Annals of Internal MedicineT

In the ClinicT

Care of the
Patient With
Abnormal Liver Evaluation

Test Results Management

L
iver tests are commonly performed in primary
care and may signal the presence of acute or
chronic liver disease. Abnormal results are
defined by standardized rather than individual lab- Practice Improvement
oratory thresholds and must be interpreted in the
context of a patient's history and examination.
The pattern and severity of liver injury may provide
clues about the cause of disease and should guide Patient Education
diagnostic evaluation with serologic testing and liver
imaging. A systematic, stepwise approach to the eval-
uation and management of abnormal liver test results
is recommended to optimize high-value care.

CME/MOC activity available at Annals.org.

Physician Writers doi:10.7326/AITC202109210

Ashley N. Tran, MD
Joseph K. Lim, MD
Yale University School of
Medicine, New Haven,
Connecticut
This article was published at Annals.org on 14 September 2021.
CME Objective: To review current evidence for evaluation, management, practice
improvement, and education of patients with abnormal liver test results.
Funding Source: American College of Physicians.
Disclosures: Dr. Tran, ACP Contributing Author, reports no disclosures of interest.
Dr. Lim, ACP Contributing Author, reports research contracts from Allergan,
Conatus Pharmaceuticals, GENFIT, Gilead, and Intercept Pharmaceuticals and
unpaid leadership roles with the American Association for the Study of Liver
Diseases, the American Gastroenterological Association, and the American College
of Gastroenterology. Disclosures can also be viewed at www.acponline.org/
authors/icmje/ConflictOfInterestForms.do?msNum=M21-0988.

With the assistance of additional physician writers, the editors of Annals of

Internal Medicine develop In the Clinic using MKSAP and other resources of
the American College of Physicians. The patient information page was written by
Monica Lizarraga from the Patient and Interprofessional Partnership Initiative at
the American College of Physicians.
In the Clinic does not necessarily represent official ACP clinical policy. For ACP
clinical guidelines, please go to https://www.acponline.org/clinical_information/
guidelines/.
© 2021 American College of Physicians

1. Woreta TA, Alqahtani SA.
Evaluation of abnormal
liver tests. Med Clin North
Am. 2014;98:1-16. [PMID:
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2. Kwo PY, Cohen SM, Lim
JK. ACG clinical guideline:
evaluation of abnormal
liver chemistries. Am J
Gastroenterol.
2017;112:18-35. [PMID:
27995906]
Evaluation
3. Newsome PN, Cramb R,
Davison SM, et al.
Guidelines on the manage-
ment of abnormal liver
blood tests. Gut.
2018;67:6-19. [PMID:
29122851]
4. Kim WR. Clinical implica-
tions of short-term variabili-
ty in liver function test
results. Gastroenterology.
2008;135:1010-1. [PMID:
18691585]
5. Lominadze Z, Kallwitz ER.
Misconception: you can't
have liver disease with nor-
mal liver chemistries. Clin
Liver Dis (Hoboken).
2018;12:96-9. [PMID:
30988921]
6. Pratt DS, Kaplan MM.
Evaluation of abnormal
liver-enzyme results in
asymptomatic patients. N
Engl J Med.
2000;342:1266-71. [PMID:
10781624]
7. Kamath PS. Clinical
approach to the patient
with abnormal liver test
results. Mayo Clin Proc.
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8917295]
© 2021 American College of Physicians
The comprehensive metabolic
panel includes such liver tests as
serum alanine aminotransferase
(ALT), aspartate aminotransferase
(AST), alkaline phosphatase (ALP),
and bilirubin. These tests are indi-
cators of hepatocyte inflammation
or cholestasis and should not be
referred to as liver function tests.
Albumin and prothrombin time
(PT) reflect hepatic synthetic func-
tion but can be affected by extra-
hepatic processes. Liver injury is
characterized as hepatocellular or
cholestatic on the basis of the se-
verity of aminotransferase eleva-
tions in relation to ALP, although
some liver diseases may be asso-
ciated with a mixed pattern of
injury (1). To date, limited evi-
dence supports the optimal
approach to evaluating abnormal
liver test results; however, experts
advocate for a systematic
approach to interpretation and
management (2, 3).
The range of “normal” results is
traditionally defined as those
found in 95% of a reference popu-
lation of healthy persons.
What features of the history
and physical examination
should clinicians look for?
The first step in the evaluation of
abnormal liver test results is to
repeat the laboratory panel and/
or perform a clarifying test (for
example, checking c-glutamyl-
transferase [GGT] if serum ALP is
elevated) (2, 6). If the result is still
abnormal, the clinician should
perform a history and physical
examination, evaluating for signs
and symptoms of specific condi-
tions to help interpret laboratory
findings and guide subsequent
evaluation. The history should
include a detailed assessment of
risk factors for liver disease, such
as alcohol and drug use, sexual
history, recent travel, and history
ITC130 In the Clinic
However, this definition is prob-
lematic because what constitutes
“healthy” varies across popula-
tions and laboratories.
Furthermore, persons may have
unrecognized liver disease, such
as nonalcoholic fatty liver disease
(NAFLD), viral hepatitis, alcoholic
liver disease (ALD), or exposure to
hepatotoxic medications or herbal
supplements (4). Studies have
proposed reference populations
and standardized ranges for ALT
by excluding patients with known
chronic liver disease; high-risk
behaviors; and NAFLD risk factors,
such as elevations in body mass
index (BMI) and cholesterol, tri-
glyceride, and glucose levels (2).
The American Association for the
Study of Liver Diseases has
defined the true upper limit of
normal (ULN) for ALT as
30 IU/L for males and 19 IU/L for
females (5). The American
College of Gastroenterology
has defined the ULN for ALT as
33 IU/L for males and 25 IU/L for
females. For ALP and bilirubin,
clinicians may rely on laboratory
cutoffs for the ULN (2).
of blood transfusion or needle-
stick injury (1, 2, 7). Clinicians
should assess for associated med-
ical conditions, such as cardiovas-
cular, metabolic, hematologic,
pulmonary, and autoimmune dis-
eases. Patients should also be
queried about a family history of
liver disease, such as Wilson dis-
ease, a1-antitrypsin (A1AT) defi-
ciency, and hemochromatosis.
Finally, a thorough review of med-
ication use (including over-the-
counter products and herbal sup-
plements) and occupational or
recreational exposure to hepato-
toxins should also be performed.
The physical examination should
assess for stigmata of chronic liver
disease, such as spider nevi, pal-
mar erythema, gynecomastia,
Annals of Internal Medicine September 2021
caput medusae, and splenomeg-
aly, which indicate end-stage liver
disease with portal hypertension
and elevated estrogen levels (2).
The presence of ascites, jaundice,
asterixis, and hepatic encephalop-
athy can suggest decompensated
cirrhosis. Physical examination
findings are often normal in a
patient with abnormal liver test
results, but certain findings may
aid in the diagnosis for specific
causes, such as Dupuytren con-
tractures, parotid gland enlarge-
ment, and testicular atrophy in
ALD (2); Kayser–Fleischer rings
and neuropsychiatric symptoms
in Wilson disease; or skin bronz-
ing or hyperpigmentation in
hemochromatosis. Hepatomegaly
associated with right upper quad-
rant tenderness can be seen in vi-
ral and alcoholic hepatitis and,
less commonly, in right-sided
heart failure or hepatic vein
thrombosis (7).
What are the broad patterns
and clinical implications of
liver injury?
The duration, relative levels,
and severity of AST, ALT, and ALP
elevations can provide clues
about the cause of liver injury
(Appendix Table, available at
Annals.org). Liver disease is con-
sidered chronic if test abnormal-
ities persist for more than 6
months (1). Hepatocellular injury
is defined as disproportionate ele-
vation of ALT and AST compared
with ALP. ALT is a more specific
marker of hepatic inflammation
because AST is also expressed in
cardiac muscle, skeletal muscle,
the kidneys, and the brain (8). The
magnitude of AST and ALT eleva-
tion may vary depending on the
cause of injury, including border-
line elevation (<2 times the ULN),
mild elevation (2 to 5 times the
ULN), moderate elevation (5 to 15
times the ULN), severe elevation
(>15 times the ULN), and massive
elevation (>10 000 U/L). Acute
liver failure is characterized by
September 2021 Annals of Internal Medicine
rapid deterioration of liver func-
tion that is accompanied by coa-
gulopathy and encephalopathy in
persons without preexisting liver
disease and requires immediate
evaluation regardless of ALT
level (2).
The AST–ALT ratio can be a useful
marker in determining the cause
of liver disease but has important
limitations. In ALD, the ratio is typi-
cally above 2 but is often above 3
with absolute values below
300 U/L; disproportionate AST
elevation may be attributable to
mitochondrial injury and alcohol-
related pyridoxine deficiency (2).
In contrast, patients with nonalco-
holic steatohepatitis (NASH) may
have a ratio below 1 (9). Although
ALT levels are higher than AST
levels in most chronic liver dis-
eases, the AST–ALT ratio may
increase with worsening fibrosis
or cirrhosis (1). Finally, a ratio
above 5 may indicate extrahepatic
injury, especially if the ALT level is
normal or minimally elevated (8).
Cholestatic injury is defined as dis-
proportionate elevation of ALP
and bilirubin compared with ALT
and AST. Elevation in ALP is not
specific to liver disease and can
occur in pregnancy and disorders
of the bones, kidneys, and intes-
tines (8). Total bilirubin is the sum
of conjugated and unconjugated
forms. Abnormalities in direct or
conjugated bilirubin are typically
associated with liver disease,
whereas indirect or unconjugated
bilirubin is elevated in hemolysis
and benign conditions, such as
Gilbert syndrome.
What is the differential
diagnosis for hepatocellular 8. Abnormal Liver Function
injury? Tests—Approach to the
Patient. Record no.
Viral hepatitis T316452. EBSCO
Hepatitis B and C are common Information Services;
1995.
bloodborne viral infections. Risk 9. Giboney PT. Mildly ele-
vated liver transaminase
factors for hepatitis C include levels in the asymptom-
injection and intranasal drug use, atic patient. Am Fam
Physician. 2005;71:1105-
unsafe injection practices, needle- 10. [PMID: 15791889]
stick injury, blood transfusion
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10. American Association for
the Study of Liver
Diseases; Infectious
Diseases Society of
America. HCV testing and
linkage to care. In:
Recommendations for
Testing, Managing, and
Treating Hepatitis C.
Updated 21 January
2021.
11. Smith BD, Morgan RL,
Beckett GA, et al; Centers
for Disease Control and
Prevention.
Recommendations for the
identification of chronic
hepatitis C virus infection
among persons born dur-
ing 1945–1965. MMWR
Recomm Rep. 2012;61:1-
32. [PMID: 22895429]
12. Summa KC, Maddur H.
Hepatitis C antibody posi-
tive, RNA negative. Clin
Liver Dis (Hoboken).
2019;14:5-7. [PMID:
31391928]
13. Hyun Kim B, Ray Kim W..
Epidemiology of hepatitis
B virus infection in the
United States. Clin Liver
Dis (Hoboken).
2018;12:1-4. [PMID:
30988901]
14. Terrault NA, Lok ASF,
McMahon BJ, et al.
Update on prevention, di-
agnosis, and treatment of
chronic hepatitis B: AASLD
2018 hepatitis B guid-
ance. Hepatology.
2018;67:1560-99. [PMID:
29405329]
15. Kamar N, Izopet J, Pavio
N, et al. Hepatitis E virus
infection. Nat Rev Dis
Primers. 2017;3:17086.
[PMID: 29154369]
16. Crabb DW, Im GY, Szabo
G, et al. Diagnosis and
treatment of alcohol-asso-
ciated liver diseases:
2019 practice guidance
from the American
Association for the Study
of Liver Diseases.
Hepatology.
2020;71:306-33. [PMID:
31314133]
© 2021 American College of Physicians
before 1992, long-term hemodial-
ysis, and high-risk sexual practices
involving blood exposure (10). In
addition, the Centers for Disease
Control and Prevention and the
U.S. Preventive Services Task
Force recommend universal
screening of all U.S. adults aged
18 to 79 years and pregnant
women regardless of age, inde-
pendent of the presence of abnor-
mal liver test results (2, 11).
Hepatitis C virus (HCV) screening
should be done with the HCV anti-
body test. A positive or indetermi-
nate result should be followed by
an HCV RNA polymerase chain
reaction assay to assess for active
infection. In addition, HCV RNA
polymerase chain reaction should
be done regardless of the HCV
antibody test result to assess for
reinfection in patients who are
immunocompromised, those who
have been exposed to HCV within
the past 6 months, or HCV anti-
body–positive persons who previ-
ously achieved spontaneous
clearance or treatment-induced
viral cure (10). A positive result
confirms active infection and war-
rants additional testing for geno-
type and liver fibrosis to guide
antiviral treatment (12).
Hepatitis B virus (HBV) is primarily
transmitted through percutaneous
or mucosal exposures to infected
blood or body fluids. In endemic
areas, primary transmission occurs
through perinatal transmission,
whereas sexual and parental
transmission is more common in
areas of low endemicity (13).
Screening is performed using
hepatitis B surface antigen
(HBsAg), which indicates active
infection; hepatitis B core anti-
body (HBcAb) to determine prior
exposure; and hepatitis B surface
antibody (HBsAb) to confirm ei-
ther natural or vaccine-mediated
immunity (2). Acute infection is
diagnosed by a positive HBcAb
IgM and HBsAg in the setting of
acute hepatitis, whereas chronic
ITC132 In the Clinic Annals of Internal Medicine September 2021
infection is diagnosed by a posi-
tive HBsAg and the presence of
HBV DNA. Persons with confirmed
chronic HBV infection should have
additional serologic testing,
including hepatitis B e antigen sta-
tus and assessment of liver fibro-
sis, to guide management (2, 14).
Hepatitis A virus and hepatitis
E virus (HEV) are transmitted
through an oral–fecal route and
typically present as an acute self-
limited hepatitis, with rare cases of
acute liver failure (2). HEV infec-
tion is less common, with higher
incidence rates in developing
countries due to contaminated
water or zoonotic infections; com-
plications include acute liver fail-
ure, particularly in pregnant
women, and chronic infection in
immunosuppressed patients,
especially those having solid
organ transplantation (15). Finally,
patients presenting with moder-
ate to massive aminotransferase
elevations should also be eval-
uated for infection by nonhepato-
tropic viruses, including herpes
simplex virus, Epstein–Barr virus,
and Cytomegalovirus (8).
Alcoholic liver disease
ALD represents a spectrum of liver
injury that ranges from hepatic
steatosis to more advanced forms,
including alcoholic hepatitis and
alcoholic cirrhosis. The upper limit
of safe drinking is 1 standard drink
(14 g of alcohol) per day for
women and 2 standard drinks per
day for men without liver disease.
Binge drinking is defined as a
pattern of drinking that brings
blood alcohol concentrations to
0.08 g/dL, which typically occurs
after 4 drinks for women and 5
drinks for men in about 2 hours
(16). Excessive alcohol consump-
tion is a common cause of liver
injury, both independently and as
a contributor to progression of
other chronic liver diseases, such
as NAFLD and viral hepatitis (2).
Studies have shown that concomi-
tant alcohol use can increase risk
for cirrhosis, hepatocellular carci-
noma (HCC), need for transplanta-
tion, and liver-related mortality
(16). Therefore, all patients with
abnormal liver test results should
be screened for alcohol use, and
complete cessation should be
recommended.
The diagnosis of ALD is supported
by an AST–ALT ratio of at least 2.
Measurement of GGT levels may
also help to identify alcohol use,
although elevations alone are not
specific to the condition (6).
Patients with alcohol-associated
steatosis are often asymptomatic,
and steatosis is typically identified
on imaging. Liver biopsy is rarely
needed to confirm the diagnosis,
and steatosis is reversible with
cessation of alcohol use (16). In
acute alcoholic hepatitis, patients
can present with low-grade fever,
malaise, anorexia, jaundice, and
tender hepatomegaly. In addition,
patients can be severely malnour-
ished, and the presentation may
be precipitated by complications
of hepatic dysfunction or portal
hypertension, such as variceal
hemorrhage, hepatic encephalop-
athy, and ascites. Alcoholic cirrho-
sis cannot be differentiated from
other causes of cirrhosis except
through careful evaluation of alco-
hol consumption and exclusion of
other causes of liver disease.
Unlike alcoholic steatosis, alco-
holic cirrhosis is nonreversible;
however, abstinence is crucial in
slowing progression of fibrosis
and in anticipation of evaluation
for liver transplantation and may
lead to improved liver function
with resolution of jaundice,
improved synthetic function, and
resolution of portal hypertension
(16).
Nonalcoholic fatty liver disease
NAFLD encompasses a spectrum
of disease ranging from simple
hepatic steatosis to NASH, which
can progress to fibrosis and cir-
rhosis and is commonly associ-
ated with metabolic conditions,
September 2021 Annals of Internal Medicine
such as obesity, diabetes mellitus,
hypertension, and dyslipidemia
(17, 18). Patients with NAFLD are
typically asymptomatic and may
present with normal or mild to
moderate aminotransferase eleva-
tions. Mildly elevated serum ferri-
tin levels are common, and
antinuclear antibodies (ANA) and
anti–smooth-muscle antibodies
(ASMA) may be present in low
titers in 20% of patients (17).
Muscle loss and sarcopenia may
be masked in patients with NASH
cirrhosis who also have obesity
(18).
Currently, no serologic test can
diagnose NAFLD; therefore, it is
essential to exclude competing
causes of steatosis and coexisting
causes of chronic liver disease.
Compatible imaging showing
fatty infiltration on ultrasonogra-
phy, computed tomography (CT),
and magnetic resonance imaging
(MRI) can establish the diagnosis
of fatty liver, but diagnosis of
NASH requires a histologic assess-
ment characterized by hepatic ste-
atosis, lobular inflammation, and
ballooning hepatocyte degenera-
tion with or without fibrosis (2).
Hepatic steatosis in isolation
seems to have a benign course in 17. Chalasani N, Younossi Z,
contrast to NASH, which may pro- Lavine JE, et al. The di-
agnosis and manage-
gress to cirrhosis and liver failure ment of non-alcoholic
fatty liver disease: prac-
(2, 17). Noninvasive tests, such as tice guideline by the
the NAFLD fibrosis score, the American Association for
the Study of Liver
Fibrosis-4 (FIB-4) index, and elas- Diseases, American
tography, may be useful in stratify- College of
Gastroenterology, and
ing patients with NASH who are at the American
Gastroenterological
risk for advanced fibrosis (2). Association. Hepatology.
2012;55:2005-23.
Autoimmune hepatitis [PMID: 22488764]
18. Wang XJ, Malhi H.
Autoimmune hepatitis (AIH) has a Nonalcoholic fatty liver
spectrum of clinical presentations disease. Ann Intern
Med. 2018;169:ITC65-
that includes acute or chronic ITC80. [PMID:
30398639]
hepatitis; cirrhosis; and, rarely,
19. Mack CL, Adams D, Assis
acute liver failure. The diagnosis is DN, et al. Diagnosis and
management of autoim-
based on compatible clinical signs mune hepatitis in adults
and symptoms; histologic abnor- and children: 2019 prac-
tice guidance and guide-
malities; and characteristic labora- lines from the American
tory findings, including elevated Association for the Study
of Liver Diseases.
AST or ALT, hypergammaglobuli- Hepatology.
2020;72:671-722.
nemia, and the presence of 1 or [PMID: 31863477]
more autoantibodies (19).
In the Clinic ITC133 © 2021 American College of Physicians

20. Bacon BR, Adams PC,
Kowdley KV, et al;
American Association for
the Study of Liver
Diseases. Diagnosis and
management of hemo-
chromatosis: 2011 prac-
tice guideline by the
American Association for
the Study of Liver
Diseases. Hepatology.
2011;54:328-43. [PMID:
21452290]
21. Roberts EA, Schilsky ML;
American Association for
Study of Liver Diseases
(AASLD). Diagnosis and
treatment of Wilson dis-
ease: an update.
Hepatology.
2008;47:2089-111.
[PMID: 18506894]
© 2021 American College of Physicians
Women are affected more fre-
quently than men (4:1), and the
age at onset seems to have bi-
modal distribution, although the
disease can present at any age.
AIH may occur in the presence of
other autoimmune conditions,
such as type 1 diabetes, systemic
lupus erythematosus, thyroid dis-
orders, and rheumatoid arthritis
(2, 19). Also, some patients may
have features of AIH and another
autoimmune liver condition, such
as primary sclerosing cholangitis
(PSC), primary biliary cholangitis
(PBC), or IgG4 disease.
Serologic markers suggestive of
AIH include ANA, ASMA, anti–
liver-kidney microsomal antibody
(anti-LKM), liver cytosol type 1
(LC-1), and soluble liver antigen
(SLA). Two common types of AIH
have been characterized on the
basis of the serologic assessment.
Type 1 AIH is characterized by the
presence of ANA, ASMA, or anti-
SLA antibodies and represents
80% of cases. Type 2 is character-
ized by the presence of anti-LKM
and/or anti-LC-1. Approximately
20% of patients who present with
features of AIH may be seronega-
tive, although they may express
autoantibodies later in the disease
(19). A clinical response to immu-
nosuppressive or anti-inflamma-
tory treatment may be the only
indication that AIH is the under-
lying condition in such patients.
Liver biopsy is recommended to
establish the diagnosis and to
guide pharmacologic treatment.
Histologic features suggestive of
AIH include interface hepatitis,
plasma cell infiltration, lobular
hepatitis, and central bridging
necrosis (19).
Metabolic/genetic disorders
Hereditary hemochromatosis (HH)
is characterized by inappropriate
iron absorption due to defects in
the HFE gene, leading to homozy-
gous mutations involving C282Y
and compound heterozygous
mutations involving H63D and
ITC134 In the Clinic
S65C (20). However, fully
expressed disease with end-organ
manifestations is seen in fewer
than 10% of homozygotes due to
low disease penetrance (2, 20). In
addition, patients become symp-
tomatic when organ iron deposi-
tion has accumulated over
decades, which generally occurs
after age 40 years, although
females can present later than
males due to iron excretion asso-
ciated with menstrual losses.
HH should be considered in
patients who present with a clini-
cal history or physical examination
suggestive of end-organ involve-
ment of iron overload within the
liver, pancreas, skin, joints, or
heart (2). Screening includes an
iron panel with ferritin levels and
transferrin saturation and should
be considered in all patients with
abnormal serum aminotransferase
levels as well as those with a family
history of HH. A transferrin satura-
tion above 45% or an elevated
ferritin level warrant further evalu-
ation with HFE gene mutation
analysis (2). Liver MRI can be used
as a noninvasive approach to
quantify hepatic iron stores. Liver
biopsy should be pursued in per-
sons with homozygous C282Y or
compound heterozygous C282Y/
H63D mutations and elevated
aminotransferase levels or a ferri-
tin level above 1000 μg/L or in
non-HFE hemochromatosis to
stage fibrosis and to quantify
hepatic iron overload to guide
therapy (2, 20).
Wilson disease is an inherited
condition characterized by
impaired biliary copper excretion
due to a defective ATP7B copper
transporter protein, which leads
to copper accumulation in the
liver, brain, corneas, and kidneys
(21). It can present clinically as
liver, neurologic, and/or psychiat-
ric disease, although neurologic
manifestations often present later
than the liver disease (2). The liver
manifestations can vary and
Annals of Internal Medicine September 2021
include asymptomatic, mild eleva-
tions in aminotransferase levels
with hepatic steatosis, acute hepa-
titis, cirrhosis, and acute liver fail-
ure associated with Coombs-
negative hemolytic anemia and
renal failure (21). Screening using
serum ceruloplasmin should be
considered in patients with abnor-
mal aminotransferase levels or a
family history of Wilson disease.
Persons should also be evaluated
for Kayser–Fleischer rings via a slit-
lamp examination, and a 24-hour
urine collection should be
obtained to quantify copper
excretion in all patients with sus-
pected Wilson disease (21). Liver
biopsy should be considered to
confirm the diagnosis, stage fibro-
sis, and quantify hepatic copper
to guide therapy. Mutation analy-
sis by whole-gene sequencing to
identify the ATP7B mutation
should also be performed in cases
of diagnostic uncertainty (2).
A1AT deficiency is characterized
by impaired inhibition of neutro-
phil elastase, leading to panacinar
emphysema, chronic obstructive
pulmonary disease, and chronic
liver disease with potential pro-
gression to cirrhosis and HCC (2,
22). Screening should be consid-
ered in persons with elevated ami-
notransferase levels or a family
history of A1AT mutations. Low
quantitative levels of A1AT carry
high sensitivity and specificity for
deficiency, but false-negative
results can occur because A1AT is
also an acute-phase reactant that
can be elevated in the setting of
inflammation (6). Patients should
also undergo phenotype testing
to look for the PiZZ mutation,
which results in severe enzyme
deficiency, or for heterozygous
phenotypes that may increase risk
for liver fibrosis or cirrhosis when
associated with coexisting chronic
liver disease (2). Although liver bi-
opsy is not required for diagnosis,
it can help establish the diagnosis
in cases of cryptogenic cirrhosis
September 2021 Annals of Internal Medicine
or when the cause is uncertain
and is characterized by pathogno-
monic periodic acid–Schiff–posi-
tive, diastase-resistant inclusions
(22).
Drug-induced liver injury and
nonhepatic causes
Almost all medications may be
associated with elevated liver
markers with or without hepato-
toxicity. Common examples
include antibiotics, antifungals,
antituberculosis drugs, anticonvul-
sants, nonsteroidal anti-inflamma-
tory drugs, statins, antiretroviral
treatment for HIV, immunomodu-
lators, anti–tumor necrosis agents,
and chemotherapy (2, 6). Persons
with severely elevated amino-
transferase levels should be
queried about acetaminophen
use, either alone or in combina-
tion with other drugs, especially in
chronic alcohol users who are at
risk for hepatotoxicity at doses
less than 4 g/d (2). Recovery of
liver injury after drug withdrawal is
often required to establish the di-
agnosis of drug-induced liver
injury. However, if the suspected
medication is essential, efforts
should be made to identify alter-
natives and/or establish a surveil-
lance plan to monitor for
progression of liver injury or liver
failure (2, 6). Biopsy may be
needed to establish a diagnosis or
to characterize the nature and se-
verity of liver injury. A useful
resource for clinicians with infor-
mation on drugs and selected
herbal and dietary supplements
that are known to cause drug-
induced liver injury is available at
livertox.nih.gov.
A wide variety of nonhepatic con-
ditions can cause chronic eleva-
tion in serum aminotransferase
levels. Patients with a history of 22. Torres-Durán M, Lopez-
bloating, changes in stool habits, Campos JL,
Barrecheguren M, et al.
or iron deficiency should be Alpha-1 antitrypsin defi-
ciency: outstanding
screened for celiac disease by questions and future
measurement of tissue transgluta- directions. Orphanet J
Rare Dis. 2018;13:114.
minase IgA and serum IgA levels. [PMID: 29996870]
Hypothyroidism and hyper-
In the Clinic ITC135 © 2021 American College of Physicians

23. Gochanour E, Jayasekera
C, Kowdley K. Primary
sclerosing cholangitis: ep-
idemiology, genetics, di-
agnosis, and current
management. Clin Liver
Dis (Hoboken).
2020;15:125-8. [PMID:
32257124]
© 2021 American College of Physicians
thyroidism have been associated
with hepatocellular and choles-
tatic liver injury in the context of
myxedema or thyrotoxicosis (2).
Persons with suspected thyroid
disease should be further eval-
uated for thyroid-stimulating hor-
mone and free triiodothyronine
and thyroxine. Creatine kinase
and aldolase should be measured
in patients with predominant AST
elevation, which can be seen in
striated muscle injury due to
inborn or acquired muscle disor-
ders, strenuous exercise, and
rhabdomyolysis (6). Other condi-
tions to consider in patients with
abnormal aminotransferase levels
include tick-borne illnesses,
Addison disease, anorexia nerv-
osa, and liver disorders of preg-
nancy (1, 2).
What is the differential
diagnosis for cholestatic injury?
Cholestasis results in increased
synthesis and release of ALP from
hepatocytes in the liver. An
increase in ALP is not always
accompanied by an increase in
bilirubin if the extent of obstruc-
tion is small. The first step is to
obtain serum GGT or fractionated
ALP isoenzymes to differentiate
hepatic ALP from nonhepatic
sources. However, if ALP is ele-
vated in the presence of other
elevated liver chemistries,
confirmation of hepatic origin
is not necessary (2).
If the elevation in ALP is confirmed
to be hepatic in origin, the next
step is to obtain a right upper
quadrant ultrasonogram to exam-
ine the hepatic parenchyma and
ductal anatomy. Biliary dilatation
suggests an extrahepatic cause,
such as choledocholithiasis or ma-
lignant obstruction. Some condi-
tions of extrahepatic cholestasis,
such as PSC, HIV/AIDS cholangi-
opathy, and cancer, may not be
apparent on an ultrasonogram
and may require further evalua-
tion with magnetic resonance
cholangiopancreatography
ITC136 In the Clinic Annals of Internal Medicine September 2021
(MRCP), endoscopic ultrasonogra-
phy (EUS), or endoscopic retro-
grade cholangiopancreatography
(ERCP) (2).
If there is no evidence of biliary
ductal dilatation on an ultrasono-
gram, further work-up for causes
of intrahepatic cholestasis should
be done. Medications should be
reviewed for possible hepatotox-
icity, and serologic tests for auto-
antibodies, such as ANA, ASMA,
and antimitochondrial antibodies
(AMA), should be sent for evalua-
tion for PBC or autoimmune chol-
angiopathy. Liver biopsy may be
needed to establish a diagnosis if
there is concern about infiltrative
diseases, such as sarcoidosis, am-
yloidosis, atypical fungal infec-
tions, tuberculosis, and cancer (2).
Infiltrative conditions are typically
characterized by elevations in ALP
that are out of proportion to
bilirubin.
PSC is characterized by chronic
inflammation and destruction of
the intrahepatic and extrahepatic
bile, leading to multifocal stric-
tures and progressive hepatic fi-
brosis (2, 23). PSC is strongly
associated with inflammatory
bowel disease, and patients may
present with fatigue, pruritus, or
cholangitis. There are currently no
serologic tests that are specific to
the diagnosis, but anti–neutro-
philic cytoplasmic antibody and
IgG may be elevated (2). The di-
agnosis is established by cholan-
giography with MRCP or ERCP in
indeterminant cases. Liver biopsy
reveals concentric periductal “on-
ion skinning” fibrosis, but it should
not be routinely performed unless
it is needed to evaluate for AIH
overlap or small-duct PSC (23).
PBC should be suspected in mid-
dle-aged women with fatigue,
pruritus, and unexplained serum
ALP elevation. The diagnosis is
confirmed by the presence of
AMA or other PBC-specific auto-
antibodies (sp100 or gp210) if
AMA is negative. In addition,
patients with PBC may have mild
elevations in serum aminotransfer-
ase levels and IgM, and nearly
50% are positive for ANA or
ASMA. Liver biopsy can substanti-
ate the diagnosis if there is histo-
logic evidence of nonsuppurative
destructive cholangitis and
destruction of interlobular bile
ducts, but it is rarely needed
unless there is concern about AIH
overlap or competing causes of
liver disease (24).
What is the differential
diagnosis for
hyperbilirubinemia?
The first step in the evaluation of
elevated total bilirubin is meas-
uring its unconjugated (indirect)
and conjugated (direct) compo-
nents. Unconjugated hyperbiliru-
binemia is defined as a direct
bilirubin fraction of less than 20%
and is rarely caused by primary
liver disease (8). It is commonly
seen in hemolytic conditions and
can be assessed by evaluating a
peripheral smear and by meas-
uring serum hemoglobin, reticulo-
cyte count, haptoglobin, and
lactate dehydrogenase. Once
hemolysis is excluded, the most
common cause of unconjugated
hyperbilirubinemia is Gilbert syn-
drome, which is due to a genetic
defect in uridine 5 0 -diphospho-
glucuronosyltransferase. Persons
are asymptomatic but may have
worsening indirect hyperbilirubi-
nemia during periods of fasting or
stress. No further evaluation is
needed if a patient has normal
liver test results otherwise (1). Less
frequent causes of indirect hyper-
bilirubinemia include resorption
of large hematomas and rare
inherited conditions, such as
Crigler–Najjar syndrome (1, 8).
Conjugated hyperbilirubinemia,
defined as a direct bilirubin frac-
tion greater than 20%, is typically
associated with hepatic parenchy-
mal disease or biliary obstruction
(25). Both hepatocellular and
September 2021 Annals of Internal Medicine
cholestatic liver injury can lead to
elevated direct bilirubin levels,
which may exceed 30 mg/dL in
cases of severe damage, such as
in alcoholic hepatitis or sepsis in a
patient with decompensated cir-
rhosis (2). Other conditions associ-
ated with direct hyperbilirubi-
nemia include effects of total
parenteral nutrition; vanishing
bile duct syndrome; and rare
inherited conditions, such as
Dubin–Johnson syndrome and
Rotor syndrome (1, 8).
What are the clinical
implications of abnormal
albumin level or PT?
Hypoalbuminemia may be a sign
of advanced liver disease or cir-
rhosis, although any significant ill-
ness can decrease albumin levels
via release of cytokines (2). In
addition, hypoalbuminemia is not
specific to the liver and may be
associated with other disease
processes, such as malnutrition,
nephrotic syndrome, congestive
heart failure, protein-losing enter-
opathy, and infection (8).
PT and international normalized
ratio (INR) reflect the activity of
coagulation factors II, V, VIII, and
X, which rely on vitamin K for syn-
thesis. A prolonged PT/INR is a
more sensitive measure of hepa-
tocellular function in acute injury
than albumin due to its shorter
half-life. An INR above 1.5 is often
a poor prognostic sign and
requires immediate evaluation if
accompanied by acute hepatitis
and hepatic encephalopathy. In 24. Lindor KD, Bowlus CL,
Boyer J, et al. Primary
the absence of liver disease, PT biliary cholangitis: 2018
can also be elevated in the setting practice guidance from
the American
of vitamin K deficiency, warfarin Association for the Study
of Liver Diseases.
therapy, heparin bolus, dissemi- Hepatology.
nated intravascular coagulation, 2019;69:394-419.
[PMID: 30070375]
and hypothermia (2). 25. Staatz CE, Tett SE.
Clinical pharmacoki-
What laboratory tests are useful netics and pharmacody-
namics of
for assessing liver fibrosis? mycophenolate in solid
Identifying hepatic fibrosis can organ transplant recipi-
ents. Clin
help prognosticate, stratify thera- Pharmacokinet.
2007;46:13-58. [PMID:
peutic and surveillance strategies, 17201457]
and monitor response to treat-
In the Clinic ITC137 © 2021 American College of Physicians

26. Loomba R, Adams LA.
Advances in non-invasive
assessment of hepatic fi-
brosis. Gut.
2020;69:1343-52. [PMID:
32066623]
27. Papastergiou V, Tsochatzis
E, Burroughs AK. Non-
invasive assessment of
liver fibrosis. Ann
Gastroenterol.
2012;25:218-31. [PMID:
24714123]
28. European Association for
Study of Liver.. EASL-ALEH
clinical practice
guidelines: non-invasive
tests for evaluation of liver
disease severity and
prognosis. J Hepatol.
2015;63:237-64. [PMID:
25911335]
29. Angulo P, Hui JM,
Marchesini G, et al. The
NAFLD fibrosis score: a
noninvasive system that
identifies liver fibrosis in
patients with NAFLD.
Hepatology.
2007;45:846-54. [PMID:
17393509]
30. Venkatesh SK, Yin M,
Takahashi N, et al. Non-
invasive detection of liver
fibrosis: MR imaging fea-
tures vs. MR elastography.
Abdom Imaging.
2015;40:766-75. [PMID:
25805619]
31. Lim JK, Flamm SL, Singh
S, et al; Clinical
Guidelines Committee of
the American
Gastroenterological
Association. American
Gastroenterological
Association Institute
guideline on the role of
elastography in the evalu-
ation of liver fibrosis.
Gastroenterology.
2017;152:1536-43.
[PMID: 28442119]
32. Simon TG, Kim MN, Luo
X, et al. Physical activity
compared to adiposity
and risk of liver-related
mortality: results from
two prospective, nation-
wide cohorts. J Hepatol.
2020;72:1062-9. [PMID:
31954204]
33. Al Ghamdi SS, Shah H..
An educational needs
assessment for patients
with liver disease. J Can
Assoc Gastroenterol.
2018;1:54-9. [PMID:
31294400]
© 2021 American College of Physicians
ment over time. Liver biopsy
remains the gold standard for
measuring liver fibrosis but is lim-
ited by its invasiveness, complica-
tions, sampling error, inter- and
intraobserver variability, and cost
(26). To overcome these limita-
tions, noninvasive assessments
have been developed.
The FIB-4 index (age, AST, ALT,
platelet count) and AST-to-platelet
ratio index (APRI) are commonly
used in clinical practice with initial
validation in patients with HCV
infection (26). Compared with the
APRI, FibroSure (FibroTest in
Europe) and HepaScore have
superior diagnostic performance
and have been extensively stud-
ied in HCV and HBV infection,
NAFLD, and ALD (27). The
FibroSure/FibroTest consists of
5 indirect laboratory parameters
(a2-macroglobulin, apolipopro-
tein A1, haptoglobin, GGT, and
total bilirubin) in combination with
the patient's age and sex and
should not be used in the setting
of Gilbert syndrome to assess
fibrosis.
The NAFLD fibrosis score and
FIB-4 index are recommended
by European expert consensus
groups as part of the diagnostic
algorithm for assessing liver fibro-
sis in patients with NAFLD (3, 28).
The NAFLD fibrosis score is cur-
rently the most studied and vali-
dated biomarker and takes into
account the patient's age; BMI;
glucose, albumin, and serum ami-
notransferase levels; and platelet
count (29).
Although serologic biomarkers
are widely available, no single
panel has emerged as the stand-
ard of care, and the choice of test
is often determined by laboratory
availability. The tests can reliably
detect cirrhosis but have poorer
reliability in detecting intermedi-
ate stages of fibrosis. Further-
more, confounding factors, such
as hepatic inflammation and
comorbid conditions, need to be
ITC138 In the Clinic
excluded when interpreting
results (28).
What are the roles of imaging
and elastography in the
assessment of fibrosis?
Traditional imaging techniques,
including ultrasonography, CT,
and MRI, have been used in clini-
cal practice to identify advanced
liver disease and cirrhosis.
Common pathologic features
include surface nodularity, seg-
mental hypertrophy, splenomeg-
aly, portosystemic collaterals,
umbilical vein canalization, and as-
cites (27, 30). Although these
modalities are useful in identifying
patients with cirrhosis, the ab-
sence of these findings does not
exclude the diagnosis, and he-
patic parenchymal changes result-
ing from early and mild fibrosis
are not easily detected using con-
ventional techniques (30).
Elastography can estimate hepatic
fibrosis by measuring liver stiff-
ness through either ultrasound or
MRI-based techniques. Common
modalities include vibration-
controlled transient elastography
(VCTE), point shear-wave elastog-
raphy, acoustic radiation force
impulse, 2-dimensional shear-
wave elastography, and magnetic
resonance elastography.
Compared with serum fibrosis
assays, VCTE has been shown to
accurately diagnose cirrhosis with
superior sensitivity and specificity
and can differentiate mild fibrosis
from more advanced disease in
patients with HCV or HBV infec-
tion, NAFLD, and autoimmune
liver disease (27, 31). A reading
greater than 12 to 15 kPa sug-
gests cirrhosis, but the threshold
may vary on the basis of the cause
of liver disease. However, VCTE
has limitations, including technical
limits for performance (diameter
of intercostal space, obesity) and
inaccuracy in patients with acute
hepatitis and cholestasis, conges-
tive heart failure, alcohol misuse,
and recent food intake (26, 31).
Annals of Internal Medicine September 2021
 Evaluation... The evaluation of abnormal liver test results should be guided by the clinical presentation as well as
the pattern and severity of injury. Any abnormality should be approached via a thorough clinical history and phys-
ical examination as well as a careful review of the patient's medication list. In addition, persons with suspected
chronic liver disease should undergo noninvasive testing for assessment of liver fibrosis. Serum biomarkers have
high negative predictive value and are useful in excluding cirrhosis but cannot distinguish among intermediate
stages of fibrosis. In comparison, elastography techniques have higher diagnostic accuracy for identifying cirrho-
sis and differentiate mild fibrosis from more advanced disease. A liver biopsy may be required to confirm the
cause of disease or to evaluate for advanced fibrosis or cirrhosis if noninvasive tests are indeterminate.

CLINICAL BOTTOM LINE

What are general management
strategies for abnormal liver
test results?
Strategies for evaluating and man-
aging abnormal test results are
shown in Figures 1 to 3.
Ambulatory patients with elevated
aminotransferase levels should
have serologic evaluation for hep-
atitis B and C (HBsAg, HBcAb,
HBsAb, HCVAb) and hemochro-
matosis (ferritin and transferrin
saturation). Abdominal ultraso-
nography should be ordered to
examine the liver parenchyma
and bile ducts. Patients should
also be offered counseling on
alcohol cessation, withdrawal of
hepatotoxic medications, lifestyle
modification for weight loss, and
avoidance of risk factors for viral
hepatitis. If serologic test results
are negative, patients can be
observed and liver chemistries
can be repeated in 3 months (1). If
liver test results are persistently
abnormal, additional serologic
evaluation is recommended.
Patients who are symptomatic or
have chronically abnormal liver
test results should have additional
work-up based on the pattern of
abnormality, with consideration of
AIH (ANA, ASMA, IgG), Wilson
disease (ceruloplasmin), and
A1AT deficiency (A1AT levels and
phenotype). Those with cholesta-
sis and evidence of ductal dilata-
tion on imaging should be further
evaluated with MRCP or EUS/
ERCP. If imaging results are nor-
mal, patients should be evaluated
Management
for PBC (AMA) and autoimmune
cholangiopathy. Clinicians should
also consider broadening the dif-
ferential to nonhepatic conditions
associated with abnormal liver
test results. Further evaluation
with CT or MRI can be considered
on the basis of symptoms or if the
initial ultrasound evaluation is sub-
optimal or equivocal. Patients with
suspected chronic viral hepatitis,
NAFLD, and ALD should undergo
risk stratification and assessment
of hepatic fibrosis using serologic
biomarkers and elastography. If
the diagnosis remains unclear,
referral to a gastroenterologist or
hepatologist should be pursued,
with consideration for liver biopsy.
The evaluation should be expe-
dited if hepatic decompensation
or evolving liver failure is a
concern.
What role should primary care
providers play in management?
Primary care providers should
perform the initial serologic
screening, which includes a com-
plete metabolic profile, a com-
plete blood count with platelets,
albumin, PT/INR, hepatitis B and C
serologic tests, iron panel, and
right upper quadrant ultrasonog-
raphy. Patients with suspected
NAFLD should also be screened
for diabetes and hyperlipidemia
and should be assessed using the
FIB-4 index or the NAFLD fibrosis
score to identify those with
advanced fibrosis. Clinicians
should offer behavioral
counseling and referrals if appro-
priate to obesity and weight loss
management, nutrition services,
endocrinology, and addiction
medicine. If liver markers remain
persistently elevated, additional
serologic evaluation or imaging
should be pursued, based on the
pattern of abnormality.
When should clinicians
consider referring the patient
to a specialist for treatment?
For patients with suspected
NAFLD and ALD without
advanced fibrosis, consultation is
usually unnecessary, but patients
require reinforcement of lifestyle
modification and ongoing assess-
ment in primary care. Referral to a
gastroenterologist or hepatologist
should be considered in patients
with unexplained and persistently
abnormal liver chemistries with a
negative serologic result and with-
out risk factors for NAFLD and
ALD or in those with NAFLD or
ALD with clinical, laboratory, or
imaging evidence of
significant liver fibrosis (3).
Clinicians should refer patients
being considered for liver biopsy,
especially if initial test results were
equivocal or if there are several
potential causes of liver disease.
Patients with suspected hepato-
biliary cancer or advanced liver
disease should be urgently
referred for an expedited
evaluation.

September 2021 Annals of Internal Medicine In the Clinic ITC139 © 2021 American College of Physicians
Figure 1. Evaluation and management of elevated aminotransferase levels.

Perform clinical history and physical examination

Discontinue hepatotoxic medications and herbal supplements
Discontinue alcohol consumption
Assess for risk factors for viral hepatitis and fatty liver disease

CBC with platelet count

AST/ALT, ALP, TB, albumin, PT/INR
Iron panel with ferritin levels and transferrin saturation
HBsAg, HBcAb, HBsAb, HCVAb with PCR confirmation if positive
Abdominal ultrasound

Assess severity of injury

Mild elevation Moderate elevation Severe elevation

2–5 times ULN 5–15 times ULN >15 times ULN

Consider additional testing Order: Order:

based on patient risk factors ANA, ASMA, immunoglobulins HAV IgM and HAV IgG
and presentation (e.g., HbA1c Ceruloplasmin ANA, ASMA, immunoglobulins
and lipid panel for fatty liver) A1AT levels and phenotype Ceruloplasmin
A1AT levels and phenotype
HSV, EBV, and CMV PCR
Serum and urine toxicology
Is diagnosis clear? Is diagnosis clear? with acetaminophen levels
Abdominal Doppler ultrasound

No Yes No Yes

Repeat liver Liver fibrosis Consider liver Liver fibrosis

tests in 3 mo assessment biopsy or assessment
Management specialist Management Is the patient clinically
as indicated referral as indicated deteriorating, or do they
have signs of acute liver
failure (encephalopathy
Are aminotransferase and elevated PT/INR)?
levels elevated?

No Yes
No Yes
No further Order:
testing ANA, ASMA, immunoglobulins
Consider Urgent referral
indicated Ceruloplasmin
urgent liver to liver
A1AT levels and phenotype
biopsy or transplantation
Consider testing for celiac sprue,
specialist center
thyroid and muscle disorders,
referral
and tick-borne illnesses
General Management Strategies
Patients with suspected NAFLD and alcoholic liver disease with low risk for
advanced fibrosis can be managed in primary care and offered counseling for
the following as appropriate:
Is diagnosis clear? • Alcohol relapse prevention
• Weight loss and nutrition
• Control of diabetes and hyperlipidemia
No Yes • Safe practices for high-risk behaviors
Patients should be referred to a gastroenterologist or a hepatologist for the following:
• High risk for advanced fibrosis or cirrhosis
Consider liver Liver fibrosis • Persistently abnormal aminotransferase levels and negative result on serologic
biopsy or assessment evaluation
specialist Management • Equivocal diagnostic testing or multiple competing causes of liver disease
referral as indicated • Suspected hepatobiliary cancer

Adapted from references 2 and 8. A1AT = a1-antitrypsin; ALP = alkaline phosphatase; ALT = alanine aminotransferase; ANA = anti-
nuclear antibodies; ASMA = anti–smooth-muscle antibodies; AST = aspartate aminotransferase; CBC = complete blood count;
CMV = Cytomegalovirus; EBV = Epstein–Barr virus; HAV = hepatitis A virus; HbA1c = hemoglobin A1c; HBcAb = hepatitis B core anti-
body; HBsAb = hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HCVAb = hepatitis C virus antibody; HSV = herpes
simplex virus; INR = international normalized ratio; NAFLD = nonalcoholic fatty liver disease; PCR = polymerase chain reaction;
PT = prothrombin time; TB = total bilirubin; ULN = upper limit of normal.

© 2021 American College of Physicians ITC140 In the Clinic Annals of Internal Medicine September 2021
Figure 2. Evaluation and management of elevated ALP level.

Perform clinical history and physical examination

Discontinue hepatotoxic medications and herbal supplements
Discontinue alcohol consumption
Repeat liver tests with either GGT or fractionated ALP isoenzymes

Are GGT and/or liver

tests elevated?

No Yes

Consider nonhepatobiliary Obtain abdominal ultrasound

disorders or conditions:
Osteomalacia
Paget disease
Biliary ductal
Fracture
dilatation?
Pregnancy (third trimester)
Blood type O and B
Childhood growth No Yes
Renal insufficiency
Hyperthyroidism
Hyperparathyroidism Order: Consider biliary
Congestive heart failure ANA obstruction
Infection AMA Order MRCP or
Cancer ASMA EUS/ERCP
Immunoglobulins

Is diagnosis
ANA or ASMA ANA, AMA, and clear?
AMA positive
positive ASMA negative
No Yes

Evaluate for Evaluate for

primary biliary autoimmune Management
Is ALP level >2
cholangitis hepatitis or as indicated
times ULN?
autoimmune
cholangiopathy
No Yes

Consider Consider liver

observation biopsy or
MRCP

Adapted from references 2 and 8. ALP = alkaline phosphatase; AMA = antimitochondrial antibodies; ANA = antinuclear antibodies;
ASMA = anti–smooth-muscle antibodies; ERCP = endoscopic retrograde cholangiopancreatography; EUS = endoscopic ultrasonogra-
phy; GGT = c-glutamyltransferase; MRCP = magnetic resonance cholangiopancreatography; ULN = upper limit of normal.

Management... The initial approach to management of abnormal liver test results is to identify the cause of liver
disease using a serologic screen and an ultrasound. The presence of fibrosis or cirrhosis can be determined using
various noninvasive tools, such as serum biomarkers and elastography, but the gold standard for diagnosis and
risk stratification is liver biopsy. Patients with mild liver disease, such as uncomplicated NAFLD or ALD, can be
safely managed by primary care, and the cornerstone of management is targeted behavioral counseling and
referral to appropriate services. However, patients in whom the diagnosis is unclear, those with advanced liver
disease, or those with a liver diagnosis requiring specialist input should be referred to a gastroenterologist or a
hepatologist for further evaluation.

CLINICAL BOTTOM LINE

September 2021 Annals of Internal Medicine In the Clinic ITC141 © 2021 American College of Physicians
Figure 3. Evaluation and management of elevated bilirubin level.

Perform clinical history and physical examination

Discontinue hepatotoxic medications and herbal supplements
Discontinue alcohol consumption
Repeat liver tests with GGT and fractionated bilirubin

Are liver tests

elevated?

No Yes

Target evaluation based on

Is elevation primarily liver test abnormalities
direct bilirubin?

No Yes

Consider hemolysis Obtain abdominal ultrasound

Order: Consider clinically overt causes:
Peripheral smear Sepsis
Reticulocyte count Effects of TPN
Haptoglobin Cirrhosis
LDH Biliary obstruction

Is hemolysis Biliary ductal

present? dilatation?

Consider biliary
No Yes Yes obstruction
No Order MRCP or
Consider Gilbert Consider EUS/ERCP
syndrome hemolytic Order:
No further testing conditions ANA
is necessary, but AMA
if diagnosis is ASMA Is diagnosis
uncertain, may Immunoglobulins clear?
send UGT1A1
genotype No Yes

Management
as indicated
ANA or ASMA ANA, AMA, and
AMA positive
positive ASMA negative

Evaluate for Evaluate for Consider liver biopsy

primary biliary autoimmune if the patient is
cholangitis hepatitis worsening over time
and persistent
elevation is otherwise
unexplained

Adapted from references 2 and 8. AMA = antimitochondrial antibodies; ANA = antinuclear antibodies; ASMA = anti–smooth-muscle
antibodies; ERCP = endoscopic retrograde cholangiopancreatography; EUS = endoscopic ultrasonography; GGT = c-glutamyltransferase;
LDH = lactate dehydrogenase; MRCP = magnetic resonance cholangiopancreatography; TPN = total parenteral nutrition.

© 2021 American College of Physicians ITC142 In the Clinic Annals of Internal Medicine September 2021

What do professional
organizations recommend
regarding management of
abnormal liver test results?
Guidelines on management of
abnormal liver test results were
Practice Improvement
published by the American
College of Gastroenterology in
2017 (2) and the British Society of
Gastroenterology in 2018 (3).

What is the role of patient
education in the management
of abnormal liver test results?
Patient education plays a crucial
role in preventing progression of
chronic liver disease and its com-
plications, such as cirrhosis and
hepatobiliary cancer. Lifestyle
interventions, including dietary
Patient Education
modification, exercise, and cessa-
tion of alcohol consumption, can
improve liver injury related to
hepatic steatosis and have been
shown to prevent HCC and liver-
related mortality (32). Education
about the risks of hepatotoxic
medications and herbal supple-
ments is also important for
preventing acute injury and liver fail-
ure. In patients with advanced liver
disease and cirrhosis, interventions
to increase the patient's knowledge
of their disease and improve adher-
ence to medications and therapies
are key factors in improving quality
of life and preventing long-term
complications (33).

In the Clinic Patient Information

https://medlineplus.gov/lab-tests/liver-function-tests

Tool Kit

In the Clinic
Information on liver function tests from the National
Institutes of Health's MedlinePlus.

https://liverfoundation.org/wp-content/uploads/2019/11/
Liver-Function-Test-Handout-2016.pdf
Handout on liver function tests from the American Liver
Foundation.
Care of the Patient
https://gi.org/topics/medications-and-the-liver
With Abnormal Liver
Information on medications and the liver from the
Test Results American College of Gastroenterology.
Information for Health Professionals
https://journals.lww.com/ajg/fulltext/2017/01000/acg_
clinical_guideline__evaluation_of_abnormal.13.aspx
The American College of Gastroenterology 2017 clinical
guideline on evaluation of abnormal liver chemistries.

https://gut.bmj.com/content/67/1/6
British Society of Gastroenterology 2018 guidelines on the
management of abnormal liver blood test results.

https://aasldpubs.onlinelibrary.wiley.com/doi/10.1002/
hep.29367
Practice guidance from the American Association for the
Study of Liver Diseases on the diagnosis and manage-
ment of nonalcoholic fatty liver disease.

https://aasldpubs.onlinelibrary.wiley.com/doi/full/
10.1002/hep.31065
2019 practice guidance and guidelines from the American
Association for the Study of Liver Diseases on diagnosis
and management of autoimmune hepatitis in adults and
children.

September 2021 Annals of Internal Medicine In the Clinic ITC143 © 2021 American College of Physicians

WHAT YOU SHOULD KNOW
ABOUT LIVER TESTS
What Are Liver Tests?
Your liver is a large organ that sits inside your belly.
Its job is to help your body digest food and get
rid of toxic substances. Liver tests show how well
your liver is working and can help your doctor
know whether you have any liver damage or
disease.
How Do They Work?
Liver tests are done by drawing your blood and
measuring certain enzymes and proteins in it. If
your liver is damaged or diseased, some of the
enzyme and protein levels might be higher or
lower than normal. Common liver tests include:
• Serum alanine aminotransferase (ALT)
• Aspartate aminotransferase (AST)
• Alkaline phosphatase (ALP)
• Gamma-glutamyltransferase (GGT)
• Albumin
• Bilirubin
• Prothrombin time (PT)
What Causes Abnormal Results?
Liver tests might show higher- or lower-than-nor-
mal results if:
• Your liver is inflamed (for example, from an infec-
tion like hepatitis)
• Your liver cells have been damaged (by substan-
ces like alcohol)
• Your liver is working harder to process toxic sub-
stances, certain herbal supplements, or medi-
cines (for example, antibiotics, antifungal
treatments, nonsteroidal anti-inflammatory drugs,
some HIV treatments, and chemotherapy)
• Your liver is physically injured
• You have a health condition that affects the liver's
production and storage abilities
Do Abnormal Results Mean That
I Have Liver Disease?
Because tests are not perfect, people with healthy
livers may occasionally have abnormal test
results.
Tests with results outside the normal range should
be repeated and followed up because they may
mean you have an underlying health condition.
Depending on the specific test and result, your
doctor may need to do additional testing for one
of the following conditions:
• Alcoholic liver disease
• Nonalcoholic fatty liver disease
• Viral hepatitis
• Autoimmune hepatitis
• Drug-induced liver injury
• Metabolic or genetic disorders
• Biliary tract disease
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https://liverfoundation.org
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Annals of Internal Medicine
What Will Happen Next if Any of
My Results Are Outside the
Normal Range?
• Your doctor will repeat the tests or perform addi-
tional ones to clarify the original result.
• If the result is still abnormal, your doctor will do a
physical examination and ask about your medical
history. This will include a review of any risk fac-
tors you have for liver disease, like alcohol or
drug use, sexual history, recent travel, history of
blood transfusions, and family history of liver dis-
ease. Your doctor will also ask what medicines or
herbal supplements you take.
• If your doctor thinks a medicine you take is caus-
ing the abnormal result, they will have you stop
taking it, find an alternative, or establish a plan to
monitor for progression of liver failure.
• Your doctor may recommend additional work-up,
including more blood tests or imaging tests (like a
CT scan, MRI, or ultrasound), or they may refer you
Patient Information
to a doctor who specializes in liver disease.
• Sometimes a liver biopsy is necessary to diag-
nose liver damage or disease. This is when a
small piece of your liver is removed and exam-
ined under a microscope for signs of disease.
What Else Should I Know?
• Drinking too much alcohol is a common cause of
liver damage and a factor in developing chronic
liver disease. If you are concerned about your
alcohol use, your doctor may be able to help you
cut down or stop drinking.
• Lifestyle changes like avoiding alcohol, stopping
certain medicines, avoiding risk factors for hepa-
titis, getting vaccinated against hepatitis, losing
weight, and managing substance use disorders
may help improve and even reverse liver injury.
Questions for My Doctor
• What caused my abnormal liver test results?
• Do I need to have other tests?
• Do I need to stop or start taking any medicine?
• What lifestyle changes can help improve my liver
function?
• Do I need to be referred to a liver specialist?
For More Information
In the Clinic Annals of Internal Medicine September 2021
 Appendix Table. Patterns of Liver Tests in Hepatobiliary Disorders*
Pattern Aminotransferases Alkaline Phosphatase Bilirubin Albumin Prothrombin Time Associated Conditions

Hepatocellular injury ::: (acute) Normal to : to Normal to : Normal or Normal or prolonged Acute:
:: (chronic) <3 times ULN Both fractions may decreased INR >1.5 that does Acute viral hepatitis
AST–ALT ratio >2 be elevated not correct with Acute ischemic injury
suggests alcoholic vitamin K indicates Toxin- or medication-induced
liver disease severe injury injury
Acute autoimmune hepatitis
Chronic:
Hepatitis B and C
Alcoholic liver disease
NAFLD
Chronic autoimmune hepatitis
Wilson disease
A1AT deficiency
Hemochromatosis
Cholestatic injury Normal to ::: :::, often >4 times Normal to : Normal or Normal Acute:
ULN decreased Choledocholithiasis
Acute cholangitis
Medication-induced injury
Cancer
Chronic:
PBC
PSC
Autoimmune cholangiopathy
Bile duct stricture
Vanishing bile duct syndrome
AIDS cholangiopathy
Cancer
Infiltrative diseases Normal to : :::, often >4 times Normal to : Normal Normal Sarcoidosis
ULN Granulomatous hepatitis
Amyloidosis
Tuberculosis
Lymphoma
Cancer
Hemolysis Normal Normal : Normal Normal Gilbert syndrome
Indirect fraction Sickle cell disease
elevated Hereditary spherocytosis
Autoimmune hemolytic anemia
Hematoma resorption

A1AT = a1-antitrypsin; ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = international normalized ratio;
NAFLD = nonalcoholic fatty liver disease; PBC = primary biliary cholangitis; PSC = primary sclerosing cholangitis; ULN = upper limit
of normal.
* Adapted from reference 8.

September 2021 Annals of Internal Medicine In the Clinic © 2021 American College of Physicians