Total and free thyroid hormone levels in chronic renal failure.
The levels of serum total thyroxine (TT4), triiodothyronine (TT3), free T3, (FT3) free T4 (FT4) and thyrotropin (TSH) were measured in 127 clinically euthyroid patients with varying grades of chronic renal failure (CRF); and 97 healthy individuals. They were grouped as: Group I containing 93 patients on conservative management; Group II containing 34 patients on regular dialysis therapy; and Group III (normals). Group I patients showed significant decrease in TT3, TT4 and FT3 levels (p less than 0.001) as compared to Group III, whereas FT4 and TSH values in group I were not significantly altered. TT3, TT4 and FT3 levels reduced as the severity of renal damage increased. Variations in TT3, TT4, FT3, FT4 and TSH levels in Group II patients were similar to those in Group I, except for a decrease in TSH levels (p less than 0.05) as compared to normals. Several thyroid function tests are abnormal in CRF patients, however, finding of normal FT4 and TSH levels would indicate functional euthyroid status.
Patients with end stage renal disease display a variety of endocrine disturbances. However, the evidence of endocrine dysfunction commonly consists only of laboratory abnormalities, many of which are not associated with apparent disease.
Thyroid function has been extensively evaluated in patients with chronic renal failure (CRF); however the results are variable. A major contribution in this field is by Ramirez and associates, who reported upto 58% prevalence of goitre in their patients on chronic haemodialysis as compared to 8% in control cases from the same geographic area. Recently, Quion-Verde et al have also reported a higher prevalence (5%) of hypothyroidism in patients with terminal renal failure in comparison with that in hospitalised patients with normal renal function (0.6%).
A few reports have appeared from India, where various parameters of thyroid function were measured in patients with CRF,,. In order to gain further insight, this study included measuring the free thyroid hormone levels, not assayed in previous Indian studies.
One hundred and twenty seven patients with no previous history of thyroid dysfunction, and with varying grades of CRF were included in this study. Ninety-three patients were on conservative treatment (Group I) and were subdivided according to the severity of renal dysfunction: Group I (a): Mild (serum creatinine value 13-2.9 mg/dl) (n = 34); Group I (b): Moderate (serum creatinine value 3.0-4.9 mg/dl) (n = 36); and Group 1(c): Severe (serum creatinine value ? 5 mg/dl) (n = 23). Remaining 34 patients who also had severe renal failure were on regular haemodialysis treatment (RDT) while awaiting a live related donor renal transplantation (Group II).
The treatment included iron salts, vitamins, aluminium hydroxide (as phosphate binder) and furesamide (40-160 mg/day) when indicated; and anti-hypertensive agents as required viz. alphamethyl dopa, calcium channel blockers, hydrallazine, clonidine and atenolol. Patients were not given any medications except for furesamide given in small doses, which are known to influence the thyroid functions.
Patients underwent haemodialysis (HD) each of 4 hours duration; thrice a week, on a disposable capillary hollow fibre dialyzer, with heparin as anticoagulant during HD. Estimations of serum total triiodothyronine (TT3), total thyroxine (TT4): and thyrotropin (TSH) were performed by RIA (kits from BARC, Mumbai). Free triidodthyronine (FT3) and free thyroxine (FT4) concentrations in the serum were measured by the method of Romelli et al, as modified by Rajan and Samuel . Results obtained in patients with CRF were compared with those in 97 normal cuthyroid individuals (Group III). Statistical analysis was done using student's unpaired 't' test, p value < 0.05 was taken as significant.
The results are shown in [Table - 1]. All patients were clinically euthyroid and non goiterous. Ninety-three patients on conservative treatment showed significant reduction in their TT3, TT4 and FT3 levels in comparison with those in normal subjects. However, TSH and FT4 levels did not show significant alterations. Mean TT3, TT4 and FT3 levels reduced as the severity of renal damage increased, showing significant difference between Group I (b) and Group I (c). Though TSH levels were lower in Group I as compared to normal, significant difference was observed between Group I (a) and I (b).
Though TT3 and FT3 levels were found to be reducing as the severity of renal damage progressed (Groups Ia, b, c), when individual values of TT3 and FT3 were plotted against their respective serum creatinine levels, no linear co-relationship was observed between these parameters.
Variations in TT3, FT3, TT4, FT4 and TSH levels in Group II patients were more or less similar to those in Group I, except for TSH levels which were slightly but significantly altered as compared to normal subjects (p).
Two individual observations encouraged us to measure various parameters of thyroid function in our patient population with CRE One was by Ramirez and associates  (vide supra) and the other was by Ganatra et al, who conducted a goitre survey in school going children of Mumbai, thereby revealing mild dietary iodine deficiency and prevalence of goitre of varying grades.
Our previous investigations in these regards had revealed that goitre was rare in CRF patients and all of them were clinically euthyroid. It also showed that TT3 and TT4 levels were lower than normal at all grades of CRF and a progressive reduction in values of TT3 and TT4 were noticed as the severity of renal failure increased. TSH levels were however, within normal limits. Since abnormalities were noted in various parameters of thyroid function in association with euthyroid state of these patients, the present study was designed for confirming our previous conclusions and for studying the FT3 and FT4 levels at the same time.
Several investigators have studied thyroid hormone levels in CRF and obtained variable results. Low TT3,,, normal TT3 low FT3, normal FT3 in patients on HD , low TT4 (low T4 syndrome),11 normal TT4,, and low normal or lower IFT48,11 levels have been reported. Basal concentrations of circulating TSH have been found at different levels in different studies. Normal levels or TSH were reported from previous Indian studies,,. Thus a multitude of defects at all levels of hypothalamic-pituitary-thyroidaloeripheral axis does seem to exist in uremia.
In the majority of studies, including the present one, TT4 concentrations were found to be low or low normal. However, FT4 levels were within normal limits. This is attributed to lowering of thyroxine binding globulin concentration as well as presence of inhibitors of thyroid hormone bindings to the thyroid binding proteins. Levels of TT3 and FT3 suffer further reductions in CRF, which is thought to be due to impairment in deiodination of T4, a principal process by which T3 is produced at peripheral levels.
Several factors are responsible for obtaining controversial results of thyroid hormone levels in CRE. The important amongst them are heterogenity of patient groups studied, methodological variations and varying treatment. There have been speculations on the nature of the presumptive inhibitors in uremia patients, and drugs have been accounted for low T3 and T4 levels. In the present study, the drugs which could have influenced the thyroid hormone levels were furesamide and heparin. Other commonly used drugs known to supress thyroid hormones like propranolol, glucocorticoids, sulphonylurea, dilantin and phenobarbitones were not given to any of the patients.
As heparin is known to acutely raise both total and free thyroxine levels in the blood, the samples for thyroid hormones estimation were drawn immediately before heparin administration. Furesamide inhibits T4 and T3 binding to serum proteins at high levels and by a concentration dependent process resulting in artifactually low, percent FT4 and estimated FT4 concentrations. 18 However, the dose of furesamide administered in this study was insufficient to influence FT4 levels.
In conclusion, our results indicated low TT3, FT3 and TT4 values in clinically euthyroid CRF patients.
However, finding of normal FT4 values (which is metabolically active fraction) and TSH would indicate functional euthyroid status. It can be presumed that FT4 values would fall, if these patients develop hypothyroidism, and TSH values would rise simultaneously. Thus, FT4 and TSH levels combined can be used for the diagnosis of hypothyroidism in presence of CRE