Low Free T4 with Normal Free T3 and Normal TSH
This pattern most commonly indicates central (secondary) hypothyroidism due to pituitary or hypothalamic dysfunction, where the pituitary fails to produce adequate TSH despite low thyroid hormone levels. 1
Primary Diagnostic Consideration: Central Hypothyroidism
Central hypothyroidism presents with low or inappropriately normal TSH alongside low free T4, distinguishing it from primary hypothyroidism where TSH would be elevated 1
The pituitary gland fails to produce adequate TSH or the hypothalamus fails to produce adequate TRH, meaning TSH cannot be used as a reliable screening test in these patients 1
In early or partial pituitary/hypothalamic dysfunction, both TSH and free T4 values may appear deceptively normal while the patient remains hypothyroid 1
Clinical suspicion of hypophysitis is frequently raised when routine thyroid function testing shows a low TSH with low free T4, suggestive of a central etiology 1
Critical Diagnostic Workup Required
Before any treatment, the following must be evaluated:
Morning cortisol and ACTH levels (around 8 am) to assess for concurrent central adrenal insufficiency, which occurs in >75% of patients with central hypothyroidism 1
MRI of the sella with pituitary cuts to evaluate for pituitary enlargement, stalk thickening, or other structural abnormalities 1
Gonadal hormones (testosterone in men, estradiol in women), FSH, and LH to assess for panhypopituitarism 1
Strict diagnostic criteria include ≥1 pituitary hormone deficiency (TSH or ACTH deficiency required) combined with MRI abnormality, or ≥2 pituitary hormone deficiencies with headache and symptoms 1
Alternative Diagnostic Possibilities
Assay interference or laboratory error:
Direct measurement of free T4 and free T3 proved to be better indices of thyroid function than total T4 and T3, even after correction for TBG levels 2
Repeat testing with a different assay method may be warranted if clinical presentation doesn't match laboratory findings 1
Recovery phase of thyroiditis:
Thyroiditis often follows a pattern of initial thyrotoxic phase followed by hypothyroidism approximately 1-2 months later, before potentially returning to normal 3
Consider recent iodine exposure (such as CT contrast) which can transiently affect thyroid function tests 4
Nonthyroidal illness:
In cases of acute illness or hospitalization, TSH can be transiently suppressed and typically normalizes after recovery 4
Consideration of watchful waiting rather than immediate treatment may be appropriate in nonthyroidal illness 4
Critical Management Principles
If central hypothyroidism is confirmed:
In the presence of both adrenal insufficiency and hypothyroidism, steroids must always be started prior to thyroid hormone to avoid an adrenal crisis 1, 5
This is the most critical pitfall to avoid—starting levothyroxine before corticosteroids can precipitate life-threatening adrenal crisis 4, 5
Physiologic doses of hydrocortisone (typically 15-20 mg daily in divided doses) should be initiated several days before levothyroxine 4
Hormone replacement approach:
Management includes replacement of deficient hormones with physiologic doses of steroids and thyroid hormone 1
Central hypothyroidism is present in >90% of patients with hypophysitis 1
Approximately 50% of patients present with panhypopituitarism (adrenal insufficiency plus hypothyroidism plus hypogonadism) 1
When to Suspect This Pattern
Clinical symptoms warranting investigation:
Headache (present in 85% of hypophysitis cases) and fatigue (66%) are the most common presenting symptoms 1
Clinically symptomatic patients with fatigue, weight changes, temperature intolerance, or cognitive symptoms warrant further investigation even with normal screening tests 4
Visual changes are uncommon but should raise immediate concern for pituitary pathology 1
High-risk populations:
Patients on immune checkpoint inhibitors (ipilimumab, nivolumab) have 10-17% incidence of hypophysitis, with median time to diagnosis of 8-9 weeks after starting therapy 1
Hypophysitis is most commonly seen with anti-CTLA-4 antibody monotherapy and combination ipilimumab/nivolumab 1
Common Pitfalls to Avoid
Never start thyroid hormone before ruling out adrenal insufficiency in patients with suspected central hypothyroidism, as this can precipitate adrenal crisis 4
Avoid missing central hypothyroidism by checking free T4 alongside TSH in patients with pituitary disease or symptoms despite normal TSH 4
Do not assume normal thyroid function based solely on normal TSH—free T4 must be evaluated in the appropriate clinical context 1
Failing to obtain MRI imaging when central hypothyroidism is suspected delays diagnosis and appropriate management 1