Background

• Liver chemistries include AST, ALT, alkaline phosphatase (alk phos), bilirubin, gamma-glutamyltransferase (GGT), which are markers of liver injury.
  • ALT is a more specific marker of hepatic injury than AST.
• Liver function tests include albumin, INR (or prothrombin time [PT]), bilirubin, and platelet count (the liver produces TPO).
  • Decreased hepatic synthetic function leads to decreased albumin and prolonged PT/INR. PT prolongation does not occur until there is extensive disruption of hepatic synthetic function with advanced liver disease or massive acute insult.

AST and ALT

• Hepatocellular damage is signaled by any elevation in AST and/or ALT.
• When interpreting AST/ALT ratio, note that AST half-life is ~18h and ALT half-life is ~48h.

• Drug-induced hepatocellular injury: acetaminophen, isoniazid, allopurinol, ketoconazole, lisinopril, losartan, phenytoin, rifampin, ritonavir, statins, among others. Use LiverTox to find medications that can cause hepatocellular injury (http://livertox.nih.gov).
• Non-hepatic causes of elevated AST/ALT (aside from the liver, AST is also present in muscle, kidney, brain, and RBCs):
  • Rhabdomyolysis – may also find concomitantly elevated CK, LDH, aldolase; AST/ALT ratio often greater than 3, but ratio declines with time due to different half-life.
  • Inherited disorders of muscle metabolism.
  • Strenuous exercise.
  • Thyroid disease.
  • Celiac disease (check anti-TTG, total IgA).
  • Anorexia nervosa.
  • Adrenal insufficiency.

Alkaline Phosphatase and GGT

• Elevation of alkaline phosphatase and GGT suggest cholestatic disease.
  • Besides the liver, alkaline phosphatase is also found in bone, kidney, intestine, and placenta.
  • Check the GGT to confirm the elevated alkaline phosphatase is hepatic in origin (GGT is specific for a liver source of elevation).
• Alkaline phosphatase may also be elevated in:
  • Biliary obstruction: choledocholithiasis, ascending cholangitis, primary biliary cirrhosis, primary sclerosing cholangitis, malignancy, strictures, abscess (amoebic or bacterial).
  • Infiltrative processes: tuberculosis, sarcoid, fungal infection, lymphoma, solid tumors (hepatocellular carcinoma or liver metastases), amyloid, and other granulomatous disease.
  • Viral hepatitis: with concomitant AST/ALT elevation.
  • Cirrhosis.
  • Drug-induced cholestasis: TMP-SMX, amiodarone, augmentin, ACE inhibitors, azithromycin, carbamazepine, clopidogrel, estrogens, and many others.
• Non-hepatic causes of elevated alkaline phosphatase include bone disease, renal failure, congestive heart failure, non-hepatic malignancies, infection, inflammation, and pregnancy (third trimester).

Bilirubin

• Isolated indirect (unconjugated) hyperbilirubinemia suggests hemolysis (including post-transfusion), Gilbert’s syndrome, Crigler-Najjar syndrome, large hematoma resorption.
• Direct (conjugated) hyperbilirubinemia suggests biliary obstruction (intrahepatic or extrahepatic), virtually any acute or chronic hepatocellular disease (e.g., hepatitis, cirrhosis, primary biliary cirrhosis, primary sclerosing cholangitis), Dubin-Johnson syndrome, and intrahepatic cholestasis of pregnancy. May also be seen with total parenteral nutrition and sepsis (particularly gram negative infection).
• Bilirubin pearls:
  • In extrahepatic obstruction due to gallstones, bilirubin levels are rarely >15 mg/dl, usually <6 mg/dl.
  • In general, in extrahepatic obstruction from other causes a bilirubin levels are rarely >30 mg/dl.
  • In intrahepatic obstruction bilirubin can reach >30 mg/dl.

Albumin

• Decreased in chronic liver disease, malnutrition, protein-losing enteropathies, nephrotic syndrome, severe acute inflammatory states.

PT/INR

• Most sensitive indicator of liver function due to the short half-life of the coagulation factors that this test measures.
• May be elevated in liver disease from vitamin K deficiency or severe hepatocellular dysfunction. Jaundice interferes with vitamin K absorption. Failure of PT correction in response to subcutaneous vitamin K may indicate severe hepatocellular injury.

Serologies

Evaluation

• Clinical history: inquire about metabolic risk factors (diabetes, hyperlipidemia), associated diseases (e.g. inflammatory bowel disease, heart failure, pulmonary disease, hematologic disease), birth country, hereditary liver disease. Any history of jaundice, pruritus, stool or urine changes, fever, abdominal pain, arthralgias/myalgias (may predate jaundice in viral or drug-induced hepatitis), anorexia, weight loss.
• Review medication list and other non-prescribed remedies: acetaminophen and other medications that contain it, herbal remedies, wild mushrooms, etc.
• Exposures and health related behaviors: alcohol, IV/intranasal drugs, tattoos, sexual history, transfusions, food poisoning, travel, sick contacts.
• Physical exam (vary based on clinical scenario): check for stigmata of chronic liver disease (spider angioma, scleral icterus, palmar erythema, ascites, hepatic encephalopathy, asterixis), splenomegaly, hepatomegaly, nodular liver/abdominal mass (malignancy), RUQ pain, JVD (congestive hepatopathy due to right heart failure).

Work-up

• Always recheck an abnormal lab test if it is unexpected or seems inconsistent with the clinical scenario.
• In general, stop offending medications and toxins.
• Obtain complete serum drug and urine toxicology.
• Consider non-hepatic causes of abnormal LFTs.
• Obtain viral hepatitis serologies.
• If concerned about autoimmune hepatitis, obtain ANA, ASMA, IgG.
• Order a complete abdominal ultrasound with Doppler to evaluate both vasculature and obstruction.
• If biliary pathology suspected, may need MRCP or ERCP.
• If infiltrative disease suspected, may need quad phase CT or MR abdomen.
• Consider liver biopsy if LFTs are persistently abnormal.

Key Points

• Hepatocellular injury is characterized by any elevation in AST and/or ALT while elevation of alkaline phosphatase and GGT is seen with cholestatic processes.

Kwo, Paul Y MD, FACG, FAASLD1; Cohen, Stanley M MD, FACG, FAASLD2; Lim, Joseph K MD, FACG, FAASLD3 ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries, American Journal of Gastroenterology: January 2017 - Volume 112 - Issue 1 - p 18-35 doi: 10.1038/ajg.2016.517