Liver function

Mariana Lazo, M.D.

DESCRIPTION

  • Multiple serum chemistries can be used to assess hepatic function and/or injury.
  • Patterns of abnormalities suggest the category of disease.
  • 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, PT (prothrombin time), ferritin and lipoproteins.
  • Abnormal liver function due to non-alcoholic fatty liver disease (NAFLD) is common in diabetes.
  • There are non-hepatic causes of abnormal liver tests (e.g. cardiac diseases, skeletal muscle and bone diseases)
  • Scores (patented and non-patented) have been developed to non-invasively estimate liver fibrosis, including (but not limited to): FIB-4, NAFLD Fibrosis Score (non-patented) and patented algorithms (Fibrotest ® [FibroSURE® in the U.S.], Enhanced Liver Fibrosis [ELF] test ®).[3][4][5]

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: jaundice, hepatomegaly, ascites, gynecomastia, testicular atrophy, spider angiomata
  • Suspicion of viral hepatitis, fatty liver disease (e.g. fatty liver in abdominal ultrasound), alcohol related disease (e.g. chronic excessive alcohol consumption)
  • Exposure to medications associated with liver injury or damage (e.g. large dose of acetaminophen, HMG Co-A reductase inhibitors, thiazolidinediones)
  • Presence of additional comorbid conditions associated with liver disease among persons with diabetes: extreme obesity, hypertriglyceridemia
  • To monitor response to treatment or track course of disease in patients with liver disease.

DIFFERENTIAL DIAGNOSIS

  • ALT and AST are abundant liver enzymes. ALT is in the highest concentration in the liver, AST is also present in heart, muscle, kidney, brain, pancreas, lung. ALP is present in nearly all tissues, primarily bone and liver. GGT is abundant in liver, kidney, pancreas and intestine.
  • 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, malignancy
  • Medications: may cause increases in one or more liver chemistry tests because of direct hepatotoxicity or cholestasis (See American Gastroenterological Association (AGA) Technical Review[1] for full list of medications).

INTERPRETATION

  • Important to obtain a medical history including: metabolic risk factors (obesity, diabetes, dyslipidemia), current and past alcohol and drug consumption, risk factors for viral hepatitis, family history of liver disease, medication use, and comorbidities.
  • ALT and AST upper limit of normal (ULN) vary depending on lab, in general: ≤ 40 U/L.[9]
  • Except for severe acute liver injury, studies have shown inconsistent correlation between the severity of liver injury in histology and serum levels of aminotransferases. However, at the population level, epidemiologic studies have shown a positive correlation between levels of ALT, AST and GGT with liver disease related- and overall- mortality.[7][11]
  • 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.
  • 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[1] for full list of medications.)
  • Increased GGT: Alcohol consumption, obesity
  • 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.
  • Elevated PT (expressed in seconds or as INR) and low 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).
  • Fibrosis scores: Available evidence suggests these may be useful to detect advanced fibrosis with moderate to poor performance for distinguishing lower stages of fibrosis. Thresholds remain controversial and disease specific.

LIMITATIONS OR CONFOUNDERS

  • Poor correlation between ALT and AST levels and hepatic fibrosis. Patients with cirrhosis may have normal or only mildly elevated ALT.[12][2][6]
  • 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.
  • Bilirrubin, ALT and AST have very high intra-individual variability. If re-tested, more than 30% of adults with elevated bilirubin, ALT or AST would be re-classified as normal. Thus repeating the tests when elevations are mild is recommended.[10]

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 a higher incidence and prevalence not only of NAFLD, but of hepatitis C and hepatocellular carcinoma compared to the general population.
  • Initial investigation for potential liver disease should include ALT, AST, GGT, AP, bilirubin, albumin, and full blood count. Interpret patterns of abnormalities given medical history.
  • Non-invasive fibrosis scores may be useful to identify patients in whom liver biopsy would be beneficial and in whom more closely monitoring may be appropriate.[4]
  • Normal levels of liver chemistry tests do not exclude the presence of chronic liver disease.
  • Extra-hepatic causes of abnormalities may need to be considered.

Basis for recommendation

  1. Green RM, Flamm S. AGA technical review on the evaluation of liver chemistry tests. Gastroenterology. 2002;123(4):1367-84.  [PMID:12360498]

    Comment: Formal recommendations on how to interpret liver function tests and comprehensive list of medications that may cause liver toxicity or injury. http://www.gastro.org

References

  1. Gawrieh S, Wilson LA, Cummings OW, et al. Histologic Findings of Advanced Fibrosis and Cirrhosis in Patients With Nonalcoholic Fatty Liver Disease Who Have Normal Aminotransferase Levels. Am J Gastroenterol. 2019;114(10):1626-1635.  [PMID:31517638]
  2. Vilar-Gomez E, Chalasani N. Non-invasive assessment of non-alcoholic fatty liver disease: Clinical prediction rules and blood-based biomarkers. J Hepatol. 2018;68(2):305-315.  [PMID:29154965]
  3. Newsome PN, Cramb R, Davison SM, et al. Guidelines on the management of abnormal liver blood tests. Gut. 2018;67(1):6-19.  [PMID:29122851]

    Comment: Recently published guideline by the Clinical Services and Standards Committee
    (CSSC) of the British Society of Gastroenterology (BSG)
    Rating: Important

  4. European Association for Study of Liver, Asociacion Latinoamericana para el Estudio del Higado. EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis. J Hepatol. 2015;63(1):237-64.  [PMID:25911335]
  5. Kleiner DE, Berk PD, Hsu JY, et al. Hepatic pathology among patients without known liver disease undergoing bariatric surgery: observations and a perspective from the longitudinal assessment of bariatric surgery (LABS) study. Semin Liver Dis. 2014;34(1):98-107.  [PMID:24782263]
  6. Kunutsor SK, Apekey TA, Seddoh D, et al. Liver enzymes and risk of all-cause mortality in general populations: a systematic review and meta-analysis. Int J Epidemiol. 2014;43(1):187-201.  [PMID:24585856]
  7. Verma S, Jensen D, Hart J, et al. Predictive value of ALT levels for non-alcoholic steatohepatitis (NASH) and advanced fibrosis in non-alcoholic fatty liver disease (NAFLD). Liver Int. 2013;33(9):1398-405.  [PMID:23763360]
  8. Neuschwander-Tetri BA, Unalp A, Creer MH, et al. Influence of local reference populations on upper limits of normal for serum alanine aminotransferase levels. Arch Intern Med. 2008;168(6):663-6.  [PMID:18362260]
  9. Lazo M, Selvin E, Clark JM. Brief communication: clinical implications of short-term variability in liver function test results. Ann Intern Med. 2008;148(5):348-52.  [PMID:18316753]
  10. Kim HC, Nam CM, Jee SH, et al. Normal serum aminotransferase concentration and risk of mortality from liver diseases: prospective cohort study. BMJ. 2004;328(7446):983.  [PMID:15028636]
  11. Mofrad P, Contos MJ, Haque M, et al. Clinical and histologic spectrum of nonalcoholic fatty liver disease associated with normal ALT values. Hepatology. 2003;37(6):1286-92.  [PMID:12774006]
  12. Dufour DR, Lott JA, Nolte FS, et al. Diagnosis and monitoring of hepatic injury. I. Performance characteristics of laboratory tests. Clin Chem. 2000;46(12):2027-49.  [PMID:11106349]

    Comment: Very detailed review of the characteristics of all liver tests, reference values, individual factors influencing their levels. An approved guideline not only by the National Academy of Clinical Biochemistry but also by the American Association for the Study of Liver Diseases.

  13. Dufour DR, Lott JA, Nolte FS, et al. Diagnosis and monitoring of hepatic injury. II. Recommendations for use of laboratory tests in screening, diagnosis, and monitoring. Clin Chem. 2000;46(12):2050-68.  [PMID:11106350]

    Comment: Detailed review of the different patterns of liver injuries and their laboratory findings. An approved guideline by the National Academy of Clinical Biochemistry

Last updated: June 11, 2020