Cephalosporin's induced hepatic enzyme derangement - An educational report

Sir,

Drug induced liver injury is the most anticipated complication of the drugs that are metabolized in the liver and cases reported in children.[1] Here in our report we tried to emphasize on drug induced liver injury recognition at the primary care level, followed by our duty of reporting to the pharmacovigilance system as maximum reaction occurs at the primary health care and goes unnoticed.

Case

One of the authors was contacted by the mother who is a nurse by profession for her six- month-old female child who had elevated levels of serum glutamate oxaloacetate transaminase (SGOT) and serum glutamate pyruvate transaminase (SGPT) after a brief illness diagnosed to be acute bronchiolitis with acute gastroenteritis for which she was been treated with oral and parenteral cephalosporin. On further enquiry, the history of illness revealed that the child was suffering from loose stools of 1-week duration and cough, cold, and fever for 4 days. She was initially treated on outpatient basis with oral suspension of Cefixime. Since her illness was not controlled on OPD basis and with new symptoms of frequent vomiting, she was admitted in a hospital. She was diagnosed with acute bronchiolitis with acute gastroenteritis and started on parenteral antibiotic Ceftriaxone calculated based on body weight empirically. The blood investigations revealed an elevation in the SGOT and SGPT levels, and other investigations were within normal range [Table 1]. The baby was continued on parental Ceftriaxone and fluid management. But serial laboratory investigations revealed an elevation in the SGOT and SGPT levels without any alteration in the other liver parameters. The child was discharged from the hospital after 6 days with oral Cefixime as maintenance. Child was advised for review after 5 days. The SGOT and SGPT levels were observed to remain static without any decrease. The child was then advised to stop oral Cefixime as the course was also completed and advised to take oral ursodeoxycholic acid tablet 100 mg. The laboratory report showed a decrease in the SGPT and SGOT levels in the subsequent investigation [Figure 1].

Table 1.

Laboratory investigations

Time	Investigations	Laboratory values	Normal values
Day of Admission	Hemoglobin (gm/dL)	12.5	11-16.5
	Total Leucocyte	15900	5000-10000
	Count (cu.mm)
	Differential count:
	Neutrophils %	48	40-70
	Lymphocytes%	46	15-30
	Eosinophils%	06	1-6
	Others	0
	Platelet count (lakhs/microlitre)	3.6	1-4
	C-Reactive Protein (mg/L)	4.55	2-5
	Serum Sodium (mmol/L)	140.1	135-148
	Serum Potassium (mmol/L)	4.76	3.5-5
	S. Alkaline Phosphatase (IU/L)	184.9	0-449
	S. Bilirubin (mg/dL)
	Total	0.3	0-0.3
	Direct	0.1
	Indirect	0.2
	Protein (gm/dL)
	Total	7.01	4.4-7.6
	Albumin	5.25	3.8-5.4
	Globulin	1.76

Figure 1.

Liver parameter SGOT and SGPT at various time points

Discussion

This is the second case as per our knowledge that is reported in a child of less than 1 year due to adverse effect of cephalosporin. There are many supporting literature where there are reports of mild hepatic injury causing insignificant rise in liver enzymes to toxic hepatitis [Table 2].[2,3,4,5,6,7,8,9,10] We also tried to find out the possible cause for the initial rise in the values at the time of admission. Since the history clearly mentions on usage of Cefixime suspension, we felt this might have created the initial increase. Apart from the above facts, the baby was also medicated with oral Cefixime post discharge during which the parameters remain elevated static. The decrease in the hepatic enzyme levels was noticed only after the Cefixime course was completed and stopped (dechallenge). With this background and since the drug is involved, we did a Naranjo probability scale and found to be scored “4“ and shows the “possibility“ [Table 3].

Table 2.

Cases documented in literature and its inference

Reference	Indication	Age/Sex	Country	Medication	Inference
Longo et al., 1998	Bronchopneumonia	80/M	France	? Oral Ceftriaxone	AST- N x 9 ALT- N x11, total bilirubin (Nx22), conjugated bilirubin (Nx15), GGT -Nx15, ALP -Nx6
Gupta A et al., 2018	Preoperative surgical prophylaxis	6/M	India	IV Cefazolin	Derangement in LFT and prothrombin time
Abdu et al., 2018	Urinary tract infection	7 months/F	Saudi Arabia	Oral Cefixime	ALT 180 X UL , and AST 250 X UL
Kaur I et al., 2011	Post-operative surgical prophylaxis	24/F	India	IV Ceftriaxone	Total bilirubin 6.5 mg/dl, Direct 4.2 Indirect 2.3 mg/dl AST 148 IU/L, ALT 164 IU/L, ALP 580 IU/L.
Kunze W. et al., 2019	Upper respiratory tract infection	15/F	Germany	Oral Cefuroxime axetil	ALT 4.88; AST 3.66; GGT 4.45; LDH 7.39; GLDH 393; ALP 4.42; Total bilirubin 58.6; Direct bilirubin 50.1
Agrawal A et al., 2014	Neck abscess	57/M	USA	Oral Cephelexin	AST-268u/L ALT-267u/L ALP-429u/L Total bilirubin-4.5mg/dL Direct bilirubin-3.5mg/dL
Chen J et al., 2008	Streptococcal pharyngitis	22/M	USA	Oral Cefdinir	Total bilirubin 15.7 mg/dl; Conjugated bilirubin12.5mg/dl ALT-96I U/L AST-66I U/L ALP-175 IU/L GGTP-77 IU/L
Peker E et al., 2009	Tonsilitis	12/M	Turkey	IV Ceftriaxone	AST-819 IU/L ALT-871 IU/L GGT-, 285 U/L; Total bilirubin-4.2mg/dL; Direct bilirubin-2.8mg/dL.
Liao PF, et al., 2019	Pneumonia	93/M	Taiwan	Iv Cefepime	All the parameters increased

Aspartate transaminase (AST); Alanine transaminase (ALP); γ glutamyl transferase (GGT); Normal/upper limit of normal (N or ULN)

Table 3.

Naranjo probability scale

Question	Yes	No	Do not know	Score
Are there previous conclusive reports on this reaction?	+1	0	0	1
Did the adverse event appear after the suspected drug was administered?	+2	-1	0	2
Did the adverse reaction improve when the drug was discontinued, or a specific antagonist was administered?	+1	0	0	1
Did the adverse event reappear when the drug was re-administered?	+2	-1	0	0
Are there alternative causes (other than the drug) that could on their own have caused the reaction?	-1	+2	0	0
Did the reaction reappear when a placebo was given?	-1	+1	0	0
Was the drug detected in blood (or other fluids) in concentrations known to be toxic?	+1	0	0	0
Was the reaction more severe when the dose was increased or less severe when the dose was decreased?	+1	0	0	0
Did the patient have a similar reaction to the same or similar drugs in any previous exposure?	+1	0	0	0
Was the adverse event confirmed by any objective evidence?	+1	0	0	0
				Score=4

So, it is the prime duty of any primary care physician or clinical pharmacologist to educate the mother regarding the observed adverse effects and to document in their summary report.

To conclude, it is always important that the liver function tests be performed before starting on cephalosporin group of drugs in children, as they might cause hepatic injury. The vigilance of reporting of adverse reaction should always be entertained from the primary care physician.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.