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Biomedical subjects

Michael C Sheppard

Publications and source records attributed to Michael C Sheppard.

12 recordsLinked to original sources
PubMed2005

Thyroid function and mortality in patients treated for hyperthyroidism.

CONTEXT: Hyperthyroidism has been reported to cause excess all-cause and circulatory mortality. Whether this can be reversed is unknown, as is the influence of mild persisting thyroid dysfunction and treatment-induced hypothyroidism. OBJECTIVES: To determine whether radioiodine treatment is associated with increased mortality and to determine the influences of mild thyroid dysfunction and the development of overt hypothyroidism treated with thyroxine (T(4)). DESIGN, SETTING, AND PARTICIPANTS: A population-based study of 2668 individuals aged 40 years or older treated for overt hyperthyroidism with radioiodine in the West Midlands region of England from 1984-2002. MAIN OUTCOME MEASURES: Cause of death compared with age- and period-specific mortality in England and Wales and assessment of the influence of T(4) therapy for radioiodine-induced hypothyroidism and subclinical thyroid dysfunction on mortality. RESULTS: In 15,968 person-years of follow-up, 554 died vs 487 expected deaths (standardized mortality ratio [SMR], 1.14; 95% confidence interval [CI], 1.04-1.24, P=.002). Increased risks of all-cause and circulatory deaths vs age- and period-specific mortality were observed in follow-up in those not requiring, or prior to, T(4) therapy. These increased risks were not observed during follow-up on T(4) therapy (circulatory disease SMR prior to T(4), 1.33; 95% CI, 1.14-1.53 vs SMR, 0.91; 95% CI, 0.70-1.17 during T(4)). Patients receiving T(4) had decreased risk of mortality vs risk in the period not requiring, or prior to, T(4) therapy (all-cause mortality hazard ratio [HR], 0.65; 95% CI, 0.54-0.79; circulatory mortality HR, 0.65; 95% CI, 0.48-0.87). Increased all-cause mortality vs the background population was observed in the period prior to T(4) therapy in follow-up associated with low, normal, and high serum thyrotropin. The SMR for ischemic heart disease increased slightly when analyzed by serum thyrotropin, high serum thyrotropin being the highest SMR (low thyrotropin SMR, 1.06; 95% CI, 0.75-1.45; normal thyrotropin SMR, 1.17; 95% CI, 0.76-1.71; high thyrotropin SMR, 1.48; 95% CI, 0.86-2.37). Comparison within the cohort showed that mild hypothyroidism prior to T(4) therapy was associated with increased risk of mortality from ischemic heart disease vs biochemical euthyroidism (HR, 2.08; 95% CI, 1.04-4.19). CONCLUSIONS: Patients treated with radioiodine for hyperthyroidism had increased mortality vs age- and period-specific mortality in England and Wales, a finding no longer evident during T(4) therapy. This supports treating hyperthyroidism with doses of radioiodine sufficient to induce overt hypothyroidism. The association within the cohort of mortality from ischemic heart disease with subclinical hypothyroidism suggests T(4) replacement should be considered should this biochemical abnormality develop after radioiodine therapy.

Adult↗
PubMed2004

Heart rate variability and turbulence in hyperthyroidism before, during, and after treatment.

Patients with subclinical and treated overt hyperthyroidism have an excess vascular mortality rate. Several symptoms and signs in overt hyperthyroidism suggest abnormality of cardiac autonomic function that may account in part for this excess mortality rate, but few studies have examined cardiac autonomic function in untreated and treated hyperthyroidism. We assessed heart rate turbulence (HRT) and time-domain parameters of heart rate variability in a large, unselected cohort of patients with overt hyperthyroidism referred to our thyroid clinic (n = 259) and compared findings with a group of normal subjects with euthyroidism (n = 440). These measures were also evaluated during antithyroid therapy (when serum-free thyroxine and triiodothyronine concentrations returned to normal but thyrotropin remained suppressed (i.e., subclinical hyperthyroidism, n = 110) and when subjects were rendered clinically and biochemically euthyroid (normal serum thyrotropin, free thyroxine and triiodothyronine concentrations, n = 219). We found that overall measures of heart rate variability and those specific for cardiac vagal modulation were attenuated in patients with overt hyperthyroidism compared with normal subjects; measurements of overall heart rate variability remained low in those with low levels of serum thyrotropin but returned to normal in patients with biochemical euthyroidism. Measurements of HRT (onset and slope) were also decreased in patients with overt hyperthyroidism, but HRT slope returned to normal values with antithyroid treatment. This study is the first to evaluate HRT in overt and treated hyperthyroidism.

Adolescent↗
PubMed2004

Efficacy of Sandostatin LAR (long-acting somatostatin analogue) is similar in patients with untreated acromegaly and in those previously treated with surgery and/or radiotherapy.

BACKGROUND AND OBJECTIVES: Somatostatin analogues have been used as an adjunct to surgery and radiotherapy in the treatment of acromegaly for over 15 years, but debate surrounds their use as primary therapy. Newman suggested that octreotide was equally effective as primary or adjuvant therapy, but the effects of previous surgery/radiotherapy may have led to a preselection bias. In an attempt to eliminate this bias, the efficacy of the depot somatostatin analogue Sandostatin LAR as primary and adjuvant therapy has been assessed using GH and IGF-I levels at diagnosis as baseline values. DESIGN: We retrospectively analysed the GH and IGF-I data from a large multicentre study in which patients' biochemical response to treatment with the depot somatostatin analogue Sandostatin LAR as primary and adjuvant therapy was assessed. We used GH and IGF-I levels at diagnosis as baseline values to eliminate any preselection bias. PATIENTS AND RESULTS: In 91 patients (42 male) studied, mean serum GH fell from 36.2 +/- 3.3 micro g/l (SEM) at diagnosis to 2.2 +/- 0.2 micro g/l after 48 weeks of treatment (P < 0.0001). In the primary (n = 34) and adjuvant (n = 57) therapy groups, mean GH fell from 30.7 +/- 5.7 to 2.6 +/- 0.4 micro g/l (P < 0.0001) and from 39.5 +/- 4.1 to 2.0 +/- 0.2 micro g/l (P < 0.0001), respectively. Sixty-two percent of patients in the primary therapy group and 70% in the adjuvant therapy group achieved GH < 2 micro g/l. Serum IGF-I levels were available in 67 patients (34 male). In the primary therapy group (n = 25) mean IGF-I fell from 764 +/- 68 to 414 +/- 31 micro g/l (P < 0.0001) at 48 weeks. In the adjuvant therapy group (n = 42) mean IGF-I was 666 +/- 50 micro g/l, falling to 384 +/- 30 micro g/l (P < 0.0001) at 48 weeks. 72% of patients achieved normal age-related IGF-I-values. There were no statistically significant differences in GH or IGF-I levels between the primary and adjuvant therapy groups at diagnosis, pre Sandostatin LAR or after 48 weeks of treatment. CONCLUSION: This retrospective study demonstrates that in a group of patients with similar diagnostic GH and IGF-I levels, Sandostatin LAR was equally effective as primary therapy in acromegalic patients as in patients previously treated with surgery and/or radiotherapy.

Acromegaly↗
PubMed2004

The role of growth hormone-receptor antagonism in relation to acromegaly.

Acromegaly is a rare but disabling condition associated with reduced life expectancy. It is caused almost invariably by a growth hormone-secreting pituitary adenoma. Transsphenoidal surgery and/or radiotherapy are still considered to be the treatment of choice, but despite recent advances in both these forms of treatment, the overall surgical cure rate remains approximately 60%, and radiotherapy is characterised by delayed effect and a high incidence of hypopituitarism. Medical therapy in the form of dopamine agonists and somatostatin analogues has traditionally been used as an adjunct to surgery and/or radiotherapy, but is increasingly being used as first line therapy in the treatment of acromegaly. Recently, a third form of medical therapy, the growth hormone receptor antagonist, pegvisomant, has been licensed for use in acromegaly. This article examines the design, properties, clinical efficacy and safety of pegvisomant.

Acromegaly↗
PubMed2003

Primary medical therapy for acromegaly.

There is now considerable evidence that the clinical outcome in patients with acromegaly can be improved very substantially by means of better surgical expertise and effective medical therapies used in a flexible and innovative manner. Medical therapy alone in patients who have not undergone surgery or radiotherapy (primary medical therapy) offers the prospect of near normalisation of GH/IGF-I levels together with substantial tumour shrinkage in a significant number of patients.

Acromegaly↗
PubMed2002

Isolation and characterization of human thyroid endothelial cells.

From collagenase digests of human thyroid, endothelial cells were separated from follicular cells by their greater adherence to gelatin-coated plates. Endothelial cells were further purified using fluorescence-activated cell sorting, selecting for cells expressing factor VIII-related antigen. Isolated cells were negative for thyroglobulin and calcitonin when examined by immunostaining. The receptor for the angiopoietins, Tie-2, was expressed by the cells, and expression was increased by agents that elevate cAMP. Nitric oxide synthase (NOS) 3, the endothelial form of NOS, was expressed by the cells and similarly regulated. Cells responded strongly to the mitogen fibroblast growth factor (FGF)-2 in growth assays but only weakly to vascular endothelial growth factor (VEGF). VEGF was, however, able to stimulate nitric oxide release from the cells consistent with their endothelial origin. The FGF receptor (FGFR1) was full length (120 kDa) and immunolocalized to the cytosol and nucleus. Thyrotropin (TSH) did not regulate FGFR1, but its expression was increased by VEGF. Thrombospondin, a product of follicular cells, was a growth inhibitor, but neither TSH nor 3,5,3'-triiodothyronine had direct mitogenic effects. Thyroid follicular cell conditioned medium contained plasminogen activator activity and stimulated the growth of the endothelial cells, but when treated with plasminogen to produce the endothelial-specific inhibitor, angiostatin, growth was inhibited. Human thyroid endothelial cell cultures will be invaluable in determining the cross talk between endothelial and follicular cells during goitrogenesis.

Blotting, Western↗
PubMed2002

Successful treatment of amiodarone-induced thyrotoxicosis.

BACKGROUND: Amiodarone-induced thyrotoxicosis (AIT) is a difficult management problem about which there are little published data. We examined whether continuing amiodarone or differentiating AIT into 2 subtypes affected outcome. METHODS AND RESULTS: The type and duration of antithyroid treatment and response were recorded in a consecutive series of 28 cases. Comparisons were made between those in whom amiodarone either was continued or stopped and between those with either possible type 1 or type 2 AIT. Of the 28 cases, 5 had spontaneous resolution of AIT; 23 received carbimazole (CBZ) alone as first-line therapy. Eleven achieved long-term euthyroidism off CBZ or on a maintenance dose. Five became hypothyroid and required long-term thyroxine. Five relapsed after stopping CBZ treatment and were rendered euthyroid with either long-term CBZ (n=3) or radioiodine (n=2). Four were intolerant of CBZ and received propylthiouracil (PTU), with good effect in 3. One was resistant to thionamide alone (CBZ then PTU) and responded to adjunctive steroids. No difference in presentation or outcome was noted between those in whom amiodarone was continued or stopped or between possible type 1 or type 2 AIT. CONCLUSIONS: Continuing amiodarone has no adverse influence on response to treatment of AIT. First-line therapy with a thionamide alone is appropriate in iodine-replete areas, thus avoiding potential complications of other drugs. Differentiating between 2 possible types of AIT does not influence management or outcome.

Aged↗
PubMed2002

Levothyroxine treatment and occurrence of fracture of the hip.

BACKGROUND: Levothyroxine sodium is widely prescribed and has been implicated as a cause of reduction in bone mineral density and, therefore, suggested to be a major contributor to the risk of osteoporotic fractures. OBJECTIVE: To investigate whether levothyroxine use increases the risk of developing osteoporotic fractures. METHODS: We conducted a population-based, case-control analysis of the risk of a femur fracture in a large cohort of patients who had been prescribed levothyroxine. We used the United Kingdom General Practice (primary care) Research Database to identify 23,183 patients who had been prescribed long-term thyroid hormone therapy and to identify for each patient taking levothyroxine 4 controls matched for age, sex, primary care practice, and duration of registration on the database. The number of patients who had sustained a fracture of the proximal femur was ascertained for each group, together with drug therapies and medical diagnoses likely to affect fracture risk. RESULTS: Of the 23,183 patients prescribed thyroid hormone, a mean +/- SE of 1.61% +/- 0.08% had sustained a fracture of the femur, compared with 1.44% +/- 0.04% of 92,732 controls (P =.06). When analyzed according to sex, a significant difference in rate of fracture between patients taking levothyroxine and controls was found in males (P =.008). Compared with controls, patients taking levothyroxine had higher reported rates of medical diagnoses and therapies, potentially confounding the fracture risk. Independent predictors of the occurrence of fracture after adjustment for other factors were age (adjusted odds ratio [AOR], 1.11; 95% confidence interval [CI], 1.10-1.11; P<.001), medical diagnoses including rheumatoid arthritis (AOR in females, 1.69; 95% CI, 1.27-2.26; P<.001), excessive use of alcohol (AOR in females, 3.05; 95% CI, 1.94-4.76; P<.001), and prescription of drugs (eg, anticonvulsants; AOR in females, 2.49; 95% CI, 2.00-3.09; P<.001). Prescription of levothyroxine was an independent predictor of fracture occurrence in males (AOR, 1.69; 95% CI, 1.12-2.56; P =.01) but not females (AOR, 1.03; 95% CI, 0.92-1.16; P =.60). CONCLUSIONS: The lack of association between fracture and levothyroxine prescription in the whole cohort is reassuring, although an independent association between levothyroxine prescription and fracture occurrence in male patients suggests that levothyroxine may contribute to fracture risk in this specific group.

Adult↗
PubMed2002

Long-term safety and efficacy of depot long-acting somatostatin analogs for the treatment of acromegaly.

Depot somatostatin analogs are now increasingly being prescribed as adjuvant and primary therapy for the treatment of acromegaly. Previous studies have shown them to be both effective and safe, suppressing GH levels to less than 2 micro g/liter in 50-65% of cases and normalizing serum IGF-I levels in 65%. However, published data on their long-term efficacy and safety is scanty. We analyzed data from 22 patients (16 female and 6 male) treated with Sandostatin LAR or Lanreotide for an average of 41 months (range 12-89). Three patients had previously been treated with surgery, two with radiotherapy, and seven with both. Ten patients had received primary medical therapy. Mean pretreatment GH levels were 13.1 +/- 3.4 micro g/liter, and IGF-I levels were 592.9 +/- 53.9 micro g/liter. Results after 12 months of therapy indicated reduction in GH (3.2 +/- 0.7 micro g/liter; P < 0.0001) and IGF-I (321.9 +/- 33.9 micro g/liter; P < 0.001) concentrations, and this was sustained at latest follow-up. Using GH criteria (serum GH < 2 micro g/liter), 46% of subjects achieved a cure at 12 months, and 36% achieved a cure long-term. Fifty-two percent achieved normal IGF-I values at 12 months, and 67% long-term. Mean fasting and 2-h plasma glucose concentrations were similar at latest follow-up and at 12 months to baseline values. Three patients developed impaired glucose tolerance within 12 months of treatment, one going on to develop frank diabetes mellitus. However, glucose tolerance improved in five patients. Five patients developed gallstones while on treatment. In summary, this study reports the long-term efficacy of the depot somatostatin analogs as either adjuvant or primary therapy. Although overall glucose tolerance did not change, the development of impaired glucose tolerance in three patients at a time when GH levels were not changing highlights the ongoing need to monitor the long-term safety of these preparations.

Acromegaly↗
PubMed2002

Clinical review 142: cardiac dysrhythmias and thyroid dysfunction: the hidden menace?

Thyrotoxicosis is often perceived as a reversible disorder without long-term consequences, perhaps because of the availability of effective treatments, but recent evidence suggests that there may, in fact, be adverse outcomes. Long-term follow-up studies have revealed increased mortality from cardiovascular and cerebrovascular disease in those with a past history of overt hyperthyroidism treated with radioiodine as well as in those with subclinical hyperthyroidism indicated by a low serum TSH concentration. Thyroid hormones exert direct effects on the myocardium as well as the systemic vasculature predisposing to dysrhythmias, especially supraventricular. Effects of thyroid hormones on the autonomic nervous system may also contribute to arrhythmogenesis. Atrial fibrillation is a recognized complication of hyperthyroidism that predisposes to embolic events. Development of atrial fibrillation, together with other supraventricular dysrhythmias (both clinically obvious and those detected only by Holter monitoring) in those with hyperthyroidism may account for increased vascular mortality. Improved detection of supraventricular dysrhythmias and therapeutic intervention (e.g. anticoagulants, antiarrhythmics) may improve the long-term vascular prognosis, but their role remains to be established in large therapeutic trials.

Arrhythmias, Cardiac↗
PubMedDate not supplied

Growth hormone--from molecule to mortality.

Growth hormone (GH) acts predominantly via insulin-like growth factor-I (IGF-I) expression. Acromegaly is associated with an increased mortality which can be reversed by optimal treatment. Somatostatin analogues are effective adjunctive therapies in patients treated with surgery and/or radiotherapy and result in tumour shrinkage in many patients. Pegvisomant is a GH analogue which inhibits functional dimerization of GH receptors, inhibits GH activity and normalizes IGF-I in over 90% of subjects. Adult GH deficiency is associated with changes in body composition, insulin status, lipid profile and Quality of Life measures. Hypopituitarism is associated with an increased mortality. Replacement with GH has clinically beneficial effects but there are no data on effects on mortality. Taller individuals are at a 20-60 percent increased risk of a range of cancers, an effect that may be mediated via IGFs. These observations suggest that there is an optimal level of circulating GH and IGF-I required to maintain normal health.

Acromegaly↗