The study, conducted at the National Center for Global Health and Medicine in Tokyo and published in BMC Endocrine Disorders, was led by Erika Sugito and Noriko Ihana-Sugiyama together with colleagues including Akiyo Tanabe. The researchers set out to address a deceptively simple question that has long lacked a rigorous answer. Graves’ disease, the autoimmune disorder in which antibodies stimulate the thyroid into overproduction, is the most common cause of sustained thyrotoxicosis, and low neutrophil counts are occasionally observed in these patients at the time of diagnosis. But whether that association is specific to Graves’ disease, or simply a feature of the hyperthyroid state itself, has remained unclear because most prior work examined only single disease groups without an appropriate comparator.

The design was deliberately conservative. The team identified all adults newly diagnosed with thyrotoxicosis at their tertiary endocrinology center between August 1, 2016, and August 31, 2021. From an initial pool of 373 patients, they applied exclusion criteria designed to strip away confounders that could independently lower neutrophil counts: anyone with an underlying condition known to cause cytopenia, and anyone taking medications known to affect neutrophils, were removed from the analysis. This filtering left 188 patients for the final comparison, a number that reflects how difficult it is to assemble a clean cohort in this field, since many patients with thyroid disease carry comorbidities or drug exposures that muddy the hematologic picture.

The remaining patients were sorted into four etiological groups, and the classification rested on a key immunological marker. One hundred fourteen patients had Graves’ disease confirmed by a positive test for thyroid-stimulating hormone receptor antibodies, or TRAb, the autoantibodies that drive the disease. Twelve patients had TRAb-negative Graves’ disease, a less common presentation in which the clinical picture suggests Graves’ but the antibody test comes back negative. Thirty-seven patients had painless thyroiditis, a form of thyroid inflammation that releases preformed hormone into the circulation without overproduction, and twenty-five had subacute thyroiditis, a painful, often post-viral inflammation of the gland. This four-way split allowed the investigators to ask whether the autoimmune, antibody-driven form of thyrotoxicosis behaves differently from the destructive forms with respect to blood counts.

Neutropenia was defined in the study as a neutrophil count below 1,800 cells per microliter of blood, a conventional clinical threshold below which infection risk begins to rise. The results showed a clear signal in one direction and an absence of signal in another. Median neutrophil counts were significantly higher in the subacute thyroiditis group than in the other three groups, suggesting that the acute inflammatory response typical of that condition may transiently push neutrophil production upward. Yet when the researchers looked at the proportion of patients who actually crossed the neutropenia threshold, the differences between groups failed to reach statistical significance. Neutropenia was found in 7.0 percent of the TRAb-positive Graves’ group, 8.3 percent of the TRAb-negative Graves’ group, and 10.8 percent of the painless thyroiditis group, with the subacute thyroiditis group showing the lowest frequency.

Two further analyses sharpened the interpretation. First, the researchers compared neutrophil counts between the TRAb-positive and TRAb-negative Graves’ disease groups and found them comparable, which argues against the idea that the detectable autoimmune antibody itself is what drives the low counts. Second, they examined whether the severity of thyroid hormone excess predicted the degree of neutropenia by correlating free thyroxine, or FT4, levels with neutrophil counts within each group. The correlation was absent. In other words, within each disease category, a patient with very high thyroid hormone levels was no more likely to have depressed neutrophils than a patient with milder biochemical derangement, which weighs against a simple dose-dependent effect of thyroid hormone excess on the bone marrow.

The biological backdrop to these findings is worth unpacking. Neutrophils are produced in the bone marrow from hematopoietic stem cells and circulate for only hours to days, making their counts a sensitive barometer of marrow output and peripheral consumption. Several mechanisms have been proposed to explain why thyrotoxic patients might run low. Autoimmune destruction of neutrophils, analogous to the autoimmune process attacking the thyroid itself in Graves’ disease, is one candidate. Direct suppression of granulopoiesis by excess thyroid hormone is another. A third possibility, often raised in the literature, is that antithyroid drugs such as methimazole and propylthiouracil, which are mainstays of Graves’ treatment, cause neutropenia as an adverse effect. By restricting the analysis to newly diagnosed, treatment-naive patients and excluding those on count-altering medications, the Japanese team effectively removed the drug effect from the equation and asked about the disease itself.

The answer they obtained, that neutropenia is not preferentially tied to Graves’ disease, carries practical consequences. Antithyroid drugs carry a well-known risk of severe agranulocytosis, a potentially life-threatening drop in neutrophils, and clinicians traditionally hesitate to prescribe them to patients who already have borderline or low counts at baseline. If pre-existing neutropenia turns out to be equally common across the thyrotoxicosis spectrum, then the presence of a low count at diagnosis cannot by itself be taken as evidence for a particular etiology, nor as a reason to favor one diagnostic pathway over another. Instead, the finding suggests that mild neutropenia in a thyrotoxic patient should prompt a careful search for other causes, including hematologic disorders, before it is attributed to the thyroid condition.

The authors themselves are careful about how far the conclusions can be pushed, and their caution is well founded. The cohort of 188 patients, while respectable for a single-center study, was modest, and the number of actual neutropenia events was small, with only a handful of patients in each group crossing the threshold. The subgroup sizes were also markedly imbalanced, ranging from 114 patients with TRAb-positive Graves’ disease down to just 12 with TRAb-negative disease, a disparity that severely limits statistical power to detect real differences between the smaller groups. With so few events, a true difference in prevalence could easily have escaped detection, and the authors explicitly state that their findings should be interpreted with caution and require confirmation in larger prospective studies.

Even so, the study represents a meaningful step forward in a corner of endocrinology where clinical folklore has often outpaced evidence. By assembling a contemporaneous, multi-etiology cohort at a single tertiary center, applying rigorous exclusion criteria, and anchoring the analysis to a standardized neutropenia definition, Sugito, Ihana-Sugiyama, and their colleagues have produced a benchmark against which future multicenter and prospective studies can be measured. The picture that emerges is one of a hematologic finding that accompanies thyrotoxicosis across its various forms at a roughly similar rate, apparently independent of antibody status and independent of the degree of hormone elevation. For clinicians, the message is to treat neutropenia in a thyrotoxic patient as a finding deserving of its own evaluation rather than as a signature of any single thyroid disease. For researchers, the message is that the question of mechanism, whether autoimmune, hormonal, or something else entirely, remains open, and that answering it will require cohorts far larger than any single center can provide.

Subject of Research: Prevalence of neutropenia across different etiological types of thyrotoxicosis in a Japanese retrospective cohort

Article Title: Neutropenia associated with different types of thyrotoxicosis: a Japanese cohort study

Article References: Sugito, E., Ihana-Sugiyama, N., Hashimoto, M., Kodani, N., Bouchi, R., Ohsugi, M., Ueki, K., & Tanabe, A. (2026). Neutropenia associated with different types of thyrotoxicosis: a Japanese cohort study. BMC Endocrine Disorders. https://doi.org/10.1186/s12902-026-02583-6

Image Credits: AI Generated

DOI: 10.1186/s12902-026-02583-6

Keywords: thyrotoxicosis, Graves' disease, neutropenia, TRAb, painless thyroiditis, subacute thyroiditis, thyroid, endocrinology, hematology, retrospective cohort study, free thyroxine, Japan