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clinical problem-solving

n engl j med 367;14 nejm.org october 4, 2012 1343

Three and a half years previously, at routine physi-cal examination, the patient was noted to havemildly elevated liver-enzyme levels. The level of as-partate aminotransferase was 40 U per liter (refer-ence range, 2 to 35), and the level of alanine ami-notransferase 47 U per liter (reference range, 0 to45). The levels of alkaline phosphatase, bilirubin,

and albumin were normal. The aspartate amino-transferase and alanine aminotransferase levelswere similarly elevated 1 year later, when the pa-tient began taking simvastatin for a high level ofserum low-density lipoprotein (LDL) cholesterol.

When checked 2 months later, the aspartate ami-notransferase and alanine aminotransferase levelsremained slightly elevated; since the LDL level wasnot in the target range, the simvastatin dose wasdoubled. Two months after the dose change, theaspartate aminotransferase level had increased to63 U per liter, and the alanine aminotransferase

level to 93 U per liter. Simvastatin was discontin-ued, and ultrasonography of the right upper quad-rant was unremarkable. The next month, the as-partate aminotransferase level had increased to130 U per liter, the alanine aminotransferase levelto 202 U per liter, and the alkaline phosphataselevel to 145 U per liter (reference range, 30 to 130);the bilirubin and albumin levels and the interna-tional normalized ratio (INR) were normal. Testsfor antibodies against hepatitis B and hepatitis Cwere negative, as were serologic tests for antinu-clear antibodies, antimitochondrial antibodies,and antismooth-muscle antibodies. The iron lev-el, iron-binding capacity, and serum ferritin levelwere normal. The alpha

1-antitrypsin level was low,

at 79 mg per deciliter (reference range, 113 to 263),with phenotype MZ.

The patient was asymptomatic. He was referredto a hepatologist; examination showed no scleralicterus, abdominal tenderness, hepatosplenomeg-aly, lymphadenopathy, or other abnormalities. Atthat visit, the aspartate aminotransferase level was62 U per liter, alanine aminotransferase 102 U per

liter, alkaline phosphatase 90 U per liter, and bili-rubin 1.1 mg per deciliter (19 mol per liter), withan INR of 1.0 and an albumin level of 4.5 g perdeciliter. Liver biopsy was performed, and exami-nation of the biopsy specimen showed mild ste-atosis with no fibrosis and no other clinically sig-nificant abnormalities. Periodic acidSchiff (PAS)staining with diastase revealed no alpha1-anti-trypsin globules, and iron staining showed noincrease in iron stores. The liver-enzyme levelsreturned to normal approximately 3 years after

the initial increase had been noted, and treatmentwith lovastatin at a dose of 20 mg per day was ini-tiated. At a routine physical examination 1 yearlater (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 ismore consistent with nonalcoholic than alcohol-

ic fatty liver disease, the biopsy findings do not

allow us to differentiate between these two enti-

ties. In addition, patients often have a combina-

tion of alcohol-related and nonalcohol-related

injury. Aminotransferase levels can wax and wane,

often into the normal range, in patients with ei-

ther type of injury. It is possible that the patients

statin use (particularly the increase in the dose)

contributed to the transient elevation in amino-

transferase levels several years before the current

presentation.

The patients low alpha1-antitrypsin level and

MZ phenotype warrant comment. The MZ pheno-

type is typically not associated with serious end-

organ disease. The liver injury seen in patients with

alpha1-antitrypsin deficiency is due to the accu-

mulation 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 ac-

cumulation unlikely.

On evaluation at the time of the patients current pre-sentation, the blood pressure was 138/73 mm Hg,the pulse 63 beats per minute, the temperature36.7C, and the oxygen saturation 98% while hewas breathing ambient air. The examination wasnotable for scleral icterus and a soft, nontender ab-domen with the liver edge palpable less than onefinger breadth below the costal margin. No sple-nomegaly or ascites was detected. The patient wasnot confused and had no asterixis. Laboratory stud-ies showed a normal basic metabolic panel and

complete blood count. The aspartate aminotrans-ferase level was 1545 U per liter, alanine amino-transferase 2655 U per liter, alkaline phosphatase399 U per liter, total bilirubin 5.3 mg per deciliter(91 mol per liter), direct bilirubin 4.0 mg per deci-liter (68 mol per liter), and albumin 3.8 g per deci-liter. Because the INR was not sent with the initialset of laboratory tests and the above results werereturned late on a Friday afternoon, the patient wasadvised to come to the emergency department thatevening for further evaluation.

The New England Journal of Medicine

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Th e n e w e n g l a n d j o u r n a l o f medicine

n engl j med 367;14 nejm.org october 4, 20121344

The laboratory results show severe liver injury.

The pattern of markedly elevated aminotransfer-

ase levels, with more modest elevations of the

alkaline phosphatase and bilirubin levels, is con-

sistent with hepatocellular injury. Aminotransfer-

ase levels of more than 1000 U per liter are typical

of a small number of conditions: ischemic injury,

viral injury, toxin-related or medication-relatedinjury, 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 ab-

dominal pain and fever. Acute viral hepatitis and

drug-induced liver injury are the most likely diag-

noses, since the findings in this patient are con-

sistent with either diagnosis, whether it represents

the primary disorder or a complication of a pre-

existing liver condition.

More information is needed to determine

whether the patient requires admission to thehospital. The presence of encephalopathy or co-

agulopathy 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 re-

main 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 medicineservice for acute hepatitis. He was in stable condi-tion and was asymptomatic. Additional testingrevealed that the INR was 1.1, and tests for hepati-tis B surface antigen, surface antibody, core IgM,and hepatitis A antibody were negative. A poly-merase chain reaction (PCR) assay was negative forhepatitis C virus. A PCR assay for cytomegalovirusand serologic testing for the EpsteinBarr viruswere also unremarkable. Acetaminophen and sa-licylate 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 anIgG level of 1740 mg per deciliter (reference range,620 to 1520), with normal IgA and IgM levels.

A titer for antismooth-muscle antibody was lessthan 1:20, and testing was negative for antinucle-ar antibodies and antibodies against liverkidneymicrosome type 1. Doppler ultrasonography ofthe right upper quadrant revealed patent hepatic

vasculature and unremarkable liver parenchymawithout masses. The gallbladder had nonspecificwall thickening that was probably due to under-distention, and there was no evidence of stone orsludge. There was no apparent intrahepatic or ex-trahepatic biliary dilatation, although the com-mon bile duct was not well visualized.

Given the absence of coagulopathy and encepha-

lopathy, 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 ultraso-

nography make acute biliary obstruction or large-

vessel vascular causes unlikely. Although autoan-

tibodies are absent, hypergammaglobulinemia,

with an IgG predominance, is a feature of auto-

immune hepatitis as well as other inflammatory

disorders. I remain concerned that the patients

statin medication may be implicated.

Given their recognized associations with drug-induced liver injury, the lovastatin and hydro-chlorothiazide were discontinued. The patientremained asymptomatic, with stable amino-transferase levels, and he was discharged fromthe hospital on day 3, with plans for close follow-up in the hepatology clinic. On the day of dis-charge, the aspartate aminotransferase level was1588 U per liter, alanine aminotransferase 2483 Uper liter, alkaline phosphatase 503 U per liter, totalbilirubin 7.8 mg per deciliter (133 mol per liter),and INR 1.1.

At this point, I would proceed with another percu-

taneous 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 au-

toimmune hepatitis) can help clarify the cause of

the liver injury. In addition, there may be findings

(e.g., fibrosis) that suggest chronicity of the dis-ease 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 antinu-

clear antibodies and antismooth-muscle anti-

bodies do not rule out autoimmune hepatitis.




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Liver biopsy revealed features of autoimmune hep-atitis with intensely active chronic lobular hepati-tis and active interface hepatitis with plasmacyto-sis (Fig. 1A). Substantial bridging fibrosis was seen(Fig. 1B), in contrast to the prior biopsy, which hadnot shown any fibrosis. No steatosis was observed.

The biopsy findings are consistent with autoim-mune liver injury, and the fibrosis indicates chro-

nicity. Prednisone should be administered and

perhaps azathioprine. The prognosis for a bio-

chemical remission is very good; the majority of

patients with autoimmune hepatitis have bio-

chemical improvement within 2 weeks after the

initiation of immunosuppressive therapy.

Treatment with prednisone and azathioprine wasinitiated. Three months after treatment was initi-ated, the patients liver-enzyme levels had normal-

ized. Prednisone was gradually tapered over a pe-riod of 6 months, and his liver-enzyme levels haveremained normal with azathioprine monotherapyfor more than a year.

COMMENTARY

In contrast to the broad differential diagnosis for

elevations in serum aminotransferase levels that

are less than 5 times the upper limit of the nor-

mal range, the causes of severe aminotransferase

elevations (>20 times the upper limit of the nor-

mal range) are more limited and include Wilsons

disease, acute biliary obstruction, and viral, toxic,

ischemic, and autoimmune hepatitis.1,2Although

generally regarded as a chronic liver disease, au-

toimmune hepatitis is manifested as an acute ill-

ness in about 25% of patients.3,4A retrospective

study showed that acute presentations of autoim-

mune hepatitis have distinct clinical, biochemical,

and histologic features, as compared with the

classic presentation as chronic hepatitis.5

Early diagnosis of autoimmune hepatitis isimportant, since untreated patients, even those

with mild disease, can have progression to cir-

rhosis, and untreated patients have lower 10-year

survival rates than treated patients.3Two 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-

bodies, and type 2 by positive results on testing

for antibodies against liverkidney microsome

type 1 and liver cytosol type 1. Type 2 autoim-

mune hepatitis has been described mainly in chil-

dren 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%.6Autoantibodies develop later in the disease

in some patients who are seronegative on initial

evaluation.7 Autoantibody-negative autoimmune

hepatitis is important to recognize becausepatients 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 autoan-

tibodies, serum IgG concentration, typical histo-

logic features (in particular, a plasma-cellrich

A

B

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 bridgingfibrosis (arrow) in Panel B (Masson trichrome stain).




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n engl j med 367;14 nejm.org october 4, 20121346

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 predni-

sone (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.3Pred-

nisolone 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 maintenanceregimen is then continued until disease resolu-

tion (defined as biochemical remission for a

minimum of 24 months), unless there is treat-

ment failure or drug toxicity.3,4 Relapse after

treatment withdrawal is reported in up to 60%

of patients and is generally treated with a simi-

lar regimen.4

Nonalcoholic fatty liver disease is one of the

most common causes of asymptomatic amino-

transferase elevations and chronic liver disease in

Western countries.9It encompasses a spectrum

of disorders, from simple steatosis to fibrosing

steatohepatitis that can progress to cirrhosis and

its complications, including hepatocellular carci-

noma. Associated features include insulin resis-

tance, central adiposity, dyslipidemia, and hyper-

tension.10 The diagnosis of nonalcoholic fattyliver 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 devel-

opment 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 nonalco-

holic fatty liver disease.

Statins can be safely used in patients with non-

alcoholic fatty liver disease and, in the majority of

patients with this condition, are associated withimprovement 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 af-

ter treatment initiation.13However, as suspected

in this case, these reports may represent the co-

incidental development of a new case of autoim-

mune hepatitis in a patient treated with statins,

rather than autoimmune hepatitis triggered by

statin use.13Relapse after the discontinuation of

immunosuppressive therapy and the presence of

substantial f ibrosis on liver biopsy, as was noted

on the second biopsy in this case, appear to dif-

ferentiate newly developed from drug-induced

autoimmune hepatitis, which is most commonly

associated with the use of nitrofurantoin and

minocycline.14The contribution of nonalcoholic

fatty liver disease to elevated serum aminotrans-

ferase levels may be underrecognized in patients

with other forms of chronic liver disease.15

The present case underscores the need to con-

sider the possibility of other causes of chronic

liver disease in patients with established nonalco-holic fatty liver disease, to recognize the role of

liver biopsy in diagnosis, and to consider the in-

tricate interplay of potential endogenous causes

(e.g., steatosis and immunologic factors) and ex-

ogenous 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 con-flict 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.

Table 1.Simplified Diagnostic Criteria for Autoimmune Hepatitis.*

Criterion Points

Autoantibodies

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

Titer of antinuclear or smooth-muscle antibodies 1:80, or titerof liverkidney microsomal antibodies 1:40, or presence of

antibodies against soluble liver antigen

2

IgG concentration

>Upper limit of the normal range 1

>1.10 times the upper limit of the normal range 2

Liver histologic features

Compatible with autoimmune hepatitis 1

Typical of autoimmune hepatitis 2

Absence of viral hepatitis 2

* Adapted from Hennes et al.8A total score of 6 points indicates probable autoim-mune 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 anecessary condition for the diagnosis of autoimmune hepatitis. Typical featuresof autoimmune hepatitis are interface hepatitis, lymphocytic or lymphoplas-macytic infiltrates in portal tracts and extending into the lobule, and hepaticrosette formation. Compatible features are chronic hepatitis and lymphocyticinfiltrates without all the typical features.




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627-35.Copyright 2012 Massachusetts Medical Society.

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