Case Report
PANCYTOPENIA AND LYMPHOID ORGAN HYPERPLASIA IN A PATIENT WITH GRAVES DISEASE: RESPONSE TO ANTITHYROID DRUG THERAPY
Jonathan C. Li, MD1; Deepika Nandiraju, MD2; Serge Jabbour, MD, FACP, FACE3; Alan A. Kubey, MD4,5
ABSTRACT
Objective: In rare instances, cytopenias manifest as a complication of thyrotoxicosis. Here, we report a case of Graves disease (GD) thyrotoxicosis presenting as pancyto- penia that resolved with antithyroid therapy. Methods: A 35-year-old male presented with fever and chills following an outpatient colonoscopy. Initial blood work revealed pancytopenia. Workup included viral antigen titers, blood cultures, rheumatologic antibod- ies, inflammatory markers, immunocompetency, nutrient deficiency, metal toxicity, and malignancy. Bone marrow aspirate was analyzed by microscope, flow cytometry, fluorescence in situ hybridization, and genetic analysis. Computed tomography scan of the chest, abdomen, and pelvis was obtained. Thyroid labs included thyroid-stim- ulating hormone, total triiodothyronine, free thyroxine, thyroid-stimulating immunoglobulin, anti-thyroid peroxi- dase antibody, and radioiodine uptake scan. Results: All workup above was non-revelatory except as follows. Imaging revealed thymic hyperplasia and splenomegaly. Thyroid labs revealed thyroid-stim-
ulating hormone <0.02 µIU/mL (reference range is 0.30 to 5.00 µIU/mL), free thyroxine of 4.7 ng/dL (reference range is 0.7 to 1.7 ng/dL), total triiodothyronine of 191 pg/mL (reference range is 90 to 180 pg/mL), thyroid- stimulating immunoglobulin of 522% (reference range is <140%). Bone marrow biopsy was consistent with a reactive process suggesting an infectious or autoimmune process. Radioiodine uptake scan confirmed GD. He was discharged on antithyroid medication. Two-month follow-up labs revealed improved cell counts; his absolute neutrophil count was 1.94 × 109 cells/L (reference range is 1.50 to 8.00 × 109 cells/L), hemoglobin was 12.9 g/dL (reference range is 14.0 to 17.0 g/dL), and platelets were 153 × 109 cells/L (reference range is 140 to 400 × 109 cells/L). Definitive treatment was obtained with 12 mCi of 131-iodine. Conclusion: Pancytopenia and lymphoid organ hyper- plasia (splenomegaly, thymic hyperplasia, and lymphade- nopathy) have been previously reported to be associated with thyrotoxicosis secondary to GD, rarely simultane- ously, and manifest from both thyrotoxic and immunologic mechanisms. After excluding alternative life-threatening pathologies, in such presentations, GD should be consid- ered and treated if confirmed. (AACE Clinical Case Rep. 2019;5:e388-e392)
Abbreviations: ANC = absolute neutrophil count; GD = Graves disease; LOH = lymphoid organ hyperplasia; TH = thymic hyperplasia; TSH = thyroid-stimulating hormone
INTRODUCTION
Pancytopenia is a concerning laboratory abnormality requiring urgent evaluation. Anemia, thrombocytopenia,
Submitted for publication April 17, 2019 Accepted for publication August 16, 2019 From the 1Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania and Internal Medicine and Pediatrics Residency Program, Christiana Care Health System, Newark, Delaware, 2Division of Endocrinology, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, 3Division of Endocrinology, Diabetes & Metabolic Diseases, Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, Pennsylvania, 4Division of Hospital Medicine, Thomas Jefferson University Hospital, Philadelphia, Pennsylvania, and 5Division of Hospital Internal Medicine, Mayo Clinic, Rochester, Minnesota. Address correspondence to Dr. Jonathan C. Li, 1025 Walnut Street #100, Philadelphia, PA 19107. E-mail: Jonathan.C.Li@christianacare.org. DOI:10.4158/ACCR-2019-0170 To purchase reprints of this article, please visit: www.aace.com/reprints. Copyright © 2019 AACE.
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GD-Induced Pancytopenia and LOH, AACE Clinical Case Rep. 2019;5(No. 6) e389
and neutropenia may manifest as complications of thyro- toxicosis. Here, we report a case of Graves disease (GD) thyrotoxicosis presenting with pancytopenia uniquely characterized by neutropenia, lymphopenia, and lymphoid organ hyperplasia (LOH) that resolved following antithy- roid therapy. Lymphopenia has not previously been report- ed in the setting of GD.
CASE REPORT
A 35-year-old, healthy male with family history significant for colon cancer and GD, presented with 1 day of fevers and chills following an outpatient colonoscopy. The colonoscopy was normal and only significant for non- bleeding grade 1 internal hemorrhoids. He also reported 45-pound weight loss in the setting of active dieting and exercising within a 3-month period. Vitals and labs noted fever (39.7°C), absolute neutro- phil count (ANC) of 0.47 × 109 cells/L (reference range is 1.50 to 8.00 × 109 cells/L), hemoglobin of 12 g/dL (reference range is 14 to 17 g/dL), and platelets of 70 × 109 cells/L (reference range is 140 to 400 × 109 cells/L) despite normal counts 1 year prior. His physical exam was unremarkable. Antibiotics were initiated for neutropenic fever. Thyroid labs revealed thyroid-stimulating hormone (TSH) <0.02 µIU/mL (reference range is 0.30 to 5.00 µIU/ mL), free thyroxine of 4.7 ng/dL (reference range is 0.7 to 1.7 ng/dL), total triiodothyronine of 191 pg/mL (refer- ence range is 90 to 180 pg/mL), and a thyroid-stimulat- ing immunoglobulin level of 522% (reference range is <140%). The patient’s overall trends in thyroid levels and cell count metrics throughout his complete clinical course are depicted in Figure 1.
Electrocardiogram revealed sinus rhythm. An exten- sive infectious workup was performed including tests for influenza A and B, respiratory syncytial virus, parvovirus, Epstein-Barr virus, cytomegalovirus, human immunodefi- ciency virus, and blood cultures for bacterial and fungal organisms. Rheumatologic tests were performed to assess erythrocyte sedimentation rate, rheumatoid factor, anti- cyclic citrullinated protein, and anti-nuclear antibody. Hematologic workup included total serum immuno- globulin levels (for IgA, IgG, and IgM), alpha fetoprotein, alpha 1 globulin, alpha 2 globulin, beta globulin, gamma globulin, gene rearrangement clonality analysis of immu- noglobulin heavy chain and T-cell receptor gamma, flow cytometry of peripheral blood, and fluorescence in situ hybridization analysis. Other serologic testing includ- ed lactate dehydrogenase, haptoglobin, ferritin, beta-2 microglobulin, folate, vitamin B12, copper, acetylcholine receptor-modulating antibody, and anti-thyroid peroxidase antibody. All aforementioned tests were normal. Peripheral blood smear revealed small, mature, but abnormal lympho- cytes, not representative of typical reactive lymphocytes. Chest X-ray was normal. A computed tomography scan demonstrated mild splenomegaly (15.8 cm), multiple small para-aortic retroperitoneal lymph nodes (up to 1.3 cm), and an enlarged thymus (1.9 × 3.0 cm). A magnetic resonance imaging scan showed thymic hyperplasia (Fig. 2). A bone marrow biopsy was interpreted as consis- tent with a reactive process suggesting an infectious or autoimmune process. Thyroid ultrasound showed heterogeneous enlarge- ment with the right lobe measuring 5.7 × 1.5 × 2.1 cm and the left lobe measuring 6.0 × 1.7 × 2.1 cm, most compat- ible with acute thyroiditis. Follow-up technetium scan was
Fig. 1. Trends in thyroid hormones and blood parameters. ANC = absolute neutrophil count; H1 = index hospital- ization; Hgb = hemoglobin; LLN = lower limit normal; T3 = triiodothyronine; T4 = thyroxine; ULN = upper limit normal.
e390 GD-Induced Pancytopenia and LOH, AACE Clinical Case Rep. 2019;5(No. 6)
Fig. 2. Computed tomography scan of the chest with contrast revealing an abnormally enlarged thymus reflecting thymic hyperplasia.
consistent with GD. After multispecialty consultation and literature review, pancytopenia secondary to GD was diag- nosed. The patient was initiated on methimazole at 20 mg daily with endocrinology follow up. Eight days after discharge, his ANC and platelets improved to normal measuring 1.54 × 109 cells/L and 149 × 109 cells/L, respectively, but anemia persisted with hemoglobin at 11.5 g/dL. Two months after discharge, labs remained reassuring with ANC of 1.94 × 109 cells/L, hemo- globin at 12.9 g/dL, and platelets of 153 × 109 cells/L. Four months after discharge, TSH, free triiodothyronine, free thyroxine, ANC, and platelets were within normal limits (measuring 2.30 µIU/mL, 3.1 pg/mL, 1.1 ng/dL, 1.73 × 109 cells/L, and 146 × 109 cells/L, respectively) and hemo- globin was improving toward normal at 13.6 g/dL. At this time the patient’s thyrotoxicosis was treated with 12 mCi of 131-iodine. Six months following ablation, the patient is on levothyroxine at 50 µg daily with normal thyroid func- tion tests, complete blood counts, liver function tests, and basic metabolic panel.
DISCUSSION
Our patient had a case of pancytopenia and LOH (sple- nomegaly, thymic hyperplasia, and lymphadenopathy) in the setting of GD that resolved with antithyroid therapy. These findings have all been previously reported to be asso- ciated with thyrotoxicosis secondary to GD. Leukopenia in this case was characterized by both neutropenia and lymphopenia. Lymphopenia, however, is distinctly unusual in the setting of GD.
Pancytopenia is a rare complication of GD thought to be secondary to thyrotoxicosis, immune-mediated destruction, sequestration, and vitamin deficiency (1). Thyrotoxicosis is supported by the observation that pancy- topenia is also seen in the setting of multinodular goiter and Hashimoto thyroiditis (1,2). As in this case, treatment of the hyperthyroidism causes resolution of pancytopenia (1,2). Some patients may require transfusions of red blood cells or platelets and vitamin B12 supplementation (2). The prevalence of anemia due to GD has been report- ed to be 22% with a greater incidence among men (41.6%) than women (17.5%) (3). The hyperthyroid state produces a microcytic, hypochromic anemia, with elevation in cell mass, hemoglobin A2, and fetal hemoglobin (3-5). In a pediatric GD case report, anemia was also characterized as microcytic and hypochromic, correlating inversely with serum erythropoietin and C-reactive protein levels, and resolved with antithyroid therapy (3). The hyperthyroid state elicits a variable effect on erythropoiesis dependent on the severity of hyperthyroid- ism. Thyroid hormones promote erythropoietin produc- tion to stimulate erythropoiesis; at abnormally high levels, however, thyroid hormones cause ineffective utilization of iron in bone marrow preventing effective erythropoiesis. Anemia may also manifest if, in the setting of increased demand, there is nutritional deficiency of hematopoi- etic nutrients such as iron, folate, and vitamin B12 (4,5). Aplastic anemia with bone marrow hypoplasia due to GD has also been reported (6). Concomitant autoimmune mechanisms may also present with GD and contribute to anemia including pernicious anemia secondary to autoim-
GD-Induced Pancytopenia and LOH, AACE Clinical Case Rep. 2019;5(No. 6) e391
mune atrophic gastritis (7), isolated autoimmune hemolytic anemia (8), and Evans syndrome (thrombocytopenia with hemolytic anemia) (9). Our patient was found to have a normocytic anemia with normal iron, vitamin B12, and folate levels. In concordance with the bone marrow find- ings discussed later, the anemia in this case is most likely due to thyrotoxic effects on the erythroid lineage in the bone marrow. Thrombocytopenia secondary to GD is a rare phenom- enon and may be caused by autoantibodies produced apart from thyroid-stimulating immunoglobulin. Cases of pancytopenia in GD have been attributed to primary immune thrombocytopenia (10), thrombotic thrombocyto- penic purpura (11), and Evans syndrome (9). Studies have also suggested that hyperthyroidism decreases platelet survival time (4) and increases platelet sequestration by activating the reticuloendothelial phagocyte system (12). Increased megakaryocytes in bone marrow may be seen (4). Treatment of GD often causes resolution of pancyto- penia (9,10). If thrombotic thrombocytopenic purpura is diagnosed, plasma exchange may be acutely required with the treatment of GD to prevent recurrence (11). Our patient’s platelet count nadired at 56 × 109 cells/L and he did not exhibit easy bruising or excessive bleed- ing. Adequate megakaryopoiesis was seen in bone marrow and recovery to 140 × 109 cells/L was measured 8 days after discharge. In this case, since thyroid-stimulating immunoglobulin remained high in the euthyroid state, it can be surmised that if thrombocytopenia were due to a concurrent autoimmune mechanism, platelet counts would not recover so quickly. Since platelet count resolved with thyroid status, the mechanism for thrombocytopenia in our case is most consistent with thyroid effects on the reticulo- endothelial system. Leukopenia in GD is due to neutropenia. A relative lymphocytosis is commonly seen with atypical lympho- cytes, as with our patient (4). Our patient, however, present- ed with both neutropenia and lymphopenia. Neutropenia during thyrotoxicosis was first described in 1908 with an incidence of 5 to 18% (4,13). The exact cause is not well understood. Studies report a reduction in bone marrow granulocyte reserve with a shift towards erythropoiesis, decreased systemic granulocyte survival, and normal- to-elevated granulocyte colony-stimulating factor levels among these neutropenic patients (4,14). In 1 systematic study, 43.6% of patients presenting to an outpatient hematology clinic for neutropenia tested positive for a thyroid disorder. Among this cohort, 37.2% tested positive for anti-neutrophil cytoplasmic antibodies (15). Lymphopenia, however, has not been described in the literature as a manifestation of GD; we believe this may be one of the first case reports. In our case, as in the literature, neutropenia resolved concomitantly with improved thyroid status suggesting a thyrotoxic mechanism (13).
The association between TH and GD was first described in 1912 and thoroughly reviewed by Haider et al (16) in 2017. Its incidence is unknown and is often unrecognized in clinical practice as imaging of the medias- tinum is not routinely performed for GD. TH is described as “gross, diffuse, and symmetric enlargement of the thymus” and can be further differentiated into 2 histologi- cal subtypes: true TH and thymic lymphoid hyperplasia. It is suspected that both are present in GD and contrib- ute to the finding of TH. Thyroid hormones stimulate the growth of thymic parenchyma via the thyroid-stimulating hormone receptor (17) and thymic endocrine pathways causing true TH and immunogenic mechanisms resulting in thymic lymphoid hyperplasia, which is also found in other autoimmune diseases. Although the thymus is often the autoimmune driver of disease, this is not the case in GD in which it is purely reactive (16). TH resolves with treatment of GD (16,17). Haider et al (16) recommend repeat imaging after 6 months of GD treatment with expected regression by ≥50% to be consistent with GD. Failure of regression requires addi- tional workup. In the case presented, a computed tomogra- phy scan performed 2.5 months after discharge did not note change in thymic size. In addition to TH, splenomegaly and lymphadenopa- thy have been reported in association with GD (18). Our patient had minor para-aortic lymphadenopathy and mild splenomegaly. Thyrotoxic hepatic dysfunction is well described and causes a hepatomegaly with congestive splenomegaly (19). Our patient, however, was not found to have hepatomegaly though he did have a mild transaminitis. Non-congestive splenomegaly secondary to GD is a lesser described entity in the literature and its pathogen- esis is likely the result of similar mechanisms as that of TH since the thymus, the spleen, and lymph nodes are all secondary lymphoid organs and may respond to thyroid hormones similarly (18). In another case of GD-induced pancytopenia with splenomegaly, the patient was found to have increased polyclonal B cells in circulation and in their bone marrow, supporting the concept of lymphoid hyper- plasia due to thyrotoxicosis (20). Splenomegaly is report- ed to resolve with treatment of GD (20). In our patient, however, a computed tomography scan 2.5 months after discharge did not observe any reduction in splenomegaly. In most cases of pancytopenia or cytopenia relat- ed to GD, treatment of GD leads to cell count recovery. Recovery time ranges from a few weeks to >1 year (1). As in our case, we observed improved blood count trends after methimazole initiation with normalization at least as early as 79 days after the patient’s index discharge. The response of blood counts toward normal after antithy- roid treatment and extensive negative infectious workups supports the concept that pancytopenia in this case was due to thyrotoxicosis.
e392 GD-Induced Pancytopenia and LOH, AACE Clinical Case Rep. 2019;5(No. 6)
7. Nightingale S, Vitek PJ, Himsworth RL. The haematology of
CONCLUSION
hyperthyroidism. Q J Med. 1978;47:35-47.
8. Naji P, Kumar G, Dewani S, Diedrich WA, Gupta A. Graves’ disease causing pancytopenia and autoimmune hemolytic anemia at different time intervals: a case report and a review of the litera- ture. Case Rep Med. 2013;2013:194542.
GD may cause cytopenias and LOH through both thyrotoxic and immunologic mechanisms. In the absence of other causes, these secondary pathologies respond to antithyroid therapy and treatment of the primary pathology.
9. Ushiki T, Masuko M, Nikkuni K, et al. Successful remission of Evans syndrome associated with Graves’ disease by using propyl- thiouracil monotherapy. Intern Med. 2011;50:621-625.
10. Schmohl J, Vogel W, Gallwitz B, Mohle R. Thrombocytopenia in Graves’ disease [in German]. Dtsch Med Wochenschr. 2012;137:1056.
11. Chhabra S, Tenorio G. Thrombotic thrombocytopenic purpura precipitated by thyrotoxicosis. J Clin Apher. 2012;27:265-266. 12. Kurata Y, Nishiōeda Y, Tsubakio T, Kitani T. Thrombocytopenia in Graves’ disease: effect of T3 on platelet kinetics. Acta Haematol. 1980;63:185-190.
ACKNOWLEDGMENT We thank Drs. Emma Lundsmith and Sean Clark- Garvey for their academic support and clinical precep- torship and Ms. Jennifer Wilson for her thoughtful and detailed revisions.
DISCLOSURE
13. Aggarwal N, Tee SA, Saqib W, Fretwell T, Summerfield GP, Razvi S. Treatment of hyperthyroidism with antithyroid drugs corrects mild neutropenia in Graves’ disease. Clin Endocrinol (Oxf). 2016;85:949-953.
The authors have no multiplicity of interest to disclose.
14. Ponassi A, Morra L, Caristo G, Parodi GB, Biassoni P, Sacchetti C. Disorders of granulopoiesis in patients with untreated Graves’ disease. Acta Haematol. 1983;70:19-23.
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