e388 AACE CLINICAL CASE REPORTS Vol 5 No. 6 November/December 2019
Copyright © 2019 AACE
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
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.
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,
GD-Induced Pancytopenia and LOH, AACE Clinical Case Rep. 2019;5(No. 6) e389 Copyright © 2019 AACE
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) Copyright © 2019 AACE
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-
Fig. 2. Computed tomography scan of the chest with contrast revealing an abnormally enlarged thymus reflecting thymic hyperplasia.
GD-Induced Pancytopenia and LOH, AACE Clinical Case Rep. 2019;5(No. 6) e391 Copyright © 2019 AACE
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) Copyright © 2019 AACE
CONCLUSION
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.
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
The authors have no multiplicity of interest to disclose.
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