David Olchovsky

Complex Drug-drug-disease Interactions Between Amiodarone, Warfarin, and the Thyroid Gland

Abstract: Many patients with cardiac arrhythmias require concomitant therapy with warfarin and amiodarone. Beyond the predictable pharmacokinetic drug-drug interaction requiring a significant warfarin dose reduction, the iodine-rich amiodarone affects the thyroid gland, causing overt hypothyroidism or thyrotoxicosis in 14%-18% of cases. In turn, thyroid disorders may affect warfarin sensitivity, with hypothyroidism and thyrotoxicosis resulting in increased or decreased warfarin requirements, respectively. We describe 3 patients on concomitant amiodarone and warfarin who developed amiodarone-induced thyrotoxicosis heralded by a significant decrease in warfarin requirements. We review the literature on the mechanisms of the complex drug-drug and drug-disease interactions within the thyroid gland, warfarin, and amiodarone triad. Given that significant thyroid disorders may be only mildly symptomatic and thus may escape clinical detection, we suggest that thyroid function should be tested in any patient with otherwise unexplained changes in warfarin dose requirements, particularly if concomitantly treated with amiodarone.

Association of Serum Uric Acid and Cardiovascular Disease in Healthy Adults

Studies in different populations with high risk for cardiovascular disease (CVD) have shown an association between serum uric acid (SUA) and CVD. However, only a few studies have demonstrated such an association in healthy populations. The aim of this study was to investigate the association between SUA and CVD in a cohort of men and women without diabetes or CVD. A retrospective study was conducted, with a mean 4.8-year follow-up. The outcome was the occurrence of a cardiovascular event, defined as the diagnosis of ischemic heart disease, acute coronary syndrome, acute myocardial infarction, or ischemic stroke. Mean SUA levels were 6.2 ± 1.1 mg/dl for men (n = 6,580) and 4.4 ± 1.1 mg/dl for women (n = 2,559). For women, the rate of CVD occurrence was 11.6% for the highest quartile of SUA level, compared with 5.0% to 6.5% for the lower 3 quartiles. For men, the rate of CVD occurrence was 14.0% for the highest quartile of SUA level, compared with 10.8% for the lowest quartile. The hazard ratio for CVD, adjusted for age, serum creatinine level, body mass index, systolic blood pressure, low-density lipoprotein cholesterol level, triglyceride level, plasma fasting glucose, physical activity, cardiovascular family history, use of diuretics, and current smoking, was 1.24 (95% confidence interval 1.08 to 1.41) for women and 1.06 (95% confidence interval 1.00 to 1.13) for men (p for interaction = 0.04). In conclusion, the strong association of SUA levels with CVD in women, compared with the much lesser degree in men, highlights the necessity of stratifying by gender in investigations of cardiovascular risk factors and supports exploration of SUA as a marker of CVD risk in healthy populations.

Thyrotropin Suppression by Thyroid Hormone Replacement is Correlated with Thyroxine Level Normalization in Central Hypothyroidism

We have retrospectively studied 41 patients with hypothalamic-pituitary disease and central hypothyroidism associated with hypopituitarism. Sixteen patients had nonsecreting pituitary macroadenoma, whereas different sellar and suprasellar pathologies affected all other patients. Pretreatment thyrotropin (TSH) level (mean +/- standard error of the mean [SEM]) was 2.04 +/- 0.25 mU/L (normal, 0.4-4), and gradually decreased to 0.51 +/- 0.19 mU/L (range, 0.009-3.38) by treatment with levothyroxine in a mean dose of 86 +/- 6 microg/d. TSH was suppressed by thyroid replacement to less than 0.5 mU/L in 80% of patients. Mean baseline free thyroxine (FT4) was 7.55 +/- 0.51 pmol/L (normal, 11.8-24.6) and gradually increased with thyroid hormone to 15.19 +/- 1.0 pmol/L, whereas total thyroxine (TT4) increased from 57.4 +/- 2.6 to 104.4 +/- 5.0 nmol/L (normal, 77-154). Mean pretreatment total triiodothyronine (TT3) was 1.44 +/- 0.09 nmol/L (normal, 1.1-2.7), and was not altered by treatment. Thyrotropin-releasing hormone (TRH) test was performed in 20 patients before thyroid replacement, and mean baseline and peak TSH levels were 1.33 +/- 0.3 and 7.14 +/- 1.62 mU/L, respectively. In 5 subjects TSH was stimulated to 6 mU/L or more, whereas in 5 others TSH was not affected. Based on linear regression of logarithm (Ln) TSH against FT4, a leftward shift of the TSH/FT4 ratio was demonstrated in patients with central hypothyroidism compared to 17 patients with primary hypothyroidism. Plotting measurements of TSH against FT4 for 6 individuals with central hypothyroidism showed different regression slope for each patient. Suppression of TSH by thyroid replacement to levels below 0.1 mU/L predicted euthyroidism in 92% of cases, compared to 34% when TSH was above 1 mU/L (p < 0.0001). In conclusion, in central hypothyroidism baseline TSH is usually within normal values, and is further suppressed by exogenous thyroid hormone as in primary hypothyroidism, but to lower levels. Thus, insufficient replacement may be reflected by inappropriately elevated TSH levels, and may lead to dosage increment.

Efficacy of long-term lanreotide treatment in patients with acromegaly

We investigated the effectiveness of lanreotide for the treatment of active acromegaly in a retrospectively multicenter case series including 53 patients (24 male, 29 female; mean age at diagnosis, 49.5xa0±xa013.9xa0years) with acromegaly treated with lanreotide in nine different centers. Mean tumor diameter was 20xa0±xa013xa0mm; mean basal levels of growth hormone (GH) and insulin-like growth factor I (IGF-I) were 21.3xa0±xa026.3 and 579xa0±xa0177xa0μg/l, respectively. The primary mode of treatment was surgery in 70% of patients. Twenty-nine patients received only lanreotide (Prolonged Release, Autogel), whereas 24 subjects were also treated with octreotide at another treatment stage. Primary therapy with lanreotide was administered in five patients. Maximal monthly dose of lanreotide Autogel (nxa0=xa044) was 60xa0mg in 45%, 90xa0mg in 26%, 120xa0mg in 21% and 180xa0mg in 8%. During 36xa0months of lanreotide treatment, mean IGF-I levels decreased from 443xa0±xa0238 to 276xa0±xa0147xa0μg/l (Pxa0<xa00.001), and mean GH levels, from 5.2xa0±xa06.4 to 3.2xa0±xa03.0xa0μg/l (Pxa0<xa00.001). IGF-I levels normalized in 51% of patients and decreased by >50% towards normal in 32%; the normalization rate was higher in women (65%) than men (33%, Pxa0=xa00.04). Safe random GH levels (≤2xa0μg/l) were achieved in 49% of patients. Both IGF-I normalization and safe GH levels were reached in 32% of the cohort. Lanreotide is an effective treatment for active acromegaly. Female sex was associated with higher rates of IGF-I normalization.

The association between serum uric acid and diabetes mellitus is stronger in women.

OBJECTIVEnPrevious studies have demonstrated an association between increased serum uric acid (SUA) levels and incident diabetes. Most clinical and epidemiological investigations, however, focused solely on male populations or did not analyze men and women separately. We assessed the association between SUA levels and diabetes incidence in a large cohort of apparently healthy men and women.nnnMETHODSnData were retrospectively gathered from 9140 adults who participated in annual medical screening visits during 2000-2009. Mean follow-up time was 4.8 years, and the median age was 50 years. Laboratory test results, data from physical examinations, medical history, and lifestyle information were extracted. The main outcome measure was incident diabetes, defined as two consecutive fasting glucose tests higher than 125 mg/dL. Cox proportional-hazards multivariate models were applied for measuring hazard ratios (HRs) for diabetes according to continuous and categorical levels of uric acid.nnnRESULTSnWe identified 499 new cases of diabetes (total, 5.5%: men, 6.2%; women, 3.6%) during the follow-up period. The gender-specific HRs for diabetes, adjusted for age and a set of prespecified multiple risk and protective factors, were 1.57 for each 1 mg/dL increase in SUA (95% confidence interval [CI], 1.32-1.86) in women and 1.08 (95% CI, 0.99-1.17) in men; p for interaction of SUA by gender <0.001.nnnCONCLUSIONnSUA is independently associated with diabetes outcome, considerably more in women than in men.

Differences in Heart Rate Profile During Exercise Among Subjects with Subclinical Thyroid Disease

BACKGROUNDnClinical thyroid disease is associated with changes in the cardiovascular system, including changes in heart rate during exercise. However, data on the relation between subclinical thyroid disease (SCTD) and heart rate during exercise are limited.nnnMETHODSnWe investigated 3799 apparently healthy subjects who were evaluated in the Institute for Preventive Medicine at the Sheba Medical Center. All subjects answered standard health questionnaires; were examined by a physician; completed routine blood tests including thyrotropin, free triiodothyronine, and free thyroxine levels; and underwent a treadmill exercise according to the Bruce protocol. Subjects with known thyroid disease or those who were taking thyroid-related drugs were excluded from the analysis. Heart rate profile was compared between patients with subclinical hypothyroidism (SCHypoT), patients with normal thyroid function, and patients with subclinical hyperthyroidism (SCHyperT) using propensity score matching.nnnRESULTSnSeventy patients had SCHyperT and 273 had SCHypoT. Compared with age- and sex-matched normal subjects, SCHyperT subjects had a higher resting heart rate (83±17 vs. 76±12 beats per minute [bpm], p=0.006), a significantly higher recovery heart rate (94±12 vs. 90±12u2009bpm, p=0.045), and a significantly lower heart rate reserve (80±20 vs. 87±18u2009bpm, p=0.006). Subjects with SCHypoT showed a trend toward a lower resting heart rate (75±13 vs. 77±15u2009bpm, p=0.09) and had a significantly lower recovery heart rate (88±12 vs. 90±13u2009bpm, p=0.035). There was no significant difference in exercise duration or blood pressure between subjects with SCTD and their matched normal controls.nnnCONCLUSIONSnSubjects with SCTD have a significantly different heart rate profile during rest, exercise, and recovery.

Mutation analysis of the MEN1 gene in Israeli patients with MEN1 and familial isolated hyperprolactinemia.

Multiple endocrine neoplasia type 1 (MEN‐1) is characterized by hyperfunction and tumor formation of the parathyroids, anterior pituitary and endocrine pancreas. We carried out exon‐specific, PCR‐based DNA sequencing of the coding exons of the MEN1 gene in 8 Israeli MEN1 patients: 4 familial and 4 sporadic. We similarly analyzed Israeli families with a unique phenotype of isolated hyperprolactinemia (HPRL). Four mutations were detected in 4 MEN1 patients: C to T alteration at nucleotide 2608 resulting in R108X, and three intronic insertions/deletions (a 13 basepair (bp) deletion and a 1 bp insertion both in intron 1, and a 2 bp insertion in intron 3) leading to exonic frame shifts as they encompass the splice junctions. An additional patient exhibited a compound mutation: a G to T change at position 7614 resulting in E463X, and insertion/deletion of 9 bp at position 7622‐7630 resulting in EAE466‐468X. Haplotype analysis showed no segregation of phenotype with 11q13 markers in 4 familial HPRL, and no men 1 germline mutations were detected in three representative individuals, from 3 families. Our results confirm that men 1 gene germline mutations occur in the majority of patients with clinically diagnosed MEN1, and that familial HPRL is a genetically distinct disorder. Hum Mutat 16:269, 2000.

Prolactinoma and other head and neck tumors after scalp irradiation.

Tumors of the thyroid and parathyroid glands may develop together or separately in patients who previously have been exposed to head and neck irradiation. Whether cranial irradiation confers an increased risk for pituitary adenoma remains unknown. We report the case of a 52-year-old woman who was treated during childhood for tinea capitis with scalp irradiation and later in life developed a prolactin-secreting tumor, a parathyroid adenoma, a benign thyroid lesion, and a basal cell carcinoma of the skin. She was treated successfully with bromocriptine and surgical removal of the parathyroid adenoma. Molecular analysis of the parathyroid tissue failed to demonstrate any abnormality of the multiple endocrine neoplasia Type 1 gene. This case report is the first to describe a prolactin-secreting tumor that developed in association with other endocrine neoplasia after head and neck irradiation. Our case suggests that multiple endocrine neoplasia may develop in a sporadic pattern after scalp irradiation.

Transient Post‐Partum Hypothyroidism

Abstract. Transient hypothyroidism was observed in two young women a few months following childbirth. It is suggested that throughout their pregnancy they had already suffered from auto‐immune thyroiditis, the symptoms of which were suppressed at that time, as found in many other auto‐immune diseases. Being transient, post‐partum hypothyroidism is an exception to the rule that treatment by thyroid hormone replacement should never be stopped in hypothyroidism. Post‐partum hypothyroidism has to be considered in every suspected case of post‐partum depression, because of the possible similarity in the clinical presentation.

Mutation analysis of the MEN1 gene in Israeli patients with MEN1 and familial isolated hyperprolactinemia Communicated by: Mark H. Paalman Online Citation: Human Mutation, Mutation in Brief #353 (2000) Online http://journals.wiley.com/1059-7794/pdf/mutation/353.pdf

Multiple endocrine neoplasia type 1 (MEN-1) is characterized by hyperfunction and tumor formation of the parathyroids, anterior pituitary and endocrine pancreas. We carried out exon-specific, PCR-based DNA sequencing of the coding exons of the MEN1 gene in 8 Israeli MEN1 patients: 4 familial and 4 sporadic. We similarly analyzed Israeli families with a unique phenotype of isolated hyperprolactinemia (HPRL). Four mutations were detected in 4 MEN1 patients: C to T alteration at nucleotide 2608 resulting in R108X, and three intronic insertions/deletions (a 13 basepair (bp) deletion and a 1 bp insertion both in intron 1, and a 2 bp insertion in intron 3) leading to exonic frame shifts as they encompass the splice junctions. An additional patient exhibited a compound mutation: a G to T change at position 7614 resulting in E463X, and insertion/deletion of 9 bp at position 7622-7630 resulting in EAE466-468X. Haplotype analysis showed no segregation of phenotype with 11q13 markers in 4 familial HPRL, and no men 1 germline mutations were detected in three representative individuals, from 3 families. Our results confirm that men 1 gene germline mutations occur in the majority of patients with clinically diagnosed MEN1, and that familial HPRL is a genetically distinct disorder.