What is familial hypoalbuminemic hyperthyroxinemia and how is it diagnosed in individuals with a family history of thyroid function test abnormalities?

Familial Dysalbuminemic Hyperthyroxinemia: Definition and Diagnosis

What is Familial Dysalbuminemic Hyperthyroxinemia?

Familial dysalbuminemic hyperthyroxinemia (FDH) is an inherited autosomal dominant condition caused by a mutation in the albumin gene that creates a variant albumin with abnormally high affinity for thyroxine (T4), resulting in elevated total and free T4 levels in clinically euthyroid patients with normal TSH. 1

Key Pathophysiology

• The most common mutation occurs at codon 218 of the albumin gene, with R218H being the most frequently identified variant, though R218S and R218P mutations also exist 2
• The mutant albumin causes a ninefold increase in serum total T4 and twofold increase in reverse T3 compared to normal albumin 2
• Patients remain clinically euthyroid because the actual free (biologically active) thyroid hormone concentration is normal, despite spuriously elevated measurements on most immunoassays 3

Clinical Presentation

• Patients are always clinically euthyroid with no signs or symptoms of thyrotoxicosis 1
• The condition is typically discovered incidentally on routine thyroid function testing or when evaluating family members of known cases 1
• Physical examination reveals normal thyroid findings, though goiter may occasionally be present (unrelated to FDH) 1

How to Diagnose FDH

Initial Recognition Pattern

The hallmark biochemical pattern is elevated total T4 and elevated/normal free T4 with normal TSH and normal T3 in a clinically euthyroid patient. 1

Step-by-Step Diagnostic Algorithm

Step 1: Establish Clinical Euthyroidism

• Confirm absence of hyperthyroid symptoms (weight loss, tremor, palpitations, heat intolerance) 1
• Verify normal basal sensitive TSH level, which differentiates euthyroid hyperthyroxinemia from true thyrotoxicosis 1
• This single step obviates unnecessary antithyroid therapy 1

Step 2: Identify Discordant Immunoassay Results

• Measure free T4 using two different immunoassay methods - discrepant results between methods strongly suggest analytical interference 3
• Most one-step and two-step immunoassays show falsely elevated FT4, with susceptibility ranking: Beckman ACCESS > Roche ELECSYS > FUJIREBIO Lumipulse > Siemens CENTAUR > Abbott ARCHITECT > Perkin-Elmer DELFIA 4
• Ortho VITROS is the only common immunoassay resistant to FDH interference 4
• Some FT3 assays (particularly Siemens CENTAUR) may also show spuriously elevated results in up to 30% of FDH cases 4

Step 3: Measure Thyroid Hormone Binding Proteins

• Measure total T4 (will be markedly elevated, typically >200 nmol/L) 3
• Measure thyroxine-binding globulin (TBG) - must be normal or low-normal to diagnose FDH 1, 3
• Elevated TBG would instead suggest TBG excess as the cause of hyperthyroxinemia 1
• Measure T3 - should be normal, which helps differentiate from thyroid hormone resistance syndromes where T3 is typically elevated 1

Step 4: Demonstrate Excessive T4 Binding to Albumin

• Perform radiolabeled 125I-T4 binding studies showing increased binding of T4 to the patient's serum albumin 1, 3
• This test definitively establishes excessive thyroxine binding to serum albumin and differentiates FDH from thyroid hormone resistance syndromes 1

Step 5: Obtain Family History and Screen Relatives

• Document family history compatible with autosomal dominant inheritance pattern 1
• Screen first-degree relatives with thyroid function tests - finding similar abnormal patterns in family members strongly supports FDH diagnosis 1, 3
• After establishing FDH diagnosis, family screening is advisable 1

Step 6: Genetic Confirmation

• Sequence the ALB gene (albumin gene), specifically examining exon 7 for mutations at codon 218 3, 2
• The R218H mutation is most common, but R218S and R218P variants also cause FDH 2
• Genetic confirmation is definitive and allows for accurate genetic counseling 3

Alternative Confirmatory Methods When Immunoassays Are Unreliable

• Measure free T4 using equilibrium dialysis or ultrafiltration - these reference methods are not susceptible to albumin binding interference and will show normal results in FDH 3
• These methods are more reliable but less readily available in routine clinical practice 3

Critical Differential Diagnoses to Exclude

The differential diagnosis of euthyroid hyperthyroxinemia that must be distinguished from FDH includes 5:

• Thyroid hormone resistance syndromes - typically show elevated T3 in addition to elevated T4, and radiolabeled T4 binding studies will not show excessive albumin binding 5, 1
• TSH-secreting pituitary adenomas - patients have clinical thyrotoxicosis and often neurological/visual symptoms from mass effect 5
• TBG excess - TBG levels will be elevated rather than normal 1
• Assay interference from anti-thyroid hormone antibodies - different pattern on binding studies 1

Common Pitfalls and How to Avoid Them

Critical Warning: FDH is frequently misdiagnosed as hyperthyroidism or thyroid hormone resistance, leading to unnecessary and potentially harmful treatment. 1, 3

• Never treat based on elevated free T4 alone - always confirm clinical thyroid status and check TSH 1
• When FT4 and FT3 are both elevated with non-suppressed TSH, FDH can be mistaken for resistance to thyroid hormone beta or TSH-secreting pituitary tumor 4
• In patients with coexisting autoimmune thyroid disease and FDH, TSH is the most reliable biochemical marker of true thyroid status 3
• Some genetically confirmed FDH patients may have unexpectedly normal FT4 measurements depending on the specific assay method used 4
• In infants with congenital hypothyroidism and unsuspected FDH, normal total T4 despite markedly elevated TSH can delay appropriate treatment - use free T4 by equilibrium dialysis or two-step immunoassay methods 6

When Autoimmune Thyroid Disease Coexists with FDH

• Coexistence of Hashimoto's thyroiditis or Graves' disease with FDH creates extreme difficulty in assessing true thyroid status 3
• Rely primarily on TSH levels to guide treatment decisions in this scenario 3
• Discontinuation of levothyroxine in hypothyroid patients with FDH will cause marked TSH elevation despite persistently "normal" FT4 levels 3
• Even low-dose antithyroid medication can cause profound hypothyroidism in Graves' disease patients with coexisting FDH 3