Drug-induced liver injury is a rare event. We report on a 15-year old girl de-veloping jaundice and a maculopapular rash with pruritus after oral cefuroxime therapy. Liver enzymes as well as total bilirubin and direct bilirubin were elevated. After eliminating other causes of hepatitis, cefuroxime-induced hepatocellular-cholestatic hepatitis with pancytopenia was diagnosed and cefuroxime therapy was stopped. The patient recovered quickly and was discharged without complications. The prognosis of this side-effect of cefuroxime is generally favourable; lethal courses are rare.
Drug-induced liver injury, although rare, is well studied. However, it often poses a diagnostic problem. Most cases of drug-related hepatotoxicity are due to antimicrobial drugs. With the following casuistry we would like to draw attention to this problem.
Patient’s History: only child. Father: hay fever, mother: hypertension, history of recurrent pseudocroup and urinary tract infections in infancy with no evidence of vesicoureteral reflux. Allergies: grass pollen and dog hair; vaccinations up to date; no drug abuse.
History of presenting complaint: the patient fell ill 4 days before hospitalisation with a fever up to 39.6˚C, a dry cough and a sore throat. After 3 days of persisting fever cefuroxime axetil was prescribed. After the second dose an itchy rash developed on the whole body. The patient was admitted to hospital with “suspected sinusitis” and a “rash of unknown origin”.
Clinical findings: 15-year old severely ill girl in poor general condition: throat and tonsils slightly red, no deposits; fine, itchy, partially confluent rash on the entire body.
Laboratory findings (SI units): are shown in
Coagulation diagnostics: Quick’s value, INR, PTT, fibrinogen and thrombin time within normal range; elevated d-dimer 5.68 (<0.5).
Parameter/ Day of treatment | Normal range (SI) | 1st | 2nd | 3rd | 7th | 10th | 23rd |
---|---|---|---|---|---|---|---|
CRP | 0.1 - 3.3 | 45.9 | 27.8 | 22.9 | 7.4 | ||
PCT | <0.5 | 0.5 | |||||
Hemoglobin | 7.5 - 8.7 | 8.0 | 7.1 | 7.1 | 6.1 | 7.3 | 7.7 |
Hematocrit | 0.37 - 0.47 | 0.36 | 0.33 | 0.34 | 0.28 | 0.35 | 0.36 |
WBC | 3.8 - 9.8 | 2.5 | 1.9 | 2.1 | 3.9 | 7.1 | |
Neutrophils* | 30 - 70 | 55.83 | 66.94 | 63.92 | 43.45 | 54.79 | 50.16 |
Neutrophilic staff cells† | 0 - 11 | 44 | 16 | 14 | |||
Segmented neutrophils† | 36 - 84 | 32 | 32 | 34 | |||
Platelets | 150 - 300 | 117.6 | 100.8 | 111.4 | 338.1 | 669.4 | |
D-dimer | 0 - 0.5 | 5.68 | 2.04 | ||||
ALT | 0.2 - 0.6 | 4.88 | 3.46 | 4.05 | 2.72 | 1.82 | 0.48 |
AST | 0.2 - 0.6 | 3.66 | 2.66 | 3.89 | 1.47 | 0.82 | 0.35 |
GGT | 0.08 - 0.92 | 4.45 | 3.7 | 3.73 | 3.85 | 2.73 | 0.98 |
LDH | 1.35 - 9.91 | 7.39 | 6.45 | 6.13 | 4.83 | 2.65 | |
GLDH | <80 | 393 | 396 | 125 | |||
Total Bilirubin | 2 - 17 | 58.6 | 52.4 | 15.2 | 15.2 | ||
Direct Bilirubin | 0.1 - 5.0 | 50.1 | 44.2 | 10.6 | 11.4 | ||
ALP | 0.6 - 1.85 | 4.42 | 3.76 | 5.14 | 4.23 | ||
Albumin | 34 - 50 | 24.9 | 22.2 | 31.4 | 38.8 | ||
Ferritin | 13 - 150 | 1644 | 504 | 78.3 |
*flow cytometry; †microscopic.
Alanine aminotransferase (ALT) 4.88 (0.2 - 0.6); aspartate aminotransferase (AST) 3.66 (0.2 - 0.6); γ-glutamyltransferase (GGT) 4.45 (0.08 - 0.92); lactate dehydrogenase (LDH) 7.39 (1.35 - 3.91); glutamate dehydrogenase (GLDH) 393 (<80); alkaline phosphatase (ALP) 4.42 (0.5 - 1.85); cholinesterase 61 (88 - 215); lipase 1.31 (1.22 - 6.55); total bilirubin 58.6 (2 - 17); direct bilirubin 50.1 (0.1 - 0.5); total serum protein 53.3 (64 - 82); albumin 24.9 (34 - 50); ceruloplasmin, alpha1-antitrypsin and urine findings normal.
Microbiological diagnostics: Negative results of blood culture, rapid antigen group A streptococcus test, pertussis PCR (nasopharyngeal swab), infectious mononucleosis rapid test, respiratory viruses multiplex PCR (Influenza A-, Influenza B-, Corona-, Entero-, Parecho-, Parainfluenza-, Metapneumo-, Boca-, RS-, Adeno-, Rhinovirus, Mycoplasma) and Cytomegalovirus DNA. Serological tests for toxoplasmosis, leptospirosis, hantavirusinfection and viral hepatitis including hepatitis E negative. Anti-HAV antibody positive, indicates successful vaccination. Anti-Hbsantibody negative, indicates non-response to vaccination.
No evidence of autoantibodies: AMA (anti-mitochondrial ab), ANA (antinuclear ab), anti-MPO (anti-myeloperoxidase ab), anti-PR3 (anti-proteinase 3 ab), anti-LKM (ab against endoplasmic reticulum of the liver) and anti-SLK antibodies (soluble liver antigen).
No abnormal abdominal ultrasound findings apart from a slight hepatomegaly; Normal FINDINGS on echocardiography. Chest x-ray showed slightly thickened bronchial walls, otherwise inconspicuous.
For laboratory findings over the course of hospitalization see table.
Clinical course: Treatment was initially symptomatic. Due to both the patient’s poor general condition with recurrent vomiting and paraclinical signs of bacterial infection (elevated CRP and neutrophil left shift) antibiotic therapy with cefuroxime was then continued intravenously. Additionally, clarithromycin therapy was started in view of the patient’s persistent cough until exclusion of pertussis and mycoplasma infection. The rash already been detected on admission flared up again. In the further course of illness hypoalbuminemia with edemas developed and treatment with human albumin was initiated. After eliminating other causes of hepatitis, cefuroxime-induced hepatocellular-cholestatic hepatitis with pancytopenia was diagnosed and cefuroxime therapy was stopped. The patient recovered quickly, hepatomegaly improved. The patient was discharged on the 10th day of hospital treatment fully recovered.
Liver injuryis rarely caused by drugs. Larger studies is launched on drug-induced liver injuryare scarce [
Drugs are the cause of 11% to 14% of liver disease [
Many studies indicate an increase in acute liver injury associated with antibiotic therapy. Incidence rates as high as 20 cases per 100,000 patients per year have been reported in the US [
Several studies from Wang et al. [
The pathogeneticbasis of drug-induced hepatotoxicity caused by analgesics, antirheumatics, anticonvulsants etc., but mainly by anti-infectives, is an allergic or idiosyncratic reaction [
Patients with drug-induced liver injury may present with malaise, fever esp. ifundulatory (79%), loss of appetite, nausea, vomiting, upper abdominal pain, icterus (79%) or scleral icterus, pruritus (64%) associated with maculopapular rash [
Whereas an association with leukocytopenia and thrombocytopenia has been reported [
The task of the attending clinician is to test for all relevant differential diagnoses. The following paraclinical parameters should be considered: liver enzymes, bilirubin and direct bilirubin, full blood count and differential blood count, coagulation diagnostics, laboratory tests for viral hepatitis, cytomegalovirus, Epstein-Barr virus and herpes simplex virus infection and for autoimmune hepatitis [
In our patient, cefuroxime therapy was found to be the cause of illness.
Antibiotic treatment with cefuroxime was initiated on the 4th day of fever as the clinical presentation indicated bacterial infection. Following only 2 doses of cefuroxime, an itchy rash developed on the whole body.
Drug-induced liver injury (DILI) is rarely caused by cephalosporins. In prospective studies, cephalosporins were found to be responsible for 4 out of 461 DILI cases (0.9%) in Spain, 1 out of 77 DILI cases (1.2%) in Sweden and 1 out of 96 DILI cases (1%) in Iceland. In the US, cephalosporins were more frequently responsible for drug-induced liver injury, with first-generation cephalosporins being the most common cause. Out of 33 cases of cephalosporin-induced liver injury, 19 were caused by cefazolin and 14 by other cephalosporins (5 cases due to 1st generation cephalosporins, 2 due to 2nd, 6 due to 3rd and 1 case due to 4th generation cephalosporin) [
Chen et al. [
Several similar cases have been reported: tonsillitis-ceftriaxone [
Drug-induced hepatitis is a diagnosis of exclusion. The causative drug should immediately be discontinued [
While bilirubin and liver enzyme levels in our patient returned to normal in the 4th week of illness, this may take up to 50 - 70 days after stopping the causative drug [
The prognosis of liver injury caused by antibiotics is generally benign [
The authors declare no conflicts of interest regarding the publication of this paper.
Kunze, W., Streidl, J.-P., Klemm, T. and Lutze, J. (2019) Cefu- roxime-Induced Hepatocellular-Cholestatic Hepatitis with Pancytopenia. Open Access Library Journal, 6: e5036. https://doi.org/10.4236/oalib.1105036