==== Front Clin Med Insights Case RepClin Med Insights Case RepICRspicrClinical Medicine Insights. Case Reports1179-5476SAGE Publications Sage UK: London, England 10.1177/117954761878109010.1177_1179547618781090ICR-0044382Case ReportGraves Disease Causing Pancytopenia: Case Report and Literature Review Pincet Laurence Gorostidi François ENT Surgery Department, University Hospital Centre (CHUV), Lausanne, Switzerland.Laurence Pincet, Centre Hospitalier Universitaire Vaudois (CHUV), Rue de Bugnon 46, 1011 Lausanne, Switzerland. Email: laurencepincet@gmail.com25 6 2018 2018 11 11795476187810906 2 2018 8 5 2018 © The Author(s) 20182018SAGE Publications Ltd unless otherwise noted. Manuscript content on this site is licensed under Creative Commons LicensesThis article is distributed under the terms of the Creative Commons Attribution-NonCommercial 4.0 License (http://www.creativecommons.org/licenses/by-nc/4.0/) which permits non-commercial use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access pages (https://us.sagepub.com/en-us/nam/open-access-at-sage).Background: Graves disease or other causes of thyrotoxicosis are frequently associated with cytopenia. Although anemia is the most common, other cell lineage can be affected. Pancytopenia is a rare complication of thyrotoxicosis. Case presentation: We report a case of a 33-year-old Chinese man who presented a nonsevere pancytopenia in the context of a newly diagnosed Graves disease. Restauration of euthyroid state led to progressive correction of pancytopenia. Conclusions: Literature review shows other rare cases of pancytopenia. It is usually nonsevere with just extremely rare cases of transfusion reported. Evolution was always favorable after achievement of euthyroid state. Its mechanism remains poorly understood, especially because those patients have no vitamin or iron deficiency. The exact physiopathological process remains unclear but 2 causes seem to overlap: reduced production of hematopoietic cells from the bone marrow and increased destruction or sequestration of mature hematopoietic cells. Despite unclear mechanism, the presence of hematologic abnormalities including pancytopenia must not be considered as a contraindication to antithyroid drug therapy. Graves diseasepancytopeniahyperthyroidismantithyroid drug therapycover-dateJanuary-December 2018 ==== Body Background Graves disease or other causes of thyrotoxicosis are frequently associated with cytopenia. Anemia is the most common, but other cell lineage can be affected.1–3 Pancytopenia, however, is rare. This can raise a therapeutic dilemma with antithyroid drug therapies known for hematologic side effects. Case Presentation A 33-year-old Chinese man with no past medical history presented to the emergency department with bilateral leg edemas and progressive dyspnea over 1 month. He also complained of neck swelling, palpitations, hand tremor, nycturia, stomach aches, and diarrhea since childhood, testicular and penile edema, and involuntary weight loss (12 kg) over 4 months despite a good appetite. He has lived in Switzerland for the past 10 years and had no history of professional or recreational toxic exposure. Physical examination demonstrated a voluminous thyromegaly, with leg edema from the feet to the hips, dermatitis, and a raised jugular venous pulse. Cardiac auscultation revealed an irregular heart rate, with a cardiac murmur (5/6) at Erb’s point, radiating to the carotids. Pulmonary auscultation revealed pulmonary crackles in the lung bases. The abdomen was distended with a fluid thrill sign, but pain free. On genital examination, there was a translucid painless testicular edema. He had no exophthalmia. Laboratory tests revealed pancytopenia with a nonregenerative anemia (hemoglobin = 97 g/L [normal range = 117-157 g/L], reticulocytes = 12 G/L [normal range = 25-75 G/L]), thrombopenia (T = 74 G/L [normal range = 150-400 G/L]), and leukopenia (L = 3.4 G/L [normal range = 4-10 G/L]) without agranulocytosis (neutrophil count = 1.7 G/L [normal range = 2-7.5 G/L]). Anemia workup showed no vitamin B12 or folic acid deficiency, normal haptoglobin. A blood smear showed no abnormality. The NT-proBNP was 1664 ng/L (normal range < 300 ng/L). Thyroid function test detected abnormally high levels of thyroid hormones: l-triiodothyronine (T3) = 50 pmol/L (normal range = 3.5-6.5 pmol/L), l-thyroxine (T4) > 100 pmol/L (normal range = 10-23 pmol/L), thyroid-stimulating hormone (TSH) = 0.01 (normal range = 0.5-4.70 mIU/L). Later, immunology revealed TRAK levels >30 U/L (normal range < 1.8 U/L) and antithyroperoxydase antibodies = 1508 kUI/L (normal range < 35 IU/mL). An electrocardiogram showed atrial fibrillation (cardiac frequency = 135/min), and transthoracic ultrasound (US) showed cardiomegaly with no ventricular dysfunction. Cervical US revealed an enlarged thyroid gland (total volume = 22 mL [normal range = 5.7-17 mL]) with bilateral heterogeneous enlarged lobes, without any focal suspect lesion. Color Doppler showed a highly increased “inferno” type of vascularization. Thorax X-ray showed a pulmonary edema with small pleural effusions on both sides. He was hospitalized. Treatment was started with carbimazole (15 mg, 3 times a day) with furosemide (40 mg/d) to treat global cardiac failure. Anticoagulation with rivaroxaban was also started to prevent embolisms due to atrial fibrillation. To reduce the heart beat fibrillation, metoprolol was given, with perindopril for pressure control. With treatment, symptoms improved within 5 days: the tremor stopped and he had a normal bowel transit. Spontaneous cardioversion to a normal sinus rhythm lead to the regression of the edemas and weight loss (−6 kg). Within several days, restauration of a euthyroid function was linked to the correction of hematologic values (Table 1). After discharge, the pancytopenia resolved completely and remained stable without any blood product transfusion. Table 1. Hematologic values. D1 D3 D5 D7 D9 D11 Leukocytes, G/L 3.4 2.8 3.1 3.3 3.4 4.7 Hemoglobin, g/L 97 98 102 105 102 112 Thrombocytes, G/L 74 77 78 95 104 148 Discussion and Conclusions In our case, the patient came to the emergency department because of heart failure symptoms. They were further related to the Graves disease. Pancytopenia was identified in the initial workup. With no vitamin or iron deficiency, the cause of pancytopenia was unclear. Furthermore, because the blood smear was normal, with a well-tolerated, non-severe pancytopenia, no bone marrow biopsy was performed, and the response to antithyroid treatment was assessed on repeated blood tests. Resolution of pancytopenia occured simultaneously with the return of a euthyroid state (Table 1). It is known that isolated anemia, thrombopenia, or leukopenia can be associated with thyrotoxicosis. It appears that anemia is the most associated cytopenia (10%-34%) of patients with thyrotoxicosis.1–3 Leukopenia is reported in 15% to 30% of untreated thyrotoxicosis, and thrombocytopenia is rarely observed in 2% to 5% of thyrotoxicosis cases.1,3 The association between thyrotoxicosis and pancytopenia is a rarely described in the literature (Table 2). Two major points seem relevant. First, it appears that pancytopenia is usually chronic and well tolerated. Over the 23 cases reported in the literature (Table 2), 5 were transfused with red blood cells, and 2 also received platelet transfusion. In those cases, transfusion was mainly done because of tachycardia with cardiac failure related to thyrotoxicosis, which could be worsened by anemia. We found no case report of ischemia or other severe complication of anemia, nor bleeding because of thrombocytopenia, nor synchronous infection due to leukopenia. Only 2 cases were close to agranulocytosis with 0.5 G/L neutrophils; however, none of them required growth factor treatment. Second, in all cases reported, hematologic values were corrected with correction of the thyrotoxicosis. Choice of treatment (propylthiouracil, methimazole, radioiodine therapy, or even surgery) did not matter, and normalization of the thyroid hormones values was followed by correction of the blood cell counts. Table 2. Literature review. Year Author (reference) Sex Age, y Pathology Hemoglobin, g/dL Normal range = 117-157 g/L Platelet count, G/L Normal range = 150-400 G/L WBC, G/L Normal range = 4-10 G/L Neutrophil count, G/L Normal range = 2-7.5 G/L Transfusion Recovery after the therapy Vitamin B12 deficiency 2014 Rafhati et al,4 Case 1 F 56 GD 10.6 110 2.9 1.1 No Yes No 2014 Rafhati et al,4 Case 2 F 57 GD 11.6 110 3.8 1.5 No Yes No 2014 Rafhati et al,4 Case 3 F 58 GD 8.6 72 3.22 1.48 No Yes No 2012 Raina et al5 M 27 GD 9.5 80 2.4 — No Yes No 2009 Boon-Hua Low and Kok6 F 56 GD 5.7 59 2.05 — No Yes Yes 2013 Peyman Naji et al2 M 70 GD 9 80 2.5 — No Yes No 2013 Loh Huai Heng and Tan7 M 48 GD 8.7 48 3.2 1.16 RBC T Yes Yes 2006 Lima et al,3 Case 1 M 71 GD 7.3 23 2.5 0.9 RBC T Yes Yes 2006 Lima et al,3 Case 2 F 35 GD 9.5 75 2.8 1.6 No Yes No 2006 Lima et al,3 Case 3 M 39 GD 11.9 96 3.9 No Yes No 2006 Lima et al,3 Case 4 F 38 GD 4 10 3 0.5 RBC T Yes No 2015 Subrata Chakrabarti8 F 38 GD 8.6 78 3.1 — No Yes No 2013 Tae Hoon Kim et al1 F 69 GD 8.4 17 3.1 1.7 No Yes No 2014 Garcia et al9 F 54 GD 9.5 137 2.1 0.5 No Yes No 2002 Shaw and Mehta10 M 46 GD 9.7 22 2.2 1 RBC T + P T Yes — 2015 Imai et al11 F 33 HT 9.8 105 3.5 — No Yes No 2014 Jha et al12 F 62 GD 7.4 91 3.4 — RBC T Yes No 2009 Chen et al13 F 36 GD 9.1 69 1.6 — No Yes — 1995 Ladwig et al14 F 25 GD 4.1 44 5.2 — No 0 No 2001 Soeki et al15 M 49 HT 6.5 48 2.87 1.87 No Yes No 2008 Hegazi et al16 F 43 GD 7.3 55 3.2 — No Yes No 2017 Silva et al17 F 46 GD 6.1 99 2.06 — No Yes No 2007 Das et al18 F 10 GD 4.7 22 3.5 — RBC T + P T Yes No Abbreviations: GD, Graves disease; RBC, red blood cell. These reports indicate an association between thyrotoxicosis and pancytopenia, although the underlying physiopathology remains unclear. The mechanism seems to be plural, mainly on 2 paths: reduced production of hematopoietic cells from the bone marrow and increased destruction or sequestration of mature hematopoietic cells. Indeed, thyroid hormones are known for their effect on erythropoiesis, through hyperproliferation of immature erythroid progenitors and increased secretion of erythropoietin.3 This leads to an exaggerated consumption of iron, folic acid, and vitamin B12 and can generate various forms of anemia (normochromic-normocytic, hypochromic-microcytic, or macrocytic). In the cases we reviewed, only 2 cases reported severe vitamin B12 deficiency.3,6,7 Nevertheless, a large part of patients received anyway a substitution in iron, folates, or vitamin B12 without deficiency to support the erythropoiesis. No auto-immune anemia was reported, and peripheral hemolysis was ruled out by normal values of indirect bilirubin, haptoglobin, and negative Coombs.3 Several authors3,6,9,15,17 reported association of hyperthyroidism with splenomegaly that is known to be correlated with a reduction in the erythrocyte life span with hypersplenism.6 After treatment and achievement of the euthyroid status, splenomegaly returned to normal size. The cause of leukopenia is also poorly understood. On one hand, granulopoiesis is limited by a reduced marrow granulocyte reserve,6 on the other hand, the hypothesis of immunologic destruction mechanisms has been suggested, as antineutrophil antibodies were detected in the serum of patients with thyrotoxicosis.19 Moreover, a relative lymphocytosis with cross-antigenicity between human TSH receptors and polynuclear neutrophils has been described with formation of a characteristic blood finding of Graves disease called Kocher blood picture.1 EMA Kyritsi et al20 found that thyroidopathy represents the most common disorder among apparently healthy patients with mild-to-moderate neutropenia. They showed significant patterns of parameters and markers of immunity and remarkable correlations between T3 levels and absolute neutrophil counts, TSH levels and absolute CD4+ counts, T4 levels and absolute CD4+ counts. In addition, antiplatelet antibodies have been detected in the serum of patients with Graves disease and Hashimoto thyroiditis.3,6 Hypersplenism is implicated in the same way in the reduction in lifetime of the thrombocytes. Finally, it is known that antithyroid drug therapy can cause severe hematologic disorders. Therefore, a complete blood count with reticulocyte rate seems important when hyperthyroidism is diagnosed. Identification of initial cytopenia or pancytopenia correlates with the thyrotoxicosis. This will help, in the future, to disqualify them from adverse effect of antithyroid drug therapy. If there is no agranulocytosis (contraindication to start antithyroid drugs), the presence of initial hematologic abnormalities, including pancytopenia, must not be considered as a contraindication to antithyroid drug therapy. Daily monitoring of hematologic values must be done. Pancytopenia is a rare complication of thyrotoxicosis. It is usually not severe and resolves with the restauration of euthyroid state. Extremely rare cases need transfusion. Funding:The author(s) received no financial support for the research, authorship, and/or publication of this article. Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. Author Contributions: LP provided medicine for the patient. LP and FG wrote the manuscript. All authors read and approved the final manuscript. Availability of Data and Materials: The author can be contacted for data requests. Consent for Publication: Written informed consent was obtained from the patient for publication of this case report. ==== Refs References 1 Kim TH Yoon JS Park BS et al A case of pancytopenia with hyperthyroidism . YUJM . 2013 ;30 :47 –50 . 2 Naji P Kumar G Dewani S Diedrich WA Gupta A. Grave disease causing pancytopenia and autoimmune hemolytic anemia at different time intervals: a case report and a review of the literature . Case Rep Med . 2013 ;2013 :194542 .24319463 3 Lima CS Wittmann DE Catro V et al Pancytopenia in untreated patients with Graves’ disease . Thyroid . 2006 ;16 :403 –409 .16646688 4 Rafhati AN See CK Hoo FK Badrulnizam LBM A report of three cases of untreated Graves’ disease associated with pancytopenia in Malaysia . Electron Physician . 2014 ;6 :877 –882 .25763162 5 Raina S Kaul R Mruthyunjaya M. Pancytopenia with cellular bone marrow related to Graves’ hyperthyroidism . Indian J Endocrinol Metab . 2012 ;16 :478 –479 .22629533 6 Low BH Kok VC. Hyperthyroidism with pancytopenia: a case report and literature review . Formos J Endocrin Metab . 2009 ;1 :23 –28 . 7 Loh HH Tan F. Pancytopenia in a patient with Graves’ disease . Med J Malaysia . 2013 ;68 :372 –373 .24145274 8 Chakrabarti S. Pancytopenia due to Graves’ disease: a rare scenario . Thyr Res Pract . 2015 ;12 :40 – 41 . 9 Garcia J França Ld Ellinger V Wolff M. Marrow hypoplasia: a rare complication of untreated Grave’s disease . Arq Bras Endocrinol Metabol . 2014 ;58 :953 –957 .25627052 10 Shaw B Mehta AB. Pancytopenia responding to treatment of hyperthyroidism: a clinical case and review of the literature . Clin Lab Haematol . 2002 ;24 :385 –387 .12452820 11 Imai K Ohkuchi A Nagayama S Saito S Matsubara S Suzuki M. Pancytopenia in the first trimester: an indicator of hidden hyperthyroidism . J Obstet Gynaecol Res . 2015 ;41 :1991 –1994 .26311610 12 Jha P Singh YP Ghimire B Jha BK. Pancytopenia in a surgical patient, a rare presentation of hyperthyroidism . BMC Surg . 2014 ;14 :108 .25511310 13 Chen YH Lin HJ Chen KT. Rare presentations of hyperthyroidism—Basedow’s paraplegia and pancytopenia . Am J Emerg Med . 2009 ;27 :258.e1 –258.e2 .19371562 14 Ladwig P Coles R Fischer E Spurrett B. Thyrotoxicosis in pregnancy presenting as pancytopenia . Aust N Z J Obstet Gynaecol . 1995 ;35 :457 –460 .8717580 15 Soeki T Tamura Y Kondo N et al A case of thyrotoxicosis with pancytopenia . Endocr J . 2001 ;48 :385 –389 .11523911 16 Hegazi M Kumara R Bitara Z Ibrahim E. Pancytopenia related to Graves’ disease . Ann Saudi Med . 2008 ;28 :48 –49 .18299644 17 Silva M Vieira R Bessa MM Lima JKT Marques TF. A rare case of Graves’ disease with splenomegaly and pancytopenia . Int Arch Med . 2017 ;(10 ):1755 –7682 . 18 Das PK Wherrett D Dror Y. Remission of aplastic anemia induced by treatment for Graves disease in a pediatric patient . Pediatr Blood Cancer . 2007 ;49 :210 –212 .16456859 19 Duquenne M Lakomsky D Humbert JC Hadjadj S Weryha G Leclère J. Pancytopenia resolved by the treatment of hyperthyroidism . Presse Med . 1995 ;24 :807 –810 .7630870 20 Kyritsi EM Yiakoumis X Pangalis GA et al High frequency of thyroid disorders in patients presenting with neutropenia to an outpatient hematology clinic STROBE-compliant article . Medicine . 2015 ;94 :e886 .26061308