Medical and surgical management of obesity and diabetes: what's new?

We conducted a narrative review of the medical and surgical management of people with obesity and diabetes. Results of this review showed that a 5-10% loss in body weight can be achieved with a change in lifestyle, diet and behaviour and with approved pharmacological therapies in people with obesity and diabetes. New targeted therapies are now available for patients with previously untreatable genetic causes of obesity. Compared to medical treatment, metabolic and bariatric surgery is associated with significantly higher rates of remission from type 2 diabetes and lower rates of incident macrovascular and microvascular complications and mortality. The National Institute for Health and Care Excellence and the American Diabetes Association endorse metabolic and bariatric surgery in obese adults with type 2 diabetes and there may also be a role for this in obese individuals with type 1 diabetes. The paediatric committee of the American Society for Metabolic and Bariatric Surgery have recommended metabolic and bariatric surgery in obese adolescents with type 2 diabetes. Earlier and more aggressive treatment with metabolic and bariatric surgery in obese or overweight people with diabetes can improve morbidity and mortality.

"Hidden" bone metastasis from thyroid carcinoma: a clinical note.

The (131)I-iodide ((131)I) whole-body scan, for thyroid carcinoma is at times difficult to interpret. In a diagnostic whole body (131)I scan of a patient with follicular carcinoma, a posterior skull lesion was partially hidden by overlapping facial structures. On lateral head view, the abnormality was clearly evident. SPECT/CT and MRI showed the lesion originated in the occipital bone and had enlarged into the posterior fossa. The mass was surgically removed and the patient received (131)I therapy for residual tissue. The study demonstrates a pitfall in the reading of two dimensional radioiodine images which can be overcome by SPECT or lateral imaging.

The impact of age and gender on papillary thyroid cancer survival.

CONTEXT: Thyroid cancer predominately affects women, carries a worse prognosis in older age, and may have higher mortality in men. Superimposed on these observations is the fact that most women have attained menopause by age 55 yr. OBJECTIVE: The objective of the study was to determine whether men contribute disproportionately to papillary thyroid cancer (PTC) mortality or whether menopause affects PTC prognosis. DESIGN: Gender-specific mortality was normalized using age-matched subjects from the U.S. population. Multivariate Cox proportional hazard regression models incorporating gender, age, and National Thyroid Cancer Treatment Cooperative Study Group stage were used to model disease-specific survival (DSS). PARTICIPANTS AND SETTING: Patients were followed in a prospective registry. MAIN OUTCOME MEASURE: The relationships between gender, age, and PTC outcomes were analyzed. RESULTS: The unadjusted hazard ratio (HR) for DSS for women was 0.40 [confidence interval (CI) 0.24-0.65]. This female advantage diminished when DSS was adjusted for age at diagnosis and stage with a HR encompassing unity (HR 0.72, CI 0.44-1.19). Additional multivariate models of DSS considering gender, disease stage, and various age groupings showed that the DSS for women diagnosed at under 55 yr was improved over men (HR 0.33, CI 0.13-0.81). However, the HR for DSS increased to become similar to men for women diagnosed at 55-69 yr (HR 1.01, CI 0.42-2.37) and at 70 yr or greater (HR 1.17, CI 0.48-2.85). CONCLUSIONS: Although the overall outcome of women with PTC is similar to men, subgroup analysis showed that this composite outcome is composed of two periods with different outcomes. The first period is a period with better outcomes for women than men when the diagnosis occurs at younger than 55 yr; the second is a period with similar outcomes for both women and men diagnosed at ages greater than 55 yr. These data raise the question of whether an older age cutoff would improve current staging systems. We hypothesize that older age modifies the effect of gender on outcomes due to menopause-associated hormonal alterations.

Resistance to thyroid hormone in a patient without thyroid hormone receptor mutations.

Resistance to thyroid hormone (RTH) is a clinical syndrome characterized by elevated serum thyroid hormone (TH) levels, unsuppressed thyrotropin (TSH) levels, and tissue hyposensitivity to TH. In almost all cases, the genetic basis of RTH lies in mutation of one of the two TH receptor beta (TRbeta) alleles. Recently, patients from several families with phenotypic manifestations of RTH in the absence of TR mutations have been described. We report a case of a 31-year-old woman who presented with goiter, tachycardia, elevated TH levels, unsuppressed TSH, and "inappropriately normal" levels of peripheral TH action markers. In two separate clinical evaluations, the patient exhibited typical clinical and biochemical evidence for peripheral and pituitary RTH. Surprisingly, reverse transcriptase-polymerase chain reaction (RT-PCR) of full-length TRalpha and TRbeta mRNAs, and genomic PCR using primers flanking exons encoding the carboxy-terminal region of TRbeta failed to demonstrate mutations in the TRalpha or TRbeta genes. It is likely that defects in the regulation of TR genes or mutations in transcriptional cofactors involved in TR signaling account for this patient's phenotype.

Reoperation for hyperparathyroidism in multiple endocrine neoplasia type 1.

BACKGROUND: Patients with multiple endocrine neoplasia type 1 and hyperparathyroidism often undergo multiple operations because of inadequate initial surgery, presence of supernumerary and ectopic glands, regrowth of remnant glands, or autograft hyperfunction. Management of this patient population is complex. METHODS: From January 1975 to December 2000 we performed 94 reoperative parathyroidectomies consisting of 79 neck reexplorations, 12 autograft removals, and 3 median sternotomies in 75 patients. Data were gathered by retrospective chart review and follow-up telephone interviews. RESULTS: Excluding autograft excision, reoperative surgery was successful (normocalcemia longer than 6 months) in 91%; autograft removal was successful in only 58%. With a median follow-up of 59 months, 64% of patients are currently free from hypercalcemia, and this outcome was not influenced by the total number of glands resected. The median time to recurrent hypercalcemia was 125 months. Thirty patients received an autograft after reoperation. The complication rate for all reoperations was 12%, including permanent recurrent laryngeal nerve injury in 2 patients (2.1%). CONCLUSIONS: Reoperative parathyroidectomy in patients with multiple endocrine neoplasia type 1 was safe and successful in the majority of patients; however, recurrent hyperparathyroidism is likely to develop in most individuals beyond 10 years of follow-up. The total number of glands accounted for after reoperation is not associated with successful outcome.

Extreme thyroid hormone resistance in a patient with a novel truncated TR mutant.

Resistance to thyroid hormone (RTH) is a syndrome in which patients have elevated thyroid hormone (TH) levels and decreased sensitivity to its action. We describe a child with extreme RTH and a severe phenotype. A 22-month-old female presented to the NIH with goiter, growth retardation, short stature, and deafness. Additionally, the patient had hypotonia, mental retardation, visual impairment, and a history of seizures. Brain magnetic resonance imaging showed evidence of demyelination and bilateral ventricular enlargement. The patient had markedly elevated free T3 and free T4 levels of more than 2000 pg/dl (normal, 230-420 pg/dl) and more than 64 pmol/liter (normal, 10.3-20.6 pmol/liter), respectively, and TSH of 6.88 mU/liter (normal, 0.6-6.3 mU/liter). These are the highest TH levels reported for a heterozygous RTH patient. A T3 stimulation test confirmed the diagnosis of RTH in the pituitary and peripheral tissues. Molecular analyses of the patient's genomic DNA by PCR identified a single base deletion in exon 10 of her TRbeta gene that resulted in a frameshift and early stop codon. This, in turn, encoded a truncated receptor that lacked the last 20 amino acids. Cotransfection studies showed that the mutant TR was transcriptionally inactive even in the presence of 10(-6) M T3 and had strong dominant negative activity over the wild-type receptor. It is likely that the severely defective TRbeta mutant contributed to the extreme RTH phenotype and resistance in our patient.

Multiple leiomyomas of the esophagus, lung, and uterus in multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant hereditary disorder characterized by multiple parathyroid, pancreatic, duodenal, and pituitary neuroendocrine tumors. Nonendocrine mesenchymal tumors, such as lipomas, collagenomas, and angiofibromas have also been reported. MEN1-associated neuroendocrine and some mesenchymal tumors have documented MEN1 gene alterations on chromosome 11q13. To test whether the MEN1 gene is involved in the pathogenesis of multiple smooth muscle tumors, we examined the 11q13 loss of heterozygosity (LOH) and clonality patterns in 15 leiomyomata of the esophagus, lung, and uterus from five patients with MEN1. Forty sporadic uterine leiomyomata were also studied for 11q13 LOH. LOH analysis was performed using four polymorphic DNA markers at the MEN1 gene locus; D11S480, PYGM, D11S449, and INT-2. 11q13 LOH was detected in 10 of 12 (83%) MEN1-associated esophageal and uterine smooth muscle tumors. In contrast, LOH at the MEN1 gene locus was demonstrated only in 2 of 40 (5%) sporadic uterine tumors. LOH at 11q13 was not documented in three lung smooth muscle tumors from a single patient with MEN1. Ten tumors from two female patients were additionally assessed for clonality by X-chromosome inactivation analysis. The results demonstrated different clonality patterns in multiple tumors in the same organ in each individual patient. The data indicate that leiomyomata of the esophagus and uterus in MEN1 patients arise as independent clones, develop through MEN1 gene alterations, and are an integral part of MEN1. However, the MEN1 gene is not a significant contributor to the tumorigenesis of sporadic uterine leiomyomata.

Low concentrations of the histone deacetylase inhibitor, depsipeptide (FR901228), increase expression of the Na(+)/I(-) symporter and iodine accumulation in poorly differentiated thyroid carcinoma cells.

Thyroid carcinoma accounts for the majority of deaths from endocrine cancers. A major cause of treatment failure is the inability to trap iodine. Chemotherapeutic agents with differentiating properties have been tried in an attempt to increase iodine uptake. We examined the ability of the novel histone deacetylase (HDAC) inhibitor, depsipeptide (FR901228), to modulate the expression of thyroid-specific genes. Four cell lines, two derived from follicular thyroid carcinomas (FTC 133 and FTC 236) and two derived from anaplastic thyroid carcinomas (SW-1736 and KAT-4) were used. In these four cell lines, a very low concentration of depsipeptide (1 ng/mL) increased histone acetylation and expression of both thyroglobulin and the Na(+)/I(-) symporter messenger RNAs. After 3 days, messenger RNA levels approached those of a normal thyroid control. Depsipeptide induced increases in (125)I accumulation indicated that a functional Na(+)/I(-) symporter protein was induced. Transient transfections indicate that the effects are mediated at least in part by a trans-activating factor. These in vitro results suggest that depsipeptide or other histone deacetylase inhibitors might be used clinically in thyroid carcinomas that are unable to trap iodine as an adjunct to radioiodine therapy.

Multiple endocrine neoplasia type 1: new clinical and basic findings.

Multiple endocrine neoplasia type 1 (MEN1) provides a prime example of how a rare disease can advance our understanding of basic cell biology, neoplasia and common endocrine tumors. MEN1 is expressed mainly as parathyroid, enteropancreatic neuroendocrine, anterior pituitary and foregut carcinoid tumors. It is an autosomal dominant disease caused by mutation of the MEN1 gene. Since its identification, the MEN1 gene has been implicated in many common endocrine and non-endocrine tumors. This is a brief overview of recent scientific advances relating to MEN1, including newly recognized clinical features that are now better characterized by genetic analysis, insights into the function of the MEN1-encoded protein menin, and refined recommendations for mutation testing and tumor screening, which highlight our increasing understanding of this complex syndrome.

Repaglinide-induced factitious hypoglycemia.

We report the first case of repaglinide-induced factitious hypoglycemia in a young male. This case posed a challenging diagnostic dilemma because commercial assays for repaglinide are not available. Furthermore, the patient had a series of positive diagnostic tests such as high proinsulin and localizing intra-arterial calcium stimulation suggestive of insulinoma. This case, again, demonstrates the importance of pure clinical judgment in the face of often-conflicting laboratory data in making a correct diagnosis and the requirement of definitive data for an appropriate therapeutic resolution.

Effectiveness of long-acting octreotide in suppressing hormonogenesis and tumor growth in thyrotropin-secreting pituitary adenomas: report of two cases.

BACKGROUND: The subcutaneous (s.c.) administration of somatostatin analogs, such as octreotide acetate (SMS) and lanreotide, in patients with thyrotropin (TSH)-secreting pituitary adenomas (TSPA's)--thyrotropinomas with residual tumor after initial surgical therapy is effective in controlling hyperthyroidism, as well as curtailing tumor growth in the majority of patients. Long-acting preparations of the above agents, i.e. SMS-LAR and lanreotide-SR, have been synthesized and can be administered as depot injections intramuscularly (i.m.) at intervals of several weeks. Recent studies have reported on preliminary data regarding the use of such preparations in patients with TSPA's. MATERIALS AND METHODS: We present two cases of TSPA's with residual tumor following transsphenoidal adenomectomy. Neither of the two patients underwent external beam pituitary irradiation. The presence and extent of tumoral TSH hypersecretion was assessed by standard biochemical and dynamic endocrine testing, while tumor size was evaluated by conventional radiographic techniques. RESULTS: In both patients, TSH secretion was effectively suppressed by SMS-LAR. Moreover, administration of this compound halted further tumor growth, as well as resulted in improved patient comfort, for 12 and 10 months respectively. CONCLUSION: Our date corroborate earlier reports on the usefulness of SMS-LAR in the medical management of patients with TSPA's who have residual disease after initial pituitary surgery and/or irradiation.

Ultrasound and sestamibi scan as the only preoperative imaging tests in reoperation for parathyroid adenomas.

BACKGROUND: In an effort to determine an efficient algorithm for the evaluation of patients with parathyroid adenomas in the reoperative setting, we explored the combination of using ultrasound scans (US) and sestamibi scintigraphy as the only preoperative imaging tests. METHODS: We analyzed the outcomes of 62 consecutive patients who were treated between January 1995 and May 1999 and who were referred for persistent primary hyperparathyroidism after initial surgical exploration, at which time no abnormal parathyroid glands had been found. Although all patients underwent US, computed tomography scan, magnetic resonance imaging, and sestamibi scan, we analyzed the success of localization and reoperation using only the results of US and sestamibi scan. RESULTS: Sixty-one patients (98%) underwent curative reoperations. The sensitivity, positive predictive value, and accuracy for US were 90%, 86%, and 84%, respectively; the corresponding values for sestamibi imaging were 78%, 94%, and 74%, respectively. In 58 of 62 cases (94%) preoperative US and/or sestamibi scan accurately identified the adenoma. In 3 patients for whom combined US and sestamibi scan were inaccurate, 1 adenoma was found by intraoperative US in the strap muscle; 1 adenoma was found by blind cervical thymectomy, and 1 adenoma was found by planned sternotomy that was based on computed tomography findings. CONCLUSIONS: This study supports an algorithm of obtaining US and sestamibi scan as the initial and perhaps only preoperative localization tests for patients with primary hyperparathyroidism after failed operation, at which time no abnormal glands had been found.

Forty-eight-hour fast: the diagnostic test for insulinoma.

Insulinoma causes fasting hypoglycemia due to inappropriate insulin secretion. Its diagnosis is based on demonstrating Whipple's triad during a supervised 72-h fast. For 75 yr, the 72-h fast has been the cornerstone for the diagnosis; however, it has never been critically assessed using newer assays for insulin, C peptide, and proinsulin. Thus, the aim of the current study is to assess the need for a full 72-h fast for the diagnosis of insulinoma. Patients with suspected hypoglycemia with documented glucose concentrations below 45 mg/dL were admitted to the NIH. Data obtained during the supervised fast of patients with pathologically proven insulinoma over a 30-yr period (1970-2000) were reviewed. We identified 127 patients with insulinoma. The average age of patients was 42.7 +/- 15.9 yr, with a predominance of females (62%). 107 patients had a benign tumor, 20 had malignant insulinoma, and 15 patients had multiple endocrine neoplasia type 1. The fast was terminated due to hypoglycemia in 44 patients (42.5%) by 12 h, 85 patients (66.9%) by 24 h, and 120 (94.5%) by 48 h. Seven patients fasted beyond 48 h despite subtle neuroglycopenic symptoms and glucose and insulin concentrations diagnostic of insulinoma. Immunoreactive proinsulin was elevated at the beginning of the fast in 90% of 42 patients. Proinsulin in noninsulinoma, in contrast to insulinoma, patients is usually suppressible; therefore, samples taken in the suppressed state have the greatest diagnostic value. We conclude that with the current available insulin and proinsulin assays, the diagnosis of insulinoma can be made within 48 h. Thus, the 48-h fast should replace the 72-h fast in textbooks and hospital protocols as the new diagnostic standard.

Increased levothyroxine requirements presenting as "inappropriate" TSH secretion syndrome in a patient with nephrotic syndrome.

Patients with primary thyroid failure on levothyroxine (LT4) replacement who develop nephrotic syndrome (NS) may rarely present with an increase in LT4 requirements. In this report, we describe a patient with thyroid failure following radioactive iodine ablation for Graves' disease who required an escalation of LT4 doses following the onset of NS. The case presented with disproportionately elevated TSH levels in the presence of normal (or slightly subnormal) thyroid hormone levels, thus, masquerading as a state of "inappropriate" TSH secretion. This pattern of extreme dysregulation in thyroid function indices due to urinary loss of thyroid hormones has not been previously described in NS, and, therefore, extends the spectrum of endocrine manifestations of NS.

Assessing the effects of thyroid suppression on benign solitary thyroid nodules. A model for using quantitative research synthesis.

Systematic review of the available information with a modified, largely quantitative method of research synthesis disclosed that an initial trial of thyroid hormone suppression therapy leads to clinically significant (> or = 50%) reduction of nodule size or arrest of nodule growth in a subset of patients with benign solitary thyroid nodules. In fact, in addition to objective improvements due to decreasing nodule size, L-T4 suppression therapy may benefit patients by reducing perinodular thyroid volume. Consequently, both pressure symptoms and cosmetic complaints may improve (9, 68). Additional studies for the assessment of the risks versus benefits of supraphysiologic doses of L-T4, the optimal level of thyroid suppression and the dose needed to achieve this magnitude of reduction, the optimal length of the initial trial, and the conditions for the continuation of L-T4 thyroid suppression therapy, as well as the identification of markers for patients most likely to respond to this therapy, are warranted. Finally, quantitative assessment of available evidence as described here may be applicable to the review of other controversial issues as well.

Recombinant human thyrotropin for the diagnosis and treatment of a highly functional metastatic struma ovarii.

The optimal treatment of metastatic thyroid cancer that produces high amounts of thyroid hormone has not been well defined. A 46-yr-old woman presented with a follicular thyroid carcinoma arising from a struma ovarii with hepatic metastases. After the removal of both the struma and the thyroid gland, the liver metastases showed evidence of a high degree of hormonogenesis. Brain, chest, abdomen, and bone imaging was negative for additional metastases. Because iodine uptake by most thyroid carcinomas is quite low in the absence of high levels of ambient TSH, we used recombinant human TSH (rhTSH) (Thyrogen) to achieve a concentration of 131I activity in the tumor high enough for a significant cytotoxic effect. After rhTSH administration (0.9 mg im daily for 2 consecutive days), a 131I diagnostic whole body scan confirmed the existence of 17 discrete hepatic foci of 131I uptake. To calculate the amount of 131I that would deliver an absorbed radiation dose that would be optimally cytotoxic to the metastases (>8000 rad/lesion) and not to the normal liver, we performed lesion dosimetry. Analysis of dosimetric data showed that 15 of 17 lesions would receive an adequate radiation dose following the administration of 65 mCi of 131I. Additionally, we performed whole body dosimetry to assure that this dose would not cause bone marrow toxicity. The patient was reevaluated 6 months after therapy; the liver metastases showed significant, but partial, response. In conclusion, we used the combination of rhTSH with lesional and whole body dosimetry for the treatment of highly functional metastases from follicular thyroid carcinoma arising within a struma ovarii. This strategy can be applied to determine a safe and effective dose of 131I for the treatment of any thyroid cancer metastases that produce enough TH to preclude stimulation of endogenous pituitary TSH secretion.

Pituitary macroadenoma in a 5-year-old: an early expression of multiple endocrine neoplasia type 1.

Multiple endocrine neoplasia type 1 (MEN 1) is associated with parathyroid, enteropancreatic, pituitary, and other tumors. The MEN1 gene, a tumor suppressor, is located on chromosome 11. Affected individuals inherit a mutated MEN1 allele, and tumorigenesis in specific tissues follows inactivation of the remaining MEN1 allele. MEN 1-associated endocrine tumors usually become clinically evident in late adolescence or young adulthood, as high levels of PTH, gastrin, or PRL. Because each of these tumors can usually be controlled with medications and/or surgery, MEN 1 has been regarded mainly as a treatable endocrinopathy of adults. Unlike in MEN 2, early testing of children in MEN 1 families is not recommended. We report a 2.3-cm pituitary macroadenoma in a 5-yr-old boy with familial MEN 1. He presented with growth acceleration, acromegaloid features, and hyperprolactinemia. We tested systematically to see whether his pituitary tumor had causes similar to or different from a typical MEN 1 tumor. Germ line DNA of the propositus and his affected relatives revealed a heterozygous point mutation in the MEN1 gene, which leads to a His139Asp (H139D) amino acid substitution. The patient had no other detectable germ-line mutations on either MEN1 allele. DNA sequencing and fluorescent in situ hybridization with a MEN1 genomic DNA sequence probe each demonstrated one copy of the MEN1 gene to be deleted in the pituitary tumor and not in normal DNA, proving MEN1 "second hit" as a tumor cause. Gsalpha mutation, common in nonhereditary GH-producing tumors, was not detected in this tumor. We conclude that this pituitary macroadenoma showed molecular genetic features of a typical MEN 1-associated tumor. This patient represents the earliest presentation of any morbid endocrine tumor in MEN 1. A better understanding of early onset MEN 1 disease is needed to formulate recommendations for early MEN 1 genetic testing.

Results of heterotopic parathyroid autotransplantation: a 13-year experience.

BACKGROUND: The reported success of heterotopic parathyroid autotransplantation (HPA) in patients with primary hyperparathyroidism varies from 20% to 60%. The purpose of this study was to evaluate our results with HPA to help define its role in this patient group. METHODS: Between July 1985 and June 1998, 44 patients underwent 51 HPA procedures at our institution. Twenty to 25 fragments of parathyroid tissue measuring 1 to 3 mm3 each were placed into the forearm musculature. HPA results were scored as nonfunctional (requiring calcium and vitamin D), partially functional (normocalcemia on calcium alone), fully functional (normocalcemia without supplementation), or hyperfunctional (hypercalcemia without supplementation). RESULTS: Follow-up data were available for 39 patients who underwent 46 autografts (20 immediate and 26 cryopreserved). With a median follow-up of 35 months, 19 autografts (41%) were nonfunctional; 9 autografts (20%) were partially functional; 15 autografts (33%) were fully functional, and 3 autografts (7%) were hyperfunctional. Full function was observed in 35% of immediate and 31% of delayed autografts. CONCLUSIONS: One third of parathyroid autografts develop full function, and an additional one fifth develop partial function. Recurrent hyperparathyroidism is uncommon. No benefit was observed from immediate versus delayed HPA, and the modest success rate of HPA suggests that improvements in technique are warranted.