Neutropenia in Patients With Hyperthyroidism

Systematic Review and Meta-Analysis

Lorenzo Scappaticcio; Maria Ida Maiorino; Antonietta Maio; Katherine Esposito; Giuseppe Bellastella


Clin Endocrinol. 2021;94(3):473-483. 

In This Article

Abstract and Introduction


Background and Objective: Neutropenia, a low absolute neutrophil count (ANC), may be a sign of new-onset hyperthyroidism. The aim of this systematic review and meta-analysis was to provide the most reliable estimates of prevalence, degree and response to treatments of neutropenia in the pure hyperthyroidism setting.

Methods: A comprehensive literature search was performed in PubMed and Scopus databases for retrieving articles in English and non-English languages reporting ANC values/neutropenic cases at presentation and after therapy in patients with hyperthyroidism. A proportion meta-analysis was performed with DerSimonian and Laird method (random-effects model). Pooled data were presented with 95% confidence intervals (95% CI) and displayed in a forest plot. I 2 statistic index was used to quantify the heterogeneity among the studies. Sensitivity analyses for the prevalence of neutropenia and the mean of ANC in hyperthyroid patients were performed by excluding the studies without full details. Trim and fill analysis and Egger's linear regression test were carried out to evaluate the publication bias. A two-sided P-value of <.05 was regarded as significant for all analyses. The National Heart, Lung and Blood Institute Quality Assessment Tool was used to evaluate the quality of studies included.

Results: The literature search yielded 1880 studies of which 13 studies were included for systematic review and meta-analysis. Results of the meta-analysis demonstrated that the prevalence of neutropenia in newly diagnosed and untreated patients with Graves' hyperthyroidism was 10% (CI 5%-19%, I 2 88.6%) and summary mean ANC value in neutropenic was 1.4 ± 0.3 × 109/L. In all neutropenic patients under ATD therapy neutropenia resolved, thus without the worsening of the baseline ANC values or the development of agranulocytosis. The sensitivity analyses showed similar results as those of the main analyses. For all outcomes, the publication bias was not statistically significant or not calculable.

Conclusions: Graves' disease per se is associated with neutropenia in about 10% of cases. Neutropenia usually appears as a mild to moderate laboratory abnormality with no detectable consequences. Subnormal/mild neutropenia should not be regarded as a contraindication to use ATDs, and clinicians should know that treating hyperthyroidism they have a significant chance to normalize ANC too.


Neutropenia, a low absolute neutrophil count (ANC), is found in ~1% of primary care individuals.[1] Neutropenia requires a careful diagnostic work-up, since it may be the harbinger of both serious viral and haematological disorders.[1,2] Moreover, low ANC may predispose patients to bacterial and fungal infections.[1,2]

Severe neutropenia (also called agranulocytosis when ANC is <0.5 × 109/L) is a well-known adverse event of antithyroid drugs (ATDs) that might occur when treating hyperthyroidism.[3] Indeed, according to the American Thyroid Association (ATA) guidelines (Recommendation 14, strong)[4] the occurrence of symptoms suggestive of agranulocytosis is a reason to promptly discontinue ATD therapy.

Moreover, clinicians should be aware that neutropenia may be a sign of new-onset hyperthyroidism:[5] for this reason ATA guidelines (Recommendation 15, weak)[4] suggest to check complete blood count (CBC) (including white blood cell [WBC] count with differential) prior to initiating ATD therapy and wisely indicate to reconsider the starting therapy with ATDs if baseline ANC is <1 × 109/L. Conversely, the recommended ANC cut-off to start ATD therapy is higher than that (ie 0.5 × 109/L) reported in 2011 ATA/American Association of Clinical Endocrinologists (AACE) guidelines.[6] However, to the best of our knowledge, there is no evidence that in hyperthyroid patients low baseline ANC is associated with an increased risk of ATD-induced agranulocytosis.

Therefore, finding neutropenia in the hyperthyroidism scenario is a major diagnostic and therapeutic dilemma.

The description of the association of neutropenia and hyperthyroidism was first made by Caro[7] in 1907 and confirmed one year later by Kocher[8] who proposed the triad of leucopenia, neutropenia and relative lymphocytosis as a means of early diagnosis of Graves' disease (GD). Thereafter, different studies have been carried out with the aim to study the relationship between hyperthyroidism and low ANC,[9,10] whereas others explored the effect of hyperthyroidism therapy on the neutropenia.[11–13]

Thus, considering the diagnostic and therapeutical implications of this topic, we carried out a systematic review and meta-analysis of the studies examining the ANCs in hyperthyroid patients. We first aimed at exploring the true prevalence, the degree and the response to treatments of neutropenia in the pure hyperthyroidism setting.