CASE REPORTS
Refer to: Fuller CM, Yassinger S, Donlon P, et al: Haloperidol-
induced liver disease. West J Med 127:515-518, Dec 1977
Haloperidol-Induced
Liver Disease
COLIN M. FULLER, MD
SIDNEY YASSINGER, MD
PATRICK DONLON, MD
THOMAS J. IMPERATO, MD
BORIS RUEBNER, MD
Sacramento
HALOPERIDOL, a widely used neuroleptic, is a
butyrophenone drug with phenothiazine-like prop-
erties useful in the management of psychosis. Ad-
verse reactions attributed to haloperidol include
effects on the extrapyramidal system including
parkinsonian symptoms and tardive dyskinesia,
agranulocytosis and limb malformations in the
fetus when the drug is taken during the first tri-
mester of pregnancy.' Liver dysfunction has previ-
ously been reported only as a rare complication
of haloperidol therapy. Since 1967 we are un-
aware of any published reports -of haloperidol
hepatotoxicity. In this report, two cases are de-
scribed in which significant hepatic dysfunction
developed while patients were being treated with
haloperidol.
Methods
Routine laboratory tests were done in Sacra-
mento Medical Center-University of California,
Davis, clinical laboratory. Serum glutamic oxalo-
acetic transaminase (SGOT) and serum glutamic
pyruvic transaminase (SGPT) values were deter-
mined by the methods of Henry2 (normal ranges
for SGOT and SGPT are 0 to 20 units per liter and
0 to 15 units per liter, respectively). Serum alka-
line phosphatase was determined by the method
of McComb and Bowers (normal range 20 to 80
units per liter).3 Serum bilirubin was determined
by the Jendrassick-Grof method.4 Hepatitis B
surface antigen was determined by radioimmuno-
From Section of Gastroenterology, Department of Internal
Medicine and the Departments of Psychiatry and Pathology, Uni-
versity of California, Davis, School of Medicine, Sacramento
Medical Center, Sacramento.
Submitted February 23, 1977.
Reprint requests to: Sidney Yassinger, MD, Department of
Internal Medicine, Section of Gastroenterology, UCD Professional
Building, 4301 X Street, Sacramento, CA 95817.
assay (Ausria 11-125 kits, Abbott Laboratories,
North Chicago, Illinois).
Material from the percutaneous liver biopsy
specimens was fixed in 10 percent formalin and
routinely processed for light microscopy. Sections
were stained with hematoxylin and eosin,5 Gold-
ner-Foot's modification of Masson's trichrome
stain,6 Lillie's reticulum stain7 and Mallory's
stain for iron.5
Reports of Cases
PATIENT 1. A 33-year-old chronically schizo-
phrenic woman was followed for five years as an
outpatient before admission. During that time she
received various neuroleptic agents including
haloperidol, fluphenazine and benztropine mesy-
late. Three months before the patient's admission,
overt psychotic behavior developed and she was
treated with fluphenazine and benztropine mesy-
late, with resolution of psychotic symptoms. Two
weeks later a generalized erythematous rash de-
veloped at which time administration of fluphena-
zine and benztropine mesylate was discontinued
and therapy with thiothixene was started. Psy-
chotic decompensation again recurred, and halo-
peridol was substituted for thiothixene. For the
first two weeks of haloperidol therapy, benztro-
pine mesylate was administered for control of
extrapyramidal symptoms, and then this treat-
ment was discontinued. Maintenance haloperidol
usage was 40 mg per day. Results of liver function
tests were normal at the start of haloperidol
therapy. Five weeks after initiation of treatment
with haloperidol, the patient complained of
anorexia, nausea, vomiting, lethargy, fever and
lower extremity rash. The following test values
were obtained: total bilirubin, 4.2 mg per 100
ml; SGOT 100 IU per liter; and SGPT, 130 IU per
liter. Haloperidol therapy was discontinued. Be-
cause symptoms persisted, the patient was ad-
mitted to hospital five days later. She said there
was no previous history of similar symptoms,
jaundice, recent surgical operation or general
anesthesia, other medications, ethanol use or
illicit intravenous drug use. The patient had dis-
continued the use of oral contraceptives three
months before the onset of her illness. She had
been in contact six months previously with a per-
son said to have had hepatitis.
On physical examination, the patient appeared
to be in a toxic condition though nonicteric. Tem-
perature was 38°C (100.4°F); blood pressure
supine was 120/80 mm of mercury, and sitting
THE WESTERN JOURNAL OF MEDICINE 515
 CASE REPORTS
Figure 1.-(Case 1) Note edema and massive infiltra-
tion of inflammatory cells, predominantly eosinophils,
in the vicinity of portal bile ducts. Hematoxylin and
eosin stain, reduced from X400.
it was 80/40 mm of mercury; pulse supine was
100, sitting 120; and respirations 14. There was
a general red erythematous macular rash over the
lower extremities and palms. On examination of
the abdomen, mild right upper quadrant tender-
ness was noted, but no liver or splenic enlarge-
ment. The remainder of the examination gave un-
remarkable findings.
Laboratory studies gave the following values:
hematocrit, 39.3 percent; leukocyte count, 12,800
with 29 percent polymorphonuclear neutrophils,
20 percent band forms, 48 percent lymphocytes
and 3 percent eosinophils; platelet count and pro-
thrombin time, normal; serum sodium, 136 mEq
per liter; potassium, 3.2 mEq per liter; bicarbo-
nate, 31 mEq per liter; chloride, 96 mEq per liter;
blood urea nitrogen, 9 mg per 100 ml; glucose,
120 mg per 100 ml; total bilirubin, 2.5 mg per 100
ml; conjugated fraction, 1.5 mg per 100 ml; SGPT,
100 IU per liter; alkaline phosphatase, 486 IU per
liter, and hepatitis B surface antigen, negative.
Intravenous replacement of volume deficit was
given and the patient's condition improved. A
liver biopsy was done on the second hospital day
and the specimen showed a normal general archi-
tecture. There was pronounced edema of the
portal triads with a heavy infiltrate of esosino-
phils, polymorphonuclear leukocytes and occa-
sional mononuclear cells (Figure 1). A few small
areas of necrosis were noted throughout the
parenchyma. The pathological impression was that
the changes represented a hypersensitivity reac-
tion, predominantly cholestatic, but also hepato-
516 DECEMBER 1977 * 127 * 6
cellular. The patient was discharged and followed
in the outpatient clinic on a regimen of loxapine.
All symptoms resolved and liver function tests
returned to normal. Subsequent double-dose
cholecystography failed to visualize the gallblad-
der, but intravenous cholangiography showed a
normal biliary ductal system.
PATIENT 2. A 27-year-old woman was referred
to UC Davis-Sacramento Medical Center because
of jaundice. She had been entirely well until Janu-
ary 1976, when she was admitted to hospital with
an acute paranoid schizophrenic reaction. She was
treated with haloperidol in doses up to 20 to 25
mg per day and her condition improved. After 11
days of haloperidol therapy, she discontinued tak-
ing the medication because of dry mouth and
blurred vision. Psychotic symptoms recurred and
haloperidol was reinstituted along with benztro-
pine mesylate. Four weeks after the initial dose
of haloperidol, painless jaundice, dark-colored
urine and acholic stools were noted. She said she
was taking no other medications and that there
was no history of alcohol or drug abuse, previous
jaundice, hepatitis, gallbladder disease or abdomi-
nal surgical procedures. She was admitted to a
local hospital and haloperidol therapy was dis-
continued. Total bilirubin was found to be 10.4
mg per 100 ml and serum alkaline phosphatase
was 360 units per liter; results of other chemical
studies, including SGOT and serum cholesterol de-
terminations, were within normal limits. Ultra-
sound examination showed no evidence of gall-
bladder enlargement or dilatation of the biliary
tree. She was then transferred to UC Davis-Sacra-
mento Medical Center for further evaluation.
On physical examination the patient was afeb-
rile and icteric. There were no stigmata of chronic
liver disease. The heart and lungs were normal.
The liver was 9 cm in length and the edge was
nontender. The spleen was not palpable. There
was no peripheral edema. The remainder of the
physical examination showed no abnormalities.
Laboratory studies, including a normal com-
plete blood count and differential, gave the fol-
lowing values: SGOT, 85 IU per liter; total bili-
rubin, 15.8 mg per 100 ml; conjugated fraction,
8.1 mg per 100 ml; alkaline phosphatase, 310
IU per liter; serum cholesterol, 300 mg per liter;
serum albumin, 4.2 grams per 100 ml; hepatitis B
surface antigen, negative.
In order to rule out extrahepatic biliary obstruc-
tion, endoscopic retrograde cholangiopancreatog-
 CASE REPORTS
Figure 2.-(Case 2) Note bile plugs (arrow) in cana-
liculi. Mallory's stain for iron, reduced from X1,000.
raphy was carried out. A normal biliary tree was
visualized. Percutaneous liver biopsy showed a
normal overall architecture. The portal triads
showed a scanty inflammatory infiltrate composed
of round cells. There were moderate numbers of
bile plugs in canaliculi (Figure 2), predominantly
in central zones. There was no hepatocellular ne-
crosis, granulomas or neoplasia. A diagnosis of
drug-induced intrahepatic cholestasis was made.
The patient was discharged to the care of her pri-
vate physician and within four weeks, the jaundice
abated.
Discussion
Before 1967 there were 21 reported cases of
liver dysfunction associated with haloperidol ther-
apy. Jaundice was not observed in all of the cases,
and in none was a liver biopsy performed. In
1966, Gerle critically reviewed the first 18 cases
from a patient population of 12,600 and sug-
gested that haloperidol therapy could only be im-
plicated in two of them.8 Crane added three more
cases in 1967, and concluded that the incidence
of this disorder was approximately two per one
thousand cases.9 Ebert felt these incidence figures
were similar to those for viral hepatitis, and there-
fore a distinction could not be made.'0 In 1972
Ayd suggested that the development of jaundice
in a patient receiving haloperidol was not a con-
traindication to retreatment with the drug."
Our two cases of presumed haloperidol-induced
liver dysfunction with jaundice appear to be the
first reported with liver biopsy confirmation. The
finding of edema and a heavy infiltrate of eosino-
phils in the portal triads of the liver biopsy in case
1 is consistent with hypersensitivity-induced cho-
lestasis. In this patient, the development of a rash,
fever, leukocytosis and eosinophilia are consistent
with hypersensitivity. The elevation of alkaline
phosphatase with mild hyperbilirubinemia is in
keeping with a predominantly cholestatic reaction.
The slight focal hepatic necrosis and the mild ele-
vations of SGOT and SGPT levels indicate mild
hepatocellular damage. The close temporal rela-
tion between haloperidol therapy and the appear-
ance of hepatic dysfunction as well as the absence
of reported cases of drug-induced liver injury with
fluphenazine, benztropine or thiothixene suggest
that haloperidol may have been responsible for
this hypersensitivity reaction.
Case 2 presented classic symptoms and signs of
cholestatic jaundice. Extrahepatic biliary obstruc-
tion was ruled out by a normal biliary tree at
endoscopic retrograde cholangiopancreatography.
Other drugs which can cause cholestatic features,
such as analgesics, antiarthritics, antibiotics, seda-
tives, anticonvulsants, thyroid medications, anti-
hypertensives, diuretics and hormonal agents had
not been administered. The development of jaun-
dice shortly after initiation of haloperidol therapy
and its resolution soon after its discontinuance
suggests a cause-and-effect relation between halo-
peridol and the cholestasis.
These two cases represent the two histologic
types of hepatic lesions seen in hypersensitivity
cholestasis." Our first case also showed some
hepatocellular damage. These two cases, there-
fore, show both cholestatic and hepatitic sensi-
tization reactions. It is well established that some
drugs may cause either response on different oc-
casions,'3 as is reported here. Other drugs that
can cause either a hepatic or cholestatic hepatitis
include indomethacin, phenylbutazone, novabio-
cin, propylthiouracil and diphenylhydantoin.
While haloperidol is felt to be responsible for
the significant hepatic dysfunction in the above
two cases, it is possible that benztropine mesylate
was the offending drug because both patients re-
ceived benztropine mesylate along with haloperi-
dol before the onset of their hepatic dysfunction.
This seems unlikely because benztropine mesylate
is a combination of the active portions of atropine
and diphenhydramine;14 neither the parent com-
pound nor either of its components has been re-
ported as a cause of liver dysfunction. In contrast,
haloperidol has been cited as a rare cause of
hepatotoxicity.8-10 To be more certain, however,
would have required readministering both drugs to
THE WESTERN JOURNAL OF MEDICINE 517
 CASE REPORTS
the patients. Because this procedure can cause re-
crudescence of the hepatic injury, it was felt that
rechallenge was not ethically justifiable. In spite of
not being absolutely certain as to which drug was
responsible, we felt that since haloperidol is such
a commonly used neuroleptic agent, the occur-
rence of significant liver dysfunction associated
with haloperidol and biopsy documentation should
be brought to the attention of the general medical
community.
The infrequency of reports of similar cases in
the past suggests that haloperidol induced liver
disease is a rare adverse effect, consistent with a
sensitization reaction. Cases may have occurred,
but the association possibly went unrecognized.
Therefore, when haloperidol is prescribed, the
appearance of constitutional symptoms such as
fever, chills, arthralgias or skin rash should sug-
gest the possible development of hepatic dysfunc-
tion. The determination of liver function tests in
these patients may help to ascertain the true prev-
alence of haloperidol-induced liver disease.
Summary
The cases of two patients in whom liver dys-
function developed during therapy with haloperi-
dol are described. The dosages used were within
the range recommended for severely disturbed
psychiatric patients. In one patient a generalized
hypersensitivity reaction developed; the other pa-
tient presented with painless jaundice. Biochemi-
cally, both patients showed evidence of mild
hepatocellular disease and cholestasis. In neither
patient was evidence of extrahepatic biliary ob-
struction found. Liver biopsy in the first patient
showed evidence of a hypersensitivity reaction,
with some hepatocellular necrosis, but predomi-
nant cholestasis. In the second patient, only cho-
lestasis was seen. Haloperidol is felt to be etio-
logically related to the liver disease seen in these
two patients.
REFERENCES
1. Kopelman AE, McCullan IW, Higgeness L: Limb malforma-
tions following use of haloperidol. JAMA 231:62-64, Jan 1975
2. Henry KJ, Chiamori N, Golub OJ, et al: Revised spectro-
photometric methods for the determination of glutamic-oxaloacetic
transaminase, glutamic-pyruvic transaminase and LDH. Am J
Clin Path 34:381-398, Oct 1960Q
3. McComb RB, Bowers GN Jr: Study of optimum buffer con-
ditions for measuring alkaline phosphatase activity in human
serum. Clin Chem 18:97-104, Nov 1972
4. Bauer JD: Bray's Clinical Laboratory Methods, 7th Ed. St.
Louis, CV Mosby Co, 1968, p 357
5. Manual of Histologic Staining Methods of the Armed Forces
Institute of Pathology, 3rd Ed. New York, McGraw-Hill, 1968
6. Preece A: A Manual for Histologic Technics. Boston, Little
Brown and Co, 1972, p 257
7. Derna C, Sheehan B, Mrapchok B: Theory and Practice of
Histotechnology. St. Louis, CV Mosby Co, 1973, p 140
8. Gerle B: Haloperidol clinical experience. Clin Trial J 3:380-
384, Feb 1966
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9. Crane GE: A review of clinical literature on haloperidol.
Int J Neuropsychiat 3:S110-127, Aug 1967
10. Ebert WH, Shader KI: Hepatic effects, In Shader RI,
DiMascio A (Eds): Psychiatropic Drug Side Effects. Baltimore,
Williams & Wilkins, 1969, p 190
11. Ayd RJ Jr: Haloperidol: Fifteen years of clinical experi-
ence. Dis Nerv Sys 33:465-469, Jul 1972
12. Bianchi L, DeGroot J, Desmet V, et al: Guide lines for
diagnosis of the therapeutic drug -induced liver injury in liver
bicpsies. Lancet 1:854-857, May 1974
13. Klatskin G: Drug induced hepatic injury, In Schaffner F,
Sherlock S, Leevy CM (Eds): The Liver and Its Diseases. New
York, Intercontinental Book Corp., 1974, p 170
14. Franz DN: Drugs fcr Parkinscn's disease: Centrally acting
muscle relaxants, In Goodman LS, Gilman A (Eds): The
Pharmacologic Basis of Therapeutics. New York. Macmillan Pub-
lishing Co, 1975, pp 236-239
Refer to: Wheeler M: Gamma benzene hexachloride (KWELL)
poisoning in a child-A case of combined cutaneous and
oral administration. West J Med 127:518-521, Dec 1977
Gamma Benzene-
Hexachloride (KWELL)
Poisoning in a Child
A Case of Combined Cutaneous
and Oral Administration
MARK WHEELER, MD, Seattle
GAMMA BENZENE HEXACHLORIDE (GBH), a chlori-
nated hydrocarbon pesticide that is commonly
used as a 1 percent solution or shampoo
(KWELL®) for topical treatment of scabies and
pediculosis, is potentially very toxic. The follow-
ing case illustrates the course of a nonfatal in-
gestion of GBH, a problem of which all who care
for children should be aware.
Report of a Case
A 1-year-old boy weighing 10 kg (22 pounds)
was brought to the San Francisco General Hos-
pital emergency room by his mother at 4:30 a.m.
Half an hour earlier she had found him in bed,
limp, unresponsive and breathing irregularly in a
gasping manner. He had been well until two weeks
before admission; at that time the child had been
seen by a private physician and a diagnosis of
scabies had been made. The mother had been
given prescriptions for 1 percent gamma benzene
hexachloride (KWELL) and diphenhydramine
(Benadryl®) with instructions to apply the KWELL
From the Department of Pediatrics, San Francisco General Hos-
pital, and University of California, San Francisco. Dr. Wheeler is
now with the USPHS Hospital in Seattle.
Submitted, revised, April 11, 1977.
Reprint requests to: Mark Wheeler, MD, Health Services Re-
search, USPHS Hospital, Box 3145, Seattle, WA 98114.