ACG Clinical Guideline: Evaluation of Abnormal Liver Chemistries

Paul Y. Kwo, MD, FACG, FAASLD

, Stanley M. Cohen, MD, FACG, FAASLD

, and Joseph K. Lim, MD, FACG, FAASLD

Division of Gastroenterology/Hepatology, Department of Medicine, Stanford University School of Medicine, Palo Alto,

California, USA;

Digestive Health Institute, University Hospitals Cleveland Medical Center and Division of Gastroenterology

and Liver Disease, Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, Ohio,

USA;

Yale Viral Hepatitis Program, Yale University School of Medicine, New Haven, Connecticut, USA.

Am J Gastroenterol 2017; 112:18–35; doi:10.1038/ajg.2016.517; published online 20 December 2016

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

The authors were invited by the Board of Trustees and Practice Guidelines Committee of the American

College of Gastroenterology to develop a practice guideline regarding the evaluation of abnormal liver

chemistries. We used the following resources:

1. A formal review and literature search of the world literature on MEDLINE and EMBASE

databases dealing with the evaluation of abnormal liver chemistries, studies that dealt with

normal or reference range for alanine aminotransferase (ALT) levels and what thresholds

trigger an evaluation for actionable liver disease. Studies detailing the relationship between ALT

and nonalcoholic fatty liver disease, as well as studies assessing the significance of elevated

liver chemistries on overall mortality and morbidity.

2. Guideline policies of the American College of Gastroenterology.

3. The experience of the authors and independent reviewers, as well as communication with

senior hepatologists across the United States with regard to the threshold for evaluating

abnormal liver chemistries.

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).

These guidelines are intended to be flexible and should be adjusted as deemed appropriate when

applied to individual patients. Recommendations are evidence-based where possible. On subjects

lacking rigid scientific data, recommendations are made based on the consensus opinion of the

authors. To more fully characterize the available evidence reporting the recommendations, the ACG

Practice Guideline Committee has adopted the classification used by the grading of recommendation

assessment, development, and evaluation workup with modifications. The strength of

recommendations are classified as strong or conditional. The quality of evidence supporting strong or

weak recommendations are designated by the following level is high, moderate low, or very low quality

(1). This is a practice guideline rather than a review article.

Liver chemistries that are commonly ordered in comprehensive metabolic profiles are indirect markers

of hepatobiliary disease. They are not true measures of hepatic function and thus are best referred to

as liver chemistries or liver tests, and should not be referred to as liver function tests. True tests of liver

function are not commonly performed but include measurement of hepatic substrates that are cleared

by hepatic uptake, metabolism, or both processes (2). Because of the widespread use of the

comprehensive metabolic profile testing that is done in routine practice to screen those who present

for routine evaluation as well as those who are symptomatic and/or referred for elevation of abnormal

liver chemistries, such abnormalities require a rational approach to interpretation. To date, there are

no controlled trials that have been performed to determine the optimal approach to evaluate

abnormal liver chemistries. This guideline has been developed to assist gastroenterologists and

primary care providers in the interpretation of normal and abnormal liver chemistries as well as an

approach to prioritize and evaluate those who present with abnormal liver chemistries.

Table 1. Recommendations

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).

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).

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 HBV-

infected persons. (Strong recommendation, very low level of evidence).

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).

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).

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).

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).

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).

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 anti-

trypsin (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 anti-

mitochondrial antibody. (Strong recommendation, very low level of evidence).

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).

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).

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).

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).

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, non-

alcoholic fatty liver disease; PBC, primary biliary cholangitis; PSC, primary sclerosing cholangitis; ULN, upper limit of

normal.

What are Truly Normal Liver Chemistry Tests?

Summary statements

1. A true healthy normal ALT level in prospectively-studied populations without identifiable risk

factors for liver disease ranges from 29-33 IU/L for males and 19-25 IU/L for females, and levels

above this should be assessed by physicians.

2. 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.

3. There is a linear relationship between ALT level and body mass index (BMI) that should be assessed

by physicians.

4. A normal ALT level may not exclude significant liver disease.

5. ALT levels are higher in males than females.

6. AST and ALT ULN ranges can vary between different labs.

7. Clinicians may rely on local lab ULN ranges for alkaline phosphatase and bilirubin.

Clinical Assessment of the Patient with Abnormal Liver Chemistries

Summary statements

Clinical assessment of the patient with elevated liver tests should begin with a thorough history and

physical examination.

1. History should include risk factors for underlying liver disease, associated medical conditions, use of

alcohol, and use of medications including over-the-counter products and herbal supplements.

2. Physical examination should assess for stigmata of chronic liver disease, as well as signs or

symptoms pointing to a specific liver disease etiology.

Patterns of Liver Chemistry Test Elevations

Summary statements

1. Hepatocellular injury is defined as disproportionate elevation of AST and ALT levels as compared to

the alkaline phosphatase level.

2. Cholestatic injury is defined as disproportionate elevation in alkaline phosphatase level as

compared to AST and ALT levels.

3. Mixed pattern of injury is defined as elevation of both alkaline phosphatase and AST/ALT levels.

4. Isolated hyperbilirubinemia is defined as elevation of bilirubin with normal alkaline phosphatase

and AST/ALT levels.

5. The R ratio is calculated by the formula R = (ALT value ÷ ALT ULN) ÷ (alkaline phosphatase value ÷

alkaline phosphatase ULN) with an R ratio of > 5 defined as hepatocellular injury, < 2 cholestatic

injury, and 2-5 mixed pattern.

Approach to Evaluation for Those with Elevated AST and ALT

Summary statements

1. A borderline AST and/or ALT elevation is defined as < 2X ULN, a mild AST and/or ALT elevation as 2-

5X ULN, moderate AST and/or ALT elevation 5-15X ULN, severe AST and/or ALT elevation >15X

ULN, and massive AST and/or ALT > 10,000 IU/L.

2. Fulminant hepatic failure (FHF) or acute liver failure (ALF), defined as the rapid development of

acute liver injury with severe impairment of the synthetic function as manifested by prolonged

prothrombin time and hepatic encephalopathy in a patient without obvious, previous liver disease

requires immediate evaluation regardless of ALT level.

Evaluation of Alkaline Phosphatase Level

Recommendation

1. (Table 5 and Figure 4) Right upper quadrant ultrasound should be performed in the setting of an

elevation of alkaline phosphatase; if normal, evaluation for intrahepatic causes should be

considered, including PBC, PSC, and drug- induced liver injury. (Strong recommendation, very low

level of evidence).

Evaluation of Total Bilirubin Level

Summary statements

1. (Table 6 and Figure 5) Elevated serum total bilirubin levels should be fractionated to direct and

indirect bilirubin.

2. An elevated serum conjugated bilirubin implies hepatocellular disease or biliary obstruction in most

settings.

Table 4. Causes of elevated AST and ALT

Hepatic (generally AST>ALT)

Alcoholic liver disease

Cirrhosis (of any etiology)

Ischemic hepatitis

Congestive hepatopathy

Acute Budd-Chiari syndrome

Hepatic artery damage/thrombosis/occlusion

TPN

Hepatic (generally ALT>AST)

NAFLD

Steatosis

NASH

Chronic viral hepatitis

Acute viral hepatitis

Medications and drug-induced liver injury

Prescription medications

Herbal products and supplements

Over-the-counter agents

Toxic hepatitis (amanita exposure)

Hemochromatosis

Autoimmune hepatitis

Wilson’s disease

Alpha-1-antitrypsin deficiency

Celiac disease

Acute bile duct obstruction

Liver trauma

Post-liver surgery

Veno-occlusive disease/sinusoidal obstruction syndrome

Diffuse infiltration of the liver with cancer

HELLP syndrome

Acute fatty liver of pregnancy

Sepsis

Hemophagocytic lymphohistiocytosis

Table 4. Causes of elevated AST and ALT (continued)

Non-hepatic

Skeletal muscle damage/rhabdomyolysis

Cardiac muscle damage

Thyroid disease

Macro-AST

Strenuous exercise

Heat stroke

Hemolysis

Adrenal insufficiency

ALT, alanine aminotransferase; AST, aspartate aminotransferase; HELLP, hemolysis, elevated liver tests, low platelets;

NAFLD, non-alcoholic fatty liver disease; NASH, non-alcoholic steatohepatitis; TPN, total parenteral nutrition.

Table 5. Causes of elevated alkaline phosphatase

Hepatobiliary

Bile duct obstruction

Choledocholithiasis

Malignant obstruction

Bile duct flukes

Bile duct stricture

Ductopenia

AIDS cholangiopathy

Cholestatic liver diseases

Primary biliary cirrhosis

PSC

Medications and drug-induced liver injury

Infiltrative diseases of the liver

Sarcoid

Granulomatous hepatitis

Tuberculosis

Amyloid

Metastatic cancer

Lymphoma

Table 5. Causes of elevated alkaline phosphatase (continued)

Hepatobiliary (continued)

Hepatic abscess

Hepatocellular carcinoma

Viral hepatitis

Cirrhosis

Vanishing bile duct syndrome

Ischemic cholangiopathy

Benign recurrent cholestasis

Sarcoidosis

Alcoholic liver disease

Intrahepatic cholestasis of pregnancy

Benign post-operative jaundice

ICU jaundice or multifactorial jaundice

TPN

Liver allograft rejection

Acute alcoholic hepatitis

Sickle cell liver crisis

Sepsis

Congestive heart failure

Hemophagocytic lymphohistiocytosis

Non-hepatic

Bone disease

Osteomalacia

Paget’s disease

Primary bony malignancy

Bony metastases

Hyperthyroidism

Hyerparathyroidism

Pregnancy (third trimester)

Chronic renal failure

Lymphoma

Extra-hepatic malignancy

Congestive heart failure

Childhood growth

Table 5. Causes of elevated alkaline phosphatase (continued)

Non-hepatic (continued)

Infection

Inflammation

Influx of alkaline phosphatase after a fatty meal

Blood type O and B

Myeloid metaplasia

Peritonitis

Diabetes mellitus

Gastric ulcer

Increasing age, especially women

PSC, primary sclerosing cholangitis; TPN, total parenteral nutrition.

Table 6. Causes of elevated bilirubin

Elevated unconjugated bilirubin

Gilbert’s syndrome

Crigler-Najjar syndrome

Hemolysis (intravascular and extravascular)

Ineffective erythropoiesis

Resorption of large hematomas

Neonatal jaundice

Hyperthyroidism

Medications

Post-blood transfusion

Elevated conjugated hyperbilirubinemia

Bile duct obstruction

Choledocholithiasis

Malignant obstruction

Bile duct flukes

Bile duct stricture

AIDS cholangiopathy

Viral hepatitis

Toxic hepatitis

Medications or drug-induced liver injury

Acute alcoholic hepatitis

Ischemic hepatitis

Cirrhosis

Primary biliary cirrhosis

PSC

Infiltrative diseases of the liver

Sarcoid

Granulomatous hepatitis

Tuberculosis

Metastatic cancer

Lymphoma

Hepatocellular carcinoma

Wilson disease (especially fulminant Wilson’s disease)

Autoimmune hepatitis

Ischemic hepatitis

Table 6. Causes of elevated bilirubin (continued)

Elevated conjugated hyperbilirubinemia (continued)

Congestive hepatopathy

Sepsis

TPN

Intrahepatic cholestasis of pregnancy

Benign post-operative jaundice

ICU or multifactorial jaundice

Benign recurrent cholestasis

Vanishing bile duct syndrome

Ductopenia

Dubin-Johnson syndrome

Rotor syndrome

Sickle cell liver crisis

Hemophagocytic lymphohistiocytosis

PSC, primary sclerosing cholangitis; TPN, total parenteral nutrition.