Neutropenia Associated With Different Types of Thyrotoxicosis: A Japanese Cohort Study

Technical Summary: Neutropenia Associated With Different Types of Thyrotoxicosis

Problem Statement
Neutropenia is a known, albeit occasionally observed, complication in patients with new-onset thyrotoxicosis, particularly those with Graves' disease (GD). While observational studies suggest a prevalence of 10–18% at diagnosis, the underlying mechanisms remain unclear. Proposed hypotheses include the direct effect of excess thyroid hormones on hematopoietic stem cells, the binding of thyroid-stimulating hormone receptor antibodies (TRAb) to TSH receptors on neutrophils, or altered neutrophil distribution. Clinically, the presence of pre-existing neutropenia is critical because it influences treatment decisions; specifically, it may deter clinicians from initiating antithyroid drugs (ATDs), which are the first-line treatment for GD in Japan, due to the risk of drug-induced agranulocytosis. However, existing literature predominantly focuses on GD, leaving a gap in understanding the prevalence and clinical course of neutropenia across other etiologies of thyrotoxicosis, such as painless thyroiditis and subacute thyroiditis.

Methodology
This study was a single-center, retrospective observational analysis conducted at the National Center for Global Health and Medicine (NCGM) in Tokyo. The cohort consisted of adults (≥20 years) newly diagnosed with thyrotoxicosis between August 1, 2016, and August 31, 2021.

• Inclusion/Exclusion: Patients were included if they had a confirmed first-time diagnosis of thyrotoxicosis (TSH <0.5 µU/mL and FT4 >1.7 ng/dL) with TRAb measured within 10 days. Exclusion criteria were strict: patients with underlying conditions causing cytopenia (hematologic disorders, malignancies, infections, collagen diseases, liver disease), pregnancy, or those taking medications affecting neutrophil counts (e.g., steroids, methotrexate, G-CSF) were excluded. Patients with autonomously functioning thyroid nodules were also excluded.
• Grouping: Eligible patients (n=188) were stratified into four groups based on clinical diagnosis and TRAb status:
  1. TRAb-positive GD (n=114)
  2. TRAb-negative GD (n=12)
  3. Painless thyroiditis (n=37)
  4. Subacute thyroiditis (n=25)
• Definitions and Analysis: Neutropenia was defined as a neutrophil count <1800.0/µL. The study analyzed baseline characteristics, thyroid hormone levels (TSH, FT3, FT4), and antibody status. Statistical comparisons utilized the Kruskal–Wallis test for continuous variables and chi-square or Fisher's exact tests for categorical variables. Correlations between FT4 levels and neutrophil counts were assessed using Spearman's rank correlation.

Key Results

• Demographics and Baseline: The median age across groups ranged from 42.5 to 52.0 years, with a female predominance (56.8% to 75.0%). TSH suppression was most profound in the GD groups compared to thyroiditis groups.
• Neutrophil Counts: The subacute thyroiditis group exhibited significantly higher median neutrophil counts compared to the other three groups (p < 0.01).
• Prevalence of Neutropenia:
  • TRAb-positive GD: 7.0%
  • TRAb-negative GD: 8.3%
  • Painless thyroiditis: 10.8%
  • Subacute thyroiditis: 4.0%
  • Statistical Significance: Despite the numerical variation, no statistically significant differences in the prevalence of neutropenia were found among the four groups.
• Correlations: No significant correlation was observed between FT4 levels and neutrophil counts within any specific disease group.
• Clinical Course: All patients presenting with neutropenia (n=15 total) experienced spontaneous recovery of neutrophil counts. The median time to recovery was approximately 14 days. This recovery occurred regardless of whether the patient received antithyroid medication (for GD) or no specific intervention (for thyroiditis).

Significance and Claims
The authors claim this is the first report to evaluate the frequency and subsequent clinical course of neutropenia across TRAb-positive GD, TRAb-negative GD, painless thyroiditis, and subacute thyroiditis simultaneously.

• Clinical Implication: The study suggests that the presence of neutropenia at the time of diagnosis does not necessarily indicate a contraindication for antithyroid drug therapy in GD patients, as the condition tends to resolve spontaneously alongside the normalization of thyroid function.
• Pathophysiological Insight: While the study found no difference in neutropenia prevalence between TRAb-positive and TRAb-negative GD, the slightly higher prevalence in GD and painless thyroiditis compared to subacute thyroiditis suggests that immunological mechanisms (common to GD and painless thyroiditis) may play a role in neutrophil decline, rather than thyroid hormone levels alone.
• Limitations: The authors modestly acknowledge limitations, including the small sample size for non-GD groups, the inability to accurately assess correlations due to FT4 levels exceeding assay limits, and variability in follow-up intervals for neutrophil recovery.

In conclusion, the paper posits that neutropenia associated with thyrotoxicosis is a self-limiting condition that occurs with similar frequency across different etiologies, and its presence should not automatically preclude the initiation of standard antithyroid treatments.