Today, I review, link to, and excerpt from ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries [PubMed Abstract] [Full-Text HTML] [Download Full-Text PDF]. Am J Gastroenterol. 2017 Jan;112(1):18-35. doi: 10.1038/ajg.2016.517. Epub 2016 Dec 20.
All that follows is from the above resource.
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 deficiency. 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.
INTRODUCTION
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).
Table 1. Recommendations
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 lowlevel 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 over-the-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).
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.
Summary statements:
- Liver chemistries including ALT, aspartate aminotransferase (AST), alkaline phosphatase and bilirubin are markers of liver injury, not liver function, and should be referred to as liver chemistries, or liver tests.
- Albumin, bilirubin, and prothrombin time are markers of hepatocellular function that can be influenced by extrahepatic factors.
- The laboratory measurements of ALT, AST, and alkaline phosphatase are highly reproducible.
- Elevations of AST and/or ALT, alkaline phosphatase, and bilirubin suggest hepatocellular injury and are the abnormal liver chemistries that require assessment and potential evaluation.
- ALT is a more specific marker of hepatic injury than AST.
- An elevated alkaline phosphatase level of hepatic origin may be confirmed by elevation of gamma-glutamyl transferase (GGT) or fractionation of alkaline phosphatase.
AST is present in the liver and other organs including cardiac muscle, skeletal muscle, kidney, and brain. ALT is present primarily in the liver, and thus is a more specific marker of hepatocellular cell injury (4, 5, 6). AST increase without elevation in ALT is suggestive of cardiac or muscle disease.
Typically, alkaline phosphatase elevates with obstruction of the bile ducts, which is due to increased canalicular synthesis of alkaline phosphatase with subsequent translocation to the sinusoid and is also a measure of liver injury (9).
An elevated GGT suggests that the alkaline phosphatase elevation is of hepatic origin (6).
Bilirubin comes from the breakdown of senescent red blood cells and predominantly circulates in its unconjugated form tightly bound to albumin.
Unconjugated bilirubin is reported as indirect bilirubin as determined by the van den Bergh reaction and accounts for ˜70% of the total serum bilirubin (12).
The total serum bilirubin is usually <1.1 mg/dl and an elevated direct bilirubin (conjugated bilirubin) indicates hepatocellular dysfunction or cholestasis.
Fractionation of total bilirubin is most helpful when the ALT, AST, and alkaline phosphatase levels are normal or near normal.
If the total bilirubin is elevated and fractionation shows the majority of the elevation is unconjugated bilirubin, hepatocellular disease is unlikely to be the explanation.
Conjugated bilirubin elevations are present in hepatocellular disorders as well as cholestatic disorders with impairment in bile flow.
Two markers of hepatocellular function are albumin and prothrombin time.
Albumin is a plasma protein exclusively synthesized by the liver with a circulating half-life of 3 weeks (6). A reduction in albumin (normal ≥3.5 g/dl) usually indicates liver disease of more than 3 weeks duration, although any significant illness can decrease albumin levels due to cytokine effects.
Prothrombin time is a far more sensitive measure of liver function than albumin because prothrombin time may be prolonged in patients with severe liver disease of <24 h duration (6).
As a general rule, in the absence of liver disease, a prothrombin time that is prolonged is due to vitamin K deficiency and/or steatorrhea. It should be noted that prothrombin time can also be elevated with warfarin, heparin bolus, disseminated intravascular coagulation (DIC), and hypothermia.
What are truly normal liver chemistry tests?
Summary statements:
- A true healthy normal ALT level in prospectively studied populations without identifiable risk factors for liver disease ranges from 29 to 33 IU/l for males and 19 to 25 IU/l for females, and levels above this should be assessed by physicians.
- Elevated ALT or AST above the upper limit of normal (ULN) in a population without identifiable risk factors is associated with increased liver-related mortality.
- There is a linear relationship between ALT level and body mass index (BMI) that should be assessed by physicians.
- A normal ALT level may not exclude significant liver disease.
- ALT levels are higher in males than females.
- AST and ALT ULN ranges can vary between different labs.
- Clinicians may rely on local lab ULN ranges for alkaline phosphatase and bilirubin.
Several studies and guidelines have proposed a standardized ULN for ALT based on prospectively acquired data using various methodologies (Table 2).
Examination Survey (NHANES) 1999–2002 and 2005–2008 databases, after eliminating subjects with viral hepatitis, significant alcohol use, diabetes, BMI>25, or enlarged waist circumference, and using statistical analysis, the calculated “maximum correct classification” for ULN of ALT was found to be 29 IU/l for men and 22 IU/l for women (26).
Elevated aminotransferase levels and the effect on morbidity and mortality
There is an accumulating set of data demonstrating that AST and ALT elevations correlate with morbidity and mortality (Table 3). An initial report from Germany noted that those with AST>18 U/l had a 3X increased risk of all-cause mortality (27). A Korean study found that, compared with men with AST or ALT<20 IU/l, the 30–39 IU/l group had an 8X (AST) or 9.5X (ALT) relative risk (RR) for liver-related death (28). Similar results were demonstrated from a study comparing the standardized mortality ratios in subjects from Olmsted County where higher ALT levels correlated with higher mortality with the standardized mortality ratio being 0.95 for normal ALT (defined as ULN 45 IU/l for men, 29 IU/l for females), 1.32 for 1–2X ULN, and 1.78 for >2X ULN with a similar relationship for AST levels (29).
Impact of using a lower ALT ULN on clinical practice
Utilizing a significantly lower ULN for ALT will have implications by defining many more patients as having abnormal ALT levels. For example, applying the calculated “maximum correct classification” for ULN of ALT (29 IU/l for men and 22 IU/l for women) to the NHANES databases would result in 36% of men and 28% of women being defined as having elevated ALT (26).
Some have argued against lowering of the ALT ULN due to major clinical and financial implications including increased health care costs and unnecessary evaluations, increased mental anguish and anxiety, and reducing the blood donation pool (33). Supporting these concerns was a study of 235 asymptomatic workers, in which 27% had abnormal liver tests (using lower ULN criteria), yet only six were found to have any liver disease on further evaluation although long-term mortality was not assessed in this study (34). Our belief, given the increased liver-related mortality demonstrated across multiple populations for ALT>33 IU/l for men and >25 IU/l for women, is that clinicians should be educated about the adverse long-term outcomes of these historically non-elevated levels and that a national effort should be undertaken to standardize ALT levels across all populations.
Specific diseases of the liver including diagnostic testing
Viral hepatitis
Chronic hepatitis B and C infections are common in the United States.
The screening test for chronic hepatitis C is the hepatitis C antibody, which has a sensitivity of 92–97% (42). The positive predictive value of the antibody test is highest among individuals with risk factors for exposure; false positives may be observed in 5% of cases, and as high as 30% among individuals without reported risk factors. Confirmation of chronic infection is established by a highly sensitive HCV RNA PCR assay which has high sensitivity and specificity (AASLD/IDSA/IAS-USA. HCV testing and linkage to care. Recommendations for testing, managing, and treating hepatitis C (http://www.hcvguidelines.org/full-report/hcv-testing-and-linkage-care)). Individuals confirmed to have positive RNA should be referred to a specialist for further characterization of the infection and assessment of liver fibrosis to guide the decision to pursue antiviral therapy.
Acute infection with hepatitis C is a rare presentation compared with chronic hepatitis C and is associated with higher levels of aminotransferase levels, but is typically anicteric and without clinical symptoms of hepatitis (44). The diagnosis of acute hepatitis C can be made in the setting of recent risk factors including drug use, and more recently men having sex with men has been identified as an increasingly prevalent risk factor. Testing includes anti-HCV, which is typically positive 6–8 weeks after exposure, with confirmation by measuring HCV RNA by PCR testing which must be done to confirm a case of acute hepatitis or chronic hepatitis C.
Testing for hepatitis B should be performed in all patients with persistently elevated AST/ALT levels. Chronic hepatitis B infects ˜1.5 million Americans and over 280 million individuals worldwide (23).
Characterization of an individual’s hepatitis B status can be achieved with three serologic tests, including the hepatitis B surface antigen (HBsAg) which is indicative of hepatitis B infection, the hepatitis B core antibody total which signals prior exposure, and the hepatitis B surface antibody, which signal immunity to the infection, either natural or vaccine-mediated (23).
Chronic infection is confirmed by presence of the HBsAg and/or positive viremia on a highly sensitive HBV DNA assay.
Individuals confirmed to have chronic hepatitis B should be referred to physicians with expertise in its management, and undergo further characterization of their infection with tests such as hepatitis B e antigen, hepatitis B e antibody, hepatitis B genotype, hepatitis B viral load (quantitative DNA), and fibrosis assessment, which may guide the decision for antiviral therapy.
The diagnosis of acute hepatitis B is made by a positive immunoglobulin M (IgM) hepatitis B core antibody (hepatitis B core antibody IgM) and HBsAg in the setting of an acute hepatitis (45). Unlike acute hepatitis C in adults, acute hepatitis B infection is more commonly associated with signs and symptoms of hepatitis.
Non-alcoholic fatty liver disease
NAFLD is a highly prevalent condition associated with the metabolic syndrome, and is observed most commonly in patients with co-existing disorders including obesity, diabetes mellitus, dyslipidemia, and hypertension and should be strongly considered in individuals with mild elevations of AST/ALT levels (46, 47). Unlike alcoholic liver disease, there is no unique pattern of elevation for ALT and AST levels, although in general, ALT is higher than AST levels, and levels are rarely above 300 IU/l. Although one-third of Americans may meet a broad definition of NAFLD based on the presence of hepatic steatosis, a much smaller subset have NASH which is characterized by inflammation, fibrosis, and the potential for progressive to cirrhosis.
No serological test is presently available to distinguish NAFLD from NASH or establish a diagnosis of NASH, and therefore it frequently represents a diagnosis of exclusion in which a series of diagnostic labs are obtained to first rule out alternative etiologies.
Although many individuals with NAFLD suggested by steatosis on imaging may have normal liver chemistries, the presence of abnormal liver chemistries signals a higher likelihood for NASH with or without fibrosis and therefore warrants clinical evaluation.
Compatible liver imaging for fatty liver infiltration on liver ultrasound, computed tomography, and magnetic resonance imaging (MRI) are useful to establish fatty liver itself, although liver biopsy is required to establish a diagnosis of NASH. As it is not practical to offer all patients with NAFLD a biopsy, guidelines have been established to help determine which NAFLD patients may require biopsy (46).
46. Chalasani N, Younossi Z, Lavine JE et al. The diagnosis and management of non-alcoholic fatty liver disease: Practice Guideline by the American Association for the Study of Liver Diseases, American College of Gastroenterology, and the American Gastroenterological Association. Hepatology 2012;55:2005–2023
Alcoholic liver disease
Alcohol consumption is a very common cause for elevated liver chemistries, both independently, and as a contributor to liver injury in patients with other chronic liver diseases such as hepatitis C infection. As such, directed query and characterization of alcohol intake by patients is essential to identifying alcoholic liver disease as the precipitating factor.
The definition of significant alcohol consumption has been suggested as >210 g of alcohol per week in men and >140 g per week in women (46).
Radiographically and histologically, the pattern of liver injury is similar to that of NAFLD and these can overlap as dual contributors to acute and chronic liver disease.
Specific patterns of liver injury have been commonly associated with alcoholic liver injury, including an AST:ALT ratio of at least 2:1, with values of AST or ALT rarely exceeding 300 IU/l (ref. 49). A higher ratio of AST:ALT exceeding 3:1 further increases the likelihood of alcoholic liver disease, and this ratio largely reflects the relatively lower serum activity of ALT in comparison to AST driven by pyridoxine deficiency observed in patients with alcoholic liver disease (50).
Alcohol consumption should be queried in all patients presenting with abnormal liver chemistries, and complete cessation should be recommended in all patients, and in particular those patients for whom immediate serologic examination is deferred and close surveillance is planned.
Autoimmune liver disease
Chronic autoimmune hepatitis represents an important cause of chronic liver disease which is associated with persistently elevated liver chemistries, and may occur in the presence of other autoimmune disorders such as hypothyroidism, ulcerative colitis synovitis, Sjogren’s, rheumatoid arthritis, and psoriasis.
Typically observed more commonly in women than men (4:1), it has a lower prevalence than viral hepatitis or alcoholic/NAFLD (1:6,000), and is identified by the presence of characteristic serologic markers, including anti-nuclear antibody, anti-smooth antibody, and less commonly anti-liver kidney microsomal antibody or anti-soluble liver antigen antibody.
The presence of hypergammaglobulinemia on testing for immunoglobulin G (IgG) or serum protein electrophoresis is suggestive although not diagnostic.
A diagnosis of autoimmune hepatitis requires histologic confirmation on liver biopsy which may confirm a diagnosis, exclude an overlap syndrome with related autoimmune liver disorders, and stage for liver fibrosis.
Metabolic/genetic disorders
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