J. Faber

Increased levels of TRH in cerebrospinal fluid from patients with endogenous depression

(1) A radioimmunoassay of thyrotropin releasing hormone (TRH) in cerebrospinal fluid (CSF) has been developed. The lower detection limit was 2.0 pg/ml. (2) The concentration of TRH in lumbar fluid from 20 patients with various neurological diseases averaged 5.4 pg/ml (1.9–10.7). In 2 patients the concentration was below detection limit. (3) The TRH concentration was not related to sex or age. (4) In 15 patients with endogenous depression the concentration was elevated (p<0.01), before electroconvulsive treatment (24.2 pg/ml, range: 6.9–187) as well as after such therapy (14.4 pg/ml, range 6.0–31.0). The values before and after treatment were not significantly different. (5) The concentration of TRH was not correlated to the serum thyrotropin (TSH) response to 200 μg TRH i.v. (6) Changes in TRH concentration were also unrelated to changes in the TSH response to TRH and to the clinical outcome after 6 months of observation.

Acute changes in thyroid volume and function following 131I therapy of multinodular goitre

OBJECTIVE Many textbooks claim that radioIodine (131I) treatment should be given with care to a goitre with substernal extension, for fear of acute swelling of the gland and thus respiratory problems. Since 131I Is used increasingly in the treatment of non‐toxic as well as toxic goitre we have evaluated the acute changes in thyroid volume following 131I therapy.

Free thyroxine measured in undiluted serum by dialysis and ultrafiltration: Effects of non-thyroidal illness, and an acute load of salicylate or heparin

In vitro dilution of serum during processing of a free T4 assay explains to some extent the divergent results obtained in non-thyroidal illness. If serum from such patients contains low affinity T4 protein binding inhibitors, as has been suggested, in vitro dilution will result in spuriously reduced serum free T4 measurements. If these inhibitors cross the dialysis membrane in an equilibrium dialysis assay, their inhibitory effect will be weakened, and in vitro free T4 levels will decrease, even in undiluted serum. In contrast, ultrafiltration methods on undiluted serum seem accurate. We have compared a new, commercially available dialysis technique with an in-house ultrafiltration method for free T4 measurements in undiluted serum. Control subjects (n = 41) had 14% higher free T4 (P < 0.02) by ultrafiltration. Non-thyroidally ill patients not receiving glucocorticoids or dopamine (n = 54) had unaltered free T4 levels, 28.4 +/- 10.3 pmol/l (dialysis) and 31.0 +/- 10.3 pmol/l (ultrafiltration). Dopamine infusion in somatic ill patients (n = 11) resulted in reduced free T4 in both assays but only significantly for dialysis, and subjects with familial dysalbuminemic hyperthyroxinemia (n = 8) had unaltered free T4 levels in both assays. Salicylate (1.5 g) given orally 09:00 h. (n = 5) resulted within 30 min, in increased (P < 0.01) free T4 as measured by both techniques, although more pronounced and sustained as measured by ultrafiltration. Serum TSH decreased concomitantly (P < 0.01). These findings were confirmed when salicylate was administered at 13:00 h. (n = 8). The dialysis procedure resulted in a decrease in serum salicylate of 14% (P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Thyroid volume and function after 131I treatment of diffuse non‐toxic goitre

OBJECTIVE Traditional treatment modalities of diffuse non‐toxic goitre are thyroid hormone suppression or surgery. When treating nodular non‐toxic goitre with 131I treatment a reduction in thyroid volume to about 50% has been observed. In the present study we evaluated the effect of 131I treatment of diffuse non‐toxic goitre.

Relationship between mood and TSH response to TRH stimulation in bipolar affective disorder

Moderate to severe depression and mania are associated with a reduced thyroid stimulating hormone (TSH) response to TSH releasing hormone (TRH). Continued reduction of this response after clinical recovery seems indicative of early relapse. The aim of the present study was to test the relationship between mild changes in mood and the TSH response to TRH stimulation in patients with bipolar affective disorder. Nineteen outpatients with bipolar affective disorder were followed prospectively for three years. Every third month, mood symptoms were rated using the 17-item Hamilton Depression Rating Scale (HAMD-17) and the Bech-Rafaelsen Mania Scale (BRMS). A TRH test was performed in connection with each rating session (IV injection of 200 microg TRH), and serum TSH was measured at 0, 20, and 60 min. The maximum TSH response (D-max TSH) and the temporal change in D-max TSH between succeeding rating sessions (DD-max TSH) were determined. Psychometric rating and TRH data were obtained for a total of 198 examinations. The temporal change in mood symptom rating score was negatively correlated with the temporal change in D-max TSH, thus suggesting that increasing severity of mood symptoms was related to a reduced TSH response to TRH stimulation. The temporal change in TSH response to TRH stimulation correlated with the actual score on an overall index of symptom severity. In conclusion, milder fluctuations in mood in bipolar affective disorder seem to correlate with the TSH response to TRH stimulation: Increasing severity of mood symptoms seems to be associated with reduced TSH response.

METABOLIC CLEARANCE AND PRODUCTION RATES OF 3,3′‐DIIODOTHYRONINE, 3′,5′‐DIIODOTHYRONINE AND 3′‐MONOIODOTHYRONINE IN HYPER‐ AND HYPOTHYROIDISM

Complete turnover studies of thyroxine (T4), 3,5,3′‐triiodothyronine (T3), 3,3′,5′‐triiodothyronine (rT3), 3,3′‐diiodothyronine (3,3′‐T2), 3′,5′‐diiodothyronine (3′,5′‐T2) and 3′‐monoiodothyronine (3′‐T1) were performed in each of eight healthy subjects, eight hyperthyroid and eight hypothyroid patients, using the single injection, non‐compartmental approach. The median metabolic clearance rate (litre per day per 70 kg) in controls was, T4 1·19; T3 19·7. rT3 147; 3,3′‐T2 1073; 3′,5′‐T2 256 and 3′‐T1 518. Hyperthyroid patients had increased and hypothyroid patients reduced values. The median production rate (PR) (nmol per day per 70 kg) in controls was, T4 117, T3 39, rT3 52, 3,3′‐T2 35, 3′,5′‐T2 14 and 3′‐T1 27. The PR of all iodothyronines studied was increased in hyperthyroidism, the increase in PR of T3 being the most pronounced. Hypothyroid patients had reduced PRs, a reduction which was relatively less pronounced for T3. Assuming thyroidal secretion contributes little rT3 and 3′,5′‐T2, the conversion rates (CRs) of T4 to rT3 and further to 3′,5′‐T2 were calculated. CR of T4 to rT3 in controls was in median 34%. By comparison the CR in hyperthyroid patients was increased to 56% (P < 0·05). In contrast the CR of rT3 to 3′,5′‐T2 was similar in controls and hyperthyroid patients, 26% v. 31%.

Peripheral markers of thyroid function: the effect of T4 monotherapy vs T4/T3 combination therapy in hypothyroid subjects in a randomized crossover study

Background A recent randomized controlled trial suggests that hypothyroid subjects may find levothyroxine (l-T4) and levotriiodothyronine combination therapy to be superior to l-T4 monotherapy in terms of quality of life, suggesting that the brain registered increased T3 availability during the combination therapy. Hypothesis Peripheral tissue might also be stimulated during T4/T3 combination therapy compared with T4 monotherapy. Methods Serum levels of sex hormone-binding globulin (SHBG), pro-collagen-1-N-terminal peptide (PINP), and N-terminal pro-brain natriuretic peptide (NT-proBNP) (representing hepatocyte, osteoblast, and cardiomyocyte stimulation respectively) were measured in 26 hypothyroid subjects in a double-blind, randomized, crossover trial, which compared the replacement therapy with T4/T3 in combination (50 μg T4 was substituted with 20 μg T3) to T4 alone (once daily regimens). This was performed to obtain unaltered serum TSH levels during the trial and between the two treatment groups. Blood sampling was performed 24 h after the last intake of thyroid hormone medication. Results TSH remained unaltered between the groups ((median) 0.83 vs 1.18 mU/l in T4/T3 combination and T4 monotherapy respectively; P=0.534). SHBG increased from (median) 75 nmol/l at baseline to 83 nmol/l in the T4/T3 group (P=0.015) but remained unaltered in the T4 group (67 nmol/l); thus, it was higher in the T4/T3 vs T4 group (P=0.041). PINP levels were higher in the T4/T3 therapy (48 vs 40 μg/l (P<0.001)). NT-proBNP did not differ between the groups. Conclusions T4/T3 combination therapy in hypothyroidism seems to have more metabolic effects than the T4 monotherapy.

Combined Type 2 Diabetes and Ischemic Heart Disease: Double Jeopardy

Accessible online at: www.karger.com/journals/hed Type 2 diabetes increases the risk of coronary heart disease by a factor of 2–4. Haffner et al. [1] demonstrated that the 7-year mortality among type 2 diabetics without established ischemic heart disease (IHD) was similar to that of nondiabetics who had experienced a prior myocardial infarction (MI). The combination of type 2 diabetes and IHD further increased mortality by a factor of 2 [1]. Other long-term post-MI studies have demonstrated an approximately double mortality rate in diabetics versus nondiabetics [2]. The poor prognosis in diabetes is probably mainly due to both the high frequency of risk factors for IHD as well as more widespread coronary artery disease in diabetics, as also demonstrated in two articles in this issue of Heart Drug [3, 4]. Conventional pharmacological treatment modalities, such as fibrinolysis, ASA, statins, beta-blockers and ACE inhibitors, have proven their efficacy in high-risk patients with diabetes, IHD, or both, and a general pattern is that for any given treatment the effect is greater in diabetics than in nondiabetics, i.e. numbers needed to treat are smaller among diabetics. Despite this fact, diabetics are in general treated to a lesser extent than nondiabetics [2, 5]. This might simply be because physicians do not realize the severity of the diabetic disease, and because of problems with compliance in these patients due to the many drugs prescribed. In case of an acute MI, the Diabetes and Insulin-Glucose Infusion in Acute Myocardial Infarction I (DIGAMI I) study [6] suggested a beneficial effect on survival of acute glucose-insulin infusion in diabetics. This hypothesis is now being tested prospectively in the larger, ongoing DIGAMI II study, which also focuses on long-term glycemic control. The beneficial effect of prolonged good glycemic control on the development of IHD in diabetics has been a matter of controversy. In large prospective trials, both in type 1 diabetics – Diabetes Control and Complications Trial (DCCT) [7] – and type 2 diabetics – United Kingdom Prospective Diabetes Study (UKPDS) [8] – good glycemic control tended to, but did not conclusively demonstrate a beneficial effect on the development of cardiovascular disease (CVD). However, in the UKPDS trial in type 2 diabetics, the patients were at low risk of CVD, and established CVD at entry was an exclusion criterion. In contrast, in the follow-up of the Kumamoto trial [9] good glycemic control in type 2 diabetics conclusively demonstrated reduced events of CVD, and in the UKPDS a subgroup of overweight patients demonstrated a quite substantial benefit from metformin treatment on the devel-

Diabetes in patients with chronic heart failure: a frequent combination with reduced functional status

Background: Diabetes is an independent prognostic factor in heart failure (HF) patients, and furthermore, the frequency of diabetes in HF patiemts seems to be large. We examined the real prevalence of diabetes and prediabetes in patients with chronic heart failure, attending a HF clinic. Furthermore we examined relationship of diabetes to plasma NT-proBNP levels, functional capacity and systolic cardiac function. Methods: Between September 1999 and January 2003, 406 consecutive patients with documented systolic heart failure (left ventricular ejections fraction (LVEF) 45%) were admitted to the heart failure clinic at Frederiksberg University Hospital, Denmark, on an open access basis. All the patients attending the heart failure clinic were registered in a heart failure database. The patients were classified according to the NYHA classification and had an echocardiography performed. Plasma NT-pro BNP and fasting blood glucose (FBG) were measured in a random sample of 210 patients. These patients were similar to the other 196 patients in the heart failure clinic with respect to age, sex, LVEF, NYHA class and duration of HF. Results: In the total population (n 406) LVEF was 0.29 0.1 (mean SD), age was 72.2 ( 10.3)years, 84%was classifiedasNYHAII-III, and themajority of the patients (70%) were male. The patients with known diabetes were classified in higher NYHA classes (P 0.01); LVEFwas similar: DM (28.6 8.5%) vs. non-DM (29.3 8.9%), P 0.77; log10NT-proBNP: DM (2.19 0.65) vs.non-DM (2.14 0.55), P 0.64. In the sample population (n 198), 20% had known type 2 diabetes, 12% had unknown diabetes (FBG 6.1 mmol/l), and 12% of the patients showed IFG (Impaired Fasting Glycemia, FBG: 5.6–6.0 mmol/l). The diabetic patients where similar with respect to sex and age compared to the non-diabetics but had a higher frequency of ischemic heart disease (P 0.05). Conclusions: Abnormal glucose metabolism is extremely common in heart failure patients in this population 44%. Patients with known type 2 diabetes, as compared to non-diabetics had similar systolic cardiac function and plasma NT-pro BNP level, but lower functional status (higher NYHA class). This suggests, that LVEF and plasma BNP level do not completely describe the functional impairment in type 2 diabetic patients with HF.

Thyroid Hormone Metabolism in Hypermetabolic Patients with Haematological Disorders

Turnover tracer studies of T4 and T3 using the single injection, noncompartmental approach were performed in 6 hypermetabolic patients with haematological disorders (HHD) (basal metabolic rate (BMR): median 141%, range 122-166%), in 10 controls with stable, nonthyroidal illness (NTIC), and in 14 healthy controls (HC). The main finding was an increase of approximately 30% of the production rate (PR) of both T4 and T3 in patients with HHD. Median PR of T4 was 134 nmol/day x 70 kg in HHD, compared to 78 nmol/day x 70 kg in NTIC (P less than 0.05) and 98 nmol/day X 70 kg in HC (p less than 0.1), whereas median PR of T3 was 40.3 nmol/day x 70 kg in HHD, compared to 25.6 nmol/day x 70 kg in NTIC (P less than 0.01) and 31.1 nmol/day x 70 kg in HC (P less than 0.1). An increase of similar magnitude was found for the apparent distribution volume and the pool size of both T4 and T3. In contrast, the mean transit times of the hormones were similar in the 3 groups. Patients with HHD had normal levels of basal serum TSH as well as of the TSH response to TRH. Only PR of T3 correlated to the BMR (R = 1.00, P less than 0.02). The data are compatible with an increased consumption of thyroid hormones by malignant haematologic cells, and the increase of BMR seems to be dependent on the production of T3.