Resident Editor: Scott Goldberg, M.D., Leslie Sheu, M.D.

Faculty Editor: Cindy Lai, M.D., Sarah Summerville, M.D.

BOTTOM LINE ✔ Look at pattern of abnormal labs to guide work-up ✔ Four broad categories: hepatocellulular (AST, ALT), cholestatic (bili, alk phos), infiltrative (isolated elevated alk phos), and isolated hyperbilirubinemia ✔ AST/ALT levels >1,000 U/L suggest ischemic damage, viral hepatitis, toxins

Background

• The American College of Gastroenterology released a 2017 Clinical Guideline on the evaluation of abnormal liver chemistries
• The recommended approach below targets the most common causes for abnormalities in the United States 
• Multiple studies have demonstrated that the presence of an elevated ALT has been associated with increased liver-related mortality 
• The most common cause of mildly elevated liver enzymes is nonalcoholic fatty liver disease (NAFLD) (30% of population)
• Other common causes include alcoholic liver disease, medication-induced liver injury, viral hepatitis (HBV, HCV), and hemochromatosis
• Less common causes include alpha-1 antitrypsin (A1AT) deficiency, autoimmune hepatitis, and Wilson disease
• Consider extrahepatic causes (thyroid disease, celiac, hemolysis, muscle breakdown)

Three general categories of liver enzyme tests:

1. AST (SGOT) and ALT (SGPT) reflect hepatocellular damage. AST is less specific for liver damage than ALT.
2. Conjugated (direct) bilirubin reflects severe hepatocellular injury or obstruction (cholestatic injury)
3. Synthetic liver function is based on proteins made by the liver, including albumin, PT, PTT, platelet count (not discussed here)

Signs and Symptoms

• Often asymptomatic and diagnosed on labs
• May complain of RUQ pain, nausea, vomiting, anorexia, acholic stools

Differential Diagnosis

Guided by pattern of abnormalities.

1. Hepatocyte injury pattern: elevated AST and ALT 

• Viral hepatitis (EBV, CMV, HSV, VZV, HAV, HBV, HCV, HEV), alcoholic liver disease, drugs/toxins (tylenol, statins, antibiotics), autoimmune, NAFLD ( NASH), hereditary (hemochromatosis, A1AT deficiency, Wilson disease), vascular (ischemic, congestive, Budd-Chiari)
• AST and ALT are found in hepatocytes, so damage to those cells will cause elevations in aminotransferases.
• Levels <300 U/L are non-specific, >1,000 U/L suggest ischemic damage, autoimmune hepatitis, viral hepatitis, toxin, Budd-Chiari syndrome, and Wilson’s disease 
• AST:ALT >2:1 suggestive of alcoholic liver disease (rare for AST>8x upper limit of normal and ALT>5x upper limit of normal)—although not specific as this pattern can occur in some patients with non-alcoholic steatohepatitis and hepatitis C cirrhosis
• AST >> ALT suggestive of non-liver cause of elevation (i.e., rhabdomyolosis)
• AST:ALT <1 suggestive of fatty liver disease

2. Cholestatic pattern: elevated alkaline phosphatase and direct bilirubin

• Alkaline phosphatase is found in bile ducts, so biliary stasis or bile duct infiltration can cause elevations in bilirubin and alkaline phosphatase levels.  
• Branch point is whether there is common bile duct (CBD) dilatation
  • No ductal dilatation
    • No or mild elevation of alk phos suggests biliary epithelial damage: hepatitis, cirrhosis
    • Significant elevation of alk phos suggests intra-hepatic cholestasis: PBC, meds, sex hormones, sepsis
  • Presence of ductal dilatation: Biliary obstruction (choledocholithiasis, cholangiocarcinoma, pancreatic cancer, primary sclerosing cholangitis)
• Because both alkaline phosphatase and bilirubin can be found in other parts of the body, it is important to evaluate the origin of these elevations to target work-ups appropriately 
  • Isolated indirect bilirubin elevation may be from Gilbert’s or hemolysis
  • Isolated alkaline phosphatase elevations can be seen in bone disorders
  • Elevated bilirubin & alkaline phosphatase suggest obstruction or infiltration

3. Infiltrative pattern: isolated elevated alkaline phosphatase (rare)

• Sarcoid, TB, histoplasmosis, amyloidosis, malignancy (HCC, lymphoma, metastatic), abscesses (amebic or bacterial), medications, idiopathic 

4. Isolated hyperbilirubinemia

• Unconjugated 
  • Overproduction (hemolysis, ineffective erythropoiesis) 
  • Defective conjugation (Gilbert’s, Crigler-Najar)
• Conjugated
  • Defective excretion (Dubin-Johnson, Rotor’s)

Evaluation

History and exam is key

• Ask about changes in medications or illicit drugs: e.g. statins, antibiotics, anti-epileptics, amiodarone, herbs, INH, round-the-clock acetaminophen for a few weeks
  • Common medications that cause abnormal liver tests can be found at: https://livertox.nih.gov/
• Ask about recent sexual activity, travel, alcohol, IDU (hepatitis B and C), blood transfusions
• Consider ethnicity (hepatitis B in immigrants from endemic countries)
• Consider co-morbidities (metabolic syndrome increases risk of NAFLD)
• Consider age and gender (women more likely to have autoimmune hepatitis)
• Check for stigmata of chronic liver disease, signs of volume overload, jaundice, RUQ tenderness

Further laboratory and imaging workup is guided by pattern of abnormalities:

1. Evaluation of transaminitis: 

• Look at med list for possible culprits and d/c if indicated
• Repeat labs in 6 weeks to give time for toxins/insults/alcohol damage to clear
• If still elevated, or there is high suspicion for viral hepatitis, proceed to next step.
  • 1^st pass screening: coags, ferritin and iron/TIBC, HAV, HCV Ab, HBV (HBsAg, HBsAb, HBcAb) and RUQ ultrasound. Also obtain fasting lipid profile and fasting glucose.
  • 2^nd pass (rule out non-hepatic sources): CK (muscle disorders), TSH (hypo/hyper-thyroidism), anti-transglutaminase IgA (celiac disease, especially if diarrhea or unexplained iron deficiency), consider random cortisol (adrenal insufficiency)
  • 3^rd pass (rarer hepatic diseases): 
    • For autoimmune hepatitis: ANA is most sensitive. Anti-smooth muscle Ab and anti-liver kidney microsomal Ab are more specific
    • For Wilson’s: serum ceruloplasmin +/- 24h urine copper
    • For A1AT: check phenotype (PiZZ) and AAT activity level (<80 mg/dL)
    • For NAFLD/NASH: Definitively diagnose with liver biopsy 

• Refer to hepatology for possible liver biopsy particularly for patients who have AST and ALT are persistently >2x upper limit of normal

2. Evaluation of cholestasis: 

• RUQ ultrasound (look for obstruction, dilation); if positive then consider ERCP/MRCP
• For primary biliary cirrhosis: anti-mitochondrial Ab (AMA) and liver biopsy

3. Evaluation of infiltrative pattern (isolated elevated alkaline phosphatase):

• First, confirm it is hepatic source (and not bone): 
  • Elevated GGT → likely hepatic in origin
  • Normal GGT → consider non-hepatic causes
• If hepatic alkaline phosphatase (cholestatic pattern)
  1. RUQ ultrasound 
  2. ERCP or MRCP to evaluate for stones/ductal infiltration
  3. Consider biopsy if >50% upper limit of normal for >6 months

4. Evaluation of isolated hyperbilirubinemia:

• Fractionate into direct (conjugated) and indirect (unconjugated) bilirubin
  • Mostly direct → Likely cholestasis. Consider RUQ ultrasound or CT scan to look for cholecystitis, gallstones, masses or other obstructive/infiltrative causes. Also consider defective excretion (Dubin-Johnson, Rotor)
  • Mostly indirect → consider increased production or decreased breakdown and target workup appropriately to evaluate for possible causes, including anemia (hemolysis, ineffective erythropoiesis, resorption of hematoma), drugs (e.g. rifampin), Gilbert’s, etc.
    • Consider sending reticulocyte count, LDH, peripheral blood smear
    • Withdrawal of offending drug should lead to resolution of hyperbilirubinemia within a few days.
  • Half and half → often seen with upstream obstruction such as CHF and liver failure

References

Aragon, George, "When and how to evaluate mildly elevated liver enzymes in apparently healthy patients," Cleveland Clinic Journal of Medicine 2010; 77 (3): 195-204.

Donnan, Peter et al. "Development of a decision support tool to facilitate primary care management of patients with abnormal liver function tests without clinically apparent liver disease," BMC Health Services Research 2007; 7:54.

Friedman, Lawrence, "Approach to the patient with abnormal liver biochemical and function tests," UpToDate Update Jan 25, 2013.

Kwo, Paul Y., Stanley M. Cohen, and Joseph K. Lim. “ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries.” The American Journal of Gastroenterology 112, no. 1 (January 2017): 18–35. https://doi.org/10.1038/ajg.2016.517.

McLernon, David et al.  “Health outcomes following liver function testing in primary care: a retrospective cohort study.”  Family Practice 2009; 26: 251-259.

Muhkerjee, Sandeep. “Abnormal liver function tests – approach to the patient.” DynaMed Plus. Feb 19, 2018. 

Robert and Hustead, “Causes and Evaluation of Mildly Elevated Liver Transaminase Levels,” American Family Physician 2011; 84 (9): 1003-1008.