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Evaluation of Abnormal Liver Chemistry Tests

James Panetta, DO

What are LFTs?

• Transaminases

• Alkaline phosphatase

• Bilirubin

• Gamma-glutamyl transpeptidase

• 5’ nucleosidase

• Lactate Dehydrogenase

• Albumin

• Prothrombin Time

What are LFTs?

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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

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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

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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

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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

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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?

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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

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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

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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

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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

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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

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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

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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

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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

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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

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Borderline/mild elevation

Broad differential

• AST > ALT

• ALT > AST

Borderline/mild elevationAST generally > ALT

• Medications

• Alcoholic liver disease

• Cirrhosis of any cause

• Congestive hepatopathy

• TPN

• Budd Chiari

Borderline/mild elevationALT generally > AST

• NAFLD

• Acute/chronic viral hepatitis

• Medications

• Hemochromatosis

• Autoimmune hepatitis

• Fatty liver of pregnancy/HELLP syndrome

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Borderline/mild elevation

ALT generally > AST

• Wilson’s disease

• Celiac

• Alpha-1-antitrypsine deficiency

• Acute biliary obstruction

• Liver trauma

Moderate/Severe Elevation

• Acute viral hepatitis

• Ischemic hepatitis/shock liver

• Budd Chiari

• Toxins/medications

• HELLP

• Autoimmune hepatitis

• Wilson’s disease

Massive Elevation

• Ischemic (Shock liver)

• Drugs

• Viral

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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

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Borderline/mild elevationPersistent 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

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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

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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

Alk Phos, Transaminases +/- Bilirubin Elevated

• H&P

• 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

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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

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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

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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

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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

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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

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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

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Am. J. Gastro. 112:1; 18-35

Am. J. Gastro. 112:1; 18-35

Am. J. Gastro. 112:1; 18-35

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Am. J. Gastro. 112:1; 18-35

Am. J. Gastro. 112:1; 18-35

Am. J. Gastro. 112:1; 18-35

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Am. J. Gastro. 112:1; 18-35

Am. J. Gastro. 112:1; 18-35

Am. J. Gastro. 112:1; 18-35