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| CASE REPORT |
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| Year : 2018 | Volume
: 7
| Issue : 4 | Page : 305-307 |
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Carbimazole-induced agranulocytosis – A rare case report
R Siddeswari, Sikandar Mohan, K Swamy
Department of General Medicine, Siddhartha Medical College, Government General Hospital, Vijayawada, Andhra Pradesh, India
| Date of Web Publication | 10-Jan-2019 |
Correspondence Address:
Dr. R Siddeswari
Department of General Medicine, Siddhartha Medical College, Government General Hospital, Vijayawada, Andhra Pradesh
India
 Source of Support: None, Conflict of Interest: None  | Check |
DOI: 10.4103/JDRNTRUHS.JDRNTRUHS_60_18
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 |
| Introduction | |  |
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 | | |
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.
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 | | |
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 | | |
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 | | |
| 1. | Tripathi KD. Chapter 18: Hormones and related drugs. Thyroid inhibitors. In: Essentials of Medical Pharmacology. 7 th ed. Jaypee Medical Publishers; 2013. p. 252-4.  |
| 2. | Jameson JL, Mandel SJ, Weetman AP. Chapter 405: Disorders of thyroid gland. In: Harrison's Internal Medicine. 19 th ed.. McGraw Hill; 2015. p. 2283-308. |
| 3. | Davies TF, Laurberg P, Bhan RS. Chapter 12: Hyperthyroid disorders treatment, adverse effects. In: Williams Text Book of Endocrinology. 13 th ed. Elsevier; 2016. p. 369-415. |
| 4. | Strachen MWJ, Newell-Price J. Chapter 20: Endocrine disease. The thyroid gland. In: Davidson's Principles & Practice of Medicine. 22 nd ed. Churchill Livingstone; 2014. p. 738-56. |
| 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. |
| 6. | Mohan A, Joseph S, Siddarthan N, Murali D. Carbimazole induced agranulocytopenia. J Pharmacol Pharmacother 2015;6:228-30. [ PUBMED] [Full text] |
| 7. | Mahanth S, Shobane U, Mahanth PD. Carbimazole induced agaranulocytopenia with life threatening complications. Med J DY PatilUniversity, Navi Mumbai. |
| 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. |
[Figure 1], [Figure 2], [Figure 3]
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