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CASE REPORT  
Year : 2023  |  Volume : 66  |  Issue : 1  |  Page : 168-170
Clinician's dilemma: Naproxen-induced liver injury


1 Department of Pediatric Gastroenterology Cell, Indira Gandhi Medical College, Shimla, Himachal Pradesh, India
2 Department of Pediatrics, Indira Gandhi Medical College, Shimla, Himachal Pradesh, India
3 Department of Radiology, Indira Gandhi Medical College, Shimla, Himachal Pradesh, India
4 Department of Paediatric Rheumatology, Dr Rajendra Prasad Government Medical College, Tanda, Kangra, Himachal Pradesh, India
5 Department of Pathology, SRL Ltd., Fortis Escorts, Okhla, New Delhi, India

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Date of Submission26-Jul-2021
Date of Decision30-Sep-2021
Date of Acceptance22-Oct-2021
Date of Web Publication18-Jan-2023
 

   Abstract 


Naproxen is a widely used nonsteroidal anti-inflammatory drug (NSAID) in pediatric population, used for mild-to-moderate pains, arthritis, and other immune-mediated disorders. It rarely causes clinically apparent liver injury in the adult population taking high doses of the drug over a prolonged period and is reported even rarer in pediatric population. We present a case of drug-induced liver injury (DILI) in a 13-year-old girl taking naproxen in therapeutic doses for juvenile rheumatoid arthritis. There was a complete recovery of liver function following discontinuation of naproxen therapy.

Keywords: DILI, drug-induced liver injury, juvenile rheumatoid arthritis, naproxen, nonsteroidal anti-inflammatory drug

How to cite this article:
Sharma S, Sharma A, Surya M, Guleria S, Bansal N. Clinician's dilemma: Naproxen-induced liver injury. Indian J Pathol Microbiol 2023;66:168-70

How to cite this URL:
Sharma S, Sharma A, Surya M, Guleria S, Bansal N. Clinician's dilemma: Naproxen-induced liver injury. Indian J Pathol Microbiol [serial online] 2023 [cited 2023 Feb 7];66:168-70. Available from: https://www.ijpmonline.org/text.asp?2023/66/1/168/367982





   Introduction Top


Liver injury is a known side effect of nonsteroidal anti-inflammatory drugs (NSAIDs) and can range from mild derangement of liver enzymes to hepatic failure. Naproxen, a propionic derivative of NSAID, is an over-the-counter available medication since 1994. It is widely used for its anti-inflammatory and analgesic properties in pediatric rheumatic disorders. It acts by inhibiting tissue cyclo-oxygenases (Cox-1 and Cox-2), thereby decreasing prostaglandins, which are mediators of inflammatory and pain pathways. Along with analgesic and anti-inflammatory properties, it is also used as an antipyretic. Its half-life is longer than the other commonly used NSAIDs, so it can be effectively used in a twice-daily regimen.[1] Naproxen rarely causes liver injury in adult patients taking it in high doses over a prolonged period. Naproxen-induced liver injury has been very rarely reported in pediatric age group, despite its extensive use and only one case report has been published so far.[2]


   Case Report Top


A 13-year-old girl from north India presented to our outpatient department and was admitted with sudden onset of jaundice, high colored urine, pale stools, and mild pruritus, along with vomiting and pain in the upper abdomen. There was no history of fever, chills, or loose stools. She also denied any history of complementary and alternative medicines (CAM) intake or any episode of jaundice in the family or neighborhood. Her medical history was significant, with history of juvenile rheumatoid arthritis diagnosed 1 month ago, for which she was started on oral naproxen (250 mg twice daily) and prednisolone (@1.5 mg/kg/day with rapid tapering doses). Naproxen was given in adequate dose and there was no history of overdosing or any hypersensitivity features.

On examination, her vitals were stable. She had deep icterus, with no fever or lymphadenopathy. The liver was palpable 3 cm below right costal margins with tenderness present on palpation. There were no stigmata of chronic liver disease. The liver function test was deranged, with elevated liver enzymes and bilirubin levels [given in detail in [Table 1]]. Her white blood cell (WBC) count was 6.5 × 103/mm3 (normal 4.3–10.0) and hemoglobin was 12.6 g/dL (normal 12.0–16.0). Renal function test, thyroid function test, serum albumin, and electrolytes were normal. International Normalized Ratio (INR) was 1.32 and prothrombin time was 17.3. Ultrasound abdomen showed hepatomegaly with mildly raised echotexture, periportal cuffing, and thick-walled gall bladder. Suspecting acute hepatitis, a workup was sent, however, serologies for HAV, HEV, HBV, HCV, EBV, CMV, and HIV were negative. Autoimmune hepatitis markers were also negative. Serum ceruloplasmin and 24-h urine copper were also not suggestive. Ultrasound-guided liver biopsy was done, and histopathological examination (HPE) was done, which showed preserved liver architecture with the maintained vascular relationship. Hepatic parenchyma showed perivenular hepatocanalicular cholestasis, feathery degeneration of hepatocytes, and ballooning. Portal tracts showed minimal inflammatory infiltrate comprising of polymorphs, lymphocytes, and eosinophils. Portal parenchyma showed prominent neocholangiolar proliferation with neutrophilic infiltrates, suggestive of neutrophilic cholangitis. Overall features on HPE were suggestive of cholestatic hepatitis type of drug-induced liver injury (DILI) [Figure 1] and [Figure 2].
Table 1: Timeline of LFTs and interventions

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Figure 1: (a) MT stain showing no increase in fibrosis in low magnification. (b) Liver biopsy showing marked lobular unrest and portal ductular proliferation in low magnification. (c) Portal tract showing bile ductular reaction and mixed infiltrate

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Figure 2: Liver biopsy showing hepatocyte ballooning and cholestasis

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The child was started on supportive management and naproxen was stopped immediately. She was continued on oral steroids for Juvenile Rheumatoid Arthritis (JRA). Her Liver Function Test (LFT's) improved at day 13 of hospitalization, and she was discharged on day 17 of hospitalization with improving LFTs and an improved appetite. At a follow-up of 2 months after discharge from the hospital, she was anicteric and asymptomatic [Table 1]. Her appetite was normal and was accepting orally normally with normal routine pain-free daily activity.


   Discussion Top


DILI manifests most commonly as jaundice, abdominal pain, high colored urine, nausea, and pruritis, with or without liver failure. Diagnosing DILI accurately is a challenging task, as there is a lack of availability of accurate biomarkers and also, clinical features may be similar to viral hepatitis and other causes of liver injury. So, before diagnosing DILI, all other potential causes should be excluded, including hepatic viruses, autoimmune hepatitis, systemic-onset (SoJIA), metabolic causes, ischemia, and obstructive causes.[3] Deranged LFTs with elevated serum aminotransferase levels are seen in about 4% of patients with prolonged use of naproxen in high doses. Clinically apparent liver injury is rarely seen with naproxen.[1] Ali et al.[4] have listed seven cases of DILI caused by naproxen in adults, whereas Li et al.[2] from China have reported a case of 6-year-old patient developing Stevens–Johnson syndrome and acute vanishing bile duct syndrome after taking oral amoxicillin and naproxen.

In a suspected case of DILI, liver biopsy is not required for making a diagnosis, but it is still desired for finding out the etiology, severity, extent, and prognosis of the patient. It might also give an insight into any underlying liver disease or a possible alternate etiology.[5] The pattern of liver injury in DILI can range from hepatocellular to cholestasis to massive necrosis leading to fulminant hepatic failure, however, based on the histology findings, it can be broadly classified into five patterns: acute hepatitis, acute cholestasis, cholestatic hepatitis, chronic hepatitis, and chronic cholestasis. The cholestatic hepatitis is the most commonly seen type of DILI,[6] and includes cases with a combination of cholestasis and inflammation. The inflammatory component can vary from very mild portal and lobular inflammation to severe inflammation similar to that seen in acute and chronic hepatitis. Bile plugs can be seen in hepatocytes, canaliculi, and sinusoidal macrophages and canalicular bile is diagnostic of this type of DILI. Duct injury is also commonly seen in this type (52% of cases).[5] Similar features were seen in our case with hepatic parenchyma showing perivenular hepatocanalicular cholestasis, feathery degeneration, and ballooning of hepatocytes and some inflammatory infiltrates in portal tracts. Portal parenchyma also showed features of neutrophilic cholangitis. The exact mechanism of naproxen-induced DILI is not known, but as it is metabolized by the cytochrome P450 system, so idiosyncratic injury due to a toxic metabolite may be a possibility. The recovery after an episode of DILI may be slow and LFTs may take months to years to normalize after stopping naproxen.

DILI should always be suspected if pediatric patients on prolonged medication develop jaundice, especially if they are taking NSAIDs. Also, in the absence of any specific marker, liver biopsy can be an important modality to diagnose DILI and rule out underlying chronic liver disease.

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.



 
   References Top

1.
LiverTox: Clinical and Research Information on Drug-Induced Liver Injury [Internet]. Bethesda (MD): National Institute of Diabetes and Digestive and Kidney Diseases; 2012. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547852/.  Back to cited text no. 1
    
2.
Li L, Zheng S, Chen Y. Stevens-Johnson syndrome and acute vanishing bile duct syndrome after the use of amoxicillin and naproxen in a child. J Int Med Res 2019;47:4537-43.  Back to cited text no. 2
    
3.
Davern TJ. Drug-induced liver disease. Clin Liver Dis 2012;16:231-45.  Back to cited text no. 3
    
4.
Ali S, Pimentel JD, Ma C. Naproxen-induced liver injury. Hepatobiliary Pancreat Dis Int 2011;10:552-6.  Back to cited text no. 4
    
5.
Kleiner DE. Drug-induced liver injury: The hepatic pathologist's approach. Gastroenterol Clin North Am 2017;46:273-96.  Back to cited text no. 5
    
6.
Kleiner DE, Chalasani NP, Lee WM, Fontana RJ, Bonkovsky HL, Watkins PB, et al. Hepatic histological findings in suspected drug-induced liver injury: Systematic evaluation and clinical associations. Hepatol Baltim Md 2014;59:661-70.  Back to cited text no. 6
    

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Correspondence Address:
Shruti Sharma
Paediatric Gastroenterology Cell, Indira Gandhi Medical College, Shimla, Himachal Pradesh
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ijpm.ijpm_766_21

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