Approach to Abnormal LFTs

By William E. Stevens, MD

Approach to Abnormal LFTs

The biochemical LFTs AST, ALT, ALK PHOS, BILI GGT, 5NT, 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, WBCs, and RBCs 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, WBCs 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, Wilsons 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 FDPs 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 LFTs

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 LFTs 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 LFTs 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:

Gilberts Syndrome: 3-7% population, increased in white males, Bili <6 Chronic liver diseases, advanced cirrhosis, Wilsons 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 5NT 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 LFTs Liver Biopsy Findings

81 with chronically abnormal LFTs 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 Wilsons disease Alpha-1-antitrypsin deficiency Celiac sprue CHF Thyroid and Adrenal disease Muscle diseases and strenuous exercise

Nonhepatic causes:

Laboratory Tests in Asymptomatic patients with Mild Chronically Elevated AST/ALT

Primary tests: Repeat LFTs 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 LFTs 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 LFTs 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 LFTs, Ferritin > 1000, uncertain diagnosis Treatment: Phlebotomy every 1-2 weeks until iron depleted; then 2-6 times per year

Medication Induced Abnormal LFTs

Almost any medication can cause abnormal LFTs 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 LFTs

Antibiotics: penicillin's, mycin's, floxicins, nitrofurantoin, keto and fluconazole, INH Antiseizure: dilantin, tegretol, valproic acid Statins and Niacin NSAIDs: 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

Wilsons Disease
Wilsons 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 LFTs 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