Figure.

Differential Diagnosis of Hyperthyroxinemia and Nonsuppressed TSH

High Total or Free T4 (analogue method)

Normal/high TSH

Rule out levothyroxine therapy, acute

non-thyroidal illness, and drug effects

Free T4, Direct Dialysis (DFT4)

and TSH

Normal DFT4 High DFT4

Normal/high TSH Normal/high TSH

Hyperthyroxinemia
not confirmed Suspect resistance to Suspect analytical
thyroid hormone (RTH) interference

Resistance to T4 Antibody
Thyroid Hormone (RTH) T4 Binding Proteins
Mutation Analysis TSH Antibody
(THRB gene mutation) TSH, with HAMA
Treatment

No abnormalities detected

Negative Positive

RTH very likely

Suspect TSH-secreting Possible RTH without
pituitary tumor THRB mutation
(15% of cases) Consider THRB
mutation testing on
1st degree relatives
Alpha Subunit
and TSH

Alpha subunit:TSH ratio >1 Alpha subunit:TSH ratio <1

T3 Suppression Test
(unless contraindicated)

TSH not TSH partially

suppressed suppressed

TSH-secreting
pituitary adenoma
probable

Analytical interference in the direct dialysis free T4 and TSH assays could result from benign conditions such as abnormal T4 binding
proteins (eg, familial dysalbuminemic hyperthyroxinemia), autoantibodies to T4 or TSH, or exposure to mouse monoclonal antibodies
resulting in production of human anti-mouse antibodies (HAMA). Adapted from references 1 and 2.

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