Home About us Editorial board Search Ahead of print Current issue Archives Submit article Instructions Subscribe Contacts Login 
Print this page Email this page Users Online: 84

 Table of Contents  
CASE REPORT
Year : 2018  |  Volume : 7  |  Issue : 4  |  Page : 305-307

Carbimazole-induced agranulocytosis – A rare case report


Department of General Medicine, Siddhartha Medical College, Government General Hospital, Vijayawada, Andhra Pradesh, India

Date of Web Publication10-Jan-2019

Correspondence Address:
Dr. R Siddeswari
Department of General Medicine, Siddhartha Medical College, Government General Hospital, Vijayawada, Andhra Pradesh
India
Login to access the Email id

Source of Support: None, Conflict of Interest: None


DOI: 10.4103/JDRNTRUHS.JDRNTRUHS_60_18

Rights and Permissions
  Abstract 


A 30-year-old lady with hyperthyroidism for the past 1 year was initially on carbimazole 30 mg twice orally and then changed to 30 mg once daily. She presented with intermittent fever since 3 weeks, h/o oral ulcers, difficulty in swallowing, and palpitations. Routine investigations showed anemia, neutropenia, leucopenia, and C-reactive protein elevation. Peripheral smear showed normocytic normochromic anemia with leucopenia. Widal test, RA factor test, immunoglobulin M (Ig M) dengue, Ig M Lepto, antinuclear antibody screen, cytoplasmic antineutrophil cytoplasmic antibodies, and perinuclear anti-neutrophil cytoplasmic antibodies tests were negative. Viral markers are negative.

Keywords: Agranulocytosis, carbimazole, hyperthyroidism


How to cite this article:
Siddeswari R, Mohan S, Swamy K. Carbimazole-induced agranulocytosis – A rare case report. J NTR Univ Health Sci 2018;7:305-7

How to cite this URL:
Siddeswari R, Mohan S, Swamy K. Carbimazole-induced agranulocytosis – A rare case report. J NTR Univ Health Sci [serial online] 2018 [cited 2019 Jul 16];7:305-7. Available from: http://www.jdrntruhs.org/text.asp?2018/7/4/305/249831




  Introduction Top


Carbimazole, a prodrug which gets converted into an active form methimazole, is used alone or in combination with other medications for the treatment of hyperthyroidism.[1] This therapy usually starts with two to three divided doses totaling 30–60 mg/day, but the maximal blocking dose should be 120 mg/day.[2]

Usually, within 4–8 weeks of initial therapy, thyrotoxic symptoms will diminish and circulating thyroid hormone levels will return to normal.[2],[3] If a patient was unconscious or uncooperative, carbimazole was administered rectally with good effect. No parentaral therapy is available.[4]

The typical range of daily maintenance dose is 5–30 mg/day. Common side effects associated with this drug are minor but sometimes it can cause serious blood disorders. Higher doses of methimazole taken by a patient, greater than 30 mg/day, and/or age of greater than 40 years have got higher chance for development of agranulocytosis. It can happen within 2 months of therapy which was rare and most important side effect[2],[3]; on early diagnosis and treatment, the condition is reversible.


  Case Report Top


A 30-year-old lady presented with hyperthyroidism for the past 1 year and was initially on Tab. carbimazole 30 mg twice daily and then changed to 30 mg once daily. She presented with intermittent fever (100–101°F) since 3 weeks. She also complained of difficulty in swallowing, oral ulcer palpitations, and loss of appetite with weight loss of 6 kg within 1 month (54–48 kg).

On examination, oral candidiasis, oral ulcers, and ulcer on hard palate were present [Figure 1],[Figure 2],[Figure 3]. The other parameters were as follows – temperature: 102°F; pulse rate: 140/min, regular; blood pressure: 80/50 mm of Hg; respiratory rate: 30 cycles/min. Cardiovascular system examination revealed the following: JVP not raised, no carotid bruit, S1 and S2 were normal, and no murmurs. Respiratory system showed normal vesicular breath sounds. Per abdomen showed no organomegaly.
Figure 1: Oral candidiasis and ulcers

Click here to view
Figure 2: Ulcer over palate

Click here to view
Figure 3: Healed ulcer

Click here to view


Routine investigations were done which showed anemia, neutropenia, leucopenia, and high C-reactive protein (CRP). Peripheral smear showed normocytic normochromic anemia with leucopenia. In view of hard palate, ulcer VDRL and Mantoux tests were also done which were negative. She was empirically started on intravenous antibiotics twice daily in view of neutropenia, tachycardia, and elevated CRP. In view of hypotension, inotropes along with other supportive measures were continued.

  • Complete Blood Picture (CBP) dated 2018 March 10 – Hb: 8.2 g/dL, erythrocyte sedimentation rate (ESR): 46 mm; red blood cell (RBC): normocytic normochromic, total counts: 1800 cells/cu.mm; differential count: neutrophils 8%, lymphocytes 87%, monocytes 3%; platelet count: 1.15 lakhs/cu.mm
  • Blood cultures, both aerobic and anaerobic, urine culture Widal test, RA factor test, immunoglobulin M (Ig M) dengue, Ig M Lepto, and antinuclear antibody screen were found to be negative. All viral markers were negative. Carbimazole was withheld in view of leucopenia
  • In this case, differential count showed reduced neutrophils (8%) and predominant lymphocytes
  • As the patient symptomatically recovered within short duration after stopping carbimazole and total counts became normal, bone marrow aspirate was withheld
  • Endocrinology opinion was sought during the hospital stay for modification of anti-thyroid medications. Thyroid function test was done twice and it was within the normal range; anti-thyroid medications were not started for the time being. White blood cell (WBC) count and neutrophil count became normal within 2 weeks. With the treatment she received, her counts gradually showed an improving trend and she got discharged
  • CBP dated 2018 Mar 20: Hb: 11.2 g/dL, ESR: 28 mm/h, RBC: normocytic normochromic, total counts: 8000 cells/cu.mm; differential count: neutrophils 65, lymphocytes 35%, monocytes 2%, eosinophils 3%, platelet count: 2.24 lakhs/cu.mm.



  Discussion Top


Hyperthyroidism is a common endocrine disorder which affects mainly women with a prevalence of 1%–2% and 0.1%–0.2% in men.[3] Anti-thyroid drug therapy is the main treatment for this condition.[1] A serious rare side effect of carbimazole is agranulocytosis with an incidence of 0.1%–0.3%.[3] This drug-induced agranulocytosis is a lethal condition but reversible if recognized early and treated accordingly.[1],[2],[3]

The first mechanism for this agranulocytosis was explained by Sprikkelman et al. First, when the drug gets attached with granulocyte, antibody production starts resulting in the destruction of granulocytes. Second, antibodies may target the drug metabolite complex adsorbed on the neutrophil granulocyte in the presence of plasma component. Third, the drug may trigger autoantibodies. Finally, the interaction between granulocyte antigen and the drug may induce the production of antibodies.[5]

Drug-induced agranulocytosis occurs within 1–2 months of taking the anti-thyroid medication but the onset can get delayed.[3] Usually, the WBC count returns to normal over a period of 1–2 weeks after discontinuing the offending drug and the time taken can range from 7 to 56 days. Recovery of neutrophil count depends on the number of myeloid precursor cells present in the bone marrow and may get prolonged if there is granulocyte precursor aplasia.[6]

The prognosis of this event depends on a variety of factors such as age, comorbidity, duration of severe granulocytopenia, and immediate antibiotic treatment. Successful treatment of anti-thyroid drug-induced agranulocytosis by Granulocyte Colony stimulating factor (GCSF) has been reported. It enhances the recovery of the peripheral blood granulocyte lineage which results in faster normalization of peripheral granulocyte count and reduction in chances of fatal complications such as bacterial infections.[2],[3],[5]

We can render euthyroid state by radio-iodine treatment also.[7] In 1983, a study conducted by Cooper et al. concluded that methimazole in higher doses of 30 mg/day and above 40 years of age caused greater risk for development of agranulocytosis.[8] This diagnosis is still not applicable for patients who are on chemotherapy or patients with chronic neutropenia including congenital and chronic autoimmune neutropenia.[6]

Granulocytopenia that developed during first few weeks of therapy may be difficult to interpret. In these circumstances, serial measurements of the leukocyte count should be made. If they display a downward trend, the anti-thyroid drugs should be discontinued. When serial measurements of white blood counts remain constant or return to normal, treatment need not be interrupted.[3]


  Conclusion Top


Carbimazole-induced agranulocytosis occurs generally within few weeks or months of taking the anti-thyroid medication, but onset may be delayed by 1 year with an incidence of 0.1%–0.3%. Agranulocytosis is a serious rare side effect of carbimazole. This drug-induced agranulocytosis is a lethal condition but reversible if recognized early and treated accordingly.[2],[3] De-challenge resulted in normalization of blood parameters.[2]

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.
Tripathi KD. Chapter 18: Hormones and related drugs. Thyroid inhibitors. In: Essentials of Medical Pharmacology. 7th ed. Jaypee Medical Publishers; 2013. p. 252-4.  Back to cited text no. 1
    
2.
Jameson JL, Mandel SJ, Weetman AP. Chapter 405: Disorders of thyroid gland. In: Harrison's Internal Medicine. 19th ed.. McGraw Hill; 2015. p. 2283-308.  Back to cited text no. 2
    
3.
Davies TF, Laurberg P, Bhan RS. Chapter 12: Hyperthyroid disorders treatment, adverse effects. In: Williams Text Book of Endocrinology. 13th ed. Elsevier; 2016. p. 369-415.  Back to cited text no. 3
    
4.
Strachen MWJ, Newell-Price J. Chapter 20: Endocrine disease. The thyroid gland. In: Davidson's Principles & Practice of Medicine. 22nd ed. Churchill Livingstone; 2014. p. 738-56.  Back to cited text no. 4
    
5.
Sprikkelman A, deWolf JT, Vellenga E. The application of hematopoietic growth factors in drug induced agranulocytosis: A review of 70 cases. Leukemia 1994;8 2031.  Back to cited text no. 5
    
6.
Mohan A, Joseph S, Siddarthan N, Murali D. Carbimazole induced agranulocytopenia. J Pharmacol Pharmacother 2015;6:228-30.  Back to cited text no. 6
[PUBMED]  [Full text]  
7.
Mahanth S, Shobane U, Mahanth PD. Carbimazole induced agaranulocytopenia with life threatening complications. Med J DY PatilUniversity, Navi Mumbai.  Back to cited text no. 7
    
8.
Cooper DS, Goldminz D, Levin AA, Ladenson PW, Daniels GH, Molitch ME, et al. Agranulocytosis associated with antithyroid drugs. Effects of patient age and drug dose. Ann Intern Med 1983;98:26-9.  Back to cited text no. 8
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]



 

Top
 
 
  Search
 
Similar in PUBMED
   Search Pubmed for
   Search in Google Scholar for
 Related articles
Access Statistics
Email Alert *
Add to My List *
* Registration required (free)

 
  In this article
Abstract
Introduction
Case Report
Discussion
Conclusion
References
Article Figures

 Article Access Statistics
    Viewed586    
    Printed23    
    Emailed0    
    PDF Downloaded36    
    Comments [Add]    

Recommend this journal