Liver Function Tests

Shannon Jenkins, M.D.

The diagnosis can be established noninvasively in the vast majority of patients with abnormal Liver Function Tests.

Appropriate testing can be guided by the pretest probability of specific forms of liver disease

The majority of patients in whom the diagnosis remains unclear after obtaining a history and laboratory testing will have alcoholic liver disease, fatty liver, or NASH

Enzyme tests
Aminotransferases Alkaline phosphatase Gamma glutamyl transpeptidase

Aminotransferases
Alanine aminotransferase (ALT or SGPT), Normal 10-40 IU/L Aspartate aminotransferase (AST or SGOT), Normal 10-40 IU/L

Tests of synthetic function

Albumin Prothrombin time

Tests of hepatic transport capability

Serum bilirubin

Serum Aminotransferase Levels > 500

Acute viral hepatitis Wilsons disease Severe chronic active hepatitis Common Bile Duct Stone Budd-Chiari and Veno-occlusive Disease HELLP

Serum Aminotransferase Levels > 10,000

Ischemic liver/hepatic shock Acetominophen overdose

Minimal Elevation or Normal Serum Aminotransferases

Hemochromatosis Jejunoileal bypass Chronic HCV NASH

Common Causes of Mildly Elevated Liver Transaminases

Drug-induced hepatitis
NSAIDS Antibiotics Statins Antiepileptic drugs Antituberculous drugs Acetominophen

Alcoholic Hepatitis AST:ALT ratio > 2 Both levels < 300 GGT elevated 2x normal

Alcoholic Hepatitis
[(Prothrombin time-control) x 4.6] + serum bilirubin = Discriminant Function Value If Discriminant Function Value > 32, mortality of pt > 50% within 2 years Treat with steroids or pentoxyphillin

Hepatitis B
Parenteral drug use Areas of high disease prevalence (Southeast Asia, China and sub-Saharan Africa) Check:
Hepatitis B surface antigen Hepatitis B surface antibody Hepatitis B core antibody

Hepatitis C
Parenteral exposure (blood transfusions, intravenous drug use, occupational) Cocaine use Tattoos High risk sexual behavior.

Hepatitis C
Check Hepatitis C antibody Hepatitis C RNA by PCR

Hemochromatosis
Increased Iron saturation (serum iron/TIBC)
> 45%, obtain serum ferritin

Hemochromatosis and Cirrhosis

Unlikely to develop cirrhosis, if:
< 40 years of age Absence of hepatomegaly Normal ALT and AST Serum ferritin < 1000

Increased Ferritin (> 400 ng/mL men, > 300 ng/mL in women) Check genetic studies: HFE genetic mutation Liver biopsy

Non-Alcoholic Steatohepatitis (NASH)

Mild elevations in aminotransferases (2-4 fold increase only) AST/ALT ratio < 1 Mild increase in ALP Normal albumin, INR and bilirubin

Non-alcoholic Steatohepatitis (NASH)

Common in women, DM and obesity May be asymptomatic Symptoms: fatigue, RUQ discomfort/pain U/S, CT scan or MRI reveals fatty infiltration of the liver

Liver biopsy for Non-alcoholic Steatohepatitis

Peripheral stigmata of chronic liver disease Splenomegaly Cytopenia Abnormal iron studies Diabetes and/or significant obesity in an individual over the age of 45 with elevated ALT

Unexplained ALT Elevations

Muscle Disease or Injury Celiac Disease Adrenal Insufficiency Thyroid Disease

Case 1
Patient is a 42yo female PMH significant only for HTN for which she takes no medications NKDA SH: no tobacco, no illicits, social drinker Works at a drycleaners WBC 7,000 H/H 9/27

Case 1

Platelets 101,000 AST 88, ALT 41

What is the likely cause of her elevated liver enzymes?

A. Etoh hepatitis B. Shock liver C. Halothane toxicity D. Hemochromatosis AST 2650 ALT 3900

Case 1
The same patient returns 1 month later with complaint of headaches and fatigue.

What is the likely cause of her elevated liver enzymes?

A. Etoh hepatitis B. Shock liver C. Acetominophen toxicity D. Hemochromatosis

Case 2
Patient is an 81yo male admitted secondary to AMI PMH significant for CAD, s/p MI and CHF with EF of 25% Patient had syncopal episode witnessed by nursing

Case 2
AST 19,524, ALT 16,233

What is the likely cause of his elevated liver enzymes?

A. Etoh hepatitis B. Shock liver

WBC 6,000, no bandemia C. Acetominophen toxicity Troponin 0.4, CK 220 D. Hemochromatosis

Case 3
Patient is a 58yo male Admitted secondary to generalized weakness and vague abdominal pain PMH: none Meds: none NKDA

Case 3
SH: Mild MR. Lives with his brother since the death of his parents. Occasional Etoh and tobacco No environmental exposures

Case 3
Glucose 240 AST 170, ALT 157

What is the likely cause of his elevated liver enzymes?

A. Etoh hepatitis B. Shock liver C. Acetominophen toxicity D. Hemochromatosis

Case 4
Patient is a 28yo G2P1001 at 26 weeks EGA presenting to the ED with jaundice PMH: diagnosed with TB 4 weeks prior Meds: INH, Rifampin, Ethambutol, Pyridoxine NKDA

Case 4
SH: Immigrated from Equador 7 months prior, no tobacco, Etoh or illicits BP 128/77, HR 80, R 12, Afebrile ALT 601, AST 319, ALP 251 Tbili 2.7 LDH 246

What is the likely cause of her elevated liver enzymes?

A. HELLP B. Cholestasis of pregnancy C. Drug induced hepatitis D. Hemochromatosis

What is your next step

A) Discontinue all anti-tubercular medications B) Liver biopsy C) Uric acid, platelets, 24 hour urine for protein, Ca+ D) Continue current course of therapy

Autoimmune hepatitis

Rare Causes of Elevated Transaminases

Wilsons disease Alpha-1 antitrypsin deficiency

Autoimmune Hepatitis
Primarily young to middle-aged women Associated with arthralgias, fatigue, anorexia, pruritus Often co-existence of other autoimmune diseases Increased IgG on SPEP Elevated Anti-nuclear antibodies (ANA) & anti-smooth muscle antibodies (SMA)

Wilsons Disease
Genetic disorder of biliary copper excretion Typically age 5-25, but consider the dx in age < 40 Adolescents present with liver disease Adults present with mental status change

Wilsons Disease
Decreased ALP Decreased uric acid Elevated AST and ALT, > 500 IU/L Initial screen: serum ceruloplasmin Opthalmologist for Kayser-Fleischer rings

Alpha-1 Antitrypsin Deficiency

Uncommon Chronic liver disease Decreased alpha-1 antitrypsin level Alpha-1 antitrypsin phenotype Suspect in patient with early emphysema

Alkaline Phosphatase Elevated Alkaline Phosphatase

Normal = 30-120 IU/L Check GGT to determine if elevated ALP is secondary to hepatic source Mild elevations may be seen post-prandial

Sources of Alkaline Phosphatase

Liver Bone Small intestines Placenta/Pregnancy Regan isoenzyme (lung teratoma)

Causes of Elevated ALP

Pregnancy Pancreatic Cancer Pagets disease Primary biliary cirrhosis Cholestasis Sarcoid Amyloid Hyperthyroid Hypernephroma Hodgkins disease

Intrahepatic Cholestasis
Viral hepatitis Etoh hepatitis EBV Anabolic steroids, Contraceptives CMV TPN Primary biliary sclerosis Primary sclerosing cholangitis

Extrahepatic Cholestasis
Choledocholithiasis Pancreatic or Gallbladder CA Cholangiocarcinoma Primary sclerosing cholangitis Stricture due to chronic pancreatitis AIDS cholangiopathy

Primary Biliary Cirrhosis

95% of patients with PBC are women Onset between 30-65 years of age. May be asymptomatic Symptoms: Fatigue, pruritus, hyperpigmentation, arthralgias

Primary Biliary Cirrhosis

Elevated Alkaline phosphatase levels Elevated bilirubin Mildly elevated transaminases + Antimitochondrial antibodies + Antinuclear antibodies (ANA)

Case 5
Patient is 34yo female admitted to the psychiatric ward You are consulted due to elevated liver enzymes on admission labs. Patient with tremor, confusion

Case 5
ALT 1620, AST 1550, ALP22 Na 122 Uric acid 1.1 mg/dL (normal 1.9-7.5mg/dL0

What is the likely cause of this patients elevated liver enzymes?

A. Pancreatic Cancer B. Wilsons disease C. Primary biliary cirrhosis

Case 6
58yo female with fatigue and pruritus No significant PMH No medications NKDA

Case 6
ALP 423 Total bilirubin 10.2 AST 110, ALT 133 GGT 55 (normal < 30)

What is the likely cause of this patients elevated liver enzymes?

A. Pancreatic Cancer B. Wilsons disease C. Primary biliary cirrhosis D. Autoimmune hepatitis

What test would you order now?

A. Liver biopsy B. Antimitochondrial antibodies C. Alpha-1 antitrypsin D. Antinuclear antibodies

Case 7
60yo female presenting to the ED with jaundice, fatigue and midepigastric ache that radiates to her back. Pain has been present for approximately 4 months, since she was hospitalized for MI 25 lb weight loss

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Case 7
Glucose 199 AST 156 ALT 144 ALP 155 Total bilirubin 1.1 mg/dL Direct bilirubin 0.3 mg/dL

What is the likely cause of this patients elevated liver enzymes?

A. Pancreatic Cancer B. Wilsons disease C. Primary biliary cirrhosis

Case 8
Patient is 38yo female presenting with arthralgias AST 9800, ALT 8600 Total protein 9.0 Albumin 3.5 Total bilirubin 0.7 (normal) ALP 110

What is the likely cause of this patients elevated liver enzymes?

A. Pancreatic Cancer B. Wilsons disease C. Primary biliary cirrhosis D. Autoimmune hepatitis

Case 9
71yo male with several month history of back pain PMH: CAD s/p CABG 9 years prior, HTN, hypercholesterolemia Meds: ASA, lopressor, lisinopril, pravachol NKDA

Case 9
ALP 772 IU/L Total bilirubin 0.4 mg/dL AST 35 IU/L ALT 28 IU/L GGT 15

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What is the likely cause of this patients elevated liver enzymes?

A. Pancreatic Cancer B. Wilsons disease C. Primary biliary cirrhosis D. Pagets disease

Tests of Synthetic Function

Albumin (normal = 3.5-4.8 g/dL)
Low level suggests chronic process (cancer or cirrhosis) Normal level couples with abnormal transaminases suggests acute process (viral hepatitis or choledocholithiasis)

Prothrombin time (normal =

Elevated in Vitamin K deficiency Elevated with hepatocellular dysfunction

Causes of Low Serum Albumin and Total Protein

Malnutrition Liver disease Nephrotic syndrome Protein losing enteropathy (Sprue, Crohns)

Causes of Low Serum Albumin with High/Normal Total Protein

Multiple myeloma Autoimmune hepatitis HIV Etoh hepatitis Primary biliary cirrhosis

Elevated Indirect Serum Bilirubin

Normal level < 1 Gilberts/Crigler-Najjar Blood Loss/Hemolysis Liver Disease (hepatitis, cirrhosis) Hepatic congestion secondary to CHF

Elevated Direct Bilirubin

Normal level < 2 Dubin-Johnson Syndrome Hodgkins lymphoma Biliary obstruction Hepatocellular disease

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Elevated Serum Ferritin

Hemochromatosis Hepatocellular necrosis Hodgkins disease Leukemia Hyperthyroid Uremia NASH

Elevated Lactate Dehydrogenase (Normal 50-150)

MI Pneumocystis Pneumonia Hemolytic Anemia Pancreatitis Mononucleosis

LDH 1-2 = Cardiac, RBC LDH 3 = Pulmonary LDH 4-5 = Muscle, Liver LDH 1 > 2 = MI or hemolytic anemia LDH 5 > 4 = Liver disease (cirrhosis, hepatitis, hepatic congestion)

Evaluation of Chronic MILD Elevation of Aminotransferases

Review possible link to medications, herbal therapies or recreational drugs Screen for alcohol abuse (screening instruments, AST/ALT ratio >2:1) Obtain serology for hepatitis B and C (HBsAg, HBsAb, HBcAb, HCV Ab) Screen for hemochromatosis (FE/TIBC >45 percent) Evaluate for fatty liver (AST/ALT usually < 1, obtain a RUQ ultrasound)

Exclude muscle disorders (obtain creatinine kinase or aldolase) Obtain thyroid function tests (TSH if hypothyroidism is suspected otherwise obtain a full set of thyroid function tests) Consider celiac disease (especially in patients with a history of diarrhea or unexplained iron deficiency - serum anti endomysial IgA or anti tissue transglutaminase IgA antibodies are reasonable screening tests) Consider adrenal insufficiency

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 Consider autoimmune hepatitis particularly in women and those with a history of other autoimmune disorders (check serum protein electrophoresis, obtain ANA and ASMA if positive) Consider Wilson's disease in those <40 (check ceruloplasmin, evaluate for Kayser Fletcher rings) Consider alpha-1-antitrypsin deficiency especially in patients with a history of emphysema out of proportion to their age or smoking history (obtain alpha-1antitrypsin phenotype)

References
Pratt, DS, Kaplan, MM. Evaluation of abnormal liver-enzyme results in asymptomatic patients. N Engl J Med 2000; 342:1266. Polson J, Lee WM. AASLD position paper: the management of acute liver failure. Hepatology 2005 May; 41 (5): 1179-97. American Gastoenterological Association medical position statement: evaluation of liver chemistry tests. Gastroenterology 2002 Oct;123(4):1364-6. Chopra S, Griffin PH: Laboratory tests and diagnostic procedures in evaluation of liver disease. Am J Med 1985;79:221-230. Seth SG, Gordon FD, Chopra S. Nonalcoholic steatohepatitis. Ann Intern Med 1997; 126: 137-145. Pratt DS. Approach to the patient with abnormal liver function tests. UpToDate 2005; volume 11.2.

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