CASE RECORDS OF TH E MASSACH USET TS GENERA L H OS PITA L

Case Records of the Massachusetts General Hospital

Five weeks before admission, she observed blood clots

Weekly Clinicopathological Exercises
FOUNDED BY RICHARD C. CABOT
R O B E R T E . S C U L L Y , M. D. , Editor
E U G E N E J. M A R K , M. D. , Associate Editor
W I L L I A M F. M C N E E L Y , M. D. , Associate Editor
J O - A N N E O. S H E P A R D , M. D. , Associate Editor
S A L L Y H . E B E L I N G , Assistant Editor
S T A C E Y M. E L L E N D E R , Assistant Editor
C H R I S T I N E C . P E T E R S , Editorial Staff
Case 6-2001
PRESENTATION OF CASE
A 17-year-old girl was admitted to the hospital be-
cause of progressive jaundice and weight loss.
The patient had been well until four months earlier,
when she experienced the onset of malaise, anorexia,
a sore throat, and tender cervical lymph nodes. Two
months later, she ate “hallucinogenic mushrooms.”
in her stool twice on a single day. Three weeks later,
she ate more mushrooms. Progressive jaundice subse-
quently developed, with vomiting, dark urine, and
light stools.
Ten days before admission, laboratory tests were or-
dered by the patient’s physician (Tables 1 and 2). Tests
for viral hepatitis A, B, and C and for heterophil anti-
bodies were negative. Thereafter, she vomited as often
as three times daily. Two days before admission, the
patient returned to her physician. An abdominal ul-
trasonographic study revealed periportal edema and
contraction of the gallbladder; no gallstones or dilat-
ed bile ducts were found. Laboratory tests were per-
formed (Table 2).
On the following day, the patient entered another
hospital. Laboratory tests were performed (Tables
1 and 2). A test for human chorionic gonadotropin
was negative. Vitamin K (10 mg) was injected subcu-
taneously. The next day, she was transferred to this
hospital.
The patient was a high-school student. She took no
prescribed medications. She drank alcohol in “binges”
and on one occasion had been admitted to a treatment
program because of alcohol abuse. She had smoked

TABLE 1. HEMATOLOGIC LABORATORY VALUES.*

10 DAYS BEFORE 1 DAY BEFORE 2ND HOSPITAL 3RD HOSPITAL 4TH HOSPITAL
VARIABLE ADMISSION ADMISSION ON ADMISSION DAY DAY DAY

Hematocrit (%) 40.9 Normal 44.3 42.1

Erythrocyte sedimentation rate 1
(mm/hr)
White-cell count (per mm3) 5,600 Normal 7,500 6,400
Differential count (%)
Neutrophils 64 55
Band forms 4
Metamyelocytes 1
Lymphocytes 23 27
Atypical lymphocytes 1
Monocytes 12 11
Eosinophils 1 1
Platelet count (per mm3) 193,000 273,000 258,000
Prothrombin time (sec)† 14.7 15.6 17.3 15.1
Partial-thromboplastin time 47.7 33.5 39.2 33.6
(sec)‡
Iron (mg/dl) 243
Iron-binding capacity (mg/dl) 307
Ferritin (ng/ml) 636

*To convert the values for iron and iron-binding capacity to micromoles per liter, multiply by 0.1791.
†The normal range is 11.6 to 13.6 seconds at this hospital.
‡The normal range is 22.1 to 34.1 seconds at this hospital.

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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

TABLE 2. BLOOD CHEMICAL AND ENZYME VALUES.*

10 DAYS BEFORE 2 DAYS BEFORE 1 DAY BEFORE 2ND HOSPITAL 3RD HOSPITAL 4TH HOSPITAL
VARIABLE ADMISSION ADMISSION ADMISSION ON ADMISSION DAY DAY DAY

Urea nitrogen (mg/dl) Normal 7

Creatinine Normal Normal
Protein (g/dl) 6.9 6.6
Albumin 3.8 3.5 2.5 2.7 3.2
Globulin 3.4
Ammonia Normal
Bilirubin (mg/dl)
Total 8.4 17.9 22.5 18.2 17.8
Conjugated 12.3 16.1 16.3
Electrolytes Normal Normal
Thyrotropin Normal
Glucose Normal
Calcium Normal
Aspartate aminotransferase 1745 1165 1290 1346 1179 1294
(U/liter)†
Alanine aminotransferase 1236 1452 1183 1115 1103
(U/liter)‡
Alkaline phosphatase (U/liter)§ 234 209 259 Normal 162
Lactate dehydrogenase (U/liter)¶ 354
g-Glutamyltransferase (U/liter)¿ 142

*To convert the value for urea nitrogen to millimoles per liter, multiply by 0.357. To convert the values for conjugated and total bilirubin
to micromoles per liter, multiply by 17.1.
†The normal range is 13 to 39 U per liter at the referring hospital and 9 to 25 at this hospital.
‡The normal range is 7 to 52 U per liter at the referring hospital and 7 to 30 at this hospital.
§The normal range is 34 to 104 U per liter at the referring hospital and 15 to 350 at this hospital.
¶The normal range is 140 to 271 U per liter at the referring hospital.
¿The normal range for the patient’s age is 5 to 40 U per liter at this hospital.

marijuana since the age of 15 years. Her menses were
irregular; her last period had occurred three months
before admission. She reported that there was no pos-
sibility of pregnancy. She had lost about 10 kg in
weight during her illness. A distant paternal relative
had inflammatory bowel disease. The patient had no
history of intravenous drug use or tattooing and did
not have any risk factors for human immunodeficiency
virus infection.
The temperature was 36.3°C, the pulse was 53, and
the respirations were 18. The blood pressure was
80/45 mm Hg.
On examination, the patient was thin and had deep-
ly icteric skin and sclerae. There was no evidence of
chronic liver disease, lymphadenopathy, or Kayser–
Fleischer rings. The lungs and heart were normal. The
liver edge, which was minimally tender, descended
2 cm below the right costal margin; the spleen was
not felt. There was no peripheral edema, digital club-
bing, or cyanosis. Asterixis was not detected, and a
neurologic examination showed no abnormalities. The
patient refused a rectal examination.
Laboratory tests were performed (Tables 1 and 2).
A test of a urine specimen for toxic drugs was positive
for cannabinoids; tests of blood and urine specimens
for more than 100 other toxic agents, including ace-
taminophen, alcohol, and salicylates, were negative.
Vitamin K (10 mg daily) was administered intrave-
nously, and an oral preparation of vitamin E was given.
Fluids and electrolytes were infused intravenously. The
temperature did not exceed 36.8°C on any day, and
the systolic blood pressure ranged from 100 to 115
mm Hg on most occasions. Mild nausea steadily im-
proved. There was no vomiting or hematochezia af-
ter admission, and she continued to have no abdom-
inal pain. Repeated physical examinations revealed no
change.
On the second hospital day, laboratory tests were
performed (Tables 1 and 2). The serum amylase and
lipase levels and the urinary copper level were normal.
An ultrasonographic examination of the abdomen,
performed while the patient was in a nonfasting state,
revealed prominent bile ducts surrounded by hypo-
echoic areas within both hepatic lobes — findings sug-
gestive of mild intrahepatic bile-duct dilatation and
periportal lymphedema; the liver had minimally het-
erogeneous echogenicity. The common bile duct had
a normal caliber (2 mm) at the porta hepatis. The gall-
bladder was contracted, probably because of the pa-
tient’s postprandial state. Scanty free fluid was present

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 CASE RECORDS OF TH E MAS SACH USET TS GENERA L H OS PITA L

A in the subhepatic space. Computed tomographic (CT)

B DR. MAUREEN M. JONAS*: May we review the im-
C tracted and surrounded by fluid, and there is free fluid
Figure 1. Transverse CT Scans of the Abdomen Obtained after
the Oral and Intravenous Administration of Contrast Material.
Areas of low attenuation around the main portal vein (Panel A,
arrow) at the porta hepatis and around the portal triads (Panel B,
arrows) represent lymphedema. The biliary ducts appear nor-
mal, without dilatation. There is a small-to-moderate amount of
ascites in Morison’s pouch (Panel C, arrow).
scans of the abdomen and pelvis (Fig. 1), obtained
after the oral and intravenous administration of con-
trast material, showed a moderate amount of free fluid
in the abdomen and pelvis and periportal hepatic ede-
ma, without definite intrahepatic ductal dilatation.
The gallbladder was contracted and surrounded by a
small amount of ascitic fluid. There was no evidence
of thickening of the bowel wall, obstruction or dilata-
tion of the bowel, or colitis.
On the third hospital day, the patient remained
alert and coherent. Laboratory tests were performed
on this day and the following day (Tables 1 and 2).
A diagnostic procedure was performed.
DIFFERENTIAL DIAGNOSIS
aging studies?
DR. SUDHA ANUPINDI: The ultrasonographic study
of the liver showed decreased echogenicity in the por-
tal triads, suggesting the presence of ductal dilatation
or fluid around the ducts, or both.
The CT scans obtained after the oral and intrave-
nous administration of contrast material show areas
of attenuation around the portal vessels (Fig. 1A and
1B), especially around the main portal vein, indicating
the presence of lymphedema around the ducts rather
than ductal dilatation. The liver is homogeneous, and
there is no evidence of chronic disease. There is fluid
in Morison’s pouch, a finding consistent with the pres-
ence of mild ascites (Fig. 1C). The gallbladder is con-
in the pelvis. All these findings are consistent with an
acute injury of the liver parenchyma.
DR. JONAS: This 17-year-old girl had a two-week
history of vomiting, weight loss, jaundice, and elevated
aminotransferase levels. Her illness on admission can
be described as fulminant hepatitis, since she had se-
vere hepatic dysfunction, evidenced by coagulopathy,
within eight weeks after the first manifestation of liver
disease. Although encephalopathy is common in adults
with fulminant hepatitis, it is less frequent in children
with this type of illness, especially in its early stages.
This patient had no clinical features of chronic liver
disease, such as clubbing, spider angiomas, and sple-
nomegaly. If present, such features might have sug-
gested that her present illness resulted from decom-
pensation of a chronic illness. The abnormalities on
the CT scan are most consistent with the presence of
an inflammatory hepatic process; there is no radio-
graphic evidence of chronic liver disease. The differ-
ential diagnosis in this case is therefore that of acute,
severe hepatic disease in an adolescent (Table 3).
Infectious hepatitis can be fulminant. In the United
States, the pathogens that cause fulminant hepatitis

*Associate in gastroenterology, Children’s Hospital; associate professor

of pediatrics, Harvard Medical School — both in Boston.

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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
TABLE 3. DIFFERENTIAL DIAGNOSIS OF FULMINANT
HEPATITIS IN AN ADOLESCENT.
Infectious hepatitis
Hepatitis A
Hepatitis B
Epstein–Barr virus (infectious mononucleosis)
Genetic and metabolic disorders
Wilson’s disease
Ornithine transcarbamylase deficiency (in a heterozygote)
Impaired fatty acid oxidation
Liver diseases associated with pregnancy
Acute fatty liver of pregnancy
HELLP syndrome (hemolysis, elevated liver-enzyme
levels, and a low platelet count)
Autoimmune hepatitis
Type 1
Type 2
Seronegative hepatitis
Giant-cell hepatitis with autoimmune hemolytic anemia
after infancy
Autoimmune hepatitis with polyglandular autoimmune
syndrome
Overlapping features of autoimmune hepatitis and auto-
immune cholangiopathy
Toxin-mediated hepatic injury
Medications
Herbal preparations
Drugs of abuse
Miscellaneous
Budd–Chiari syndrome
Metastatic disease of the liver
Sepsis
in adolescents are hepatitis B virus, hepatitis A virus,
and Epstein–Barr virus. In this case, serologic tests
were negative for infections with these agents. Al-
though the virus may be rapidly cleared in patients
with fulminant hepatitis B virus infection, serologic
evidence of infection is usually found at presentation.
Acute infection with hepatitis A virus is characterized
by the presence of IgM antibodies to hepatitis A virus
in the serum, even if the disease is fulminant on pres-
entation. Thus, these infections are unlikely in this
case. Although the patient’s current illness is sugges-
tive of infectious mononucleosis, the episode resem-
bling mononucleosis occurred four months earlier.
The absence of both heterophil antibodies and atyp-
ical lymphocytosis is evidence against the diagnosis of
hepatitis due to infection with Epstein–Barr virus.
Also, her disease does not resemble either the mild
form of hepatitis that is often seen in patients with
infectious mononucleosis or the fulminant form with
erythrophagocytosis and a rapid onset of multiorgan
failure, which is much less common.
Genetic and metabolic disorders may be manifested
initially as fulminant hepatitis. In adolescents, the most
common of these disorders is Wilson’s disease. Al-
though patients with Wilson’s disease are more likely
to present with chronic liver disease or an asymptomat-
ic aminotransferase elevation, or with a neuropsychi-
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atric disorder in the case of older persons, a fulminant
illness is occasionally encountered.1,2 It is typically
characterized by severe hepatic dysfunction, hemolytic
anemia with a negative Coombs’ test, renal insufficien-
cy, hypouricemia, a low level of serum alkaline phos-
phatase, and markedly increased excretion of urinary
copper, with progression to death over a period of sev-
eral days unless liver transplantation is performed. Kay-
ser–Fleischer rings are not always found, but their
presence strongly supports the diagnosis. The normal
urinary copper excretion in this patient effectively rules
out the diagnosis of fulminant Wilson’s disease. A fe-
male child or adolescent who is heterozygous for a
deficiency of ornithine transcarbamylase, a urea-cycle
enzyme, may present with fulminant hepatic disease
suggestive of Reye’s syndrome, but marked jaundice
is uncommon, and adolescents with the disorder usu-
ally have a history of similar episodes. Other metabolic
disorders, which are typically found in younger chil-
dren, are unlikely in this case because of the absence
of radiographic evidence of a fatty liver, hepatomeg-
aly, hypoglycemia, acidosis, and hyperammonemia.
Acute, severe liver diseases associated with pregnan-
cy,3 such as acute fatty liver of pregnancy and the
HELLP syndrome (hemolysis, elevated liver-enzyme
levels, and a low platelet count), are typically seen in
the third trimester or at the end of the second trimes-
ter. Pregnancy was ruled out in this patient.
Patients with autoimmune liver diseases may also
present with fulminant hepatitis. These disorders are
chronic but occasionally have no overt manifestations
until an acute, severe form develops that is indistin-
guishable from fulminant hepatitis.4,5 Type 1 autoim-
mune hepatitis, the most common of these disorders,
has a peak incidence in adolescence and is more com-
mon in females than in males. It is characterized by
hypergammaglobulinemia and the presence of anti-
nuclear antibodies, anti–smooth-muscle antibodies, or
both in the serum. Type 2 autoimmune hepatitis usu-
ally occurs in young children of either sex. It is classi-
fied as autoimmune hepatitis because of the presence
of anti–liver/kidney microsomal antibodies in the se-
rum. Type 3 autoimmune hepatitis, which is charac-
terized by the presence of antibodies to soluble liver
antigen, is the least common type. Seronegative auto-
immune hepatitis is indistinguishable clinically and his-
tologically from type 1 autoimmune hepatitis. Patients
with these disorders may present with markedly ele-
vated serum aminotransferase levels and coagulopathy.
Autoimmune cholangiopathy, such as primary scleros-
ing cholangitis, is usually a more indolent process,
without marked jaundice and coagulopathy except in
the final stages of the disease. However, cases with fea-
tures of both primary sclerosing cholangitis and auto-
immune hepatitis have been described.6
Autoimmune liver disease should be considered in
this case, since the patient had rectal bleeding, consid-
erable weight loss, and a family history of inflammatory
 CASE RECORDS OF TH E MAS SACH USET TS GENERA L H OS PITA L
bowel disease. The association between autoimmune
liver disease and inflammatory bowel disease is well es-
tablished, but there was no clinical or radiographic
evidence of the latter disorder in this case. Common
radiographic findings in acute autoimmune hepatitis
include hepatomegaly with heterogeneous echogenic-
ity, as in this case, but also splenomegaly and peripor-
tal lymphadenopathy, which were not present in this
case. Also, the patient’s marked jaundice, the absence
of hypergammaglobulinemia, and the improvement in
chemical and hematologic laboratory values during the
first few days of hospitalization are not characteristic
of autoimmune hepatitis. The diagnoses of post-infan-
tile hepatitis with hemolytic anemia and autoimmune
polyglandular syndrome are not relevant in this case.
Nonetheless, tests for the autoantibodies I have men-
tioned would have been useful in order to rule out
the more common types of autoimmune hepatitis.
Miscellaneous causes of fulminant hepatitis, which
have been ruled out in this patient, include the Budd–
Chiari syndrome (hepatic venous outflow obstruc-
tion), metastatic infiltration of the liver, and sepsis.
The last broad category of disease to be considered
is toxin-mediated liver injury. Hepatotoxic substances
to which an adolescent may be exposed include med-
ications, herbal preparations, and drugs of abuse. This
patient has a history of recreational substance abuse.
She reported or had biochemical evidence of binge
drinking, ingestion of hallucinogenic mushrooms, and
use of marijuana. In addition, substances not indicated
in the patient’s history must be considered. The neg-
ative results of a screening test for prescribed or illicit
drugs are not definitive because the test may not screen
for all potentially hepatotoxic drugs, and in this case,
it was performed at least 12 days after the signs and
symptoms of liver disease first appeared. Drug-induced
liver disease is often a diagnosis of exclusion if the pa-
tient does not report exposure to the drug and if tox-
icologic testing does not show evidence of the drug or
its metabolites. Thus, as in this case, an extensive eval-
uation may fail to identify a specific cause.
There are several patterns of acute toxin-induced
liver disease.7 Some agents cause acute injury of hep-
atocytes, which can result in massive or submassive he-
patic necrosis. Acinar zone 3 (pericentral) necrosis is
characteristic of many toxic injuries, but zone 1 (peri-
portal) injury occurs in some cases. Chronic hepato-
cellular injury may result from exposure to certain tox-
ins over a period of months or years, leading to chronic
hepatitis with fibrosis and even cirrhosis. A pattern of
microvesicular steatosis is characteristic of liver injury
due to toxins such as valproic acid or aspirin, and mac-
rovesicular steatosis is associated with injury due to al-
cohol or methotrexate. Pure cholestasis, without hep-
atocellular injury, although uncommon, can be caused
by anabolic or contraceptive steroids. Some drugs and
toxins cause both hepatocellular and bile-duct injury,
and ductopenia occasionally ensues. Some toxins cause
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primary vascular damage such as peliosis hepatis, veno-
occlusive disease, and vasculitis; others cause granulo-
matous reactions. Thus, if toxin-mediated liver disease
is suspected, histologic examination of the liver may
suggest the type of toxin8 and may provide important
clues to the type and duration of exposure and injury.
In the United States, the most common cause of
drug-associated fulminant hepatitis is an overdose of
acetaminophen. The overdose is usually intentional,
representing a suicide attempt, in adolescents and
adults, with occasional accidental overdoses in in-
fants and young children.9 In patients with chronic al-
coholism, an overdose of acetaminophen or smaller
doses of acetaminophen ingested over a period of
months or years may cause irreversible hepatic in-
jury10 because chronic induction of cytochrome P-450
oxidative pathways by alcohol leads to overproduc-
tion of the toxic acetaminophen metabolite N-acetyl-
p-benzoquinonimine. Starvation, through depletion
of glutathione stores, increases the risk of acetamin-
ophen hepatotoxicity. Although this patient reported
binge drinking, she did not have a history of chronic
ingestion. She was malnourished, at least at the time
of presentation. The negative test for acetaminophen
does not rule out an overdose, especially since the test
was performed long after the onset of symptoms.
Some of the symptoms were characteristic of aceta-
minophen overdose, including nausea and vomiting
followed by signs of hepatic injury, but there was no
evidence of the involvement of other organs, such as
renal failure, and there was no history of a suicide at-
tempt. Finally, the full extent of hepatocellular dys-
function is usually apparent two to four days after an
acetaminophen overdose.9 For these reasons, the di-
agnosis is unlikely in this case, but it must be ruled
out since effective therapy (acetylcysteine) is available.
This patient had a strong history of recreational
drug use, and several drugs and substances of abuse
may cause considerable hepatic injury. These include
ethanol, cocaine, solvents ingested by inhalation (glue
sniffing) such as toluene and trichloroethylene,11 phen-
cyclidine (angel dust),12 and 3,4-methylenedioxy-
methamphetamine (MDMA), also known as ecstasy.
Although hallucinogenic mushrooms have neuropsy-
chiatric toxic effects, they are usually not hepatotoxic.
Amateur collectors of wild mushrooms for cooking
may accidentally ingest hepatotoxic mushrooms, such
as the amanita and lepiota varieties, leading to an acute
gastrointestinal illness followed by severe hepatic in-
jury within a day or two.13,14
Chronic alcoholism can lead to a spectrum of liver
diseases, ranging from mild steatosis to cirrhosis and its
complications to fulminant hepatic failure. The acute
disorder (alcoholic hepatitis)15 is characterized by hep-
atomegaly, jaundice, anorexia, weight loss, weakness,
and other signs and symptoms to a variable extent.
Laboratory manifestations include leukocytosis, mac-
rocytic anemia, and slight aminotransferase elevations,
 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne
usually with higher values for aspartate aminotrans-
ferase than for alanine aminotransferase. This poten-
tially fatal disorder is usually associated with long-term
ingestion of alcohol rather than binge drinking.
In the mid-1980s, the hepatotoxic effects of cocaine
overdoses were reported.16 In most cases, the liver
damage was part of a syndrome that included rhabdo-
myolysis (which itself can cause increases in the levels
of both aspartate aminotransferase and alanine amino-
transferase), disseminated intravascular coagulation,
hypotension, hypoxemia, and hyperpyrexia, with a his-
tologic pattern of centrilobular necrosis, often asso-
ciated with microvesicular steatosis.17 Since this patient
had none of the other manifestations of cocaine hep-
atotoxicity and since it is usually not an isolated ab-
normality, cocaine hepatotoxicity is an unlikely cause
of her illness.
MDMA is a synthetic stimulant and hallucinogen
related to amphetamine, methamphetamine, and mes-
caline. Illicit use of MDMA originated in Great Brit-
ain and other parts of Europe; became popular in the
late 1980s and early 1990s, most often at late-night
parties (called raves), rock concerts, and nightclubs;
and has been increasing steadily in both urban and
suburban areas of the United States. The drug is most
commonly available in tablet form but is also available
as a powder, which may be snorted or smoked but
is rarely injected. The number of seizures of MDMA
tablets submitted to the laboratories of the Drug
Enforcement Administration increased from 196 in
1993 to more than 216,300 in the first five months
of 1999.18
MDMA causes a syndrome similar to that caused
by cocaine, with fulminant hyperthermia, disseminated
intravascular coagulation, rhabdomyolysis, and acute
renal failure.19 Occasionally, severe dehydration leads
to excessive fluid intake and water intoxication.20 Se-
vere hepatotoxic effects may be part of this general
syndrome.21 MDMA is metabolized by the cyto-
chrome CYP2D6. Rats with a deficiency of this en-
zyme have an elevated thermal response to MDMA,22
suggesting that persons with a genetic deficiency of
CYP2D6 (5 percent of whites) may be predisposed
to MDMA-related hyperthermia and liver disease.
Either sporadic or regular ingestion of MDMA may
have isolated, severe acute hepatotoxic effects 23 over
a period of days or weeks.24 Repeated episodes of liver
damage have been reported.25 The damage may be
fatal, and urgent liver transplantation has been per-
formed in some cases.26
Two types of MDMA toxicity have been described.
One type is similar to cocaine toxicity, with acute, pro-
found systemic effects such as hyperthermia, rhabdo-
myolysis, and renal failure and with the development
of severe liver injury shortly after ingestion. The sec-
ond type, apparently unrelated to hyperthermia, is
characterized by delayed, sometimes fulminant, hep-
atitis, without other systemic manifestations. MDMA
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can be detected by toxicologic screening in cases of
acute but not delayed toxicity; in cases of delayed tox-
icity, it is uncertain whether MDMA or one or more
of its metabolites are responsible.
Liver-biopsy specimens are characterized by central
and midzonal necrosis in patients with the acute, sys-
temic type of MDMA toxicity and by massive necrosis
or focal necrosis with inflammation in patients with
delayed, isolated hepatotoxic effects.20 Steatosis may
be present, and eosinophilic infiltration of tissue occurs
in some cases, suggesting an immune mechanism.
Other chemicals with direct hepatotoxic effects are
also associated with eosinophilia, including methylene-
dianiline, a compound related to MDMA that caused
the so-called Epping jaundice in Britain in the 1960s,
and aniline-denatured rapeseed cooking oil, which
causes the toxic oil syndrome.
The widespread abuse of MDMA makes it an im-
portant cause of hepatic injury. Because the liver inju-
ry may be delayed and may not be accompanied by
the systemic features of MDMA use, toxic effects of
this drug should be suspected in young adults who
have a hepatitis-like illness without another obvious
cause. This patient may have presented with delayed
hepatotoxic effects after ingesting MDMA.
CLINICAL DIAGNOSES
? Autoimmune hepatitis.
? Toxic hepatitis.
DR. MAUREEN M. JONAS’S DIAGNOSIS
Fulminant hepatitis (delayed type) associated with
the use of 3,4-methylenedioxymethamphetamine
(ecstasy).
PATHOLOGICAL DISCUSSION
DR. FIONA M. GRAEME-COOK: The diagnostic
procedure was a percutaneous liver biopsy. Microscop-
ical examination of the specimen revealed evidence of
acute cholestatic hepatitis. The hepatocytes in zone 3
were enlarged, with feathery degeneration of their cy-
toplasm, indicative of intracellular cholestasis (Fig. 2).
Canalicular bile casts were also evident throughout the
lobule (Fig. 3). Doubling of the hepatic cords with
rosette formation, which was most apparent in zone
2 (between the periportal and pericentral zones), and
scattered mitoses throughout the lobules (Fig. 4) were
evidence of regeneration. Moderate hepatic necrosis
was present in all three zones in the form of acido-
phil bodies and spotty foci of necrosis surrounded by
inflammatory cells. The portal tracts were expanded,
with an extensive collapse of reticulin fibers in zone
1 (Fig. 5), and reactive changes included prominent
cholangioles and inflammatory-cell infiltration. The
portal tracts were edematous and contained a mod-
erate inflammatory-cell infiltrate composed of many
eosinophils and histiocytes (Fig. 6).
These changes are diagnostic of acute cholestatic
 CASE RECORDS OF TH E MAS SACH USET TS GENERA L H OS PITA L

Figure 2. Enlarged Hepatocytes in Zone 3 (Hematoxylin and

Eosin, ¬150). Figure 3. Canalicular Bile Plugs (Arrows) and Feathery Degen-
The cytoplasm is bubbly, with feathery degeneration indicative eration of Hepatocytes (Perl’s Iron Stain, ¬300).
of intracellular cholestasis.

hepatitis. Although it may be associated with viral
infection, the combined findings of cholestasis, cho-
langitis, eosinophils, and histiocytes constitute strong
evidence of a hypersensitivity reaction, probably a
reaction to drugs. Extensive necrosis, predominantly
in zone 3, with widespread steatosis is characteristic
of the toxic effects of mushroom ingestion.14 Alcohol-
ic liver disease is recognized by the combination of
steatosis, Mallory’s hyaline bodies, and neutrophilic
steatonecrosis with polymorphonuclear-cell infiltra-
tion. Although alcoholism is occasionally associated
with a cholestatic syndrome, the characteristic histo-
logic findings in patients with alcoholism, including
bile plugs in ductules, are absent in this case. Mari-
juana is not associated with any recognizable hepatic
injury. The pattern of hepatic injury in this case is
not characteristic of any of the drugs this patient re-
ported using except MDMA.
MDMA may also cause hyperpyrexia with liver fail-
ure. In the initial fatal cases, massive hepatic necrosis
with microvesicular steatosis, a finding consistent with
the presence of heat stroke, was reported.20 Subse-
quently, a spectrum of liver diseases unassociated
with hyperpyrexia have been reported in users of
MDMA.21,24,25 The clinical spectrum has ranged from
a mild, self-limited illness to death, and the patholog-
ical changes have ranged from mild cholestatic hepa-
titis to submassive necrosis with nodular regeneration.
Variability in the duration of drug use, the absence of
a correlation between the dose and hepatic changes,
and the presence of eosinophils suggest a hypersen-
sitivity or idiosyncratic drug reaction. In rare cases,
hepatitis has been reported after a single dose of
MDMA, but the recurrence of hepatitis with repeat-
ed use of the drug is consistent with an immune mech-
anism. Although most cases of MDMA-related liver
damage without fulminant hepatic failure have eventu-
ally resolved, rare cases have evolved into chronic liver
disease, sometimes associated with hepatic scarring.
DR. ROBERT E. SCULLY: Dr. Hoppin, would you
give us follow-up information on the patient?
DR. ALISON G. HOPPIN: Because the liver findings
were more consistent with toxic injury than with au-
toimmune hepatitis, we specifically asked the patient
whether she had taken MDMA. She had taken it on
several occasions during the previous two months and

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 The Ne w E n g l a nd Jo u r n a l o f Me d ic i ne

Figure 4. Diffusely Thickened Hepatic Cords and a Mitotic Fig-

ure (Arrow) Indicative of Regeneration (Hematoxylin and
Eosin, ¬150).

Figure 6. Portal Tract Containing Eosinophils (Short Arrow) and

Histiocytes with Damaged Bile Duct (Long Arrow) (Hematoxy-
lin and Eosin, ¬150).
The liver parenchyma has a regenerative pattern. An apoptotic
hepatocyte is indicated by the arrowhead.

as recently as a week before admission, when she al-

ready had jaundice. She agreed that she would no
longer use the drug, but she is prone to high-risk be-
havior and may have related health problems in the
future.
Within 24 hours after the liver biopsy, the patient’s
liver-enzyme levels and coagulopathy had begun to
improve. Her liver function has subsequently been
normal.
DR. SCULLY: What is the usual prognosis for pa-
tients with this condition?
DR. JONAS: Some patients have died, some have
required liver transplantation because of fulminant
hepatitis, and some have recovered with only sup-
portive care provided.
ANATOMICAL DIAGNOSIS
Figure 5. Paraportal Collapse of Reticulin Fibers, Indicating Pa- Acute cholestatic hepatitis associated with the use of
renchymal Necrosis (Arrows) (Foot’s Reticulin Stain, ¬80). 3,4-methylenedioxymethamphetamine (ecstasy).

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 CASE RECORDS OF TH E MAS SACH USET TS GENERA L H OS PITA L

REFERENCES American mushrooms, with particular emphasis on Amanita phalloides-like

1. McCullough AJ, Fleming CR, Thistle JL, et al. Diagnosis of Wilson’s
disease presenting as fulminant hepatic failure. Gastroenterology 1983;84:
161-7.
2. Walia BN, Singh S, Marwaha RK, Bhusnurmath SR, Dilawari JB. Ful-
minant hepatic failure and acute intravascular haemolysis as presenting
manifestations of Wilson’s disease in young children. J Gastroenterol Hepa-
tol 1992;7:370-3.
3. Knox TA, Olans LB. Liver disease in pregnancy. N Engl J Med 1996;
335:569-76.
4. Gregorio GV, Portmann B, Reid F, et al. Autoimmune hepatitis in child-
hood: a 20-year experience. Hepatology 1997;25:541-7.
5. Ben-Ari Z, Broida E, Monselise Y, et al. Syncytial giant-cell hepatitis
due to autoimmune hepatitis type II (LKM1+) presenting as subfulminant
hepatitis. Am J Gastroenterol 2000;95:799-801.
6. Boberg KM, Fausa O, Haaland T, et al. Features of autoimmune hepa-
titis in primary sclerosing cholangitis: an evaluation of 114 primary scleros-
ing cholangitis patients according to a scoring system for the diagnosis of
autoimmune hepatitis. Hepatology 1996;23:1369-76.
7. Zimmerman HJ, Ishak KG. General aspects of drug-induced liver dis-
ease. In: Lewis JH, ed. Drug-induced liver disease. Vol. 24. Philadelphia:
W.B. Saunders, 1995:739-58.
8. Ishak KG, Zimmerman HJ. Morphologic spectrum of drug-induced he-
patic disease. In: Lewis JH, ed. Drug-induced liver disease. Vol. 24. Phil-
adelphia: W.B. Saunders, 1995:759-86.
9. Makin AJ, Wendon J, Williams R. A 7-year experience of severe aceta-
minophen-induced hepatotoxicity (1987-1993). Gastroenterology 1995;
109:1907-16.
10. Seeff LB, Cuccherini BA, Zimmerman HJ, Adler E, Benjamin SB.
Acetaminophen hepatotoxicity in alcoholics: a therapeutic misadventure.
Ann Intern Med 1986;104:399-404.
11. Meadows R, Verghese A. Medical complications of glue sniffing.
South Med J 1996;89:455-62.
12. Armen R, Kanel G, Reynolds T. Phencyclidine-induced malignant hy-
perthermia causing submassive liver necrosis. Am J Med 1984;77:167-72.
13. Lampe KF, McCann MA. Differential diagnosis of poisoning by North
intoxication. Ann Emerg Med 1987;16:956-62.
14. Ramirez P, Parilla P, Sanchez-Bueno F, et al. Fulminant hepatic failure
after Lepiota mushroom poisoning. J Hepatol 1993;19:51-4.
15. Mendenhall CL. Alcoholic hepatitis. In: Schiff L, Schiff ER, eds. Dis-
eases of the liver. 7th ed. Vol. 2. Philadelphia: J.B. Lippincott, 1993:856-
74.
16. Perino LE, Warren GH, Levine JS. Cocaine-induced hepatotoxicity in
humans. Gastroenterology 1987;93:176-80.
17. Wanless IR, Dore S, Gopinath N, et al. Histopathology of cocaine
hepatotoxicity: report of four patients. Gastroenterology 1990;98:497-
501.
18. MDMA (ecstasy). Washington, D.C.: Department of Justice, Drug
Enforcement Administration, 1999.
19. Henry JA, Jeffreys KJ, Dawling S. Toxicity and deaths from 3,4-meth-
ylenedioxymethamphetamine. Lancet 1992;340:384-7.
20. Milroy CM, Clark JC, Forrest ARW. Pathology of deaths associated
with “ecstasy” and “eve” misuse. J Clin Pathol 1996;49:149-53.
21. Ellis AJ, Wendon JA, Portmann B, Williams R. Acute liver damage and
ecstasy ingestion. Gut 1996;38:454-8.
22. Colado MI, Williams JL, Green AR. The hyperthermic and neurotoxic
effects of “ecstasy” (MDMA) and 3,4 methylenedioxyamphetamine
(MDA) in the dark agouti (DA) rat, a model of the CYP2D6 poor metab-
olizer phenotype. Br J Pharmacol 1995;115:1281-9.
23. Dykhuizen RS, Brunt PW, Atkinson P, Simpson JG, Smith CC. Ecsta-
sy induced hepatitis mimicking viral hepatitis. Gut 1995;36:939-41.
24. Andreu V, Mas A, Bruguera M, et al. Ecstasy: a common cause of se-
vere acute hepatotoxicity. J Hepatol 1998;29:394-7.
25. Fidler H, Dhillon A, Gertner D, Burroughs A. Chronic ecstasy (3,4-
methylenedioxymethamphetamine) abuse: a recurrent and unpredictable
cause of severe acute hepatitis. J Hepatol 1996;25:563-6.
26. Brauer RB, Heidecke CD, Nathrath W, et al. Liver transplantation for
the treatment of fulminant hepatic failure induced by the ingestion of ec-
stasy. Transpl Int 1997;10:229-33.
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