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Stig Valdemarsson

Changes in plasma lipid concentrations are well known metabolic consequences of thyroid dysfunction. The alterations are most prominent in hypothyroidism which is typically associated with pronounced hypercholesterolemia and frequently also with moderate hypertriglyceridemia. Hyperthyroidism, on the other hand, is often accompanied by decreased levels of serum cholesterol. Although the pathophysiological mechanisms for these lipoprotein abnormalities are not clarified, it is well known that these changes are completely reversible. Since thyroid disease is rarely associated with secondary alterations in other organs involved in plasma lipoprotein metabolism, patients with thyroid dysfunction provide an unusually clean model for dynamic studies on the regulation of lipoprotein metabolism in man. The present investigations focus on the relationships between thyroid hormones and key enzymes in lipoprotein metabolism, and on the impact of enzyme alterations on the plasma lipoprotein profile. Besides improving our understanding of the pathogenesis of the dyslipoproteinemias in thyroid dysfunction per se, such information

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Stig Valdemarsson and Mario Monti

Valdemarsson S, Monti M. Increased ratio between anaerobic and aerobic metabolism in lymphocytes from hyperthyroid patients. Eur J Endocrinol 1994;130:276–80. ISSN 0804–4643

While an increased oxygen consumption is accepted as one consequence of hyperthyroidism, only few data are available on the role of anaerobic processes for the increased metabolic activity in this disease. In this study we evaluated the relative importance of anaerobic and aerobic metabolism for the metabolic activity in lymphocytes from patients before and after treatment for hyperthyroidism. Total lymphocyte heat production rate (P), reflecting total cell metabolic activity, was determined in a plasma lymphocyte suspension using direct microcalorimetry. The contribution from aerobic metabolism (O2 – P) was calculated from the product of the lymphocyte oxygen consumption rate and the enthalpy change for glucose combustion, and the anaerobic contribution as the difference between P and O2 – P. The total lymphocyte heat production rate P was 3.37 ± 0.25 (sem) pW/cell (N = 11) before and 2.50 ± 0.11 pW/cell (N = 10) after treatment for hyperthyroidism (p < 0.01) as compared to 2.32 ± 0.10 pW/cell in a control group (N = 18). The aerobic component O2 – P amounted to 1.83 ± 0.11 pW/cell in the patient group before and 1.83 ± 0.08 pW/cell after treatment and to 1.71 ± 0.16 pW/cell in 10 controls. Out of P, the O2 – P component corresponded to 56.8 ± 4.4% in the hyperthyroid state and to 73.7 ± 3.2% after treatment (p < 0.01) as compared to 73.4 ± 4.4% in the 10 euthyroid controls. It was concluded that the increased metabolic activity demonstrated in lymphocytes from hyperthyroid patients cannot be explained by an increased oxygen-dependent consumption. This suggests that cell function may be comparatively more dependent on anaerobic metabolism during thyroid hormone excess and that adenosine triphosphate generation thereby has to be supplied through an increased metabolism of energy-rich substrates along anaerobic metabolic pathways.

Stig Valdemarsson, Department of Internal Medicine, Lund University Hospital, S-221 85 Lund, Sweden

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Stig Valdemarsson, Julie Ikomi-Kumm and Mario Monti

Abstract.

A discrepancy between the clinical impression of disease activity and basal serum levels of growth hormone is often seen in patients with acromegaly. A slightly better relation has been found to serum levels of IGF-I, but a technique for evaluation of cell metabolic activity in this disease is still missing. For this purpose we used microcalorimetry to determine heat production rate in lymphocytes from 15 patients with acromegaly. The mean heat production rate was 2.90±0.15 pW/cell, significantly higher than in 13 healthy subjects, 2.31±0.12 pW/cell (p<0.01). Heat production rates did not correlate significantly with basal growth hormone levels, but increased, in a statistically significant manner (p<0.001), in parallel with the score index used to evaluate the clinical activity of the disease. Using the technique of microcalorimetry we could thus demonstrate an increased metabolic activity at a cellular level in patients with acromegaly, a finding that is in accordance with the view that an increased cell metabolic activity is a component of the disease process in acromegaly.

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Stig Valdemarsson, Julie Ikomi-Kumm and Mario Monti

The role of the Na/K pump for the increased cell energy expenditure in hyperthyroidism was studied by measuring total lymphocyte heat production rate in samples with and without ouabain inhibition of Na/K ATP-ase. In addition, the relative contribution of aerobic processes to lymphocyte thermogenesis was calculated from oxygen consumption measurements. In 12 patients with clinical and laboratory hyperthyroidism total lymphocyte heat production rate was 3.19±0.21 pW/cell, significantly higher than in 7 patients with subclinical hyperthyroidism (2.14±0.11 pW/cell) and in 15 euthyroid subjects (2.26±0.11 pW/cell) (p<0.001). The relative decrease in lymphocyte heat production rate after ouabain, giving a quantitative measure of the activity of the Na/K ATP-ase and reflecting the importance of Na/K pump function for the overall rate of lymphocyte metabolism, was not significantly different between the groups: 19.5±3.6% in hyperthyroid patients, 14.2±2.3% in subclinical hyperthyroid patients and 17.8±3.1% in euthyroid subjects. According to the rate of lymphocyte oxygen consumption, aerobic processes represented 58.4±6.7% of total lymphocyte energy expenditure in hyperthyroid patients, not significantly different from subclinical hyperthyroidism (62.6±8.4%) or from euthyroidism (66.6±2.7%). These data do not support the hypothesis of a specific role of the Na/K pump function for the increased cell thermogenesis in hyperthyroidism and indicate a parallel stimulation of aerobic and anaerobic processes by thyroid hormone excess.

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Stig Valdemarsson, Julie Ikomi-Kumm and Mario Monti

Abstract.

We used microcalorimetry to measure lymphocyte heat production rate in patients with clinical and laboratoy hyperthyroidism (serum TSH ↓, serum FT4 ↑, serum FT3 ↑ ), subclinical hyperthyroidism (serum TSH ↓, serum FT4 ↑, serum FT3=), and subclinical hypothyroidism (serum TSH ↑, serum FT4 ↓, serum FT3=) compared with healthy controls (N= 13). The lymphocyte heat production rate was significantly correlated to the free thyroxine level (r=0.53, p<0.01) and to the free triiodothyronine level (r=0.51, p<0.01) when calculated from pooled data for the three patients groups. The hyperthyroid patients (N = 8) had a significantly increased lymphocyte heat production rate, 3.43±0.25 pW/cell, as compared with 2.31±0.12 pW/cell in the control group (p<0.001). The groups with subclinical hyperthyroidism (N = 7) and subclinical hypothyroidism (N=9) had lymphocyte heat production rates of 2.14±0.11 and 2.56±0.15 pW/cell, respectively, not significantly different from that in the controls. Consistently, there was no significant difference between patients with subclinical hyperthyroidism (N=5) and controls (N=5) with regard to lymphocyte energy production as calculated from separately measured oxygen comsumption rates in vitro, 1.36±0.20 and 1.56±0.12 pW/cell, respectively. Thus microcalorimetry seems to be suitable for studying the influence of thyroid hormones on cellular metabolism. Subclinical thyroid dysfunction does not seem to alter the overall rate of lymphocyte metabolism.

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Stig Valdemarsson, Pavo Hedner and Peter Nilsson-Ehle

Abstract. We have studied the effects of l-thyroxine substitution on lipoprotein concentrations, on the activities of lipoprotein lipase (LPL) and hepatic lipase (HL), and on the elimination rate of exogenous triglyceride in a homogeneous group of patients with hypothyroidism of pituitary origin. All were deficient of sex hormones but not of corticosteroids during the observation period.

Before treatment total plasma cholesterol, LDL cholesterol, and triglyceride levels were significantly higher than in a euthyroid control group but not as high as in patients with overt primary hypothyroidism. The activities of LPL and HL were also intermediate between those of euthyroid and overt primary hypothyroid subjects, and there was a significant reduction of the elimination rate of exogenous triglyceride. No changes were found for HDL cholesterol levels.

When the patients with secondary hypothyroidism were compared to patients with primary hypothyroidism, matched for thyroid function levels, age, sex, and weight, there were no differences with regard to plasma lipoprotein concentrations or post-heparin lipase activities.

In 3 patients with secondary hypothyroidism the lipoprotein profiles were studied by zonal ultracentrifugation and found to agree well with changes observed in primary hypothyroidism.

l-thyroxine substitution produced a normalization of lipase activities and lipoprotein concentrations in patients with secondary hypothyroidism. We conclude that there are no fundamental differences in the disturbances of the lipoprotein metabolism in primary and secondary forms of hypothyroidism.

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Stig Valdemarsson, Arnold Leckström, Per Westermark and Anders Bergenfelz

Valdemarsson S, Leckström A, Westermark P, Bergenfelz A. Increased plasma levels of islet amyloid polypeptide in patients with primary hyperparathyroidism. Eur J Endocrinol 1996;134:320–5. ISSN 0804–4643

Amylin, also named islet amyloid polypeptide (IAPP), is a protein that is processed and released from pancreatic β-cells in parallel with insulin. Islet amyloid polypeptide is currently studied with regard to a role for insulin resistance in non-insulin-dependent diabetes. To elucidate a possible function of IAPP for impaired glucose tolerance in primary hyperparathyroidism (pHPT), we studied plasma IAPP levels during an oral glucose tolerance test (OGTT) in seven pHPT patients before and 8 weeks after surgery and in six healthy subjects. The β-glucose level of the patient groups was 4.34 ± 0.12 mmol/l before and 3.97 ± 0.16 mmol/l after surgery (NS), while the serum level of insulin was significantly higher before (16.9 ± 2.8 mIU/l) than after (8.9 ± 1.9 mIU/l) the operation (p < 0.05), indicating a moderately increased insulin resistance in pHPT. The basal plasma levels of IAPP were significantly higher in pHPT patients before than 8 weeks after surgery (9.71 ± 1.05 and 4.30 ± 0.82 pmol/l, respectively; p < 0.01). When compared to the plasma IAPP level of the controls at 1.80 ± 0.38 pmol/l, pHPT patients had higher IAPP values both before (p < 0.01) and at 8 weeks after (p < 0.05) operation, There was a significant correlation between the serum levels of insulin and plasma levels of IAPP in pHPT patients before (r = 0.87, p < 0.01) as wells as 8 weeks after surgery (r = 0.69, p < 0.05). The area under the curve for IAPP during OGTT in pHPT patients was 1872.4 ± 187.7 pmol·min/l, which is significantly higher than after surgery 1010.8 ± 93.7 pmol· min/l) (p < 0.05) and compared to the area for the controls at 840.3 ± 49.9 pmol min/l (p< 0.01). In conclusion, pHPT is associated with an increased plasma level of IAPP, correlated to the serum insulin level, but persistently higher than in controls also 8 weeks after surgery. Possibly, increased IAPP levels can have a role for impaired glucose tolerance in pHPT. The hyperparathyroid state might have a specific role for the release of this peptide, otherwise closely connected to insulin secretion.

Stig Valdemarsson, Department of Internal Medicine, Lund University Hospital, S-221 85 Lund, Sweden

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Stig Valdemarsson, Per Hansson, Pavo Hedner and Peter Nilsson-Ehle

Abstract. Lipoprotein concentrations and activities of lipoprotein lipase (LPL) and hepatic lipase (HL) were measured in 70 subjects with thyroid function ranging from overt hypothyroidism over subclinical hypothyroidism and euthyroidism to hyperthyroidism.

In parallel with serum T3 (S-T3) concentrations increasing from low in hypothyroidism to high in hyperthyroidism there were gradually higher HL activities over the full spectrum of thyroid function, accompanied by decreasing levels of total and low density lipoprotein (LDL) cholesterol. High density lipoprotein (HDL) cholesterol was lower (P < 0.05) in hyperthyroidism than in euthyroidism but not significantly changed in the hypothyroid groups. HL was correlated to S-T3 (r = 0.77, P< 0.001), LDL cholesterol to log S-T3 (r = -0.76, P < 0.001), and LDL cholesterol to log HL (r = -0.55, P <0.001).

The activity of LPL was decreased (P< 0.001) in overt hypothyroidism compared to euthyroidism but, in contrast to HL, the activity of LPL was not increased in hyperthyroidism. The plasma triglyceride (P-TG) concentration was elevated (P< 0.01) in overt hypothyroidism but not significantly changed in subclinical hypothyroidism or in hyperthyroidism. The LPL activity was correlated to log S-T3 (r = 0.45, P < 0.001), P-TG to log S-T3 (r = -0.37, P< 0.01) and P-TG to log LPL activity (r= -0.71, P<0.001).

Our results demonstrate that thyroid hormones influence HL and LPL activities in different ways, suggesting different mechanisms of action. Changes in HL activity seem to be an important mechanism for the disturbance of cholesterol metabolism in thyroid dysfunction while the thyroid hormone influence on LPL seems to be of importance mainly for the disturbance in triglyceride metabolism.

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Stig Valdemarsson, Birger Fagher, Pavo Hedner, Mario Monti and Peter Nilsson-Ehle

Abstract. Direct microcalorimetry was used for measurements of heat production in cell suspensions of platelets and adipocytes, obtained from hypothyroid patients before and after 3 months on full l-thyroxine substitution.

Platelet heat production was significantly lower than normal before treatment and increased in all 10 patients studied; the mean value increased from 51.3 ± 1.6 fW/cell before to 57.1 ± 1.8 fW/cell after therapy (P< 0.001).

Similarily, adipocyte heat production was initially significantly lower than normal and increased during treatment in all 6 patients investigated. The mean value for heat production per adipocyte was 18.8 ± 1.7 pW/cell before and 32.4 ± 2.5 pW/cell after therapy (P < 0.025), which is still below the level recorded in lean healthy subjects. The adipocyte size did not change significantly. The increase in adipocyte heat production was correlated to the increase in S-triiodothyronine levels (r = 0.84, P <0.05).

In hypothyroidism, the total metabolic activity seems to be comparatively more reduced in adipocytes than in platelets. A difference may exist between these cells with regard to recovery of normal metabolic acitivity during treatment for hypothyroidism. Direct microcalorimetry appears to be an adequate method for monitoring net metabolic effects of thyroid hormones in these cells.

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Birgitta Bülow, Svante Jansson, Claes Juhlin, Lars Steen, Marja Thorén, Hans Wahrenberg, Stig Valdemarsson, Bo Wängberg and Bo Ahréen

Group-author : on behalf of the Swedish Research Council Study Group of Endocrine Abdominal Tumours

Objectives: To examine the risk of developing adrenal carcinomas and clinically overt hypersecreting tumours during short-term follow-up in patients with adrenal incidentalomas.

Design: 229 (98 males and 131 females) patients with adrenal incidentalomas were investigated in a prospective follow-up study (median time 25 months; range 3–108 months). The patients were registered between January 1996 and July 2001 and followed until December 2004. Twenty-seven Swedish hospitals contributed with follow-up results.

Methods: Diagnostic procedures were undertaken according to a protocol including reinvestigation with computed tomography scans after 3–6 months, 15–18 months and 27–30 months, as well as hormonal evaluation at baseline and after 27–30 months of follow-up. Operation was recommended when the incidentaloma size increased or if there was a suspicion of a hypersecreting tumour.

Results: The median age at diagnosis of the 229 patients included in the follow-up study was 64 years (range 28–84 years) and the median size of the adrenal incidentalomas when discovered was 2.5 cm (range 1–8 cm). During the follow-up period, an increase in incidentaloma size of ≥0.5 cm was reported in 17 (7.4%) and of ≥1.0 cm was reported in 12 (5.2%) of the 229 patients. A decrease in size was seen in 12 patients (5.2%). A hypersecreting tumour was found in 2% of the hormonally investigated patients: Cushing’s syndrome (n = 2) and phaeochromocytoma (n = 1). Eleven patients underwent adrenalectomy, but no cases of primary adrenal malignancy were observed.

Conclusions: Patients with adrenal incidentaloma had a low risk of developing malignancy or hormonal hypersecretion during a short-term follow-up period.