Discussion:
Familial dysalbuminaemic hypethyroxinaemia (FDH) is an important cause
of thyroid function tests being discordant. It was initially Identified
in 1979 by Henneman et and the term was introduced in 1982. Precise
defect identified only in 1994 independently by Petersen et al [3].
It is the most common inherited cause of increase in serum TT4 in the
Caucasian population. It has the highest prevalence in communities of
Portuguese or Hispanic origin. It is an autosomal dominant disorder with
a prevalence rate is 0.08-0.17% and is the most common form of
inherited euthyroid hyperthyroxinaemia. It has no sex predilection and
any age group be affected. Patient’s family history is an important
aspect.
It is caused by a heterozygous mutation in albumin gene on chromosome
4q13 which causes an increased affinity for thyroxine (relative to its
affinity to T3) to albumin than for thyroxine binding globulin
[4,5]. The mutation increases affinity for T4 by upto 60%. A few
different variants have been described which leads to varying affinity
of T4 to albumin. Arginine to histidine substitution in codon 218 lead
to 10 to 15 fold greater affinity of T4 to albumin, arginine to proline
substitution can lead to 14 to 27 fold greater affinity, arginine to
histidine substitution in codon 222 can lead to 9 times greater affinity
and arginine to isoleucine substitution has also been described. In
another variant where a L66P mutation resulted in 40 fold increased
affinity to T3 and only 1.5 fold affinity to T4. The condition was
called familial dysalbuminemic hypertriiodothyroninemia [7]
Individuals are clinically euthyroid with elevated total T4 and elevated
or normal free T4 values within normal TSH levels. FT3 may be slightly
elevated. Coexistence of acquired high TBG or significant thyroid
malfunction may confound the diagnosis of dysalbuminemic
hyperthyroxinemia.
FDH can be confused with hyperthyroidism or thyroid hormone resistance.
Binding of drugs by albumin and the release of thyroid hormone to the
tissues are not altered in ways that have clinical significance. The
importance in diagnosing FDH and differentiating it from other
conditions is that it is harmless and if not identified then it could
lead to erroneous thyroidectomy or drug therapy [3]. The analogue
methods used for measuring free T4 levels in FDH can result in
artefactually high FT4 levels but is normal when measured by direct
methods such as ultrafiltration or equilibrium dialysis methods [6].
Factors in serum can give false estimations and these include 1) heparin
which can cause an artefactual elevation in measured concentrations of
FT4/FT3 by displacement of T4 and T3 from their carrier proteins, 2)
anti-iodothyronine antibodies which can bind the tracer and give false
estimations, 3)HAAs or heterophile antibodies that block the assay
antibody and variant thyroid hormone binding proteins (e.g. albumin in
FDH) with altered affinity for T4 [1].