Gastroenterology Report Advance Access published August 29, 2016

Gastroenterology Report, 2016, 13

doi: 10.1093/gastro/gow025
Case report

Downloaded from http://gastro.oxfordjournals.org/ at SUNY Health Science Center at Brooklyn - Medical Research Library on November 11, 2016
CASE REPORT

Cetirizine-induced hepatotoxicity: case series and

review of the literature
Adil Coskun1,*, Irfan Yavasoglu2, M. Hadi Yasa1, Nil Culhaci3,
Vahit Yukselen1
1
Department of Gastroenterology, Adnan Menderes University, School of Medicine, Aydin, Turkey,
2
Deparment of Hematology, Adnan Menderes University, School of Medicine, Aydin, Turkey and
3
Department of Pathology, Adnan Menderes University, School of Medicine, Aydin, Turkey
*Corresponding author. Department of Gastroenterology, Adnan Menderes University, School of Medicine, TR-09100, Aydin, Turkey. Fax: 90-256-2120146;
Tel: 90-256-4441256; E-mail: [email protected]

Abstract
Drug-induced liver damage is a frequently encountered clinical table caused by many drugs. Cetirizine is a widely preferred
and prescribed antihistaminic agent for allergic disorders due to its non-sedative properties. In view of the literature, we
present four cases of hepatotoxicity due to cetirizine use. We conclude that in patients with high levels of liver enzymes of
unknown origin, cetirizine as well as other hepatotoxic drugs should be reconsidered.

Key words: cetirizine, hepatotoxicity

Introduction revealed that he had been diagnosed with contact dermatitis

and that 10 mg/day cetirizine had been started by a dermatology
Cetirizine is a cholinergic, nonsedating, second-generation specialist three days previously. He had no history of alcohol
histamine-1 receptor-blocking agent widely used in allergic dis- use nor any other drug use or chronic disease. His physical ex-
orders. Its elimination has been reported to be slow in the el- amination was normal. Biochemical tests revealed total choles-
derly and in people with liver disease [1]. Severe liver failure terol 228 mg/dL (normal range 140220 mg/dL) and triglycerides
and cholestatic and hypersensitivity hepatitis induced by anti- 163 mg/dL (normal range 40160 mg/dL); total bilirubin, total
histamines such as cyproheptadine, loratadine and terfenadin protein, albumin, globulin, lactate dehydrogenase (LDH), amy-
have been reported previously [2,3]. Increases of alanine amino- lase and fasting blood glucose levels were within normal limits.
transferase (ALT) [2], hepatitis [48], and cholestasis [911] due Leucocyte, erythrocyte and thrombocyte counts were normal.
to cetirizine use have been also reported. Here we report four HBsAg, anti-HCV, anti-HAV IgM, Anti-HEV, CMV IgM, and EBV-
hepatotoxicity cases resulting from cetirizine use and review VCA were negative; his anti-HB level was positive. IgG, IgM and
the literature. IgA levels were within normal ranges, while IgE was high
(303 IU; normal range 0100 IU). Antinuclear antibody (ANA),
antimitochondrial antibody (AMA) and anti-smooth muscle an-
Case presentation tibody (ASMA) were negative. Abdominal ultrasound examina-
Case 1: A 46-year-old male patient was admitted with com- tion of the liver was normal. In the peripheral blood smear, 66%
plaints of fatigue over the past seven days. His medical history neutrophils, 28% lymphocytes, 4% eosinophils and 2%

Submitted: 14 May 2016; Revised: 10 June 2016; Accepted: 17 June 2016

C The Author(s) 2016. Published by Oxford University Press and Sixth Affiliated Hospital of Sun Yat-Sen University
V
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/
licenses/by-nc/4.0/), which permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited.
For commercial re-use, please contact [email protected]

1
 2 | Adil Coskun et al.

monocytes were detected. Serum iron level, iron-binding capac- Case 3: A 66-year-old female patient was admitted with fa-
ity, ferritin, ceruloplasmin and thyroid function tests (TFTs) tigue and jaundice. She had been started on cetirizine for the
were within normal limits. Liver biopsy was planned but was complaint of itching a week ago. She had no alcohol or any
not approved by the patient. Cetirizine was discontinued imme- other drug use. Her physical examination revealed jaundice of
diately. He was advised not to take any medicine and to avoid the skin and sclera and palpable liver under her ribcage at the
any intake harmful to the liver. In the follow-up two weeks midclavicular line. Total, direct and indirect bilirubins were
later, ALT was 45 U/L (normal range 1340 U/L), and gamma- 9.36, 6.39 and 2.97 mg/dL, respectively, and eosinophils were in-
glutamyl transferase (GGT) was 264 U/L (normal range 950 U/L). creased in the peripheral smear. Iron parameters, TFT and other
In the second follow-up, GGT was 95 U/L (normal range 950 U/ biochemical values were normal. ANA, AMA and ASMA were

Downloaded from http://gastro.oxfordjournals.org/ at SUNY Health Science Center at Brooklyn - Medical Research Library on November 11, 2016
L), and ALT, aspartate aminotransferase (AST) and other tests negative. HBsAg, anti-HBc, anti-HCV, anti-HBs, anti-HAV IgM,
were within normal ranges two months later. CMV IgM, EBV-VCA and Salmonella and Brucella agglutination
Case 2: A 21 year-old female patient was admitted with com- tests were negative. Abdominal ultrasonography revealed hepa-
plaints of generalized jaundice and fatigue. She had been tomegaly, and magnetic resonance cholangiopancreatography
started on cetirizine five days previously for complaints of (MRCP) was normal. Liver biopsy revealed enlarged cells with
itching. No other drug or alcohol use was involved. Her physical macrosteatosis, cholestasis and mixed inflammatory infiltration
examination was normal except for jaundice. Total bilirubin with increased eosinophils in portal areas and parenchyma
was 6.3 mg/dL, and direct bilirubin was 2.4 mg/dL, while total (Figure 1). Cetirizine was immediately discontinued. In the
cholesterol, triglycerides, total protein, albumin and whole follow-up, GGT was 90 U/L, while AST, ALT and other biochemi-
blood counts were within normal range. Iron parameters and cal tests were all normal three weeks later.
TFT were normal. HBsAg, anti-HBc IgM, anti-HCV, anti-HBs, Case 4: A 40-year-old female patient, who had been pre-
anti-HAV IgM, CMV IgM, EBV-VCA and Salmonella and Brucella scribed cetirizine, 10 mg/day, four days previously by a derma-
agglutination levels were negative. ANA, AMA and ASMA were tologist because of generalized itching complaint, was admitted
negative. Abdominal ultrasonography revealed mild hepato- to our department with the complaint of fatigue. She did not
megaly and hepatosteatosis grade I. Liver biopsy was planned have a history of any other drug or alcohol use. Her physical
but the patient did not approve. Cetirizine-induced toxic hepati- examination, iron parameters, TFT and other laboratory test re-
tis was considered, and the drug was stopped. In the follow-up, sults were normal except for AST, ALT, ALP and GGT. HBsAg,
ALT was 139 U/L, AST 53 U/L, alkaline phosphatase (ALP) 71 U/L anti-HBs, anti-HBc IgM, anti-HAV IgM, anti-HCV, CMV IgM, EBV-
(normal range 40140 U/L) and GGT 20 U/L, while bilirubins re- VCA and Salmonella and Brucella agglutination tests were neg-
turned to normal two weeks later. All biochemical tests re- ative. Abdominal ultrasonography was normal. Cetirizine was
turned to their normal ranges a month later. discontinued. Liver biopsy was not performed due to lack of the
patients approval. In follow up as month later, her biochemical
values had returned to normal.
Demographic features and laboratory test results of these
four cases at their admission are presented in Table 1.

Discussion
Drug-induced liver damage is a frequently encountered clinical
table and is encountered as side effects of many drugs.
Asymptomatic patients may be admitted with elevated liver
function tests results as well as with hepatitis findings. There
are three types of hepatotoxic drug reaction based on biochemi-
Figure 1. Liver biopsy of Case 3 shows macrosteatosis places (A, hematoxylin- cal parameters: hepatocellular damage, cholestatis and mixed
eosin staining, x100) and mixed inflammatory infiltration including eosinophils; type. Classification is based on the following formula using ALP
(B, hematoxylin-eosin, x200) in portal areas and parenchyma. and ALT levels: R ratio (ALT/ upper limit of normal range) /

Table 1. Patient characteristics and laboratory test results

Case 1 Case 2 Case 3 Case 4

Age (years) 46 21 66 40
Sex Male Female Female Female
Duration of cetirizine use (days) 3 5 7 4
IgE level (IU) 303 30 17 36
Eosinophil count 420 100 1000 100
AST (NR: 1040 U/L) 419 188 685 47
ALT (NR: 1340 U/L) 461 443 667 59
ALP (NR: 40140 U/L) 153 404 111 843
GGT (NR: 950 U/L) 545 44 144 411
R ratio 10,57 3,84 21,1 0,24
Hepatic damage type Hepatocellular Mixed Hepatocellular Cholestatic
RUCAM score 10 10 11 9

ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; GGT: gamma-glutamyl transferase; NR: normal range; R ratio (ALT/
upper limit of normal range) / (ALP/ upper limit of normal range); RUCAM: Roussel Uclaf Causality Assessment Method
 Cetirizine-induced hepatotoxicity | 3

(ALP/ upper limit of normal range). (1) If the R ratio is  5 or ALT Conflict of interest: The authors declare no conflict of interest.
exceeds twice the upper limit, the reaction is classified as hepa-
tocellular toxicity; (2) if the R ratio is  2 and ALT is over the nor-
mal limit, the reaction is designated as cholestatic toxicity; and
References
(3) if the R ratio is between 2 and 5, the reaction is mixed type 1. Campoli-Richards D, Buckley M and Fitton A. Cetirizine. A a
[12]. Based on this classification, Case 1 and Case 3 were evalu- review of its pharmacological properties and clinical poten-
ated as hepatocellular, Case 2 was mixed, and Case 4 was the tial in allergic rhinitis, pollen-induced asthma, and chronic
cholestatic type. urticaria. Drugs 1990;40:76281.
Hepatotoxicity can also be categorized as immune and non- 2. Arendt C and Bernheim J. Double-blind comparison of main-

Downloaded from http://gastro.oxfordjournals.org/ at SUNY Health Science Center at Brooklyn - Medical Research Library on November 11, 2016
immune. Hepatotoxicity involving the immune system is also tenance treatment of chronic idiopathic urticaria by cetiri-
referred to as allergic reaction or hypersensitivity [13]. The pres- zine and terfenadine. Curr Ther Res 1989;46:72434.
ence of eosinophils in a peripheral blood smear, increased eo- 3. Larrey D, Palazzo L and Benhamou JP. Terfenadine and hepa-
sinophil count and elevated blood IgE level in Case 1 suggested titis. Ann Intern Med 1985;103:634.
hypersensitivity. 4. Bera F, Sipruhis JP, Jonville-Bera AP, et al. Cytolytic hepatic in-
Since our patients had no history of alcohol use, blood trans- volvement after administration of cetirizine (Zyrtec (in
fusion, tooth extraction, any surgical operation, close contact French). Gastroenterol Clin Biol 1993;17:7701.
with hepatitis patients, history of a systemic disease or any 5. Pompili M, Basso M, Grieco A, et al.Recurrent acute hepatitis
other drug use, cetirizine was considered to the likely cause for associated with use of cetirizine. Ann Pharmacother
the increased values of the liver tests (AST, ALT, ALP, GGT and 2004;38:18447.
total bilirubin). Any other sources causes that may cause hepa- 6. Sanchez-Lombrana JL, Alvarez RP, Saez LR, et al. Acute hepati-
totoxicity such as viral causes, autoimmune causes, gallstones, tis associated with cetirizine intake. J Clin Gastroenterol
hemochromatosis and endocrinological causes (hypothyroidism 2002;34:4935.
and hyperthyroidism) hepatitis were ruled out through viral se- 7. Watanabe M, Kohge N and Kaji T. Severe hepatitis in a patient
rology, ultrasonography, ANA, AMA, ASMA, ferritin, iron, serum taking cetirizine. Ann Intern Med 2001;135:1423.
iron-binding capacity, free T3, free T4 and TSH examinations. If 8. Jurawan R and Smith A. Severe hepatitis in a primary scleros-
available, measurement of serum cetirizine level, or challenge ing cholangitis patient receiving recent cetirizine therapy. N
test could have supported the strenght of our diagnosis. In diag- Z Med J 2010;123:1067.
nosing druginduced hepatotoxicity, measurement the levels of 9. Daz-Sa  nchez A, Marn-Jimenez I and Aldeguer M. Benign re-
liver-kidney microsomal antibody (anti-LKM2), and the antibody current intrahepatic cholestasis simulating cetirizine-
against cytochrome P450 may be useful [5]. In our cases, re-use induced toxic hepatitis (in Spanish). Gastroenterol Hepatol
of the drug did not encountered. Tests to measure the serum 2010;33:689.
levels of liver-kidney microsomal antibody (anti-LKM2), and the 10. Rodrguez-Go  mez SJ, Zamora-Martnez T, Bailador-Andres C,
antibody against cytochrome P450 were not available. Liver et al. Severe intrahepatic cholestasis associated with cetiri-
biopsy was approved and performed in only one patient. zine (in Spanish). Gastroenterol Hepatol 2009;32:3834.
A markedly high GGT level immediately suggested a toxic 11. Fong DG, Angulo P, Burgart LJ, et al. Cetirizine-induce chole-
cause [2,4]. Drug-induced hepatitis has been reported in many stasis. J Clin Gastroenterol 2000;31:2503.
studies [14]. High levels of liver enzymes and possible hepatitis 12. Danan G and Benichou C. Causality assessment of adverse re-
development have been shown in various studies [2,3]. actions to drugs-I. A novel method based on the conclusions
Although it has been suggested that elevated liver enzyme lev- of international consensus meetings: application to drug-
els could sometimes result from cetirizine use [1,2], hepatitis induced liver injuries. J Clin Epidemiol 1993;46:132330.
has been reported in only five case reports in the literature [4 13. Leise MD, Poterucha JJ and Talwalkar JA. Drug-induced liver
8]. In two of the four cases, cetirizine was used for allergic der- injury. Mayo Clin Proc 2014;89:95106
matitis, but it was discontinued due to elevated levels of liver 14. Chitturi S, Teoh NC and Farrell GC. Hepatic drug metabolism
enzymes. When the drug was later accidentally re-administered and liver disease caused by drugs. In: Feldman M, Friedman
to the same patient , liver enzymes were again reported to be in- LS, Brandt LJ (eds). Gastrointestinal and Liver Disease, volum 2,
creased [4,5]. It is interesting that in our four cases, all enzyme 10th ed. Philadelphia: Saunders, 2016, 144277.
levels except for GGT were within normal limits at the follow-up 15. Sahai A and Villeneuve JP. Terfanadineinduced cholestatic
two months after cetirizine had been stopped. The literature re- hepatitis. Lancet 1996;348:5523.
veals liver function tests returning to normal limits within three 16. Freneaux E, D Larrey, Berson A, et al. Hepatitis caused by cy-
months in terfenadin and cyproheptadine-induced hepatitis proheptadine (Periactine). A case and review of the literature
cases [15,16]. We conclude that, in patients with high levels of (in French). Gastroenterol Clin Biol 1988;12:5735.
liver enzymes and hepatitis of unknown cause, cetirizine as well
as other hepatotoxic drugs should be suspected.