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Backgrounds <p>Familial dysalbuminemic hyperthyroxinemia (FDH) can mimic inappropriate secretion of TSH (IST) in thyroid function tests, and conventional methods may fail to detect assay interference, potentially leading to misdiagnosis as resistance to thyroid hormone (RTH) or TSH-secreting pituitary adenoma (TSHoma).</p> Methods <p>We retrospectively analyzed hospitalized patients with suspected IST over a five-year period, identifying 12 cases each of FDH and RTH, and 37 cases of TSHoma. Characteristics of genetically confirmed FDH patients and their families were summarized. Clinical and biochemical features were compared across the three groups, with cases having confounding thyroid pathology or pituitary hormone co-secretion excluded from biochemical analyses.</p> Results <p>A positive family history was noted in 10 of 12 FDH cases, with two patients also diagnosed with papillary thyroid carcinoma and one with Graves’ disease. The FDH group showed significantly lower median TSH, FT3, and rT3 levels, along with a higher TT4 (µg/dL)/TT3 (ng/mL) ratio compared to the RTH and TSHoma groups (all <i>p</i> &lt; 0.05). ROC analysis identified optimal cutoffs for distinguishing FDH: a TT4/TT3 ratio of 10.99 for FDH vs. RTH (AUC = 0.982, 90.0% sensitivity, 100.0% specificity) and 9.94 for FDH vs. TSHoma (AUC = 1.000, 100.0% sensitivity and specificity). FT3/upper limit of normal (ULN) ratio cutoffs of 1.2 (vs. RTH, AUC = 0.905) and 1.3 (vs. TSHoma, AUC = 0.872) also showed strong discriminative value (all <i>p</i> &lt; 0.01). The somatostatin analogue (SSA) test showed a stepwise increase in 24-hour/2-hour TSH suppression ratio: RTH (22.83%) &lt; FDH (40.59%) &lt; TSHoma (75.45%) (<i>p</i> &lt; 0.001).</p> Conclusions <p>FDH should be carefully considered in the differential diagnosis of IST. The TT4/TT3 and FT3/ULN ratios are useful for diagnostic discrimination. The SSA test response in FDH appears physiological and may help define a diagnostic continuum between RTH and TSHoma. These findings require validation in larger cohorts.</p>

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Differential diagnosis of familial dysalbuminemic hyperthyroxinemia , RTH, and TSHomas: A single-center retrospective analysis

  • 期刊论文

  • 发表日期：

    2026年4月1日

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  • Yuanmeng Li,
  • Ke Zhang,
  • Xiaofeng Chai,
  • He Liu,
  • Xinqi Cheng,
  • Xi Wang,
  • Yue Chi,
  • Naishi Li,
  • Xiaolan Lian

摘要

Backgrounds

Familial dysalbuminemic hyperthyroxinemia (FDH) can mimic inappropriate secretion of TSH (IST) in thyroid function tests, and conventional methods may fail to detect assay interference, potentially leading to misdiagnosis as resistance to thyroid hormone (RTH) or TSH-secreting pituitary adenoma (TSHoma).

Methods

We retrospectively analyzed hospitalized patients with suspected IST over a five-year period, identifying 12 cases each of FDH and RTH, and 37 cases of TSHoma. Characteristics of genetically confirmed FDH patients and their families were summarized. Clinical and biochemical features were compared across the three groups, with cases having confounding thyroid pathology or pituitary hormone co-secretion excluded from biochemical analyses.

Results

A positive family history was noted in 10 of 12 FDH cases, with two patients also diagnosed with papillary thyroid carcinoma and one with Graves’ disease. The FDH group showed significantly lower median TSH, FT3, and rT3 levels, along with a higher TT4 (µg/dL)/TT3 (ng/mL) ratio compared to the RTH and TSHoma groups (all p < 0.05). ROC analysis identified optimal cutoffs for distinguishing FDH: a TT4/TT3 ratio of 10.99 for FDH vs. RTH (AUC = 0.982, 90.0% sensitivity, 100.0% specificity) and 9.94 for FDH vs. TSHoma (AUC = 1.000, 100.0% sensitivity and specificity). FT3/upper limit of normal (ULN) ratio cutoffs of 1.2 (vs. RTH, AUC = 0.905) and 1.3 (vs. TSHoma, AUC = 0.872) also showed strong discriminative value (all p < 0.01). The somatostatin analogue (SSA) test showed a stepwise increase in 24-hour/2-hour TSH suppression ratio: RTH (22.83%) < FDH (40.59%) < TSHoma (75.45%) (p < 0.001).

Conclusions

FDH should be carefully considered in the differential diagnosis of IST. The TT4/TT3 and FT3/ULN ratios are useful for diagnostic discrimination. The SSA test response in FDH appears physiological and may help define a diagnostic continuum between RTH and TSHoma. These findings require validation in larger cohorts.