The Journal of Emergency Medicine, Vol. -, No. -, pp.

1–14, 2016
Published by Elsevier Inc.
0736-4679/$ - see front matter

http://dx.doi.org/10.1016/j.jemermed.2016.10.016

Clinical
Review

ELEVATED LIVER ENZYMES: EMERGENCY

DEPARTMENT–FOCUSED MANAGEMENT

Eric Sulava, MD,* Samuel Bergin, MD,† Brit Long, MD,‡ and Alex Koyfman, MD§
*Department of Emergency Medicine, Naval Medical Center Portsmouth, Portsmouth, Virginia, †Department of Emergency Medicine,
University Medical Center of Southern Nevada, Las Vegas, Nevada, ‡Department of Emergency Medicine, San Antonio Military Medical
Center, Fort Sam Houston, Texas, and §Department of Emergency Medicine, The University of Texas Southwestern Medical Center, Dallas, Texas
Reprint Address: Brit Long, MD, 3841 Roger Brooke Dr., Fort Sam Houston, TX 78234

, Abstract—Background: Liver function test (LFT) ab-
normalities are a common problem faced by emergency phy-
sicians. This has become more common with the
introduction of laboratory panels and automated routine
laboratory testing. Fortunately, not all patients with irregu-
larities in liver enzymes possess underlying pathology. This
emergency medicine focused review provides a discussion
of the various biochemical tests, their underlying biological
basis, and an algorithmic approach to the interpretation of
abnormalities. Objective: Our aim was to provide emer-
gency physicians with an overview of the evaluation and
management of patients with elevated LFTs. Discussion:
The liver is a complex organ with multiple roles. The key
biochemical markers of hepatic function can be organized
into the groupings of hepatocellular, cholestatic, or func-
tioning liver, based on underlying enzymatic roles. Patho-
logic alterations to these markers can be algorithmically
assessed by separating disease processes of these groupings,
followed by assessment of the magnitude of enzymatic eleva-
tion. This review conducts an in-depth evaluation of the dif-
ferential diagnosis and emergency department–centered
clinical response of elevated LFTs based on subcategories
This clinical review has not been published, it is not under
consideration for publication elsewhere, its publication is
approved by all authors and tacitly or explicitly by the respon-
sible authorities where the work was carried out, and that, if
accepted, it will not be published elsewhere in the same form,
in English or in any other language, including electronically
without the written consent of the copyright holder.
of mild, moderate, and severe transaminase elevation. Con-
clusions: By understanding the biochemical basis of each
LFT, it is possible to correlate laboratory findings to a pa-
tient’s clinical presentation. An algorithmic approach can
be taken to help narrow the spectrum of a differential diag-
nosis. This may assist providers in ensuring appropriate
management and evaluation of the patient with elevated
LFTs. Published by Elsevier Inc.
, Keywords—liver function test; hepatitis; aspartate
aminotransferase; alanine aminotransferase; g-glutamyl
transpeptidase; alkaline phosphatase; prothrombin time;
albumin
INTRODUCTION
In today’s medical system, abnormal laboratory values
can prompt expensive, unnecessary, and potentially
harmful further diagnostic evaluations. A 2012 retrospec-
tive, multicenter cohort study of patients presenting to the
emergency department (ED) found that laboratory testing
had a direct effect on ED length of stay, with a mean in-
crease of 10 min for every five individual tests ordered
(1). With routine incorporation of hepatic tests in blood
chemistry panels, an understanding of the pathophysio-
logic basis of liver function tests (LFTs) is important in
order to establish appropriate clinical correlation and pa-
tient disposition.

RECEIVED: 11 July 2016; FINAL SUBMISSION RECEIVED: 18 September 2016;

ACCEPTED: 14 October 2016

1
2 E. Sulava et al.

Table 1. Key Biochemical Markers Involving Hepatic Function (2–5)

FuncƟon Assessed Test Physiological FuncƟon Site Found

Aspartate Liver, skeletal muscle, heart, kidney,
Aminotransferase Important enzymes in amino-acid brain
“Hepatocellular
metabolism, allowing for entrance to Krebs
Arrangement” Alanine Cycle Greatest concentra on in the Liver
Aminotransferase
Enzyme that transports metabolites across
cell membranes. Is present in the bile duct Liver, Bone > intes ne, placenta,
Alkaline Phosphatase
epithelial cells, therefore: biliary stasis = kidney
release of the enzyme

Catalyzes the transfer of a γ – Glutamyl group

γ – Glutamyl Hepatocytes, biliary epithelial cells
“CholestaƟc between amino acids. Important for the
and renal tubules
transpep dase synthesis and breakdown of glutathione.
Arrangement”
Catabolic product of hemoglobin which is Serum and Liver. Comparison of
released in the unconjugated form, and ‘conjugated’ and ‘unconjugated’
Bilirubin
conjugated to a water soluble product by bilirubin eleva ons will determine
hepa c cells. whether intrahepa c.

Albumin Main protein of human blood plasma. Liver or dietary

FuncƟonal Liver
Mass Prothrombin Time
Assay of the extrinsic pathway of coagula on. Liver (synthesizes vitamin k
Assesses factors I, II, V, VII, and X. dependent clo ng factors)

LIVER BIOLOGY: A LITTLE UNDERSTANDING
GOES A LONG WAY
The liver is a complex organ with multiple roles. Hepato-
cytes are organized into primary functioning units called
the liver acinus, each of which is bordered by the ‘‘portal
triad’’ consisting of a branch of the hepatic artery, portal
vein, and bile duct. This organization allows the liver to
complete a wide array of tasks: glucose storage, glycogen
breakdown, carbohydrate–fat–protein metabolism, bile
synthesis, liproprotein–plasma protein synthesis, detoxi-
fication, and waste product metabolism. All of these in-
teracting roles can be impacted during liver disease,
with corresponding alteration in LFT panel.
An LFT panel typically includes aspartate aminotrans-
ferase (AST), serum alanine aminotransferase (ALT), g-
glutamyl transpeptidase (GGT), alkaline phosphatase
(ALP), prothrombin time (PT), and albumin. Clinically,
LFT results are described as being in a ‘‘hepatocellular’’
or ‘‘cholestatic’’ arrangement based on the pattern of
elevation. Of the commonly available liver chemistries,
the only true measurements of hepatic synthetic function
are the PT and albumin (2). A hepatocellular pattern de-
picts a disproportionate elevation in the AST and ALT
in comparison to ALP. The inverse, a disproportionate
elevation of ALP in comparison to the transaminases,
represents a cholestatic pattern. Total bilirubin can be
elevated in either pattern and may indicate an extrahe-
patic disorder. Table 1 explains the physiologic function
and anatomic location of these laboratory tests in relation
to the referenced ‘‘patterns of elevation.’’
Aminotransferases are used to monitor and detect
the progression of hepatocellular injury. AST and
ALT are abundant hepatic enzymes crucial to citric
acid cycle function. ALT and AST are released from
damaged hepatocytes into the blood after hepatocellu-
lar injury or death. Both aminotransferases are highly
concentrated in the liver, but ALT is considered to be
more specific to liver damage. AST is amply ex-
pressed in the brain, skeletal muscle, kidney, and
heart. Aminotransferase levels vary based on age and
sex, so institutional reference limits should be specif-
ically defined (3).
ALP is an enzyme that transports metabolites across
cell membranes. Liver and bone disease are the most
common causes of pathological elevation, though other
sites of origin include the intestines, kidney, and placenta
(4). Due to the high body tissue prevalence, non-
pathologic processes, like pregnancy, can cause elevation
in laboratory values. During pregnancy, ALP begins to
rise by late in the first trimester and can reach twice
normal values by term (6). In the liver, ALP is present
in the bile duct epithelial cells; thus, biliary stasis can in-
crease the release of the enzyme (5). Given the overlap in
values with liver and bone disease, GGT can be used to
differentiate the location of release. GGT is a glycopro-
tein located on the membranes of cells with high secre-
tory or absorptive activities, which is not abundant in
bone. GGT is not routinely included in liver enzyme
panels, but should be considered if the clinical picture
does not clearly identify the source of an ALP elevation.
Table 2 demonstrates the associated conditions that are
ED Management of Elevated LFTs 3

Table 2. Algorithm Overview of Alkaline Phosphatase Elevation (4–6)

GGT = g-glutamyl transpeptidase; ERCP = endoscopic retrograde cholangiopancreatography; MRCP = magnetic resonance cholangio-
pancreatography; ACE = angiotensin converting enzyme; AMA = antimitochondrial antibody.

commonly seen with abnormalities in the laboratory tests etiology. This can be further specified into intrahepatic
mentioned. or extrahepatic cholestasis by identifying the presence
As Table 2 summarizes, the GGT allows for the ALP of biliary duct dilatation on a right upper quadrant
elevation to be categorized as a hepatic or non-hepatic (RUQ) ultrasound (6). Further diagnostic evaluation of
4 E. Sulava et al.

Table 3. Common Liver Tests and Associated Conditions (2)

Liver Test Abnormal In:

Aminotransferases Hepatocellular injury (ethanol, hepa s, ischemic injury, NAFLD) acute biliary obstruc on
(AST, ALT) [Rare: hyperthyroidism, celiac disease, skeletal muscle disease]
Alkaline Cholestasis, canalicular injury, children during bone growth, bone disease, pregnancy
phosphatase (plancetal)
GGT Cholestasis, medica ons, ethanol
[Rare: anorexia nervosa, hyperthyroidism, myotonic dystrophy]
Bilirubin -Any acute or chronic liver disease
-Congenital disorders of bilirubin metabolism
AST = aspartate aminotransferase; ALT = serum alanine aminotransferase; NAFLD = non-alcoholic fatty liver disease; GGT = g-glutamyl
transpeptidase.

intrahepatic or extrahepatic cholestasis will likely take
place in either the outpatient or inpatient setting, depend-
ing on the patient’s hemodynamic stability and clinical
picture. For extrahepatic cholestasis, this includes evalu-
ating and treating for a biliary obstruction with endo-
scopic retrograde cholangiopancreatography (ERCP) or
magnetic resonance cholangiopancreatography (MRCP)
(6). These procedures are explained in the section on
biliary tract disease. Due to the extensive differential
diagnosis, evaluation for intrahepatic cholestasis will
take place largely outside of the emergency setting. As
Table 2 shows, the differential partly consists of primary
biliary cirrhosis, viral hepatitis, and sarcoidosis. In sum-
mary, Table 3 gives an overview of the associated condi-
tions that are commonly seen with abnormalities in the
each of the laboratory tests mentioned.
DISCUSSION
Initial Evaluation
When evaluating a patient with abnormal liver biochem-
ical tests, the initial focus will be identifying potential
risk factors of liver disease. The medical history should
evaluate conditions with associated hepatobiliary disease,
as seen in Table 4 (2,7–10). The social and medication
history will assess for potential hepatotoxins, including
medications, drugs, and alcohol. Other rarer etiologies
of hepatotoxicity include recreational mushroom
picking (Amanita phalloides) and occupational
exposure to chemicals like vinyl chloride. The patient
should be asked about the use of over-the-counter
(OTC) medications, herbal remedies, dietary supple-
ments, and illicit drug use. The type and route of illicit
drug use should be identified, as i.v. drug use is a risk fac-
tor for viral hepatitis. Other risk factors for viral hepatitis
include blood transfusion before 1992, travel to endemic
hepatitis areas, and exposure to patients with jaundice (4).
During the evaluation, a focused physical examination
should be completed, with particular attention to the
abdomen and liver. In cases of chronic liver disease,
stigmata of cirrhosis can be seen (i.e., spider nevi, palmar
erythema, gynecomastia, and caput medusa). Other com-
mon features of alcoholic cirrhosis include Dupuytren’s
contractures (persistent digit flexion), parotid gland
enlargement, and testicular atrophy (11). The abdominal
examination should note the size and consistency of the
liver. An enlarged tender liver could be due to acute viral
hepatitis, while an enlarged, hard, nodular liver repre-
sents a possible malignancy. Palpation may also reveal
RUQ tenderness with associated Murphy’s sign, suggest-
ing cholestatic disease. The major physical examination
findings of each syndrome will be explained in detail
here.

Table 4. Past Medical Conditions with Associated Hepatobiliary Disease (2,7,8,9,10)

Past Medical CondiƟon Associated Hepatobiliary Disease

Right-sided Heart Failure Conges ve Hepatopathy
Diabetes Mellitus & Obesity Nonalcoholic Fa y Liver Disease
Pregnancy Gallstones, Nonpathologic ALP Eleva on
Inflammatory Bowel Disease Primary Sclerosing Cholangi s, Gallstones
Early Onset Emphysema Alpha-1 an trypsin deficiency

ALP = alkaline phosphatase.

ED Management of Elevated LFTs 5

Table 5. Algorithm Overview of Transaminase Elevation (13–27)

NAFLD = non-alcoholic fatty liver disease; DILI = drug-induced liver injury; AST = aspartate aminotransferase; ALT = alanine aminotrans-
ferase; RUQ US = right upper quadrant ultrasound; ACS = acute coronary syndrome; CHF = congestive heart failure; IVF = intravenous
fluids; PPI = proton pump inhibitor; Abx = antibiotics; NPO = nothing per os; HAV = hepatitis A virus; IgM = immunoglobulin M; PEP =
post-exposure prophylaxis; HBIG = hepatitis B immunoglobulin.

DIFFERENTIAL BASED ON MAGNITUDE OF
TRANSAMINASE ELEVATION
The National Health and Nutrition Examination Survey
evaluated 6,800 American patients and found elevated
liver transaminase levels in up to 8.9% of the survey pop-
ulation (12). With this high a prevalence, an algorithmic
approach can aid in evaluation. Both the magnitude and
ratio of AST and ALT can aid in narrowing the spectrum
of disease. True reference ranges for these enzymes vary
between laboratories and will therefore be addressed by
magnitudes elevated above normal. The magnitude of
6 E. Sulava et al.
Table 6. Selected Medications Associated with Elevated Liver Transaminase Levels (14)
Acarbose (Precose) Acetaminophen
Amiodarone Baclofen (Lioresal)
Germander (T. chamaedrys) HAART
Isoniazid Ketoconazole
Losartan (Cozaar) Methotrexate
Omeprazole (Prilosec) Pyrazinamide
Risperidone (Risperdal) SSRIs
Tetracyclines Trazodone
HAART = highly active antiretroviral treatment; NSAID = nonsteroidal anti-inflammatory drug; SSRI = selective serotonin reuptake inhibitor.
aminotransferase elevation with correlations to liver pa-
thology can be categorized as mild (<5), moderate
(5–10), or marked elevation (>10). To supplement
the following text, Table 5 summarizes the initial differ-
ential and evaluation of transaminase abnormalities,
organized by the magnitude of elevation.
Mild Transaminase Elevation
Non-alcoholic fatty liver disease. Nonalcoholic fatty liver
disease (NAFLD) is the most common cause of mildly
altered liver enzyme levels in the Western world, with a
prevalence of 23% among American adults (12). Of
note, it is a diagnosis of exclusion. NAFLD is a contin-
uum, ranging from benign steatosis to steatohepatitis
and cirrhosis (28). The fatty liver change occurs second-
ary to metabolic syndrome: obesity, diabetes mellitus, hy-
pertension, and dyslipidemia (13). After the emergence
of childhood obesity over the last 2 decades, NAFLD is
now found in a bimodal distribution of age, affecting
both children aged 2–19 years and adults aged 40–
50 years (29). NAFLD patients usually present with
vague complaints and the incidental finding of transami-
nase elevation. The transaminase levels rarely exceed 4
the upper limit of normal with an AST/ALT ratio of < 2
(13). Other conditions should be ruled out with history,
examination, and laboratory testing. Treatment of this
disorder is going to be completed through outpatient
follow-up. Lifestyle modification with weight loss, blood
sugar control, and reduction of cholesterol is the mainstay
of therapy.
Drug-induced liver injury. Idiosyncratic drug-induced
liver injury (DILI) covers a wide spectrum of disease
and accounts for 13% of acute liver failure cases in the
United States (30). DILI is a broad term applied to any
Allopurinol (Zyloprim)
Buproprion (Wellbutrin)
kava (P. methys cum)
Lisinopril (Zestril)
NSAIDs
Rifampin
Sta ns
Valproic acid (Depakene)
injury to the liver by a prescribed medication, OTC medi-
cation, herb, or dietary supplement. The National Insti-
tutes of Health maintains a searchable database of >
1,000 DILI-associated substances (31). A 2008 study on
300 DILI patients in the United States listed amoxi-
cillin/clavulanate (8%), nitrofurantoin (4%), isoniazid
(4%), and trimethoprim-sulfamethoxazole (4%) as the
most common inducing agents, excluding acetaminophen
(32). Table 6 includes other commonly reported medica-
tions (14). Statins are frequently associated with elevated
transaminase levels in new-onset users; however, recent
data show that increases in transaminase levels have not
been proven to be significantly different than those in pa-
tients taking placebo, and that elevated transaminase
levels spontaneously resolve in up to 70% of persons tak-
ing statins, even with continued use (33,34).
Diagnostically, approaching a patient with DILI is
difficult due to the vast array of possible sources and clin-
ical presentation. A list of all medications, herbals, and
OTC medication should be obtained. It is important to
determine whether DILI is the primary diagnosis or sim-
ply a correlating factor to disease. Other common causes
of liver dysfunction (viral hepatitis, alcohol related,
Epstein-Barr virus, NAFLD, and biliary obstruction)
must be considered. Discontinuation of the offending
substance is the mainstay of treatment. All non-
essential medications should be removed, following a
risk–benefit discussion with the patient. Depending on
severity, supportive care with 2- to 4-week follow-up lab-
oratory tests in the primary care setting is appropriate
(15). A small subset of DILI patients present with
elevated levels of g-globulins and antinuclear or anti–
smooth muscle antibodies. These patients are classified
as having drug-induced autoimmune-like hepatitis,
which is responsive to prednisone therapy; this will likely
be identified outside the ED setting (35).
ED Management of Elevated LFTs
Alcohol-induced liver injury. The liver is the main site of
alcohol metabolism and a major target organ of alcohol-
induced injury. There are three basic forms of alcohol-
related liver disease: alcoholic fatty liver disease, alco-
holic cirrhosis, and alcoholic hepatitis. Of note, alcoholic
hepatitis can cause moderate LFT elevation. Fatty liver
disease and cirrhosis are chronic issues due to a long
history of alcohol use. The clinical manifestations of
long-standing alcohol disease depend on its severity
and chronicity (2,16,17).
Fatty liver disease it typically asymptomatic, while
cirrhosis may have the classic findings of ascites, spider
angiomata, gynecomastia, and palmar erythema. Diag-
nostic evaluation for patients with a strong history of
chronic alcohol abuse will include complete blood count,
LFT (serum transaminases, bilirubin, ALP, GGT, and al-
bumin), coagulation studies, and a complete chemistry
panel. If other risk-taking behaviors are reported (such
as unprotected sex and i.v. drug use), viral hepatitis panels
are appropriate. The characteristic biochemical results
include an AST/ALT ratio > 2, with elevated GGT. The
AST elevation is usually < 8 the upper limit of normal,
and the ALT elevation is typically < 5 the upper limit of
normal, categorizing chronic alcohol disease as mild to
moderate transaminase elevation (2). Hematologic find-
ings in patients with alcoholic liver disease may include
thrombocytopenia with a macrocytic anemia.
Long-standing alcoholics are at risk for poor nutrition
with electrolyte and vitamin abnormalities, including
vitamin B-12, B-1, and folate deficiency. The mainstay
of treatment for chronic alcohol abuse will be the recom-
mendation of abstinence from alcohol. Acute treatment in
the ED includes vitamin, nutrient, and electrolyte reple-
tion (16). Due to the synergistically destructive effect of
chronic alcohol disease and thiamine deficiency, these pa-
tients are at risk for Wernicke-Korsakoff syndrome. Sup-
plementation with an i.v. bag of fluid containing
thiamine, folic acid, and magnesium sulfate is recom-
mended (17). Depending on the history, these patients
are at risk for acute alcohol withdrawal, which should
be considered.
Moderate Transaminase Elevation
Alcoholic hepatitis. A 2015 United States study on >
550,000 hospitalizations demonstrated the rate of alco-
holic hepatitis (AH)-related hospitalizations has signifi-
cantly increased in the last decade, accounting for
significant morbidity, mortality, and financial burden
(36). Although the term alcoholic hepatitis represents a
spectrum of disease ranging from asymptomatic steatohe-
patitis to acute hepatic encephalopathy, it is typically
used to describe the acute onset of alcohol-induced jaun-
dice, anorexia, fever, and tender hepatomegaly. Patients
with AH are usually 40–50 years old, with risk factors
7
including female sex, Hispanic ethnicity, drinking multi-
ple types of alcohol, drinking alcohol between meal
times, poor nutrition, and obesity (37,38). As with all
alcohol-related liver disease, the amount of alcohol con-
sumption that places an individual at risk for developing
AH is not known, but most patients with AH drink >
100 g/d (39). Patients often stop drinking as they become
ill, so it is common for patients to decrease their alcohol
intake several weeks before presentation. Due to the acute
hepatic inflammation, physical examination often dem-
onstrates hepatomegaly with RUQ tenderness. An
audible hepatic bruit has been reported in a minority of
patients. AH can be an acute complication of chronic
cirrhosis and may present with stigmata of chronic liver
disease (38).
Patients with AH typically present with moderate
elevations of AST and ALT (<300 IU/mL), AST/ALT ra-
tio >2, elevated serum bilirubin, elevated GGT, moderate
leukocytosis (neutrophils), and elevated international
normalized ratio (INR) (18). The clinical and laboratory
features mentioned are often adequate to confirm the
diagnosis of AH in a patient with a long history of heavy
alcohol use, after appropriate rule out of mimicking dis-
orders. The differential diagnosis for AH is extensive,
including DILI, acute viral hepatitis, ischemic hepatitis,
nonalcoholic steatohepatitis (NASH), and chronic liver
disease. Initial evaluation includes an acute viral hepatitis
panel, consisting of anti-hepatitis A IgM, hepatitis B sur-
face antigen, anti-hepatitis B core IgM, and anti-hepatitis
C virus (HCV) antibodies, with a transabdominal ultra-
sound (Doppler) to evaluate for viral hepatitis, biliary
obstruction, and Budd-Chiari syndrome. If the diagnosis
is not certain, a liver biopsy can establish the diagnosis
with greater certainty. Understandably, although gener-
ally recommended, a majority of these interventions are
unrealistic in the emergent setting. Supportive care will
be the primary focus of an emergency physician, with
the diagnostics organized by an admitting team or outpa-
tient provider. Supportive care in acute episodes of AH
includes alcohol abstinence, prevention, and treatment
of alcohol withdrawal, fluid management, nutritional sup-
port, infection surveillance, and proton-pump inhibitor
prophylaxis. Various scores have been developed to
determine disease severity and additional therapy. The
Maddrey discriminant function (DF) score is a calcula-
tion using PT and serum bilirubin that estimates overall
mortality risk. Patients with a score > 32
(DF = [4.6  (PT control PT)] + serum bilirubin)
have high short-term mortality and may benefit from
glucocorticoid therapy (19). Typical course is prednisone
40 mg for 28 days, followed by an appropriate taper.
Admitting teams may discuss pentoxifylline, a tumor ne-
crosis factor inhibitor, which has been suggested as
replacement therapy for glucocorticoids. This has overall
8 E. Sulava et al.

Table 7. Therapies for Alcoholic Hepatitis (18,19,38,39)

Treatment Clinical Purpose Dose

Fluid management Maintain appropriate perfusion and menta on As clinically relevant

PPI Prophylaxis Mi gate pep c complica ons with variceal or Dependent on choice of medica on
hyptertensive bleeding
Nutri onal support Reverse malnutri on, does not improve short-term 35-40 kcal/kg of body weight per
survival day, 1.2-1.5g protein/kg/day
Psychotherapy Maintain abs nence, no clear evidence of benefit Op mum approach and frequency
not determined
Cor costeroids Reduce inflamma on, reduces mortality with severe 40mg prednisolone orally per day for
AH up to 28 days
Pentoxifylline Ablate TNF-alpha, helps maintain kidney func on, 400mg orally, three mes daily
improves in-hospital survival
Infliximab Ablate TNF-alpha, increases risk of infec on Most effec ve dose has not been
determined
Etanercept Ablate TNF-alpha, increases risk of infec on Most effec ve dose has not been
determined
Vitamin E Ablate oxidant-mediated liver injury Most effec ve dose has not been
determined

PPI = proton pump inhibitor; AH = alcoholic hepatitis; TNF = tumor necrosis factor.

weak supporting data and currently has little utility in the
ED. Table 7 shows the other therapy options for acute
AH. Most are not indicated due to risk for increased mor-
tality or lack of overall benefit (18).
Biliary tract disease.The third National Health and Nutri-
tion Examination Survey estimated that, in the United
States, 6.3 million men and 14.2 million women had
gallbladder disease, making it a very common primary
complaint in the ED setting (40). Gallstones can cause
significant colicky pain, biliary obstruction, or ascending
biliary infection, depending on their size and location.
Risk factors for biliary disease include age > 40 years, fe-
male sex, number of pregnancies, obesity, family history,
diabetes mellitus, cirrhosis, hemolysis, and medications
(41). Medications commonly involved in biliary disorders
include estrogen, oral contraceptives, octreotide, clofi-
brate, and ceftriaxone (42). Patients with uncomplicated
gallstone disease typically present with RUQ pain, which
radiates to the scapula and worsens with eating. A lodged
stone can lead to biliary obstruction and cholangitis,
presenting with Charcot’s triad of fever, jaundice, and
RUQ pain. If left untreated, cholangitis can cause sepsis
and altered mental status, making up Reynold’s pentad.
Acute cholecystitis will show a moderate to severe in-
crease of transaminases, depending on the severity of
the disease. As disease progresses to choledocholithiasis
and cholangitis, patients will produce elevated serum to-
tal bilirubin, direct bilirubin, ALP, GGT, and, at times,
leukocytosis (4). Confirmation of the diagnosis requires
additional imagining. RUQ ultrasound may reveal gall-
stones, thickened gallbladder wall, sonographic Mur-
phy’s sign, or dilated common bile duct. If the RUQ
ultrasound is inconclusive, a hepatoiminodiacetic acid
scan (HIDA) is indicated, but unfortunately is often not
readily available in the ED setting. In this test,
technetium-labeled HIDA is taken up by the hepatocytes
and excreted into the bowel. A normal study will have
visualization of contrast in the gallbladder, common
bile duct, and small intestine by 30–60 min. Failure to
do so identifies a blockage. Cholescintigraphy has a sensi-
tivity and specificity for acute cholecystitis of approxi-
mately 90% to 97% and 71% to 90%, respectively (20).
ED management depends directly on the severity and
type of biliary disease. Uncomplicated biliary colic, char-
acterized as a well-appearing afebrile patient with normal
lipase and electrolytes and no signs of cholecystitis, is a
non-emergent condition that can be addressed in the
outpatient setting. Patients can be discharged with surgi-
cal follow-up for an elective cholecystectomy, following
pain control with nonsteroidal anti-inflammatory drugs
(NSAIDs) or opioids. A commonly used NSAID is ketor-
olac, which is dosed at 30–60 mg (i.v./intramuscular) de-
pending on age and renal function. Symptomatic or
complicated cholecystitis patients will likely require
admission and should be placed nil per os while receiving
i.v. hydration, analgesia, and antiemetics. A surgical
consultation is appropriate, depending on clinical status.
ED Management of Elevated LFTs
If choledocholithiasis is suspected, further diagnostics
are needed. The admitting team will organize an ERCP or
MRCP, depending on the patient’s clinical status and risk.
ERCP is both diagnostic and therapeutic, while MRCP is
much less invasive. Due to serious complications of
pancreatitis, bleeding, and perforation, ERCP is reserved
for patients who are at high risk for having a common bile
duct stone, particularly if there is evidence of cholangitis
(43). As mentioned previously, sepsis is an immediate
concern for acute cholangitis patients. If sepsis is consid-
ered, antibiotics should be initiated in the ED after collec-
tion of blood cultures. As always, patient well-being is the
primary concern and therefore hemodynamic stabiliza-
tion with broad-spectrum antibiotic treatment takes pre-
cedence over laboratory retrieval. Although there is no
consensus for a superior regimen for biliary sepsis, broad
coverage for gram-negative and anaerobic organisms is
generally recommended. Once admitted, antibiotic ther-
apy will be modified to reflect blood culture results. Con-
sultations for ERCP biliary drainage should be placed as
soon as possible if available. Percutaneous transhepatic
cholangiography can be considered when ERCP is un-
available, unsuccessful, or contraindicated (21).
Severe Transaminase Elevation
Acute viral hepatitis. Although the incidence of hepatitis
A, hepatitis B, and hepatitis C have all been declining
over the past 2 decades, their clinical relevance remains,
and they continue to be reportable diseases (44). While
few patients will require hospitalization and exact deter-
mination of viral hepatitis is unlikely in the ED, early
initiation of diagnosis is important. On initial evaluation
serologic hepatitis panels, transaminases (10–100 in-
crease, with ALT > AST) and bilirubin (5–25 mg/dL)
should be obtained. The most common emergent inter-
ventions for patients with viral hepatitis will consist of
fluid and electrolyte corrections due to diarrhea and vom-
iting. Some patients with altered mental status with
reduction in hepatic synthetic function (INR > 1.5 or hy-
poglycemia) should be admitted and observed for
possible fulminant hepatitis (45).
Hepatitis A virus (HAV), a fecal–oral RNA virus, has
had a nationally routine childhood vaccine since 2005,
with a corresponding decrease in incidence. The primary
risk factors are now men who have sex with men, i.v. drug
users, and international travelers (22,44,46). Symptoms
of HAV include gradual development of fever, nausea,
vomiting, diarrhea, abdominal pain, and occasional
jaundice, after a 2- to 8-week incubation period. Clinical
research has shown that only 10%–30% of HAV patients
develop these symptoms, making clinical suspicion
heavily historically based (46). Because the maximal
viremia and infectivity are before onset of symptoms,
9
HAV is diagnosed with an antibody test, anti-HAV IgM
(47). Treatment is primarily symptomatic, although im-
mune serum globulin can help in post-exposure prophy-
laxis. Hand washing and proper food preparation are
the primary defenses (46). Hepatitis E (HEV) is similar
to HAV in the aspects of transmission (fecal–oral), and
symptomatology. HEV, known for causing significant
disease in pregnant women, lacks a widespread vaccine.
Its geographical distribution is primarily limited to
Asia, Africa, and Russia. The diagnosis of HEV is
made via serum or stool polymerase chain reaction
(PCR), or by the detection of IgM antibodies to HEV. Un-
fortunately, there are no commercial tests for HEV
licensed in the United States, and Centers for Disease
Control and Prevention research laboratories must be
contacted for testing (48). Ribavirin and pegylated inter-
feron are being investigated as potential treatments for
chronic HEV (49,50).
Hepatitis B (HBV) is a profoundly infectious envel-
oped DNA virus that has highest incidence, like HAV,
among men who have sex with men and with i.v. drug
users. Age strongly determines likelihood of chronic car-
rier state, with it occurring in only 10% of adults
compared to 90% of neonates (23). The symptoms
include malaise, fever, nausea, vomiting, occasional
arthralgia, and resolving jaundice (51). A notable differ-
ence is the absence of diarrhea in HBV. Diagnosis is es-
tablished using HB-surface antigen, HB-core IgM
(acute), HB-core IgG (chronic), and HB-envelope antigen
(corresponds to infectivity). While the infection may be
occult, it can occasionally lead to fulminant hepatitis, he-
patic failure, and encephalopathy; this is most common in
the presence of an HBV and hepatitis D virus (HDV) co-
infection. Fulminant hepatitis is recognized via altered
mentation and spontaneous mucosal bleeding (52).
Post-exposure prophylaxis for unvaccinated and vacci-
nated (dependent on titer) patients may include one-
time hepatitis B immune globulin and HBV vaccine.
HDV is only found in patients who are actively infected
with HBV, with a worldwide incidence of approximately
5% of chronic HBV carriers. Presence of HDV is sugges-
tive of a more sinister disease course (53).
HCV is most common among i.v. drug users, HIV-
positive patients, those with > 20 sexual partners, and per-
sons who received blood transfusions before 1992 (54).
Like other viral hepatitis causes, acute HCV infections
are typically asymptomatic. However, unlike HAV and
HBV, progression to chronic hepatitis with HCV is very
common and approaches 90% of patients (55). Diagnosis
is partially performed by elimination of other causes and
can be confirmed via HCV enzyme immunoassay, PCR,
or enzyme-linked immunosorbent assay. Classically,
treatment may include interferon alfa-2b (with or without
polyethylene glycol) and ribavirin (24). There are now
10
newer and very effective medications, ledipasvir and so-
fosbuvir, with treatment protocols dependent on the geno-
type (56). Post-exposure prophylaxis is unclear at this
time.
Ischemic injury.Severe transaminase elevations are due to
global hepatocellular injury or necrosis, which can be
caused by an acute hypoxic event. The liver’s complex
vascular supply and high metabolic rate make it vulner-
able to circulatory disturbances. Ischemic hepatitis, also
referred to as ‘‘shock liver,’’ refers to severe hepatic injury
secondary to acute hypoperfusion. This injury is not
mediated by an inflammatory process, as the name hepa-
titis implies, but by hemodynamic instability. This in-
cludes global circulatory compromise from extrahepatic
sources, like acute coronary syndrome, decompensated
heart failure, sepsis, and trauma. More focal causes of he-
patic hypoperfusion include hepatic artery thrombosis,
portal vein thrombosis, surgical ligation, or hepatic sickle
cell crisis (57). The hemodynamic instability is usually
apparent clinically before evidence of liver injury ap-
pears. Laboratory chemistries usually show a rapid rise
in serum aminotransferases to >25 the upper limit of
normal, followed by a dramatic increase in lactate dehy-
drogenase (LDH). The transaminase levels will peak
within 3 days of the initiating event and, in the absence
of continued clinical decline, will normalize by days
7–10 (25). Managing ischemic hepatitis includes hemo-
dynamic resuscitation, with close monitoring of end-
organ perfusion. After acute stabilization of the patients
in the ED, immediate transfer to intensive care unit–level
care should occur.
Acetaminophen toxicity. Acetaminophen, the most
widely used analgesic-antipyretic in the United States,
is the most common cause of drug-induced hepatic fail-
ure (4). The Annual Report of the American Associa-
tion of Poison Control reported that, in 2014, there
were > 70,000 acetaminophen-related overdoses, result-
ing in 107 deaths (58). The medication’s potency is
partially due to its rapid and complete uptake in the in-
testinal tract, causing peak concentrations 1.5–2 h after
administration. When doses exceed the maximum daily
recommendations of 80 mg/kg in children and 4 g in
adults, acetaminophen begins to rapidly deplete hepatic
glutathione stores via the overproduction of N-acetyl-p-
benzoquinone imine (NAPQI) by the cytochrome 450
pathway. When hepatic glutathione stores are depleted,
NAPQI begins to cause irreversible oxidative hepato-
cyte injury and hepatocellular centrilobular necrosis.
Patients who are chronic alcoholics have increased
CYP2E1 activity, which further depletes glutathione
levels and puts them at increased risk for acetamino-
phen toxicity (59). Other medications that cause a
E. Sulava et al.
similar reaction include anticonvulsants, antitubercu-
losis drugs (e.g., isoniazid-rifampin), and trimetho-
prim-sulfamethoxazole.
Clinical manifestations of acetaminophen overdose
are often mild and nonspecific, but because of the impor-
tance of a proper ingestion timeline, a four-stage clinical
course has been developed. Stage 1 represents 0.5–24 h
after the overdose with nausea, vomiting, diaphoresis,
pallor, and malaise. Progression to stage two, 24–72 h af-
ter ingestion, includes rapid transaminase elevation with
symptomatic hepatic injury of RUQ pain, hepatic
enlargement, and abdominal tenderness. LFT abnormal-
ities peak during stage 3, representing 72–96 h, during
which time the severe complications of hepatic encepha-
lopathy, hyperammonemia, and bleeding diathesis can
occur. Death can occur in this stage from a combination
of multiorgan failure and lactic acidosis (26). Stage 4
represent the recovery phase 96 h post ingestion.
For further evaluation, a 4-h post-ingestion acetamin-
ophen serum level should be obtained. If the ingestion
was > 4 h ago, a level should be drawn immediately. If
the time of ingestion is unknown, it is recommended to
obtain a level immediately and then again in 4 h for
continued monitoring. The time of ingestion and acet-
aminophen serum level will be evaluated with the
Rumack-Matthew nomogram to determine the severity
of acetaminophen toxicity and the need for treatment
with N-acetylcysteine (NAC). NAC rapidly repletes
glutathione stores, preventing toxic metabolite formation
if given within 8 h of ingestion. NAC was found to be safe
for administration up to 24 h after ingestion, noting the
treatment was more effective if given within the first
8 h (60). It can be provided intravenously with a 20-h pro-
tocol or orally with a 72-h protocol. Food and Drug
Administration–approved dosage regimen for oral NAC
starts with a loading dose of 140 mg/kg, followed by 17
doses, each at 70 mg/kg, given every 4 h. Intravenous
administration of NAC is generally preferred. The tradi-
tional treatment strategy is a ‘‘three bag approach’’ that
provides a total of 300 mg/kg of NAC over 20 h. This
is completed by administering a loading dose of
150 mg/kg over 1 h, followed by a 4-h infusion at
12.5 mg/kg. Finally, the third bag is a 16-h infusion at
6.25 mg/kg (61). A 2016 retrospective trial of 599 pa-
tients demonstrated that a simplified ‘‘two bag approach’’
lowered the incidence of nonallergic anaphylactic reac-
tions and adverse events. This technique consists of
administering a 4-h infusion at 50 mg/kg, followed by a
16-h infusion of 6.25 mg/kg (27). There were no differ-
ences in treatment outcomes, but follow-up studies are
needed to further validate this treatment protocol. Other
treatment includes gastrointestinal decontamination
with 1 g/kg activated charcoal, if within 4 h of ingestion
(62).
ED Management of Elevated LFTs
Hepatic injury in trauma.A 2012 Journal of the American
Medical Association meta-analysis listed blunt abdom-
inal trauma (BAT) as the causal agent for presentation
to the ED in 80% of abdominal injury causes. Of these pa-
tients, approximately 13% will have an intra-abdominal
injury, most commonly involving the liver or spleen
(63). Initial management of the trauma patient is directed
at rapid identification of life-threatening injuries with
prompt stabilization of the patient’s hemodynamic status.
As Advanced Trauma Life Support teaches, primary
assessment follows the ‘‘ABCDE’’ pattern, standing for:
Airway, Breathing, Circulation, Disability, and Exposure.
After the primary survey, a more thorough physical ex-
amination can determine the likelihood of intra-
abdominal injury. On a review of > 10,000 patients, the
physical examination findings that most strongly asso-
ciate with the presence of intra-abdominal injury
included seatbelt sign, rebound tenderness, hypotension,
abdominal distention, and guarding (63). The absence
of the findings mentioned does not rule out underlying pa-
thology, therefore, an impressive mechanism of injury or
heightened physician gestalt justifies further evaluation.
The following steps of the trauma management, including
determination of imaging modalities and resuscitation ef-
forts, are determined by the patient’s presenting injuries
and response to initial treatment efforts. This varies
widely, depending on type and severity of injury, making
a comprehensive review of trauma management outside
the scope of this article on laboratory abnormalities.
Unfortunately, routine laboratory tests are typically
of limited value in the acute trauma setting. Due to
the extensive range of mechanism of injury and resultant
pathology, it is difficult to categorize BAT into a specific
magnitude on the ‘‘mild–moderate–severe’’ transami-
nase elevation scale. There is evidence to support that
a higher magnitude elevation of transaminase concentra-
tion correlates with increased likelihood of severe
injury. A study of 99 BAT patients showed that AST
and ALT concentrations raised over twice the normal
limit correlated with major hepatic injuries. Although
the study possesses a small sample size, the data pro-
duced an odds ratio of 8.44 (95% confidence interval
1.64–43.47) (64). More recent studies have attempted
to use LFT as a screening tool to determine low-risk pa-
tients suitable for observation. A 2016 study of 676 BAT
patients identified AST $109 U/L and ALT $97 U/L as
optimal cutoff values in predicting the presence of liver
injury. Simultaneous AST and ALT elevation had a 78%
sensitivity and 88% specificity for the presence of he-
patic injury. More importantly, the study resulted a
98% negative predictive value, meaning that normal
transaminase values could be helpful to help determine
the need for further imaging in an otherwise stable
trauma patient (65).
11
In the ED, the disposition of hepatic trauma is largely
determined based on hemodynamic stability. A hemody-
namically unstable trauma patient with confirmed intra-
abdominal process should be transferred rapidly to the
operating room for evaluation and management. In unsta-
ble patients, the focused assessment of sonography in
trauma examination is commonly used as an imaging mo-
dality. Ultrasound, especially in the emergency or trauma
setting, possesses a poor sensitivity for solid organ in-
juries. One study of 152 trauma patients showed that ul-
trasound had only an 11% sensitivity for liver injuries
(66). Therefore, a stable patient with suspected hepatic
trauma requires an additional evaluation to determine
whether surgical intervention is needed. To confirm he-
patic injury, an i.v. contrast-enhanced computed tomogra-
phy of the abdomen can be used (67). This will identify
the type and class of hepatic injury, while evaluating
the abdomen and diaphragm for injury.
Fortunately, most hepatic injuries heal spontaneously
with nonoperative management, which consists of obser-
vation or arteriography with embolization. Operative
intervention is only needed in 14% of hepatic trauma pa-
tients, most of which present with hemodynamic insta-
bility (68). Nonoperative management is the treatment
of choice for hemodynamically stable patients with he-
patic injury, regardless of injury grade. A review of
35,510 hepatic injuries from 1994 to 2003 showed that
91% of adults were successfully managed nonoperatively
(69). Reasons to consider operative management include
hemodynamic instability after initial resuscitation, peri-
tonitis or other indication for abdominal surgery, gunshot
injury, absence of an appropriate clinical environment to
provide monitoring, or means to complete or urgent
abdominal exploration should the clinical picture change
(69,70). In 2012 the Eastern Association for Surgery of
Trauma updated the guidelines for hepatic injuries in
trauma, advocating for nonoperational management
(71). The guidelines state that routine laparotomy is not
indicated in the hemodynamically stable patient without
peritonitis, and that angiography with embolization may
be considered as a first-line intervention for a patient
who is a transient responder to resuscitation (71). As al-
ways, the need for surgical intervention should be dis-
cussed with the surgical staff available for any
concerning trauma patient.
CONCLUSIONS
LFTs are commonly ordered laboratory tests with a vari-
ety of abnormalities in a vast array of disorders. An un-
derstanding of the biochemical basis of each test allows
providers to correlate laboratory findings to a patient’s
clinical presentation. By separating common hepatic dis-
orders into subcategories based on the magnification of
12
transaminase elevation, a more simplistic approach can
be taken to help narrow the spectrum of a differential
diagnosis. This can be used to help eliminate waste in
costly and unnecessary follow-up studies by maximizing
the understanding of what an LFT result represents.
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14 E. Sulava et al.

ARTICLE SUMMARY
1. Why is this topic important?
Liver function test (LFT) abnormalities are common in
the emergency department, and a wide differential exists
for these elevations. Some conditions may require imme-
diate management.
2. What does this review attempt to show?
This review provides an overview of the evaluation and
management of patients with elevated LFTs, specifically
what findings require further emergent treatment.
3. What are the key findings?
Due to the liver’s multiple roles and complexity, many
conditions and medications can significantly alter liver
function. These alterations are manifested with LFTs,
which are biochemical markers of hepatic function. A
change in LFTs can be organized into hepatocellular,
cholestatic, or functioning liver mass. The magnitude of
marker elevation assists with further management and
determining the etiology.
4. How is patient care impacted?
This discussion and review of LFT abnormalities pro-
vides emergency providers with an approach to manage-
ment and treatment of several conditions that can have
significant morbidity and mortality.