مخاطبین محترم : رزیدنتهای داخلی و فلوهای غدد
خلاصه و مفید از:
Euthyroid hyperthyroxinemia due to binding protein
Both T4 and T3 circulate in blood bound to one of three binding proteins:
• Thyroxine-binding globulin (TBG)
• Transthyretin (TTR; thyroxine-binding prealbumin [TBPA])
99.97 % of circulating T4 and 99.7 % of circulating T3 are bound to these proteins.
T4 binding is distributed as follows: TBG – 75 % ; TTR – 15 % ; and albumin – 10 %.
T3 is less avidly bound to TBG and TTR.
TBG excess —
Hereditary —an X-linked dominant disorder characterized by increased synthesis of TBG
• Estrogens — Estrogens increase the glycosylation of TBG, which slows its clearance,
serum TBG (and total T4 and T3) concentrations are increased substantially (25 to 50 % ) in:
• pregnant women
• women receiving an OCP
• postmenopausal women receiving estrogen therapy
• and patients with estrogen-secreting tumors,
and serum TBG concentrations are increased slightly (10 to 25 % ) in:
women receiving tamoxifen , and raloxifene
• Hepatitis — Patients with acute or subacute hepatitis,
• Drugs — Several drugs raise serum TBG concentrations, including 5-fluorouracil, perphenazine , clofibrate , heroin , and methadone .
• Acute intermittent porphyria —via an uncertain mechanism
The T3-resin uptake test was designed in part to detect abnormalities in serum TBG.
In states of TBG excess, resulting in a low T3-resin uptake
Serum free T4 index = serum total T4 x THBR
The changes in T3-resin uptake :
Hyperthyroidism — high serum total T4, high T3-resin uptake or THBR, high serum free T4 index
TBG excess — high serum total T4, low T3-resin uptake or THBR, normal serum free T4 index
Hypothyroidism — low serum total T4, low T3-resin uptake or THBR, low serum free T4 index
TBG deficiency — low serum total T4, high T3-resin uptake or THBR, normal serum free T4 index
serum TBG can be measured directly by radioimmunoassay.
Familial dysalbuminemic hyperthyroxinemia — FDH
most often occurring in patients of Hispanic background, in whom it occurs in perhaps 0.2 %, the inheritance of FDH is autosomal dominant.
It is characterized by production of mutant albumin molecules that have a low affinity but high capacity for T4 , but not T3
Affected patients have high serum total T4 concentrations but are euthyroid and have normal serum TSH concentrations, free T4 index is high
Serum from patients with FDH binds more radiolabeled T4 than does serum from normal subjects, thereby documenting that serum T4 binding is increased.
also by electrophoresis of binding proteins in the presence of radiolabeled T4. serum T4 and free T4 index can be measured in the patient’s relatives;
A variant of albumin with 40-fold increased affinity for T3 but only 1.5-fold increased affinity for T4 has been described in a Thai family: familial dysalbuminemic hypertriiodothyroninemia
Other causes of euthyroid hyperthyroxinemia
Reduced thyroxine deiodination —
Several drugs inhibit extrathyroidal T4 deiodination to T3:
amiodarone, propranolol in high doses, ipodate and iopanoic acid
Other conditions —
Several other disorders can also cause euthyroid hyperthyroxinemia:
• Acute psychosis, acting via an uncertain
• From 1 to 10 % of pt hospitalized for acute psychosis have modestly usually transient elevated serum T4 .
• High altitude and amphetamines, presumably mediated by a central nervous system mechanism.
• Symptomatic hyponatremia may be associated with small increases in serum total T4
• Generalized thyroid hormone resistance results in high serum T4 concentrations associated with normal or slightly high serum TSH . These patients may be euthyroid, or have clinical manifestations of hypothyroidism or even hyperthyroidism, because the receptor defect can vary in different organs
• Appropriate T4 replacement therapy (with normalization of serum TSH concentrations) results in serum T4 are 1 to 2 mcg/dL (13 to 26 nmol/L) higher than in normal subjects .
euthyroid hypothyroxinemia due to binding protein abnormalities —
TBG deficiency — occurs in the following settings:
• Hereditary —an X-linked recessive disorder
• Hormonal abnormalities —
• Androgens (high doses) reduce serum TBG , and can result in a reduction in T4 requirement in hypothyroid patients ,
• glucocorticoid administration, Cushing’s syndrome, and acromegaly .
• Nephrotic syndrome
• Drugs — L-asparaginase , danazol , and niacin all by decreasing TBG production.
Starvation and poor nutrition can cause reductions in both serum TBG and albumin concentrations.
Displacement of T4 from binding proteins —
Several drugs, including:
salicylates, salsalate , high doses of furosemide (especially in patients with renal failure)
and some NSAIDS ( fenclofenac and mefenamic acid) inhibit the binding of T4 to TBG.
As a result, serum total T4 fall, but serum free T4 are normal.
Heparin : can result in spuriously low serum T4 . It does so by activating lipoprotein lipase, thereby generating FFA that inhibit T4 binding to albumin
The same phenomenon may occur in vivo in patients with severe nonthyroidal illness who have low serum albumin concentrations (which bind free fatty acids ).
other causes of euthyroid hypothyroxinemia
Anticonvulsant drugs —
In euthyroid patients, both phenytoin and carbamazepine increase nondeiodinative metabolism of T4 and T3, and displace the hormones from binding proteins; the net effect is a 20 to 40 % reduction in serum free T4 and T3 , but no change in serum TSH .
Thus, the thyroid status in patients treated with phenytoin or carbamazepine who have normal pituitary function should be assessed by measuring serum TSH alone.
Hypothyroid patients treated with T4 may need an increase in dose after phenytoin or carbamazepine treatment is initiated .
Oral T3 administration —
used by some psychiatrists as adjunctive therapy in patients with depression who respond poorly to tricyclic antidepressant drug therapy
Exogenous T3 suppresses pituitary TSH production and therefore thyroidal T4 synthesis and secretion.
Thus, these patients have low serum T4 , normal or slightly elevated T3 , and low serum TSH .