Sethu Reddy

Value of repeating a nondiagnostic thyroid fine-needle aspiration biopsy.

OBJECTIVE To assess the value of repeating a biopsy when the initial thyroid fine-needle aspiration (FNA) biopsy is nondiagnostic. METHODS Between 1990 and 2003, 4,311 thyroid FNAs were performed at the Cleveland Clinic Foundation, of which 220 (5%) were nondiagnostic. Among 189 patients whose medical records were available for retrospective review, 106 underwent a repeated FNA (FNA #2), and 14 had a second repeated FNA (FNA #3). Thyroid ultrasonography was used in the evaluation in 113 FNAs. RESULTS The first and second repeated FNAs were diagnostic in 58% (62 of 106 patients) and 50% (7 of 14 patients), respectively. The rate of malignant disease in patients with no repeated FNAs versus 1 or more repeated FNAs was 4.8% (4 of 83) versus 11.3% (12 of 106), respectively. Ultrasound-guided FNA yielded a diagnosis among 33 of 113 biopsies (29.2%), and FNA without ultrasound guidance provided a diagnosis in 30 of 159 biopsies (18.9%). Thus, the use of thyroid ultrasonography significantly improved the likelihood of establishing a diagnosis (P = 0.017). We found that repeating the FNA up to 2 times provides a diagnosis in up to 60% of cases. CONCLUSION The overall prevalence of thyroid cancer in patients with nondiagnostic FNA is not trivial--8.5% in our study group of 189 patients. An aggressive approach toward nondiagnostic FNA biopsies is recommended, with performance of at least 2 repeated FNA biopsies, preferably with the help of ultrasound guidance.

Management of nondiagnostic thyroid fine-needle aspiration biopsy: survey of endocrinologists.

OBJECTIVE To evaluate the approach of endocrinologists in the setting of nondiagnostic thyroid fine-needle aspiration (FNA) biopsies. METHODS In 2002, we surveyed physicians attending the national annual meetings of the American Association of Clinical Endocrinologists and the Endocrine Society of North America, using a 13-item questionnaire. The responses were tallied and analyzed. RESULTS Of the 143 respondents, 139 were endocrinologists, with a male:female ratio of 2.5:1. Most respondents were involved in a medical practice in North America, but Europe, Asia, New Zealand, and Australia were also represented. Of those performing thyroid FNA biopsy, 31% used thyroid ultrasound guidance. Among the survey respondents, 16%, 49%, 20%, and 15% performed less than 2, 2 to 5, 6 to 10, and more than 10 thyroid FNA biopsies per month, respectively. Among the respondents, 13.5%, 44%, 28.5%, 10%, and 4% had non-diagnostic rates of less than 5%, 5 to 10%, 11 to 20%, 21 to 30%, and more than 30%, respectively. The approach of the respondents to an initially nondiagnostic FNA was repeated FNA biopsy in 87%, observation in 7%, levothyroxine suppression in 4%, and thyroid scintigraphy in 2%. Respondents believed that the most cost-effective approach in a patient with nondiagnostic FNA was repeated biopsy (82%), monitoring the size of the thyroid nodule (17%), and surgical referral (<1%). No one was willing to repeat the thyroid biopsy more than three times. CONCLUSION On the basis of findings in our survey, most endocrinologists repeat thyroid FNA at least once when confronted with a nondiagnostic result. No published studies have demonstrated the cost-effectiveness of this approach versus proceeding to surgical intervention or observation. We hope that this survey will encourage further studies on this issue.

Role of metabolically active hormones in the insulin resistance associated with short-term glucocorticoid treatment

BackgroundThe mechanisms by which glucocorticoid therapy promotes obesity and insulin resistance are incompletely characterized. Modulations of the metabolically active hormones, tumour necrosis factor alpha (TNF alpha), ghrelin, leptin and adiponectin are all implicated in the development of these cardiovascular risk factors. Little is known about the effects of short-term glucocorticoid treatment on levels of these hormones.Research methods and proceduresUsing a blinded, placebo-controlled approach, we randomised 25 healthy men (mean (SD) age: 24.2 (5.4) years) to 5 days of treatment with either placebo or oral dexamethasone 3 mg twice daily. Fasting plasma TNFα, ghrelin, leptin and adiponectin were measured before and after treatment.ResultsMean changes in all hormones were no different between treatment arms, despite dexamethasone-related increases in body weight, blood pressure, HDL cholesterol and insulin. Changes in calculated indices of insulin sensitivity (HOMA-S, insulin sensitivity index) were strongly related to dexamethasone treatment (p < 0.001).DiscussionOur data do not support a role for TNF alpha, ghrelin, leptin or adiponectin in the insulin resistance associated with short-term glucocorticoid treatment.

AUTOANTIBODIES TO IA-2 AND GAD65 IN PATIENTS WITH TYPE 2 DIABETES MELLITUS OF VARIED DURATION: PREVALENCE AND CORRELATION WITH CLINICAL FEATURES

OBJECTIVE To determine the prevalence of autoantibodies to IA-2 (IA-2Ab) and glutamic acid decarboxylase (GADAb) in type 2 diabetes, their relationship to disease duration, and their importance in management decisions. METHODS We undertook a study of 101 patients with type 2 diabetes (defined as nonketotic hyperglycemia at diagnosis) of varied duration (median, 4 years). Results were compared with those from 36 patients with type 1 diabetes also of varied duration (median, 2 years). IA-2Ab and GADAb were measured by radioligand-binding assays with use of in vitro-synthesized, 35S-labeled antigens. RESULTS Of the 101 patients with type 2 diabetes, 20 (20%) were positive for GADAb; only 4 of these 20 were positive for IA-2Ab. In comparison, 75% of patients with type 1 diabetes were positive for GADAb, IA-2Ab, or both (P<0.0001). The coincidence of IA-2Ab positivity in GADAb-positive patients with type 2 diabetes was significantly lower than in patients with type 1 diabetes (20% versus 73%, respectively; P = 0.002). All four IA-2Ab- and GADAb-positive patients with type 2 diabetes required insulin and were younger than those positive for GADAb alone (P = 0.018). GADAb positivity in patients with type 2 diabetes was highly associated with insulin requirement (P = 0.004), with an odds ratio of 5.8 in predicting insulin dependence. Among patients with type 2 diabetes receiving insulin therapy, disease duration was significantly shorter (P = 0.025) and body mass index was significantly lower (P<0.001) in GADAb-positive versus GADAb-negative patients. In contrast to type 1 diabetes, in which GADAb values were negatively correlated with disease duration (r = -0.34; P = 0.044), no significant correlation with disease duration was observed in type 2 diabetes (r = -0.166; P = 0.48). CONCLUSION Irrespective of duration of disease, measurement of IA-2Ab and GADAb can help to identify those patients with type 2 diabetes most likely to require insulin therapy.

A Simple Screening Method for Individuals at Risk of Developing Type 1 Diabetes: Measurement of Islet Cell Autoantibodies (GADA, IA-2A, and IAA) on Dried Capillary Blood Spots Collected on Filter Paper

There is limited information regarding the use of dried capillary blood spots collected on a filter paper (FP) to test for islet cell antibodies. The aim of this study was to validate the use of dried capillary blood spots collected on a FP for the analysis of islet cell antibodies. FP eluates were tested using both single and combined assay for antibodies to glutamic acid decarboxylase (GADA) and/or to the protein tyrosine phosphatase like IA-2 (IA-2A), and a single assay for antibodies to insulin (IAA). The results were compared with those of serum assays. Ninety-one subjects were studied. Forty had Type 1 diabetes mellitus (T1DM) and 51 were first-degree relatives (FDR) of patients with T1DM. The GADA and IA-2A were measured by radio-binding assays, which utilize 35S-labeled GAD65 and IA-2. IAA was measured by a microtiter plate assay using 125I-labeled insulin. Twenty-six of those with T1DM (65%) and 5 of the FDRs (10%) had at least 1 positive test on the single serum assays. The FP combi-assay for GADA and IA-2A had 97.8% concordance rate when compared with serum single assays for GADA and IA-2A. The concordance rate for individual assays were 96.7% for GADA, and 100% for both IA-2A and IAA There was significant correlation of the antibody levels between FP and serum specimen for all 3 antibodies. We conclude that antibody screening performed using dried capillary blood spots collected on a FP correlates well with serum assays, and provides an easy alternative for population screening.

ADVANCES IN THE TREATMENT OF DIABETES MELLITUS IN THE ELDERLY : DEVELOPMENT OF INSULIN ANALOGUES

SummaryCurrent insulin therapy only crudely mimics physiological secretion of insulin. Part of this difficulty is related to the hexameric structure of pharmacological preparations of insulin. This structure delays the absorption of insulin from the injection site, results in changes in the time to peak insulin action, and causes changes in its duration of action as a function of changing dosage. These changes occur with both regular and intermediate acting insulin.Insulin analogues, which are monomeric, will have a faster onset of action (more closely approximating endogenous insulin) and greater reproducibility of effect. Insulin analogues with low isoelectric points may provide more stable basal delivery as support to endogenous insulin production (i.e. monotherapy) or in conjunction with prandial insulins or oral agent therapy. The main advantages of these preparations in elderly diabetic patients may be a reduced risk of hypoglycaemia, improved predictability of response, and greater flexibility in more frail elderly patients, such as those with variable oral intake or compromised renal function.

METASTATIC MALIGNANT INSULINOMA IN A PATIENT WITH TYPE 2 DIABETES MELLITUS: CASE PRESENTATION AND LITERATURE REVIEW

OBJECTIVE To describe the occurrence of metastatic malignant insulinoma in a patient with preexisting type 2 diabetes mellitus. METHODS We present a detailed case report, with clinical, biochemical, and imaging findings, and summarize the data from 21 similar cases in the literature. RESULTS The occurrence of malignant insulinoma in a patient with preexisting diabetes is very rare and thus can be a diagnostic challenge. In our patient with type 2 diabetes, endogenous hyperinsulinism was confirmed by demonstrating elevated insulin and C-peptide levels during hypoglycemic episodes in the absence of sulfonylurea on a blood screen. Abdominal computed tomographic scan and magnetic resonance imaging revealed a pancreatic mass as well as metastatic lesions in the liver. The pancreatic mass was removed and confirmed to be a malignant insulinoma. This procedure was followed by disappearance of the hypoglycemic episodes as well as the diabetes for a few months. On follow-up, however, more metastatic lesions appeared in conjunction with a protracted course of hypoglycemia that necessitated treatment with antihypoglycemic agents and, 3 years after the initial surgical intervention, culminated in the death of the patient. CONCLUSION Our patient is one of the few subjects known to have a malignant insulinoma in conjunction with preexisting diabetes. A high degree of suspicion for the presence of an insulinoma should be maintained when unexplained hypoglycemic episodes occur in a patient with previously stable diabetes.

AGING, DIABETES, AND FALLS

KEY POINTS Falls are a major health issue for older adults, leading to adverse events and even death. Older persons with type 2 diabetes are at increased risk of falling compared to healthy adults of a similar age. Over 400 factors are associated with falls risk, making identification and targeting of key factors to prevent falls problematic. However, the major risk factors include hypertension, diabetes, pain, and polypharmacy. In addition to age and polypharmacy, diabetes-related loss of strength, sensory perception, and balance secondary to peripheral neuropathy along with decline in cognitive function lead to increased risk of falling. Designing specific interventions to target strength and balance training, reducing polypharmacy to improve cognitive function, relaxation of diabetes management to avoid hypoglycemia and hypotension, and relief of pain will produce the greatest benefit for reducing falls in older persons with diabetes. Abbreviation: DPN = diabetic polyneuropathy.

Poor correlation of serum alpha-subunit concentration and magnetic resonance imaging following pituitary surgery in patients with nonfunctional pituitary macroadenomas.

OBJECTIVE To review the clinical utility of measuring serum alpha-subunit as a marker for residual tumor in a group of patients with surgically resected nonfunctional pituitary adenomas. METHODS In this retrospective cross-sectional chart review using the pituitary database at the Cleveland Clinic, we identified patients with nonfunctional pituitary macroadenomas over a 4-year period (2000-2004) and selected those patients who had an elevated alpha-subunit concentration measured before pituitary surgery. Presurgery and post-surgery measurements of alpha-subunit, luteinizing hormone, follicle-stimulating hormone, and thyroid-stimulating hormone were documented. Findings from preoperative and postoperative pituitary magnetic resonance imaging (MRI) were reviewed. RESULTS We identified 54 patients who were evaluated for nonfunctional pituitary macroadenomas during the study period. Of the 39 who underwent pituitary surgery, 34 had a serum alpha-subunit concentration measured before surgery. Eight of 34 patients had elevated preoperative alpha-subunit levels with a median value of 1.8 ng/mL (range, 1.0-3.4 ng/mL). Of the 8 patients, 7 had follow-up MRI a median of 12 months (range, 6-52 months) after surgery. One patient was lost to follow-up. Three of 7 patients had persistently elevated alpha-subunit levels postoperatively; in 2 of these 3, MRI did not identify residual tumor. Among the 4 patients with postoperative normalization of alpha-subunit, 2 patients had residual tumor on MRI. CONCLUSION The discrepancy between alpha-subunit levels and postoperative MRI calls into question the value of routine alpha-subunit measurement as a tumor marker in patients with nonfunctional pituitary macroadenomas.

Rushing to Wholistic Diabetes Care

Diabetes continues to be a challenge to all aspects of our society. In both direct and indirect costs, diabetes has a disproportionate amount attributed to it. It is in everyone’s interest to support improved diabetes management. Though the onslaught of diabetes has been compared to a tsunami, in truth, unlike a tsunami lasting for a day, the diabetes waves are likely to go on for decades. For the practitioner, the diagnosis is only the first step. Earlier diagnosis and advances in treatment are necessary to prevent the long-term complications of diabetes. We’re also learning more about the natural history of diabetes, the genetic risk factors, and nutritional factors so that we may be able to develop preventive approaches. We must not forget that diabetes is not just a gluco-centric disorder but a metabolic disorder. To stress this point, nonalcoholic steatohepatitis (NASH) is proving to be as prevalent in our society as type 2 diabetes. The hope is that earlier recognition and treatment of NASH will also ameliorate the tsunami of diabetes. The fascinating conditions of lipodystrophies also give us valuable insights in to the link between fat metabolism and glucose regulation. Nutrition therapy of diabetes is an evolving concept, with periodic fine-tuning based on the latest research. Nutrition remains the cornerstone of diabetes management. Metformin has been available before many of our colleagues were born and has come to be regarded as the foundational therapy for type 2 diabetes. It behooves us all to reflect on the history of metformin and its clinical utility. Insulin has been around for almost a hundred years, and there continues to be “tweaking” of the insulin molecule and its formulations to make it more practical and predictable. With all of the new treatments available for type 2 diabetes, some wonder if we need any more therapies. Clearly, there are still unmet needs, and the Holy Grail for diabetes therapy is an agent that can prevent the b-cell burnout and dramatically change the natural history of type 2 diabetes.