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ORIGINAL ARTICLE
Year : 2021  |  Volume : 27  |  Issue : 1  |  Page : 26-29

Risk of hepatic toxicity and drug response in patients with chronic suppurative otitis media


1 Department of ENT, Jinnah Sindh Medical University, Karachi, Pakistan
2 Department of Pharmaceutical Chemistry, Institute of Pharmaceutical Sciences, Jinnah Sindh Medical University, Karachi, Pakistan
3 Dean of Faculty of Pharmacy, Federal Urdu University of Science and Technology, Karachi, Pakistan
4 Department of Pathology, Jinnah Post Medical College, Karachi, Pakistan
5 Department of ENT, Jinnah Post Medical College, Karachi, Pakistan
6 Head of Pharmaceutical Chemistry, School of Pharmacy, Dow University of Health Sciences, Karachi, Pakistan

Date of Submission19-Feb-2020
Date of Decision03-Jun-2020
Date of Acceptance12-Jun-2020
Date of Web Publication26-Oct-2021

Correspondence Address:
Dr. Shafaque Mehboob
Assistant Prof, Department of Pharmaceutical Chemistry, Institute of Pharmacy, Jinnah Sindh Medical University, Karachi
Pakistan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/indianjotol.INDIANJOTOL_25_20

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  Abstract 


Objective: The aim of the current study was to evaluate the risk of hepatic and renal toxicity in patients with chronic suppurative otitis media (CSOM) and the effects of antibiotics (ciprofloxacin and co-amoxicillin) on it. Methods: This is a case–control study conducted on patients and healthy volunteers divided into four groups; G1 (negative control), G2 (positive control), G3 (patients treated with ciprofloxacin), and G4 (patients treated with co-amoxicillin). The study was conducted in Jinnah Postgraduate Medical College in Karachi, Pakistan, from May 2018 to October 2018. Results: There was a significant (P < 0.05) increase in total bilirubin, direct bilirubin, alkaline phosphatase, Serum glutamic pyruvic transaminase (SGPT), and Gamma-glutamyl transferase (GGT) in patients of G2 (positive control) as compared to G1 (negative control). However, the treatment with antibiotics may recover the normal liver enzyme levels except direct bilirubin and SGPT. An insignificant increase in blood glucose levels and urea was found in G2, G3, and G4 with insignificant increased creatinine levels. Conclusion: Hepatic toxicity may be induced in patients with CSOM, particularly if not properly treated. Therefore, precautions with proper follow-up of liver function test should be taken in CSOM.

Keywords: Antibiotics, chronic suppurative otitis media, hepatic toxicity, liver function test


How to cite this article:
Rafi S M, Mehboob S, Mejabeen, Tariq N, Khan H, Mehboob M. Risk of hepatic toxicity and drug response in patients with chronic suppurative otitis media. Indian J Otol 2021;27:26-9

How to cite this URL:
Rafi S M, Mehboob S, Mejabeen, Tariq N, Khan H, Mehboob M. Risk of hepatic toxicity and drug response in patients with chronic suppurative otitis media. Indian J Otol [serial online] 2021 [cited 2021 Dec 2];27:26-9. Available from: https://www.indianjotol.org/text.asp?2021/27/1/26/329097




  Introduction Top


Chronic suppurative otitis media (CSOM) is the infection of the middle ear usually with perforation, otorrhea, and otalgia.[1],[2] This condition persists for more than 6 weeks.[3] The World Health Organization showed that the global prevalence of CSOM is approximately 65–330 million per year. The prevalence rate of this infection in Southeast Asia is 5.2% which makes this area included among the highly prevalent area and much higher than the rate (4%) considered as highly alert.[4] However, CSOM is reported to be one of the leading causes of hearing loss not only in Asia but also all globally.[1]

One of the studies showed that hearing loss or impairment due to several reasons is associated with hyperbilirubinemia[5] and risk factors of acute kidney injury.[6] In addition to this, different antibiotics such as penicillin, cephalosporins, carbapenems, and quinolone that are widely prescribed in different infections including CSOM can cause hepatic toxicity.[8] Ciprofloxacin was found to be one of the most sensitive drugs[7] with lesser side effects and co-amoxicillin with most resistance in CSOM, but both drugs can alter the concentration of liver enzymes. Moreover, depression or anxiety was reported to cause liver damage[9] or associated with renal impairment.[10] Reported studies showed that patients of CSOM presented the significant correlation between hearing loss with depression, stress, and anxiety.[11] Diabetes mellitus was also found significantly correlated with CSOM as a risk factor.[12]

Keeping all these factors in view, the aim of the present study was to evaluate the risk factors of hepatic and renal toxicity with diabetic mellitus in patients with CSOM and also the drug response (ciprofloxacin and co amoxicillin) on it.


  Methods Top


The current study was performed in diagnosed patients of CSOM after ethical approval of the Institutional Review Board of Jinnah Sindh Medical University in the ear, nose, and throat department of a tertiary care hospital from May 2018 to October 2018 in a local population of Karachi. This case–control study was conducted on 120 patients and 40 volunteers who were divided into four groups (forty participants in each group); G1 (negative control), G2 (positive control), G3 (patients treated with ciprofloxacin), and G4 (patients treated with co-amoxicillin).

Inclusion/exclusion criteria

It included adult patients 18–60 years old, both the genders with one or both side ear presentation of CSOM without any hepatic, renal, or metabolic disorder or history of neurological disorder or profound psychological distress, cardiac arrest, and family history of sensorineural hearing loss or using hearing aid. Patients above 60 years or pediatric population and chronic or acute infection in the last past 6 months were excluded in the study.

Sample size calculation

The Minimum sample size was (n = 67) calculated by OPENEpi (WHO), taking the prevalence of CSOM in South Asia (5.2%) and 95% confidence interval, taking 5% margin of error.[1] However, more patients were enrolled according to the study design.

Secondary data from Jinnah Postgraduate Medical College were collected from the enrolled CSOM patients to gather information of liver function tests, creatinine, and urea and blood glucose (random) levels from May to October 2018.

Statistical analysis

Statistical analysis was done using one-way ANOVA of independence (P < 0.05) and group comparison by post hoc test (Tukey), if a statistically significant difference was observed.


  Results Top


There was no significant difference observed in random blood glucose levels and serum urea levels between healthy controls (G1) and patients of CSOM be it treated or not (G2, G3, and G4). Significant increased creatinine levels were observed in CSOM patients (G2, G3, and G4) than healthy controls (G1) as shown in [Table 1], but it was under the reference range of healthy limits of creatinine.[13]
Table 1: Serum random blood glucose, urea, and creatinine values presented as mean

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The current study showed significantly (P < 0.05) high mean total bilirubin (mg/dl) levels in G2 (positive control), which was 1.81 ± 0.31 in contrast with participants of G1 (negative control) which was 0.618 ± 0.08. However, observed values of G3: (ciprofloxacin) and G4: (co amoxicillin) which were 0.427 ± 0.23 and 0.610 ± 0.34 respectively were also significantly lower than G2 of positive control as shown in [Figure 1].
Figure 1: Serum total bilirubin presented as mean in the serum of G1 (negative control) from G2: (positive control), G3: Ciprofloxacin (1000 mg), and G4: Co-amoxicillin (1000 mg)

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In the same way, direct bilirubin was significantly (P < 0.05) high in G2 (positive control) which was 0.79 ± 0.053 as compared to G1 (negative control) which was 0.22 ± 0.057 as shown in [Figure 2]. In this case, G4: (co amoxicillin) showed lower levels of direct bilirubin which was 0.23 ± 0.024) than G3: (ciprofloxacin) which was 0.55 ± 0.049.
Figure 2: Direct bilirubin presented as mean in the serum of G1 (negative control) from G2: (positive control), G3: Ciprofloxacin (1000 mg), and G4: Co-amoxicillin (1000 mg)

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The serumconcentration of SGPT (IU/L) of G1 (negative control) was significantly ( 22.69 ± 12.19) than G2 (positive control) (65.1 ± 14.40). However observed values of G3: (ciprofloxacin) and G4: (co amoxicillin) were concentration 42.27 ± 15.14 and 48.35 ± 17.04 IU/L respectively, as shown in [Figure 3].
Figure 3: SGPT levels presented as mean in the serum of G1 (negative control) from G2: (positive control), G3: Ciprofloxacin (1000 mg), and G4: Co-amoxicillin (1000 mg)

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Alkaline phosphatase (ALP) (IU/L) levels in G2 (positive control) which was 447.35 ± 27.04 was significantly higher than G1 (negative control) which was 167.53 ± 32.19. However ALP levels of G3: (ciprofloxacin) was 165.9 ± 45.14 and G4: (co amoxicillin) was 260.72 ± 24.404, as shown in [Figure 4].
Figure 4: Alkaline phosphatase levels presented as mean in the serum of G1 (negative control) from G2: (positive control), G3: Ciprofloxacin (1000 mg), and G4: Co-amoxicillin (1000 mg)

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The current study showed the mean total GGT (IU/L) levels of G2 (positive control) which was 23.75 + 6.87 was significantly higher than G1 (negative control) which was 12.55 + 7.45, G3: (ciprofloxacin) which was12.6 + 8.48 and G4: (co amoxicillin) which was 12.74 + 9.91. The results showed that there was no significant difference in GGT concentration between healthy individuals (G1) and treated (G3 and G4), as shown in [Figure 5].
Figure 5: GGT levels presented as mean with ± standard deviation in serum of G1 (negative control), G2: (positive control), G3: Ciprofloxacin (1000 mg), and G4: Co-amoxicillin (1000 mg)

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  Discussion Top


CSOM is one of the leading causes of hearing loss,[1] and literature shows that hearing loss may lead to several complications such as hepatic and renal toxicity.[5],[6] Reported studies also showed that CSOM was associated with profound hearing loss and depression.[11] One of the studies also showed its relation with diabetes mellitus.[12] Therefore, the current study was conducted to determine the relationship between renal or hepatic toxicity or diabetes with CSOM.

Table 1 shows that CSOM patients did not show significantly high random blood glucose and markers of renal complication were also found insignificant. These values found within normal range for random blood glucose[14] and urea levels.[13] Creatinine levels were observed high in CSOM patients, particularly in untreated patients (G2) but also under limited range.[13]

The present study showed that serum bilirubin (total and direct bilirubin), SGPT, ALP, and GGT concentrations in untreated patients of CSOM (positive control) were significantly increased as compared to healthy volunteers without infection (negative control). This reflected the possible risk of hyperbilirubinemia and hepatotoxicity in patients with CSOM without treatment. Moreover, 19 patients (23.75%) had a mean value of 1.04 mg/dl for total bilirubin (normal range is <1 mg/dl) and 18 patients (22.5%) had a mean value of 0.336 mg/dl for total bilirubin (normal range is <0.25 mg/dl) which indicated very alarming situation.

Higher levels of bilirubin, SGPT, ALP, and GGT [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5] are the indication of the early stage of hepatic disorder or injury such as primary sclerosis, cholangitis, bile duct obstruction, or chronic liver cirrhosis. These conditions require ultrasound confirmation for diagnosis.[15],[16]

These findings show that CSOM may alter liver enzyme concentration in the blood which needs to be checked. The elevated levels of bilirubin in the current study may also be due to depression in patients with CSOM infection as shown in previous study[11] or high inflammatory markers in CSOM patients such as immunoglobulin E[17] and also tumor necrosis factor gamma[18] which can elevate bilirubin.[9],[19],[20]

In the current study, ALP levels of 18 patients (22.5%) were 440 mg/dl (normal range is up to 330 mg/dl) which showed that these patients are at high risk of hepatic toxicity. Studies showed that high ALP levels enhance the tendency to progress toward the advanced stage of liver disorders such as liver cancer, lymphoma, or infiltrative disease. In these conditions, the correlation of hyperbilirubinemia, GGT alterations, and ultrasound with the medical history of the patients, help the clinicians to further investigate on the basis of liver biopsy.[19],[20]

Ciprofloxacin and co-amoxicillin are widely used in CSOM infection. Studies showed that ciprofloxacin is the drug of choice in CSOM and co-amoxicillin in the pediatric population.[7] The current study showed that ciprofloxacin produced better results than co-amoxicillin in normalizing ALP up to the normal level, but co-amoxicillin was more effective than ciprofloxacin up to the normal level in direct bilirubin. As far as total bilirubin and GGT concentration was concerned, insignificant difference between ciprofloxacin (G3) and co-amoxicillin (G4) from healthy volunteers (negative control) and also between ciprofloxacin (G3) and co-amoxicillin (G4) was observed. However, both the drugs could not revert the normal levels of SGPT which showed that antibiotics may treat CSOM but patient of CSOM may still have risk of hepatotoxicity.

The normalization of liver enzymes showed that CSOM-induced liver toxicity may revert back if CSOM is treated. However, antibiotics are also well known to induce liver toxicity which could be the reason that even treated patients are at the risk of hepatic toxicity.


  Conclusion Top


CSOM can increase liver enzyme serum concentration and may lead to the hepatic toxicity, particularly if not treated. Ciprofloxacin and co-amoxicillin can decrease the elevated liver enzymes sem concentration in patients of CSOM but up to the normal levels. Therefore, patients should be follow-up with proper liver function test.

Financial support and sponsorship

This study was financially supported by Jinnah Sindh Medical University, Karachi, Pakistan.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Pukander J. Clinical features of acute otitis media among children. Acta Otolaryngol 1983;95:117-22.  Back to cited text no. 1
    
2.
Harkness P, Topham J. Classification of otitis media. Laryngoscope 1998;108:1539-43.  Back to cited text no. 2
    
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World Health Organization. WHO Model List of Essential Medicines. 17th list. Geneva. World Health Organization; 2011.  Back to cited text no. 3
    
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Acuin JM. Chronic suppurative otitis media: A disease waiting for solutions. Comm Ear Hearing H 2007;4:17-9.  Back to cited text no. 4
    
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Olds C, Oghalai JS. Audiologic impairment associated with bilirubin induced neurologic damage. In: Seminars in Fetal and Neonatal Medicine. Vol. 20: WB Saunders; 2015. p. 42-6.  Back to cited text no. 5
    
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Izzattisselim S, Purnami N. Characteristics of hearing loss in patients with chronic kidney disease undergoing hemodialysis. Indian J Otol 2020;26:43-6.  Back to cited text no. 6
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7.
Abdullah FE, Khatri PK, Alzadjali NA, Ali AD, Bhagia G. Ear infections in Karachi: The frequency and antibiotic resistance of bacterial isolates. Pak J Med 2011;27:77-81.  Back to cited text no. 7
    
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Ghersi-Egea JF, Gazzin S, Strazielle N. Blood-brain interfaces and bilirubin-induced neurological diseases. Curr Pharm Des 2009;15:2893-907.  Back to cited text no. 9
    
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Cirillo L, Cutruzzulà R, Somma C, Gregori M, Cestone G, Pizzarelli C, et al. Depressive symptoms in dialysis: Prevalence and relationship with uremia-related biochemical parameters. Blood Purif 2018;46:286-91.  Back to cited text no. 10
    
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Mehboob S, Rafi ST, Ahmed N, Mehjabeen . Association of hearing loss with depression, anxiety and stress in patients suffering from Chronic Suppurative Otitis Media. Pak J Med Sci 2019;35:510-4.  Back to cited text no. 11
    
12.
Kumari MS, Meganadh KR, Madhavi J, Jyothy A. Prevalence of otological disorders in diabetic cases with hearing loss. J Diabetes Metabolism 2016;7:1-5.  Back to cited text no. 12
    
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Aono T, Matsubayashi K, Kawamoto A, Kimura S, Doi Y, Ozawa T. Normal ranges of blood urea nitrogen and serum creatinine levels in the community-dwelling elderly subjects aged 70 years or over-correlation between age and renal function. Nihon Ronen Igakkai Zasshi 1994;31:232-6.  Back to cited text no. 13
    
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Thomas T, Prabhata S, Valsangkar S. Diabetes screening and the distribution of blood glucose levels in rural areas of North India. J Family Community Med 2015;22:140-4.  Back to cited text no. 14
    
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Velayudham LS, Farrell GC. Drug-induced cholestasis. Expert Opin Drug Saf 2003;2:287-304.  Back to cited text no. 15
    
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Betro MG, Oon RC, Edwards JB. Gamma-glutamyl transpeptidase in diseases of the liver and bone. Am J Clin Pathol 1973;60:672-8.  Back to cited text no. 16
    
17.
Lasisi AO, Arinola OG, Olayemi O. Role of elevated immunoglobulin E levels in suppurative otitis media. Ann Tropical Paediatrics 2008;28:123-7.  Back to cited text no. 17
    
18.
Mehboob S, Rafi T, Mehjabeen, Saleem D, Mehboob M, Ahmed H. Effects of ceftazidime with and without imipramine and bromazepam on behavior and neuro-inflammatory parameters in rats with chronic suppurative otitis. Pak J Pharm Sci. 2020;33:1311-17.  Back to cited text no. 18
    
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Gotardo BM, Andrade RG, Andrade ZA. Hepatic pathology in Capillaria hepatica infected mice. Rev da Soc Brasileira de Med Tropical 2000;33:341-6.  Back to cited text no. 19
    
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Gopal DV, Rosen HR. Abnormal findings on liver function tests. Interpreting results to narrow the diagnosis and establish a prognosis. Postgrad Med 2000;107:100-2, 105-9, 113-4.  Back to cited text no. 20
    


    Figures

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