Approach to Abnormal LFT’s

By William E. Stevens, MD

Abnormal LFT’s Epidemiology

• 0.5% of 19,877 healthy air force recruits have an LFT abnormality • Alcohol, HCV, and steatosis are the most common causes of abnormal LFT’s • Diagnosis can be established noninvasively in most cases

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, PSC 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 2 nd 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, 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, check AMA, 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 • Acute 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% • 22% ETOH Fatty Liver • 17% • 4% • 9% HCV other 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: • Nonhepatic causes: ETOH Medications, herbs Hepatitis C and B Steatosis and NASH Autoimmune hepatitis Hemochromatosis Wilson’s disease Alpha-1-antitrypsin deficiency 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, hepatosplenomegaly • AST=ALT (usually), 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 Neurologic Psychiatric fulminant liver failure chronic active hepatitis movement disorder rigid dystonia 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 26 fatty liver NASH 4 2 8 fibrosis with fatty liver cirrhosis with fatty liver 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