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clinical problem-solving

An Intricate Interplay
Richard H. Moseley, M.D., Beth Manoogian, M.D., Thomas Shehab, M.D., M.M.M.,
and Sanjay Saint, M.D., M.P.H.
In this Journal feature, information about a real patient is presented in stages (boldface type)
to an expert clinician, who responds to the information, sharing his or her reasoning with
the reader (regular type). The authors commentary follows.
From the Veterans Affairs Ann Arbor
Healthcare System (R.H.M., S.S.), and
the Department of Internal Medicine,
University of Michigan Medical School,
Ann Arbor (R.H.M., B.M., S.S.), and
Huron Gastroenterology, Ypsilanti (T.S.)
all in Michigan. Address reprint requests to Dr. Moseley at 2215 Fuller Rd.,
Ann Arbor, MI 48105, or at rmoseley@
umich.edu.

A 55-year-old man presented to his primary care physician for evaluation of multiple
symptoms. He had been experiencing sinus congestion, headaches, chills, mild nausea, fatigue, and a foggy sensation for approximately 1 week before presentation.
He reported darker urine than usual and malaise for several days before presentation.
In addition, he noticed that his eyes were turning yellow. He did not have abdominal
pain, pruritus, vomiting, melena, or hematochezia; he had not taken his temperature
but felt as though he had a fever.

N Engl J Med 2012;367:1342-7.

Given the history of dark urine and scleral icterus, I will group the potential causes
of this patients illness by first considering the causes of jaundice, which can be
obstructive or nonobstructive. Given his symptoms, nonobstructive causes are more
likely and include infection (especially viral, given the prodrome of sinus congestion
and headaches), cancer (either solid or hematologic), a medication or toxin (including
alcohol or herbal medications), and autoimmune disease. Obstructive disease could
be benign (stone or stricture) or malignant.

DOI: 10.1056/NEJMcps1011784
Copyright 2012 Massachusetts Medical Society.

The patients medical history was notable for hypertension, hyperlipidemia, seasonal
allergies, nephrolithiasis, and an episode of measles at 9 years of age that was complicated by respiratory compromise, which necessitated a tracheostomy. The family history was notable for testicular cancer in his brother. The patient worked as an engineer. He had no history of blood transfusions, tattoos, tobacco use, or illicit-drug use.
He consumed one to two alcoholic drinks per night. His only recent travel was to the
Turks and Caicos Islands 4 months before presentation. His medications included
baby aspirin, atenolol, hydrochlorothiazide, lovastatin, fexofenadine, fish oil, acidophilus, vitamin D, and calcium carbonate. He had not consumed a substantial
amount of acetaminophen recently and had not used any other over-the-counter medication or herbal supplement during the past 6 months.
The hypertension and hyperlipidemia suggest the metabolic syndrome and raise the
possibility of nonalcoholic fatty liver disease. The patients alcohol use should also
be considered as a potential predisposing factor for liver injury; patients often underestimate their alcohol intake, and even modest alcohol use can be detrimental
in patients with occult liver disease. Any medication can be associated with druginduced liver injury. Of the medications he has been prescribed, I am most concerned
about lovastatin. It would be important also to inquire about even short courses of
antibiotic agents, because antibiotics are the most frequent cause of drug-induced
liver injury. The patients travel could be relevant; the timing of the trip, however,
makes many of the common infectious illnesses hepatitis A infection, for example,
with an average incubation period of 28 days unlikely.
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clinical problem-solving

Three and a half years previously, at routine physical examination, the patient was noted to have
mildly elevated liver-enzyme levels. The level of aspartate aminotransferase was 40 U per liter (reference range, 2 to 35), and the level of alanine aminotransferase 47 U per liter (reference range, 0 to
45). The levels of alkaline phosphatase, bilirubin,
and albumin were normal. The aspartate aminotransferase and alanine aminotransferase levels
were similarly elevated 1 year later, when the patient began taking simvastatin for a high level of
serum low-density lipoprotein (LDL) cholesterol.
When checked 2 months later, the aspartate aminotransferase and alanine aminotransferase levels
remained slightly elevated; since the LDL level was
not in the target range, the simvastatin dose was
doubled. Two months after the dose change, the
aspartate aminotransferase level had increased to
63 U per liter, and the alanine aminotransferase
level to 93 U per liter. Simvastatin was discontinued, and ultrasonography of the right upper quadrant was unremarkable. The next month, the aspartate aminotransferase level had increased to
130 U per liter, the alanine aminotransferase level
to 202 U per liter, and the alkaline phosphatase
level to 145 U per liter (reference range, 30 to 130);
the bilirubin and albumin levels and the international normalized ratio (INR) were normal. Tests
for antibodies against hepatitis B and hepatitis C
were negative, as were serologic tests for antinuclear antibodies, antimitochondrial antibodies,
and antismooth-muscle antibodies. The iron level, iron-binding capacity, and serum ferritin level
were normal. The alpha1-antitrypsin level was low,
at 79 mg per deciliter (reference range, 113 to 263),
with phenotype MZ.
The patient was asymptomatic. He was referred
to a hepatologist; examination showed no scleral
icterus, abdominal tenderness, hepatosplenomegaly, lymphadenopathy, or other abnormalities. At
that visit, the aspartate aminotransferase level was
62 U per liter, alanine aminotransferase 102 U per
liter, alkaline phosphatase 90 U per liter, and bilirubin 1.1 mg per deciliter (19 mol per liter), with
an INR of 1.0 and an albumin level of 4.5 g per
deciliter. Liver biopsy was performed, and examination of the biopsy specimen showed mild steatosis with no fibrosis and no other clinically significant abnormalities. Periodic acidSchiff (PAS)
staining with diastase revealed no alpha1-antitrypsin globules, and iron staining showed no
increase in iron stores. The liver-enzyme levels
returned to normal approximately 3 years after

the initial increase had been noted, and treatment

with lovastatin at a dose of 20 mg per day was initiated. At a routine physical examination 1 year
later (4 months before the current presentation),
the liver-enzyme levels were still normal.
This history is consistent with fatty liver disease.
Although the patients history of alcohol use is
more consistent with nonalcoholic than alcoholic fatty liver disease, the biopsy findings do not
allow us to differentiate between these two entities. In addition, patients often have a combination of alcohol-related and nonalcohol-related
injury. Aminotransferase levels can wax and wane,
often into the normal range, in patients with either type of injury. It is possible that the patients
statin use (particularly the increase in the dose)
contributed to the transient elevation in aminotransferase levels several years before the current
presentation.
The patients low alpha1-antitrypsin level and
MZ phenotype warrant comment. The MZ phenotype is typically not associated with serious endorgan disease. The liver injury seen in patients with
alpha1-antitrypsin deficiency is due to the accumulation of abnormal protein in the endoplasmic
reticulum. The absence of a positive result on PAS
diastase staining of a liver-biopsy specimen a year
and a half earlier makes clinically significant accumulation unlikely.
On evaluation at the time of the patients current presentation, the blood pressure was 138/73 mm Hg,
the pulse 63 beats per minute, the temperature
36.7C, and the oxygen saturation 98% while he
was breathing ambient air. The examination was
notable for scleral icterus and a soft, nontender abdomen with the liver edge palpable less than one
finger breadth below the costal margin. No splenomegaly or ascites was detected. The patient was
not confused and had no asterixis. Laboratory studies showed a normal basic metabolic panel and
complete blood count. The aspartate aminotransferase level was 1545 U per liter, alanine aminotransferase 2655 U per liter, alkaline phosphatase
399 U per liter, total bilirubin 5.3 mg per deciliter
(91 mol per liter), direct bilirubin 4.0 mg per deciliter (68 mol per liter), and albumin 3.8 g per deciliter. Because the INR was not sent with the initial
set of laboratory tests and the above results were
returned late on a Friday afternoon, the patient was
advised to come to the emergency department that
evening for further evaluation.

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The laboratory results show severe liver injury.

The pattern of markedly elevated aminotransferase levels, with more modest elevations of the
alkaline phosphatase and bilirubin levels, is consistent with hepatocellular injury. Aminotransferase levels of more than 1000 U per liter are typical
of a small number of conditions: ischemic injury,
viral injury, toxin-related or medication-related
injury, and autoimmune liver disease. Although
acute gallstone disease with choledocholithiasis
can cause this pattern of laboratory findings, this
diagnosis is unlikely, given the absence of abdominal pain and fever. Acute viral hepatitis and
drug-induced liver injury are the most likely diagnoses, since the findings in this patient are consistent with either diagnosis, whether it represents
the primary disorder or a complication of a preexisting liver condition.
More information is needed to determine
whether the patient requires admission to the
hospital. The presence of encephalopathy or coagulopathy would suggest acute liver failure and
necessitate admission for further evaluation and
treatment. In this case, as long as the INR is not
elevated, and assuming that the patient can remain hydrated and maintain nutrition, he does
not absolutely require admission. The fogginess
he reports may be early encephalopathy, but that
alone would not alter my suggested treatment.
The patient was admitted to the general medicine
service for acute hepatitis. He was in stable condition and was asymptomatic. Additional testing
revealed that the INR was 1.1, and tests for hepatitis B surface antigen, surface antibody, core IgM,
and hepatitis A antibody were negative. A polymerase chain reaction (PCR) assay was negative for
hepatitis C virus. A PCR assay for cytomegalovirus
and serologic testing for the EpsteinBarr virus
were also unremarkable. Acetaminophen and salicylate levels were below the reference ranges,
ethanol testing was negative, and a urine drug
screen was negative for illicit substances. Quanti
tative immunoglobulin levels were notable for an
IgG level of 1740 mg per deciliter (reference range,
620 to 1520), with normal IgA and IgM levels.
A titer for antismooth-muscle antibody was less
than 1:20, and testing was negative for antinuclear antibodies and antibodies against liverkidney
microsome type 1. Doppler ultrasonography of
the right upper quadrant revealed patent hepatic

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vasculature and unremarkable liver parenchyma

without masses. The gallbladder had nonspecific
wall thickening that was probably due to underdistention, and there was no evidence of stone or
sludge. There was no apparent intrahepatic or extrahepatic biliary dilatation, although the common bile duct was not well visualized.
Given the absence of coagulopathy and encephalopathy, I would continue to classify this patient
as having an acute liver injury rather than acute
liver failure. The negative results on testing for
hepatitis A, hepatitis B, and hepatitis C virtually
rule out those infections. The findings on ultrasonography make acute biliary obstruction or largevessel vascular causes unlikely. Although autoantibodies are absent, hypergammaglobulinemia,
with an IgG predominance, is a feature of autoimmune hepatitis as well as other inflammatory
disorders. I remain concerned that the patients
statin medication may be implicated.
Given their recognized associations with druginduced liver injury, the lovastatin and hydrochlorothiazide were discontinued. The patient
remained asymptomatic, with stable amino
transferase levels, and he was discharged from
the hospital on day 3, with plans for close followup in the hepatology clinic. On the day of discharge, the aspartate aminotransferase level was
1588 U per liter, alanine aminotransferase 2483 U
per liter, alkaline phosphatase 503 U per liter, total
bilirubin 7.8 mg per deciliter (133 mol per liter),
and INR 1.1.
At this point, I would proceed with another percutaneous liver biopsy for several reasons. First, the
presence and nature of an acute inflammatory
infiltrate (e.g., interface [periportal] hepatitis, with
a plasma-cellrich inflammatory infiltrate in autoimmune hepatitis) can help clarify the cause of
the liver injury. In addition, there may be findings
(e.g., fibrosis) that suggest chronicity of the disease and the presence of preexisting liver disease.
I predict the liver biopsy will show evidence
of autoimmune hepatitis with plasma-cellrich
infiltrates and perhaps some degree of bile-duct
injury, given the elevated alkaline phosphatase
level. The negative results on testing for antinuclear antibodies and antismooth-muscle antibodies do not rule out autoimmune hepatitis.

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clinical problem-solving

Liver biopsy revealed features of autoimmune hepatitis with intensely active chronic lobular hepatitis and active interface hepatitis with plasmacytosis (Fig. 1A). Substantial bridging fibrosis was seen
(Fig. 1B), in contrast to the prior biopsy, which had
not shown any fibrosis. No steatosis was observed.
The biopsy findings are consistent with autoimmune liver injury, and the fibrosis indicates chronicity. Prednisone should be administered and
perhaps azathioprine. The prognosis for a biochemical remission is very good; the majority of
patients with autoimmune hepatitis have biochemical improvement within 2 weeks after the
initiation of immunosuppressive therapy.

Treatment with prednisone and azathioprine was

initiated. Three months after treatment was initiated, the patients liver-enzyme levels had normalized. Prednisone was gradually tapered over a period of 6 months, and his liver-enzyme levels have
remained normal with azathioprine monotherapy
for more than a year.

C OM MEN TA R Y
In contrast to the broad differential diagnosis for
elevations in serum aminotransferase levels that
are less than 5 times the upper limit of the normal range, the causes of severe aminotransferase
elevations (>20 times the upper limit of the normal range) are more limited and include Wilsons
disease, acute biliary obstruction, and viral, toxic,
ischemic, and autoimmune hepatitis.1,2 Although
generally regarded as a chronic liver disease, autoimmune hepatitis is manifested as an acute illness in about 25% of patients.3,4 A retrospective
study showed that acute presentations of autoimmune hepatitis have distinct clinical, biochemical,
and histologic features, as compared with the
classic presentation as chronic hepatitis.5
Early diagnosis of autoimmune hepatitis is
important, since untreated patients, even those
with mild disease, can have progression to cirrhosis, and untreated patients have lower 10-year
survival rates than treated patients.3 Two types of
autoimmune hepatitis have been proposed on the
basis of differences in immunoserologic markers;
type 1 is defined by positive results on testing for
antinuclear antibodies and smooth-muscle anti-

n engl j med 367;14

Figure 1. Liver-Biopsy Specimen Showing Features

of Autoimmune Hepatitis.
A plasma-cellrich inflammatory infiltrate (arrow) is
present in Panel A (hematoxylin and eosin), and bridging
fibrosis (arrow) in Panel B (Masson trichrome stain).

bodies, and type 2 by positive results on testing

for antibodies against liverkidney microsome
type 1 and liver cytosol type 1. Type 2 autoimmune hepatitis has been described mainly in children in Europe and is rare in the United States.
Among patients with type 1 disease, the reported
prevalence of antinuclear antibodies alone is 13%,
smooth-muscle antibodies alone 33%, and both
54%.6 Autoantibodies develop later in the disease
in some patients who are seronegative on initial
evaluation.7 Autoantibody-negative autoimmune
hepatitis is important to recognize because
patients with this condition (such as the one we
describe) typically have a favorable response to
glucocorticoid therapy.4
A diagnostic scoring system for autoimmune
hepatitis has been developed for use in practice
that is based on the presence and level of autoantibodies, serum IgG concentration, typical histologic features (in particular, a plasma-cellrich

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Table 1. Simplified Diagnostic Criteria for Autoimmune Hepatitis.*

Criterion

Points

Autoantibodies
Titer of antinuclear or smooth-muscle antibodies 1:40

Titer of antinuclear or smooth-muscle antibodies 1:80, or titer

of liverkidney microsomal antibodies 1:40, or presence of
antibodies against soluble liver antigen

IgG concentration
>Upper limit of the normal range

>1.10 times the upper limit of the normal range

Liver histologic features

Compatible with autoimmune hepatitis

Typical of autoimmune hepatitis

Absence of viral hepatitis

* Adapted from Hennes et al.8 A total score of 6 points indicates probable autoimmune hepatitis, and a score of 7 or more points definite autoimmune hepatitis.
The sum of the points for the categories of autoantibody titers is limited to 2.
Evidence of hepatitis on histologic assessment of a liver-biopsy specimen is a
necessary condition for the diagnosis of autoimmune hepatitis. Typical features
of autoimmune hepatitis are interface hepatitis, lymphocytic or lymphoplasmacytic infiltrates in portal tracts and extending into the lobule, and hepatic
rosette formation. Compatible features are chronic hepatitis and lymphocytic
infiltrates without all the typical features.

interface hepatitis), and negative serologic testing

for viruses (Table 1).8 The score in this case,
which was based on these simplified criteria, was
consistent with probable autoimmune hepatitis.
Treatment with either prednisone alone (at a
dose of 60 mg daily) or a combination of prednisone (at a dose of 30 mg daily) and azathioprine
(at a dose of 50 mg, or 1 to 2 mg per kilogram
of body weight, daily) is recommended in cases of
severe autoimmune hepatitis, on the basis of data
from randomized clinical trials; combination
therapy is generally preferred because the lower
dose of glucocorticoid reduces side effects.3 Prednisolone in equivalent doses can be substituted
for prednisone. Glucocorticoids are tapered over
a 4-week period to a level required to maintain a
biochemical remission, and this maintenance
regimen is then continued until disease resolution (defined as biochemical remission for a
minimum of 24 months), unless there is treatment failure or drug toxicity.3,4 Relapse after
treatment withdrawal is reported in up to 60%
of patients and is generally treated with a similar regimen.4
Nonalcoholic fatty liver disease is one of the
most common causes of asymptomatic amino1346

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transferase elevations and chronic liver disease in

Western countries.9 It encompasses a spectrum
of disorders, from simple steatosis to fibrosing
steatohepatitis that can progress to cirrhosis and
its complications, including hepatocellular carcinoma. Associated features include insulin resistance, central adiposity, dyslipidemia, and hypertension.10 The diagnosis of nonalcoholic fatty
liver disease requires that there is no history of
substantial alcohol consumption, although the
definition of substantial alcohol consumption and
the effect of obesity on thresholds for the development of alcoholic fatty liver disease remain
unclear.9,11 The initial liver-biopsy findings in
this case, as well as the negative serologic tests,
were consistent with the diagnosis of nonalcoholic fatty liver disease.
Statins can be safely used in patients with nonalcoholic fatty liver disease and, in the majority of
patients with this condition, are associated with
improvement in liver enzyme abnormalities.12
Rare cases of liver injury with an autoimmune
phenotype have been reported in patients taking
statins, typically occurring within 4 months after treatment initiation.13 However, as suspected
in this case, these reports may represent the coincidental development of a new case of autoimmune hepatitis in a patient treated with statins,
rather than autoimmune hepatitis triggered by
statin use.13 Relapse after the discontinuation of
immunosuppressive therapy and the presence of
substantial fibrosis on liver biopsy, as was noted
on the second biopsy in this case, appear to differentiate newly developed from drug-induced
autoimmune hepatitis, which is most commonly
associated with the use of nitrofurantoin and
minocycline.14 The contribution of nonalcoholic
fatty liver disease to elevated serum aminotransferase levels may be underrecognized in patients
with other forms of chronic liver disease.15
The present case underscores the need to consider the possibility of other causes of chronic
liver disease in patients with established nonalcoholic fatty liver disease, to recognize the role of
liver biopsy in diagnosis, and to consider the intricate interplay of potential endogenous causes
(e.g., steatosis and immunologic factors) and exogenous causes (e.g., drugs) of liver injury.
Dr. Saint reports owning stock in and receiving payment as
an advisory board member of Doximity. No other potential conflict of interest relevant to this article was reported.
Disclosure forms provided by the authors are available with
the full text of this article at NEJM.org.

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clinical problem-solving
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3. Manns MP, Czaja AJ, Gorham JD, et
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5. Kessler WR, Cummings OW, Eckert G,
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6. Czaja AJ, Freese DK. Diagnosis and

treatment of autoimmune hepatitis. Hepatology 2002;36:479-97.

7. Gassert DJ, Garcia H, Tanaka K,
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11. Ruhl CE, Everhart JE. Joint effects of

body weight and alcohol on elevated serum alanine aminotransferase in the

United States population. Clin Gastroenterol Hepatol 2005;3:1260-8.
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Hepatology 2005;41:690-5.
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Kahn SE, Lee SP. Contribution of metabolic factors to alanine aminotransferase
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