Excerpts From The 2017 Guidelines On The Evaluation Of Abnormal Liver Tests From The ACG

ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries is an outstanding resource for all clinicians [PubMed Abstract] [Full Text PDF] Am J Gastroenterol. 2017 Jan;112(1):18-35. doi: 10.1038/ajg.2016.517. Epub 2016 Dec 20.

This post contains excerpts from the above article:

Abstract:

Clinicians are required to assess abnormal liver chemistries on a daily basis. The most common liver chemistries ordered are serum alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase and bilirubin. These tests should be termed liver chemistries or liver tests. Hepatocellular injury is defined as disproportionate elevation of AST and ALT levels compared with alkaline phosphatase levels. Cholestatic injury is defined as disproportionate elevation of alkaline phosphatase level as compared with AST and ALT levels. The majority of bilirubin circulates as unconjugated bilirubin and an elevated conjugated bilirubin implies hepatocellular disease or cholestasis. Multiple studies have demonstrated that the presence of an elevated ALT has been associated with increased liver-related mortality. A true healthy normal ALT level ranges from 29 to 33 IU/l for males, 19 to 25 IU/l for females and levels above this should be assessed. The degree of elevation of ALT and or AST in the clinical setting helps guide the evaluation. The evaluation of hepatocellular injury includes testing for viral hepatitis A, B, and C, assessment for nonalcoholic fatty liver disease and alcoholic liver disease, screening for hereditary hemochromatosis, autoimmune hepatitis, Wilson’s disease, and alpha-1 antitrypsin defi ciency. In addition, a history of prescribed and over-the-counter medicines should be sought. For the evaluation of an alkaline phosphatase elevation determined to be of hepatic origin, testing for primary biliary cholangitis and primary sclerosing cholangitis should be undertaken. Total bilirubin elevation can occur in either cholestatic or hepatocellular diseases. Elevated total serum bilirubin levels should be fractionated to direct and indirect bilirubin fractions and an elevated serum conjugated bilirubin implies hepatocellular disease or biliary obstruction in most settings. A liver biopsy may be considered when serologic testing and imaging fails to elucidate a diagnosis, to stage a condition, or when multiple diagnoses are possible.

These recommendations are intended for use by physicians and health care providers and suggest preferred approaches to the diagnoses and evaluation of those with abnormal liver tests.(Table 1 ).

1. Before initiation of evaluation of abnormal liver chemistries, one should repeat the lab panel
and/or perform a clarifying test (e.g., GGT if serum alkaline phosphate is elevated) to confirm
that the liver chemistry is actually abnormal. (Strong recommendation, very low level of
evidence).

2. Testing for chronic hepatitis C is conducted with anti-HCV and confirmation is performed
with HCV-RNA by nucleic acid testing. Risk factors for hepatitis C include history of intranasal
or intravenous drug use, tattoos, body piercings, blood transfusions, high risk sexual conduct,
and those born between 1945 and 1965. Testing for acute hepatitis C is with anti-HCV and
HCV RNA by nucleic acid testing. (Strong recommendation, very low level of evidence).

3. Testing for chronic hepatitis B is conducted with HBsAg testing. Testing for acute hepatitis B
is with HBsAg and IgM anti-HBc. The following groups are at highest risk: persons born in
endemic or hyperendemic areas (HBsAg prevalence >2%), men who have sex with men,
persons who have ever used injection drugs, dialysis patients, HIV-infected individuals,
pregnant women, and family members, household members, and sexual contacts of HBVinfected persons. (Strong recommendation, very low level of evidence).

4. Testing for acute Hepatitis A (IgM HAV) should occur in patients presenting with acute
hepatitis and possible fecal-oral exposure. Testing for acute hepatitis E (IgM HEV) should also
be considered in those returning from endemic areas and whose tests for acute hepatitis A,
B, and C are negative. (Strong recommendation, very low level of evidence).

5. Patients with elevated BMI and other features of metabolic syndrome including diabetes
mellitus, overweight or obesity, hyperlipidemia, or hypertension with mild elevations of ALT
should undergo screening for NAFLD with ultrasound. (Strong recommendation, very low
level of evidence).

6. Women consuming more than 140 g per week or men consuming more than 210 g per week
who present with AST>ALT should be considered at risk for alcoholic liver disease and should
be counseled for alcohol cessation. (Strong recommendation, very low level of evidence).

7. All patients with abnormal liver chemistries in the absence of acute hepatitis should undergo
testing for hereditary hemochromatosis with an iron level, transferrin saturation, and serum
ferritin. HFE gene mutation analysis should be performed in patients with transferrin
saturation ≥45% and/or elevated serum ferritin. (Strong recommendation, very low level of
evidence).

8. Patients with abnormal AST and ALT levels, particularly patients with other autoimmune
conditions, should undergo testing for autoimmune liver disease including ANA, ASMA, and
globulin level. (Strong recommendation, very low level of evidence).

9. Patients with persistently elevated AST and ALT levels, especially patients <55 years of age,
should undergo screening for Wilson’s disease with serum ceruloplasmin testing. In the
setting of low ceruloplasmin, confirmatory testing with 24-h urinary copper and slit-lamp eye
examination to identify pathognomonic Kayser–Fleischer rings should occur. (Strong
recommendation, very low level of evidence).

10. Patients with persistently elevated AST or ALT should undergo screening for alpha-1 antitrypsin (A1AT) deficiency with alpha-1 anti-trypsin phenotype. (Strong recommendation, very
low level of evidence).

11. Physicians should ask patients with abnormal liver chemistries about prescribed and overthe-counter medications, non-prescribed complementary or alternative medicines, and
dietary or herbal supplements which may be associated with DILI. (Strong recommendation,
very low level of evidence).

12. A liver biopsy may be considered when serologic testing and imaging fails to elucidate a diagnosis, to stage a condition, or when multiple diagnoses are possible. (Strong recommendation, very low level of evidence).

13. An elevation of alkaline phosphatase should be confirmed with an elevation in GGT. Given its lack of specificity for liver disease, GGT should not be used as a screening test for underlying liver disease in the absence of other abnormal liver chemistries. (Strong recommendation, very low level of evidence).

14. Patients with alkaline phosphatase elevation with or without elevation of bilirubin should undergo testing for PBC (formerly named primary biliary cirrhosis) with testing for antimitochondrial antibody. (Strong recommendation, very low level of evidence).

15 Patients with alkaline phosphatase elevation with or without elevation of bilirubin should undergo testing for PSC with MR cholangiography or ERCP in conjunction with IgG4. (Strong recommendation, very low level of evidence).

16 In those with ALT and/or AST levels <5X ULN, the history and laboratory testing should assess for viral hepatitis B and C, alcoholic and NAFLD, hemochromatosis, Wilson’s disease, alpha-1- anti-trypsin deficiency, autoimmune hepatitis and consider drugs/supplement related injury. (Strong recommendation, very low level of evidence).

17 In those with ALT and/or AST levels 5–15X ULN, evaluation should also assess for acute hepatitis A, B, and C in addition to all etiologies for AST/ALT elevation less than 5x ULN. (Strong recommendation, very low level of evidence).

18 In those with ALT and/or AST levels >15X ULN, or massive elevation ALT of >10,000 IU/l, evaluation should also assess for acetaminophen toxicity and ischemic hepatopathy (shock liver). (Strong recommendation, very low level of evidence).

19 A patient presenting with acute hepatitis with an elevated prothrombin time, and/or encephalopathy requires immediate referral to liver specialist. (Strong recommendation, very low level of evidence).

Abbreviations for the above recommendations: ALT, alanine aminotransferase; ANA, anti-nuclear antibody; ASMA, anti-smooth antibody; AST, aspartate aminotransferase; BMI, body mass index; DILI, drug-induced liver injury; GGT, gamma-glutamyl transferase; HAV, hepatitis A virus; HBc, hepatitis B core antigen; HBsAg, hepatitis B surface antigen; HCV, hepatitis C virus; HEV, hepatitis E virus; HFE, hereditary hemochromatosis; IgM, immunoglobulin M; MR, magnetic resonance; NAFLD, nonalcoholic fatty liver disease; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; ULN, upper limit of normal.

 

Resources:

(1) ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries is an outstanding resource for all clinicians [PubMed Abstract] [Full Text PDF] Am J Gastroenterol. 2017 Jan;112(1):18-35. doi: 10.1038/ajg.2016.517. Epub 2016 Dec 20.

(2) EASL-ALEH Clinical Practice Guidelines: Non-invasive tests for evaluation of liver disease severity and prognosis [PubMed Citation] [Full Text HTML] [Full Text PDF]. J Hepatol. 2015 Jul;63(1):237-64. doi: 10.1016/j.jhep.2015.04.006. Epub 2015 Apr 21.

(3) Clinical Practice Guidelines  [This link is to 25 Guidelines on Liver Diseases] from the Journal of Hepatology of The European Society for the Study of the Liver (EASL)

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