase with age Isolated mild transient elevations are common, resolve spontaneously, are associated with no pathology Abnormally low levels occur in hypothyroidism, pernicious anemia, zinc deficiency, Wilson’s disease High elevations imply cholestasis due to intrahepatic, extrahepatic or infiltrative processes Elevations occur due to enzyme induction and synthesis, levels may be normal with acute biliary obstruction

Gamma Glutamyl Transpeptidase (GGT) Found in liver, biliary epithelium, spleen, pancreas, heart, lung, brain. Not found in bone Primarily useful in confirming hepatic origin of an elevated alkaline phosphatase Induced by ETOH, anticonvulsants, coumadin, etc Most sensitive indicator for hepatobiliary disease Very nonspecific; not very useful

5’ Nucleotidase (5 NT) Found in liver, biliary epithelium, intestine, brain, heart, pancreas Very specific for hepatobiliary disease Levels correlate closely with alkaline phosphatase Useful in confirming hepatic origin for elevated alkaline phosphatase

Lactate Dehydrogenase (LDH) Widespread, ubiquitous isoenzyme Elevations are due to cellular necrosis Massive elevations are suggestive for ischemic necrosis Limited diagnostic utility

Albumin Liver synthesizes 10 gm/d Serum half life is 20 days Synthetic ability and serum levels decrease with progressive liver disease Levels vary depending on nutritional status, volume status, vascular integrity, catabolism, urine and stool losses Low levels are not specific for liver disease

Pro Time (PT) Liver synthesizes Factors I, II, VII, IX, X, and degrades FDP’s Elevations of PT are not specific for liver disease Elevations that are due to liver disease are good indicators for severity of liver disease

Bilirubin Derived from catabolism of hemoglobin Two forms: water soluble--conjugated--direct water insoluble--unconjugated--indirect Direct bilirubin increases due to defects in hepatic bilirubin excretion: biliary obstruction or hepatocellular disease Indirect bilirubin increases due to increased hemoglobin breakdown or defects in hepatic uptake or conjugation

Evaluation of Abnormal LFT’s Do a history: some liver diseases are more common in certain ages and genders Age <40: Autoimmune, Wilson's Dis >40: NASH, Hemochromatosis, Biliary obstruction Sex male: Hemochromatosis female: Autoimmune, PBC

Evaluation of Abnormal LFT’s Do a history How long have they been abnormal? How much Alcohol? Any risk factors for viral hepatitis: IVDA, blood transfusion, tattoos, intranasal cocaine, multiple sex partners, multiple body piercing Autoimmune symptoms: rashes, arthralgias, myalgias, thyroid problems, Sjogrens symptoms Weight changes, anorexia Cholestatic symptoms: RUQ pain, fever, chills, pruritus, jaundice, dark urine, light colored stools Review medications, herbs, OTC medications

Evaluation of Abnormal LFT’s Do a physical exam Spider angiomas Enlarged liver and spleen Abdominal tenderness Findings of cirrhosis: ascites, edema, encephalopathy, palmer erythema, gynecomastia, testicular atrophy, caput medusa Cardiac exam, heart murmurs, JVD

Abnormal LFT Syndromes Isolated elevation of Bilirubin Elevations of Alkaline Phosphatase and Bilirubin: Cholestasis Massive elevations of AST / ALT Mild chronic elevations of AST / ALT

Approach to an Isolated Elevation of Bilirubin Elevations occur from Bilirubin overproduction Impaired bilirubin uptake, conjugation, or excretion First fractionate bilirubin: conjugated vs. unconjugated Unconjugated hyperbilirubinemia: Increased bilirubin production: hemolysis, hematoma, dyserythropoiesis (check haptoglobin) Impaired bilirubin conjugation: Gilbert’s Syndrome: 3-7% population, increased in white males, Bili <6 Chronic liver diseases, advanced cirrhosis, Wilson’s Disease, estrogens Crigler-Najjar syndrome types I and II, extremely rare Impaired hepatic bilirubin uptake: rifampin, probenicid, CHF, etc. Conjugated hyperbilirubinemia: Dubin-Johnson Syndrome: abnormal excretion of bilirubin into bile ducts Rotor Syndrome: defective intrahepatic storage of bilirubin Both very rare; asymptomatic jaundice in 2nd decade of life

Approach to Cholestasis Elevations of Alkaline Phosphatase and Bilirubin History: abdominal pain, fever, pruritis, jaundice, medications, ?IBD If isolated Alk Phos elevation; confirm liver as source with 5’NT or GGT or Alk Phos isoenzymes Ultrasound If US is abnormal Biliary obstruction: CBD stones, strictures or biliary and pancreatic malignancies Hepatic malignancy If US normal Consider medications: steroids, erythromycins, chlorpromazine, etc. TPN, sepsis, post-operative cholestasis, “intrahepatic cholestasis of acute illness” PBC, PSC, Vanishing bile duct syndrome Infiltrative diseases, steatosis/NASH, sarcoid, granulomatous liver disease If Alk Phos is <1.5 x abnormal and US is normal, and patient is asymptomatic, then serial follow up is reasonable Otherwise, consider MRCP then Liver Biopsy or ERCP

Primary Biliary Cirrhosis Median age 50, Female:Male 9:1 presents with fatigue, pruritis hepatospleenomegaly AMA+ 95% Liver biopsy: ductopenia with inflamed damaged intrahepatic bile ducts, granulomas, biliary cirrhosis Treatment: manage osteoporosis, osteomalacia, fat soluble vitamin deficiency, pruritus, cholesterol, steatorrhea Ursodeoxycholic acid

Approach to Massive AST/ALT Elevations (>2000) Limited differential diagnosis: Drugs/Toxins: Tylenol, ETOH + Tylenol, other idiosyncratic reactions, mushrooms, herbs Viral Hepatitis: A,B,C,D,E, HSV, Giant Cell virus, others Ischemic Hepatitis: hypotension, CHF, arrhythmias, cocaine CBD Stone Autoimmune Hepatitis

Approach to Mildly Abnormal AST /ALT: 100 Consecutive Blood Donors with Mildly Abnormal ALT Findings after H & P, serologies and ultrasound: 48% ETOH 22% Fatty Liver 17% HCV 4% other 9% no identifiable explanation

Mildly Abnormal LFT’s Liver Biopsy Findings 81 with chronically abnormal LFT’s and negative H & P and serologic evaluation 84% Hepatic steatosis or NASH 6% advanced fibrosis or cirrhosis 8% normal Summary Most etiologies are identified by history, physical, basic serologies or ultrasound Most cases still with diagnostic uncertainty are due to ETOH or Hepatic Steatosis / NASH Liver Biopsy aides management in ~18% Complication rate of liver biopsy ~1-3% Severe complications occur in 0.1%

Causes of Mild Chronic Elevation of AST/ALT Hepatic causes: ETOH Medications, herbs Hepatitis C and B Steatosis and NASH Autoimmune hepatitis Hemochromatosis Wilson’s disease Alpha-1-antitrypsin deficiency Nonhepatic causes: Celiac sprue CHF Thyroid and Adrenal disease Muscle diseases and strenuous exercise

Laboratory Tests in Asymptomatic patients with Mild Chronically Elevated AST/ALT Primary tests: Repeat LFT’s HCV antibody HBV Surface antigen HBV Surface antibody HBV Core antibody Transferrin saturation, ferritin Secondary tests: ANA, ASMA Ceruloplasmin (age<40) Alpha-1-antitrypsin phenotype Ultrasound

Alcohol Related Liver Disease 14 million alcoholics in U.S. 2 million in U.S. with alcohol related liver disease >14,000 liver related deaths per year due to alcohol prevalence is higher in men; women are more susceptible to liver injury risk of liver injury increases with consumption of over 30 gm/d ETOH; only 10% who consume over 80 gm/d get liver disease AST:ALT >2-3:1 GGT >2x elevated AST and ALT usually less than 300

Hepatic Steatosis and NASH Most common cause of unexplained abnormal LFT’s 25% ultrasounds in U.S. show “fatty liver” Likelihood for advanced disease increases if: age >40, Type 2 Diabetes Mellitus, Obesity, Hyperlipidemia May have RUQ pain, hepatospleenomegaly AST=ALT, levels usually <200 Consider liver biopsy for diagnosis and staging. Liver biopsy looks like alcoholic hepatitis Treatment: weight loss, improve DM and lipid control, stop ETOH, ?ursodeoxycholic acid, ?metformin, ?Vit E

Viral Hepatitis C and B Hepatitis C 3-4 million in U.S 90% have “risk factors”, 30% have normal LFT’s HCV antibody is 97% sensitive HCV RNA PCR is confirmatory test Treatment: PEG interferon + Ribavirin Hepatitis B 1 million in U.S. Increased in homosexuals, African and Asian immigrants, HCV risk factors HBV S Ab+, HBV Core Ab+ = immunity, prior disease HBV S Ag+ = presence of disease HBV E Ag+ or HBV DNA + = active viral replication, infective Treatment: PEG interferon, or Lamivudine, Adefovir, Entecavir

Hemochromatosis Primary genetic hemochromatosis; 1/200 (0.5%) Caucasians Secondary hemochromatosis due to chronic hemolysis May have RUQ pain, arthritis, impotence, diabetes, hepatomegaly, skin pigmentation Transferrin Saturation >45%, elevated Ferritin HFE testing: C282y, H63d mutations account for 90%; 10% Caucasians are heterozygotes Liver Biopsy if Age>40, abnormal LFT’s, Ferritin > 1000, uncertain diagnosis Treatment: Phlebotomy every 1-2 weeks until iron depleted; then 2-6 times per year

Medication Induced Abnormal LFT’s Almost any medication can cause abnormal LFT’s Ask when medications were started; OTC medications, herbal preparations Stop probable offending medications Risk/Benefit analysis if medication must be continued. Liver Biopsy may be helpful.

Medications that Cause Elevated LFT’s Antibiotics: penicillin's, mycin's, floxicin’s, nitrofurantoin, keto and fluconazole, INH Antiseizure: dilantin, tegretol, valproic acid Statins and Niacin NSAID’s: diclofenac Sulfonylureas: glypizide Vitamin A Herbs: germander, chaparral, mahuang, gentian Drugs: ecstasy, cocaine, PCP, glues, solvents

Autoimmune Hepatitis 150,000 in U.S.; female:male, 4-6:1 40% have other autoimmune diseases: thyroid, RA, UC, Sjogrens, ANA, ASMA + 70% Elevated Ig G Treatment: prednisone + imuran

Wilson’s Disease Wilson’s disease gene facilitates biliary copper excretion. Age of onset 6-40 Various presentations: Hepatic fulminant liver failure chronic active hepatitis Neurologic movement disorder rigid dystonia Psychiatric neuroses, depression Diagnosis: low ceruloplasmin, high 24 hour urine copper, liver biopsy, Kayser-Fleischer rings present in 95% Treatment: Penicillamine, Trien, Zinc

Alpha-1-Antitrypsin Deficiency Protease inhibitor; inhibits neutrophil elastase; modulating inflammatory cascades 1/1500 Caucasians Abnormal phenotype causes retention of A-1-AT in hepatocytes Normal: MM; most abnormal: ZZ other variants: MZ, MS, SS, SZ Neonatal or childhood cholestatic hepatitis In adults: emphysema and cirrhosis

Asymptomatic Patients with Abnormal ALT and Negative Serologic Evaluations 1124 patients with chronically elevated ALT 81 patients had NEGATIVE serologic evaluations All had Liver Biopsy. Findings: 41 fatty liver 26 NASH 4 fibrosis with fatty liver 2 cirrhosis with fatty liver 8 normal

Mild Elevations of LFT’s Epidemiology 19,877 Air Force recruits 99 (0.5%) had ALT >55 Only 12 (12%) had a cause identified HBV, HCV, Autoimmune, Gallstones 88% no identifiable cause identified

Hepatobiliary Syndromes Hepatitic pattern: elevated AST, ALT Cholestatic pattern: elevated Alk Phos, Bili Acute versus chronic elevations Massive versus mild elevations