Physiology of Familial Dysalbuminemic Hyperthyroxinemia (FDH)
Lecture: Physiology of Familial Dysalbuminemic Hyperthyroxinemia (FDH)
1. Introduction & Clinical Context
Definition:
FDH is an inherited benign condition causing elevated total thyroxine (T₄) in blood tests
without true hyperthyroidism.
Genetics:
Typically autosomal dominant; caused by albumin mutations that increase its affinity for T₄.
Clinical importance:
- Patients have high total T₄ on lab tests but are euthyroid—no signs or symptoms of true
thyroid hormone excess.
- Misinterpretation can lead to unnecessary interventions.
Learning objective:
Understand how altered T₄ binding impacts laboratory measurements versus actual
physiological hormone action.
---
2. Normal Physiology of Thyroid Hormones
a. Production & Circulation
- Thyroid hormone synthesis: T₄ and T₃ are produced by the thyroid gland; T₄ is the major
product but is less active.
- Transport in plasma:
~0.03% of T₄ is free (unbound)—the biologically active fraction that enters cells.
The remainder is bound, mostly to:
- Thyroxine-binding globulin (TBG) (~70-75%)
- Transthyretin (TTR) (~10-15%)
- Albumin (~10–15%)
b. Equilibrium & Feedback Regulation
- Free hormone hypothesis: Only free T₄ is available to tissues and exerts feedback
inhibition on the hypothalamic-pituitary-thyroid axis.
- Homeostatic equilibrium: A change in binding protein levels or affinities shifts the
distribution between bound and free fractions, but feedback mechanisms restore free
hormone to normal levels (if the axis is intact).
---
3. Pathophysiology of FDH
a. Altered Binding – Molecular Mechanism
- Mutations in the albumin gene create variant albumin with increased affinity for T₄.
- Consequence: More T₄ is bound by albumin—raises total T₄ measured in assays—but free
T₄ remains normal.
b. Effects on Laboratory Measurements
- Total T₄ is falsely elevated.
- Total T₃ may be normal or mildly elevated.
- Free T₄ (accurate methods) is normal.
- TSH is typically normal.
c. Physiological Implication
- Euthyroid: normal metabolic rate, heart rate, reflexes.
- Feedback remains functional: normal TSH.
---
4. Clinical & Diagnostic Correlation
a. Presentation
- Often asymptomatic, detected incidentally.
- Family history may show similar patterns.
b. Differential Diagnosis
- Thyroid hormone resistance
- TBG excess
- Assay interference
- True hyperthyroidism
c. Confirmatory Investigations
- Free T₄ by equilibrium dialysis.
- Normal TSH.
- Genetic testing (optional).
- Family studies.
d. Implications for Treatment
- No treatment needed.
---
5. Summary Table
| Parameter | Typical FDH Result | Physiologic State |
| ------------------ | --------------------- | --------------------- |
| Total T₄ | Elevated |— |
| Free T₄ (accurate) | Normal | True euthyroid status |
| TSH | Normal | Feedback intact |
| Clinical signs | Absent | Euthyroid |
---
6. Integration with Guyton & Ganong
- Free hormone concept: alterations in binding don't necessarily alter function.
- Feedback loops: pituitary senses free hormone, not total hormone.
- Binding equilibrium: total hormone rises, free hormone regulated.
---
7. Clinical Vignette
Case: 25-year-old woman, routine screening.
- Total T₄: high
- Free T₄: normal
- TSH: normal
- No symptoms.
Discussion:
- Mechanisms: altered binding.
- Investigation: accurate free T₄ assay.
- Management: reassure.
---
8. Key Takeaways
1. FDH is a benign inherited alteration in albumin binding.
2. Free T₄-TSH axis remains intact.
3. Accurate free hormone measurement avoids misdiagnosis.
4. Binding dynamics + feedback loops are essential concepts.
5. Recognizing FDH prevents unnecessary treatment.
Final Thought:
FDH illustrates how understanding hormone binding and feedback is essential for
interpreting labs and guiding care.
