Clinical Tests> Gastrointestinal>

DESCRIPTION

• Multiple serum chemistries assayed to assess hepatic function and/or injury.
• Tests indicative of: 1) liver inflammation : ALT (alanine aminotransferase) and AST (aspartate aminotransferase); 2) cholestasis or biliary obstruction: bilirubin (total includes both direct and indirect bilirubin), ALP (alkaline phosphatase) and GGT (gamma-glutamyltransferase); and 3) synthetic function: albumin and PT (prothrombin time).
• Abnormal liver function due to non-alcoholic fatty liver disease (NAFLD) is common in diabetes.

ASSAYS

• Serum ALT, AST, ALP and bilirubin (total and direct) are measured indirectly by using a spectrophotometer.
• PT, reported as the INR, measured from citrated whole blood: 1 full blue top, mixed gently. The vacutainer must be filled to the tube's drawing capacity to achieve the proper blood to anticoagulant ratio.

INDICATIONS

• Symptoms suggestive of liver disease: jaundice, dark urine, or light-colored bowel movements, loss of appetite, fatigue, vomiting of blood, bloody or black bowel movements, swelling or pain in the abdomen, unusual weight changes.
• Signs suggestive of liver disease: hepatomegaly, ascites
• Exposure to medications associated with liver damage (e.g. HMG Co-A reductase inhibitors, thiazolidinediones), contact with people that have viral hepatitis, excessive alcohol consumption.
• Presence of additional comorbid conditions associated with liver disease among persons with diabetes: extreme obesity, hypertriglyceridemia, alcohol use
• To monitor response to treatment or track course of disease in patients with liver disease.

DIFFERENTIAL DIAGNOSIS

• Increased AST: primary liver disease, acute myocardial infarction, muscle trauma and diseases, pancreatitis, intestinal surgery, burns, renal infarction, pulmonary embolism.
• Increased ALT: primary liver disease, biliary obstruction, pancreatitis. ALT > AST viral hepatitis, AST> ALT alcoholic liver disease.
• Increased ALP: biliary obstruction, primary liver disease (changes parallel GGT), infiltrative liver disease, bone diseases, hyperparathyroidism, hyperthyroidism. 
• Increased GGT: biliary obstruction, primary liver disease (changes parallel ALP), alcohol consumption, pancreatitis
• Increased bilirubin: biliary obstruction, primary liver disease, hemolytic anemias, hypothyroidism
• Medications: may cause increases in one or more liver chemistry tests because of direct hepatotoxicity or cholestasis (See American Gastroenterological Association (AGA) Technical Review for full list of medications). 

INTERPRETATION

• ALT and AST are abundant liver enzymes. AST is also present in heart, muscle. ALP is present in nearly all tissues, primarily bone and liver. GGT is abundant in liver, kidney, pancreas and intestine.
• ALT and AST normal ranges vary depending on lab, in general: <40 U/L.
• Mild ALT and AST elevations (ALT and AST less than 5 times the upper limit of normal (ULN)) should be rechecked before extensive work-up is undertaken. Possible causes: chronic hepatitis C or B, acute viral hepatitis, NAFLD, hemachromatosis, autoimmune hepatitis, medications, alcohol-related liver injury, Wilson's disease. Moderately elevated ALT and AST (ALT and AST 5-15 times the ULN) should be investigated without waiting to confirm the persistence of abnormal ALT, possible causes: entire spectrum of liver diseases that may cause either mild or severe elevations. Severe ALT and AST elevations (ALT and AST greater than 15 times the ULN) suggest severe acute liver cell injury: acute viral hepatitis, ischemic hepatitis or other vascular disorder, toxin-mediated hepatitis, acute autoimmune hepatitis.
• Bilirubin is a heme degradation product excreted in the bile, it requires conjugation in the liver before its secretion.
• Hyperbilirubinemia: Investigate if caused by direct (conjugated) or indirect (unconjugated) fraction of bilirubin. Pre-hepatic causes (increased production, decreased liver uptake) cause increase of indirect. Intra-hepatic or post-hepatic causes (decreased hepatic excretion), increase of direct. Increased production: hemolysis. Decreased liver uptake: Gilbert Syndrome, found in 5% population, benign. Decreased hepatic excretion: bile duct obstruction, primary biliar cirrhosis, primary sclerosing cholangitis, benign recurrent cholestasis, hepatitis, cirrhosis, medications, sepsis, total parenteral nutrition, Dubin-Johnson Syndrome, medications (See AGA Technical Review for full list of medications). 
• Increased GGT: Alcohol consumption
• Increased ALP and GGT: bile duct obstruction, primary biliary cirrhosis, primary sclerosing cholangitis, benign recurrent cholestasis, infiltrative disease of the liver (sarcoidosis, lymphoma, metastasic disease)
• Isolated elevated ALP (extra-hepatic disease): bone disease, pregnancy, chronic renal failure, lymphoma, congestive heart failure.
• Abnormal PT (expressed in seconds or as INR) and albumin levels: indicate severe hepatic synthetic dysfunction and indicates progression to cirrhosis or impending hepatic failure.
• Other commonly used tests to assess potential causes of hepatic diseases include: viral markers (IgM Hepatitis A Virus, HBsAg, Total Anti-HBc, IgM anti-HBc, anti-hepatitis C antibody), immunologic markers (ANA, SMA, anti-LKM-1, AMA), genetic diseases (hereditary hemochromatosis: transferrin saturation, ferritin, hepatic iron index; Wilson's disease: serum ceruloplasmin, urinary copper; a1-antitrypsin deficiency: serum electrophoresis), hepatocellular carcinoma marker (AFP: alfa-Fetoprotein) and imaging studies (ultrasound, CT, MRI).

LIMITATIONS OR CONFOUNDERS

• Poor correlation between ALT and AST levels and hepatic fibrosis. Patients with cirrhosis may have normal or only mildly elevated ALT.
• For ALT, AST, ALP and bilirubin samples, hemolysis can cause significant increases. Samples need to be stable at 0 to 4 ° C over 1 to 3 days.
• ALT and AST: increase with strenuous exercise and muscle injury. Meals have no effect. ALT is increased with higher BMI.
• ALP levels increase with food intake, pregnancy and smoking.
• Bilirubin levels increase with fasting. Light exposure decrease bilirubin.

EXPERT COMMENTS

• Among people with type 2 diabetes (T2DM), liver disease is one of the leading causes of death.
• In addition, patients with T2DM have have a higher incidence and prevalence not only of NAFLD, but of hepatitis C and hepatocellular carcinoma compared to the general population.
• Liver tests are not always specific for the liver because there are extra-hepatic sources.
• Normal levels of liver chemistry tests (including ALT) do not exclude the presence of disease.

Basis for Recommendations

• Green RM, Flamm S; AGA technical review on the evaluation of liver chemistry tests.; Gastroenterology; 2002; Vol. 123; pp. 1367-84;
  ISSN: 0016-5085;
  PUBMED: 12360498
  Rating: Basis for recommendation
  Note: http://www.gastro.org
  Comments:Formal recommendations on how to interpret liver function tests and comprehensive list of medications that may cause liver toxicity or injury.
  
  

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