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Current Drug Safety, 2014, 9, 000-000

Paracetamol-Induced
Hepatitis

Stevens

Johnson

Syndrome

and

Cholestatic

Raoudha Slim*,1, Neila Fathallah1, Amina Aounallah2, Mehdi Ksiaa3, Badreddine Sriha4,
Rafiaa Nouira2 and Chaker Ben Salem1
1

Department of Clinical Pharmacology. Faculty of Medicine of Sousse, Tunisia

Department of Dermatology, Farhat Hached University Hospital, Sousse, Tunisia

Department of Gastroenterology, Sahloul University Hospital, Tunisia

Department of Anatomocytology, Farhat Hached University Hospital, Sousse, Tunisia

Abstract: Stevens-Johnson syndrome (SJS) is an uncommon life-threatening skin disease, generally induced by drugs.
Extracutaneous manifestations of the syndrome can occur, and may involve the conjunctiva, buccal mucosa,
gastrointestinal and genitourinary tracts. Cholestatic hepatitis has been rarely described in SJS.
A 29-year-old woman was admitted with generalized cutaneous eruption. A self-medication with paracetamol had been
started three days earlier. Clinical signs and skin biopsy were consistent with SJS. Five days later, the patient developed
jaundice. Serial liver function tests showed rising transaminases, bilirubin, alkaline phosphatase and -glutamyl
transferase. Liver biopsy was performed and was consistent with the diagnosis of drug-induced cholestatic hepatitis.
Adequate supportive care was provided to the patient. Skin lesions disappeared within two weeks. Jaundice disappeared
progressively, and liver tests returned to normal.
Herein, we report the first case of SJS associated with cholestatic hepatitis after ingestion of therapeutic doses of
paracetamol.

Keywords: Cholestasis, drug-induced, eruption, hepatitis, paracetamol, Stevens-Johnson syndrome.

INTRODUCTION
Steven Johnson Syndrome (SJS) is a rare, but a severe
form of hypersensitivity reaction affecting 1 to 6 cases per
million person-years [1]. It is characterized by systemic
symptoms and epidermal detachment of less than 10% of
body surface area. Etiology may be drug induced, infectious,
malignant or idiopathic. The most commonly reported
medications associated with SJS include antiepileptics,
antimicrobials and non steroidal inflammatory drugs [1].
Paracetamol, a widely used analgesic-antipyretic drug, is
generally well tolerated. Paracetamol induced SJS has been
rarely reported. Herein, we report the first case of SJS
associated with cholestatic hepatitis occurring after ingestion
of therapeutic doses of paracetamol.
CASE REPORT
A 29-year-old woman with no medical history and no
known allergies to drugs was admitted to the department of
dermatology with generalized cutaneous eruption.
A self-medication with paracetamol had been started for
headache three days earlier (500 mg twice daily). On
admission, the patient was apyrexial and had normal vital
*Address correspondence to this author at the Dpartement de
Pharmacologie Clinique, Facult de Mdecine de Sousse, Avenue Mohamed
Karoui, 4002 Sousse, B.P.: 126, Tunisia; Tel: 00 216 98 618 242;
Fax: 00 216 73 224 899; E-mail: raoudha_slim3yahoo.fr
1574-8863/14 $58.00+.00

signs. Physical examination showed diffuse erythematous

rash with flaccid blisters involving large areas of the body
surface. Her eye, mouth and pharyngeal mucosa were also
affected by multiple erosive lesions. Nikolsky's sign was
positive. Epidermal detachment was observed in less than
10% of her body surface area. Paracetamol was immediately
discontinued. There was no history of alcohol or toxins
consumption and there was no herbal medication or other
drugs used. Skin biopsy showed epidermal necrosis and
minimal perivascular lymphohistocytic infiltration in the
upper dermis. Diagnosis of paracetamol-induced SJS was
established. Laboratory investigation revealed the following:
white blood cell count of 5.3 x109/L (normal range: 4-10
x109/L); there was no eosinophilia. Renal function tests were
normal. Liver test values included: aspartate transaminase
(AST) 23 IU/L (normal <37 IU/L), alanine aminotransferase (ALT) 31 IU/L (normal <40 IU/L), total bilirubin
(BT) 67mol/L (normal <17mol/L), direct bilirubin
53mol/L (normal <5mol/L), Alkaline phosphatase (ALP)
942 IU/L (normal range: 80-250 IU/L), and -glutamyl
transferase (GT) 454 IU/L (normal range: 5-28 IU/L).
Prothrombin time was within normal range. Test results for
hepatitis A, B, and C virus were negative as well as for
cytomegalovirus (CMV), Epstein-Barr virus (EBV) and
Mycoplasma pneumonia. Tests for anti-smooth muscle
antibody, anti-mitochondrial antibodies, and anti-LKM1
were also negative. Five days later, the patient developed
jaundice. The abdomen was diffusely tender, without
organomegaly. Serial liver function tests showed rising
2014 Bentham Science Publishers

Current Drug Safety, 2014, Vol. 9, No. 3

Slim et al.

Graphic 1. Time course of liver tests. ALT = alanine aminotransferase; AST = aspartate aminotransferase; ALP = alkaline phosphatase;
GGT = -glutamyl transferase; TB = total bilirubin; PT = prothrombin time. *Date of paracetamol initiation: 11/07. *Date of paracetamol
withdrawal: 14/07.

transaminases, bilirubin and

Prothrombin time (Graphic 1).

GT,

and

decreased

Abdomen ultrasonography showed normal gallbladder

and bile duct. Liver biopsy was performed 22 days after
admission, and revealed intrahepatic centrolobular
cholestasis with portal polymorphous infiltrate and numerous
eosinophils. Hepatocyte necrosis was also present. There
was no portal fibrosis, no granuloma, and no ductular
proliferation (Fig. 1).
These histopathologic features were consistent with the
diagnosis of drug-induced hepatotoxicity. Paracetamolinduced SJS associated with cholestatic hepatitis was the
probable diagnosis. The patient received a short course of
intravenous steroid treatment (methylprednisone 1mg/kg per
day for 4 days) with antihistamine (desloratadine 5 mg once

daily) and adequate supportive care including fluid and

electrolyte management. Skin lesions were treated with
topical corticosteroid. Cutaneous eruption disappeared
within two weeks. Jaundice regressed progressively and
hepatic tests normalized slowly. She had been instructed to
avoid paracetamol therapy in the future. On follow-up at 7
and 13 months, the patient was asymptomatic with normal
liver function tests (Graphic 1).
DISCUSSION
SJS is an immune-mediated reaction due to various
etiological factors such as drugs, infections (Mycoplasma
pneumonia,
cytomegalovirus,
herpes
virus,
etc.),
malignancy, and radiation therapy [2]. The syndrome usually
begins within 1 to 14 days of ingestion of the offending

Fig. (1). (A) Liver biopsy revealing severe cholestasis (arrow) predominating in the centrolobular zones. (B) Portal and lobular eosinophilic
infiltrates (small arrow) with necrosis predominate in the central zones (large arrow).

Paracetamol-Induced Stevens Johnson Syndrome and Cholestatic Hepatitis

agent. Clinically, SJS is characterized by polymorphic

lesions like erythematous macules, papules, plaques,
vesicles, and bullae in less than 10% of the total body
surface. The Nikolsky sign which is defined as a
dislodgement of intact superficial epidermis by a shearing
force, indicating a plane of cleavage in the skin [3], should
be sought, and is generally positive in SJS.
Oral, genital, and conjunctival mucosa is often involved
in the form of erosion or ulceration. In addition to severe
cutaneous manifestations, SJS may be accompanied by
systemic manifestations involving lungs, gastrointestinal
tract and kidneys [2]. The simultaneous association between
SJS and intrahepatic cholestasis, related to adverse drug
reactions is very rare. Only a few cases of hepatic
involvement associated with SJS caused by medications such
as vancomycin [4], ibuprofen [5, 6] and mefenamic acid [7]
were reported. In these cases, cholestatic liver disease was
either minor without symptoms, or severe responsible for
jaundice and liver failure. It often disappears after
discontinuation of the offending drug, but in some cases, it
may progress to cirrhosis. Paracetamol is generally well
tolerated and the most reported cutaneous adverse reactions
are anaphylaxis, urticaria, and maculopapular eruption.
Hypersensitivity syndrome may also occur with paracetamol,
but only a few cases of SJS have been reported following
exposure to the drug [8, 9].
Paracetamol hepatotoxicity is well known and it is more
commonly associated with overdose or use of high doses
[10]. Liver toxicity has also been reported with therapeutic
dosage, particularly if other predisposing factors are present,
such as chronic alcohol consumption, viral infection,
prolonged fasting and protein-deficient diets. Our patient
presented with SJS associated with cholestatic hepatitis
occurring after using therapeutic doses of paracetamol.
According to objective causality assessment using the
Naranjo probability scale, paracetamol-induced SJS with
cholestatic hepatitis was probable in our patient [11]. The
possible mechanism by which this association occurs is
immune-mediated destruction and subsequent sloughing of
the epithelial lining of the bile ducts, causing obstruction.
This reaction can be minor or severe and can even cause
death. Management of SJS includes early identification and
withdrawal of the offending drug, supportive care and
topical skin management. Treatment of hepatic cholestasis
includes supportive care, avoidance of hepatotoxic
medications and hepatic enzyme inductors, as well as
monitoring of liver function tests in order to evaluate the
progression of liver disease and the possible need for liver
transplantation. Corticosteroids have been used in the

Received: February 25, 2014

Current Drug Safety, 2014, Vol. 9, No. 3

treatment of SJS and in some cases may have contributed to

the improvement in liver function tests [4].
CONCLUSION
Clinicians should be aware of the risk of severe
hypersensitivity reactions associated with paracetamol, a
generally well tolerated drug. The skin involvement may be
also associated with a symptomatic cholestatic liver disease.
Management involves early identification and withdrawal of
the offending drug as well as rapid initiation of supportive
therapies.
CONFLICT OF INTEREST
The authors confirm that this article content has no
conflict of interest.
ACKNOWLEDGEMENTS
Declared none.
PATIENT CONSENT
Declared none.
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Revised: June 8, 2014

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Accepted: June 10, 2014

DISCLAIMER: The above article has been published in Epub (ahead of print) on the basis of the materials provided by the author. The Editorial Department
reserves the right to make minor modifications for further improvement of the manuscript.

PMID: 25158788