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CASE REPORT
Year : 2020  |  Volume : 17  |  Issue : 3  |  Page : 149-151

Antithyroid drug-induced pancytopenia followed by acute lymphoblastic leukemia: A rare case


1 Department of Medicine, SP Medical College, Bikaner, Rajasthan, India
2 Department of Pathology, SP Medical College, Bikaner, Rajasthan, India
3 Department of Medical Oncology, SP Medical College, Bikaner, Rajasthan, India

Date of Submission15-Jun-2020
Date of Acceptance28-Jul-2020
Date of Web Publication20-Jan-2021

Correspondence Address:
Dr. Hardeva Ram Nehara
Department of Medicine, SP Medical College, Bikaner - 334 001, Rajasthan
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/trp.trp_45_20

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  Abstract 


Antithyroid drugs (ATDs) have been used for the management of hyperthyroidism and rarely may cause life-threatening side effects such as agranulocytosis and pancytopenia. Lymphocytes of patients who develop agranulocytosis while on ATD may undergo blast transformation when exposed in vitro to ATD. A 26-year-old man with Graves' disease was found to have pancytopenia after treatment with carbimazole for 2 months, which was improved with supportive treatment. The patient restarted carbimazole and presented 4 months later with a diagnosis of acute lymphoblastic leukemia (ALL). This case of ALL was likely attributed by re-exposure to carbimazole, though the association of ALL with autoimmune thyroid disease cannot be denied.

Keywords: Acute lymphoblastic leukemia, antithyroid drugs, Graves' disease, pancytopenia


How to cite this article:
Nehara HR, Gupta BK, Parmar S, Kumar V, Sihag D, Beniwal S. Antithyroid drug-induced pancytopenia followed by acute lymphoblastic leukemia: A rare case. Thyroid Res Pract 2020;17:149-51

How to cite this URL:
Nehara HR, Gupta BK, Parmar S, Kumar V, Sihag D, Beniwal S. Antithyroid drug-induced pancytopenia followed by acute lymphoblastic leukemia: A rare case. Thyroid Res Pract [serial online] 2020 [cited 2021 Jun 22];17:149-51. Available from: https://www.thetrp.net/text.asp?2020/17/3/149/307556




  Introduction Top


Antithyroid drugs (ATDs) are largely used in the treatment of hyperthyroidism. Side effects were reported in <10% of the cases, especially hematological, hepatic, or skin allergies. Most severe hematological manifestations are pancytopenia and agranulocytosis.[1] Lymphocytes of patients who develop agranulocytosis while taking ATD may undergo blast transformation when exposed in vitro to ATD.[2] We present a rare case of a gentleman with Graves' disease, who developed pancytopenia after 2 months of therapy with carbimazole, which was recovered with treatment. The patient restarted carbimazole even after advice to avoid ATDs and for alternative treatment, and 4 months later, he was diagnosed with acute lymphoblastic leukemia (ALL).


  Case Report Top


A 26-year-old man was diagnosed with Graves' disease after presenting with weight loss, diarrhea, tremor, heat intolerance, and diffuse goiter. Initial investigations were normal including complete blood counts (CBCs) and biochemistry, except thyrotoxicosis. He has commenced on carbimazole 20 mg BD and propranolol 40 mg TDS.

Two months later, he presented with fever and sore throat for 5 days and hematuria for 2 days. He was febrile and tachycardic with pallor, submandibular lymphadenopathy, exudative pharynx, diffuse goiter, and unremarkable systemic examination. Laboratory investigations on admission revealed normocytic normochromic anemia (reticulocyte count: 0.05%), agranulocytosis and thrombocytopenia, normal biochemical panel, and normal thyroid panel except suppressed thyroid-stimulating hormone [Table 1]. Dengue NS1/IgM, HIV, HbsAg, HCV, and rapid malaria test was negative. A chest radiograph, ultrasound abdomen, urine microscopy, and peripheral blood film were normal. Blood and throat swab cultures were sterile. Bone marrow aspiration revealed severe hypoplasia without any atypical cells [Figure 1]. Thus, the diagnosis of ATD-induced pancytopenia was kept. The patient was given a broad-spectrum antibiotic and granulocyte-colony stimulating factor (G-CSF, filgrastim) 300 mcg/day for 10 days and intravenous methylprednisolone 1 g/day for 5 days, and carbimazole was discontinued. White blood cell counts (WBCs) and platelet started improving and fever settled on day 5, and he was discharged on day 11 on antibiotics and propranolol. On day 10 of discharge, his CBC was normalized and thyroid function revealed thyrotoxicosis [Table 1]. He was referred for radioactive iodine ablation and advised to avoid ATDs in the future.
Table 1: Blood investigations

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Figure 1: Photograph of bone marrow aspirate shows hypocellular marrow with markedly reduced hematopoietic precursors without any atypical cell (Giemsa, ×40)

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He was lost to follow-up and started carbimazole 20 mg OD again after consultation with his primary care physician. He was asymptomatic for 4 months after restarting carbimazole, and then, he again admitted to our department with a 15-day history of low-grade fever and fatigue and bleeding from the nose and gum for the last 2 days. On examination, he had tachycardia, pallor, petechiae, generalized lymphadenopathy, hepatomegaly, and splenomegaly. Laboratory investigation revealed a WBC of 1.000 × 109/L, hemoglobin 5.7 g/dl, and platelets 0.15 × 109/L. Peripheral blood film revealed pancytopenia. Workup for fever was unremarkable. Ultrasound abdomen revealed hepatosplenomegaly. Thyroid ultrasound showed homogenously enlarged lobes, heterogeneous echotexture, and increased vascularity. Bone marrow aspiration showed ALL with 85% blasts [Figure 2]. The patient was referred to a medical oncologist and was started on multicentric protocol (MCP 841) chemotherapy for ALL and was treated for 2.5 years and was on remission. Immunohistochemistry, cytogenetic, and molecular analysis was not done due to financial constraints. After the diagnosis of ALL, the patient was not on any ATDs, was not tested for thyroid profile, and was not consulted for hyperthyroidism. Two months after completion of ALL treatment, the patient again consulted to our department with symptoms suggestive of hyperthyroidism. Blood investigation revealed thyrotoxicosis and normal hemogram [Table 1]. After counseling, the patient was agreed for radioiodine ablation. The preablation Tc99 scan revealed increased uptake, and the patient was given 10 mCi of I131 [Figure 3]. The patient was again lost to follow-up and consulted to our department 6 months after radio iodine-ablation with symptoms suggestive of hypothyroidism. Blood investigations were unremarkable except hypothyroidism, and the patient was started on thyroxin replacement. The patient was doing well at last follow-up 1 month back with normal CBC and thyroid profile.
Figure 2: Photograph of bone marrow aspirate shows lymphoblastic leukemia in which lymphoblasts have fine chromatin, nuclear indentation, basophilic cytoplasm, and inconspicuous nucleoli (Giemsa, ×100)

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Figure 3: 99mTc pertechnetate thyroid scan showing enlarged thyroid gland with homogenously increased tracer uptake in both the lobes suggestive of Graves' disease

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  Discussion Top


Agranulocytosis is a rare complication of ATDs with an incidence of 0.1%–0.4%, and pancytopenia is ever rarer with an incidence of <0.01%.[3],[4] The pathogenesis of ATD-induced pancytopenia is unclear; however, direct cytotoxic effect by ATD or autoimmune reaction for bone marrow precursors are possible mechanisms. Most cases of ATD-induced pancytopenia usually develop within 3 months after the start of therapy.[5] In our patient, pancytopenia developed about 2 months after the start of carbimazole.

The diagnosis of ATD-induced pancytopenia is made when patients show a granulocyte count of <500/cmm, a hemoglobin concentration of <11.0 g/dl, and a platelet count of <100 × 109/liter.[4] The management of ATD-induced pancytopenia is largely supportive, with early diagnosis, hospitalization, broad-spectrum antibiotics, and blood and platelet transfusion. Besides this, glucocorticoids, G-CSF, cyclosporine, androgens, and antithymocyte globulin have been used. G-CSF administration leads to a mean shortened recovery period of 2 days.[1] Abrupt cessation of antithyroid medication can trigger a thyrotoxic state, so alternative methods, such as radioactive iodine and urgent thyroidectomy, should be considered.[1]

Lymphocytes of patients who develop agranulocytosis while taking thionamides undergo blast transformation when exposed in vitro to ATD and consequently should not be given again.[2] Continuing ATD treatment in patients with agranulocytosis might cause permanent damage to the marrow.[6] In this case, the patient developed ATD-induced pancytopenia, and the drug was discontinued. However, the patient continued to take carbimazole for further 4 months and presented with ALL. No other associated risk factors of ALL were found. To the best of our knowledge, this is the first reported case of ALL in a patient with Grave's disease treated with ATD following pancytopenia. It is not clear whether ALL in this patient is a consequence of ATD or an association with Graves' disease, as an association of autoimmune thyroid disease and ALL has been previously reported which may be related to immunologic dysregulation. Since thyroid hormones are important regulators of hematopoiesis and utilize receptors similar to the differentiating factors, further studies are warranted to see this association.[7]

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.

Acknowledgments

We are grateful to Dr. Tarun Jain, Department of Nuclear Medicine, MGMC, Jaipur, for helping in radio-ablation and the patient for giving consent and cooperating during management.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

1.
Thomas D, Moisidis A, Tsiakalos A, Alexandraki K, Syriou V, Kaltsas G. Antithyroid drug-induced aplastic anemia. Thyroid 2008;18:1043-48.  Back to cited text no. 1
    
2.
Williams AB, Williams RI. Williams's Textbook of Endocrinology. 14th ed. Philadelphia: Elsevier; 2016. p. 380.  Back to cited text no. 2
    
3.
Psomadakis C, Creamer A, Baynes C. Carbimazole-induced pancytopaenia. Br J Hosp Med (Lond) 2016;77:248-9.  Back to cited text no. 3
    
4.
Watanabe N, Narimatsu H, Noh JY, Yamaguchi T, Kobayashi K, Kami M, et al. Antithyroid drug-induced hematopoietic damage: A restrospective cohort study of agranulocytosis and pancytopenia involving 50,385 patients with Graves' disease. J Clin Endocrinol Metab 2012; 97:49-53.  Back to cited text no. 4
    
5.
Honda M. Successful treatment of methimazole-induced severe aplastic anemia by granulocyte colony-stimulating factor, methylprednisolone, and cyclosporin: Case report. ISRN Endocrinol 2011;2011:732623.  Back to cited text no. 5
    
6.
Tajiri J, Noguchi S. Antithyroid drug-induced agranulocytosis: How has granulocyte colony-stimulating factor changed therapy? Thyroid 2005;15:292-7.  Back to cited text no. 6
    
7.
Moskowitz C, Dutcher JP, Wiernik PH. Association of thyroid disease with acute leukemia. Am J Hematol 1992;39:102-7.  Back to cited text no. 7
    


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  [Figure 1], [Figure 2], [Figure 3]
 
 
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