Levothyroxine for the Treatment of Subclinical Hypothyroidism and Cardiovascular Disease.

Subclinical hypothyroidism is a biochemical condition defined by elevated serum thyroid-stimulating hormone levels in the setting of normal levels of the peripheral thyroid hormones, thyroxine and triiodothyronine. Thyroid hormones act on the heart through various mechanisms and subclinical hypothyroidism has been associated with risk factors for cardiovascular disease, such as hypertension and dyslipidemia. In addition, evidence from multiple studies supports an association between subclinical hypothyroidism and cardiovascular disease. However, the use of levothyroxine in subclinical hypothyroidism to reduce cardiovascular disease risk is not clearly beneficial. Treatment with levothyroxine may only provide benefit in certain subgroups, such as patients who are younger or at higher risk of cardiovascular disease. At present, most of the international societal guidelines advise that treatment decisions should be individualized based on patient age, degree of serum thyroid-stimulating hormone (TSH) elevation, symptoms, cardiovascular disease (CVD) risk, and other co-morbidities. Further study in this area is recommended.

Antibody-Mediated Extreme Insulin Resistance: The Importance of Pre-Treatment Screening.

We report the case of a 56 year-old Hispanic male with a 10-year history of type 2 diabetes who presented with abrupt onset of hyperglycemia resistant to escalating doses of intravenous insulin infusion (>2500 units daily). He was diagnosed with antibody-mediated insulin resistance given the presence of hyperglycemia despite receiving >200 units insulin/day, a lack of identifiable precipitants for diabetic ketoacidosis or hyperosmolar hyperglycemic state, and elevated insulin antibodies. He underwent pre-immunomodulatory therapy screening for infections, rheumatologic disorders, and malignancy, which uncovered a new diagnosis of latent tuberculosis. While concurrently being treated for latent tuberculosis, he successfully responded to immunomodulatory therapy with rituximab, dexamethasone, and cyclophosphamide. Insulin was discontinued completely, and he maintained appropriate glycemic control on oral diabetic agents (metformin and pioglitazone). This case supports the use of immunomodulatory therapy for the treatment of antibody-mediated insulin resistance and highlights the importance of pre-immunomodulatory therapy screening to uncover occult infection or identify underlying neoplastic/rheumatologic disease prior to immunosuppression.

REDUCING INAPPROPRIATE SERUM T3 LABORATORY TEST ORDERING IN PATIENTS WITH TREATED HYPOTHYROIDISM.

Objective: Choosing Wisely is a campaign of the American Board of Internal Medicine that aims to promote evidence-based practices to reduce unnecessary ordering of tests or procedures. As part of this campaign, the Endocrine Society advises against ordering a serum total or free triiodothyronine (T3) level when assessing levothyroxine dosing in hypothyroid patients. This study was performed to assess and reduce inappropriate laboratory ordering practices among providers who manage patients with hypothyroidism within a large U.S. academic health system. Methods: A best practice alert (BPA) in the health record was developed and implemented following the collection of baseline data. This alert consisted of a popup window that was triggered when a serum T3 laboratory test was ordered for patients prescribed levothyroxine. The alert required user acknowledgement before the serum T3 laboratory test could be ordered. Results: During the 6-week period prior to launching the BPA, serum T3 tests were ordered a mean of 162.3 ± 15.4 (standard deviation) occurrences per 10,000 patients per week. Over a 15-week period following implementation of the BPA, the frequency of serum T3 orders steadily decreased and resulted in >44% fewer inappropriate tests being ordered. Conclusion: Although national societal guidelines recommend against ordering serum T3 concentrations while monitoring patients with hypothyroidism managed with levothyroxine, these laboratory tests are frequently ordered. Development of a triggered alert in the health record may reduce inappropriate monitoring practices, decrease costs, and improve utilization of limited health-care resources for this common clinical condition. Abbreviations: ATA = American Thyroid Association; BPA = best practice alert; T3 = triiodothyronine; TSH = thyroid-stimulating hormone.

Acute Hyperglycemia Due to Topical Corticosteroid Administration.

We present the case of a 71-year-old man with longstanding, previously well-controlled type 1 diabetes who developed acute hyperglycemia. His insulin requirements, via his insulin pump, increased to nearly five times his typical daily dose. The patient was admitted for evaluation and treatment and started on an insulin infusion. He had minimal insulin requirements with the insulin infusion. History revealed recent use of a super potent topical corticosteroid for a psoriasis flare. The patient was transitioned back to his insulin pump, using his prior to admission settings. He was advised to discontinue using his topical corticosteroid. He had no further hyperglycemic episodes. The clinical presentation is suggestive of corticosteroid-induced hyperglycemia, suggesting that clinically significant changes can occur even with short duration use, particularly with high potency steroids used. This is to our knowledge the first case reported in which the patient required a very significant amount of extra insulin (nearly five times his typical total daily dose) after using high potency topical steroid cream. This case highlights the potentially detrimental effect of topical corticosteroid use in patients with diabetes.

Effect of Serum Triglycerides on Clinical Outcomes in Acute Pancreatitis: Findings From a Regional Integrated Health Care System.

OBJECTIVES: The aim of this study was to evaluate the effect of serum triglycerides on the development of multiple or persistent organ failure in patients with acute pancreatitis. METHODS: A retrospective cohort study was conducted among patients hospitalized for acute pancreatitis between 2006 and 2013. Triglyceride levels measured before and within 72 hours of admission were compared. In addition, the effect of triglyceride levels on the development of multiple or persistent organ failure during hospitalization for acute pancreatitis was assessed. RESULTS: Among 2519 patients, 267 patients (10.6%) developed organ failure, of which 75 patients developed multiple system organ failure and 82 patients developed persistent organ failure. Triglyceride levels in patients who developed organ failure were initially much higher than in patients who did not develop organ failure, but by 72 hours into admission, approached levels of patients who did not develop organ failure. Approximately 8% of patients had triglyceride levels greater than 500 mg/dL, the majority of which had similarly high levels before admission. CONCLUSIONS: Increased triglyceride levels were associated with the development of multiple or persistent organ failure among patients hospitalized with acute pancreatitis. Patients with high triglyceride levels at the time of admission were likely to have high triglyceride levels before admission.

Endogenous estradiol is not associated with poor physical health in postmenopausal breast cancer survivors.

BACKGROUND: Among postmenopausal breast cancer survivors, poor physical health has been associated with higher risks of breast cancer events. Obesity and physical inactivity are known risk factors for poor physical health, while circulating estrogen is an additional potential risk factor. We tested the hypothesis that the relationship between poor physical health and worse breast cancer outcomes is mediated by higher estrogen concentrations associated with body size and physical inactivity. METHODS: We used data from 1030 postmenopausal breast cancer survivors to examine the association between serum estradiol levels, body mass index (BMI), physical activity, and RAND-36-item Health Survey (SF-36) physical health. RESULTS: In univariate analysis, poor physical health was associated with higher estradiol levels, in addition to obesity and low physical activity. Higher estradiol levels were significantly associated with higher odds of poor physical health (odds ratio, OR, 1.20 [95% confidence interval 1.03-1.39]) in a multivariable model adjusting for age, cancer stage and treatment, alcohol use, and physical activity. However, the relationship between estradiol levels and poor physical health was no longer significant (OR 1.06 [0.91-1.24]) after adding BMI in the model. In multivariate analysis, only poor physical health resulted in higher risks of recurrence (hazard ratio 1.33 [95% CI 1.08-1.64]). CONCLUSIONS: These findings indicate that estradiol is related to poor physical health, but is not an independent risk factor from body size or inactivity. While obesity and physical activity in survivorship are potential targets for improving physical health, other biological processes that impact physical health, e.g. inflammation, remain to be identified.

Associations between genes in the one-carbon metabolism pathway and advanced colorectal adenoma risk in individuals with low folate intake.

BACKGROUND: Folate is essential for one-carbon metabolism, a pathway required by DNA synthesis, methylation, and repair. Low dietary and circulating folate and polymorphic variation in this pathway are associated with increased risk of colorectal adenoma and cancer. METHODS: We genotyped 882 single nucleotide polymorphisms (SNP) in 82 one-carbon metabolism genes for 1,331 cases of advanced colorectal adenoma, identified by sigmoidoscopy at baseline, and 1,501 controls from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). We evaluated associations between one-carbon genes and adenoma risk in all subjects and stratified by folate intake. We applied the Adaptive Rank Truncated Product (ARTP) method to assess statistical significance at the gene and pathway levels. RESULTS: Folate intake was inversely associated with advanced colorectal adenoma risk [odds ratio (OR) by quartile = 0.85, P = 1.9 × 10(-5)]. We found no statistically significant associations between one-carbon genes and adenoma risk in all subjects. As hypothesized, we observed a statistically significant pathway-level association (P = 0.038) in the lowest quartile of folate; no significant associations were found in higher quartiles. Several genes including adenosine deaminase (ADA) and cysteine dioxygenase (CDO1) contributed to this signal (gene-level P = 0.001 and 0.0073, respectively). The most statistically significant SNP was rs244072 in ADA (P = 2.37 × 10(-5)). CONCLUSIONS AND IMPACT: Stratification by dietary folate and application of the ARTP method revealed statistically significant pathway- and gene-level associations between one-carbon metabolism genes and risk of advanced colorectal adenoma, which were not apparent in analysis of the entire population. Folate intake may interact with associations between common variants in one-carbon metabolism genes and colorectal adenoma risk.

Estrogen metabolism and risk of breast cancer in postmenopausal women.

BACKGROUND: Estrogens are recognized causal factors in breast cancer. Interindividual variation in estrogen metabolism may also influence the risk of breast cancer and could provide clues to mechanisms of breast carcinogenesis. Long-standing hypotheses about how estrogen metabolism might influence breast cancer have not been adequately evaluated in epidemiological studies because of the lack of accurate, reproducible, and high-throughput assays for estrogen metabolites. METHODS: We conducted a prospective case-control study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO). Participants included 277 women who developed invasive breast cancer (case subjects) and 423 matched control subjects; at PLCO baseline, all subjects were aged 55-74 years, postmenopausal and not using hormone therapy, and provided a blood sample. Liquid chromatography-tandem mass spectrometry was used to measure serum concentrations of 15 estrogens and estrogen metabolites, in unconjugated and conjugated forms, including the parent estrogens, estrone and estradiol, and estrogen metabolites in pathways defined by irreversible hydroxylation at the C-2, C-4, or C-16 positions of the steroid ring. We calculated hazard ratios (HRs) approximating risk in highest vs lowest deciles of individual estrogens and estrogen metabolites, estrogens and estrogen metabolites grouped by metabolic pathways, and metabolic pathway ratios using multivariable Cox proportional hazards models. All statistical tests were two-sided. RESULTS: Nearly all estrogens, estrogen metabolites, and metabolic pathway groups were associated with an increased risk of breast cancer; the serum concentration of unconjugated estradiol was strongly associated with the risk of breast cancer (HR = 2.07, 95% confidence interval [CI] = 1.19 to 3.62). No estrogen, estrogen metabolite, or metabolic pathway group remained statistically significantly associated with the risk of breast cancer after adjusting for unconjugated estradiol. The ratio of the 2-hydroxylation pathway to parent estrogens (HR = 0.66, 95% CI = 0.51 to 0.87) and the ratio of 4-hydroxylation pathway catechols to 4-hydroxylation pathway methylated catechols (HR = 1.34, 95% CI = 1.04 to 1.72) were statistically significantly associated with the risk of breast cancer and remained so after adjustment for unconjugated estradiol. CONCLUSIONS: More extensive 2-hydroxylation of parent estrogens is associated with lower risk, and less extensive methylation of potentially genotoxic 4-hydroxylation pathway catechols is associated with higher risk of postmenopausal breast cancer.

Analysing breast cancer microarrays from African Americans using shrinkage-based discriminant analysis.

Breast cancer tumours among African Americans are usually more aggressive than those found in Caucasian populations. African-American patients with breast cancer also have higher mortality rates than Caucasian women. A better understanding of the disease aetiology of these breast cancers can help to improve and develop new methods for cancer prevention, diagnosis and treatment. The main goal of this project was to identify genes that help differentiate between oestrogen receptor-positive and -negative samples among a small group of African-American patients with breast cancer. Breast cancer microarrays from one of the largest genomic consortiums were analysed using 13 African-American and 201 Caucasian samples with oestrogen receptor status. We used a shrinkage-based classification method to identify genes that were informative in discriminating between oestrogen receptor-positive and -negative samples. Subset analysis and permutation were performed to obtain a set of genes unique to the African-American population. We identified a set of 156 probe sets, which gave a misclassification rate of 0.16 in distinguishing between oestrogen receptor-positive and -negative patients. The biological relevance of our findings was explored through literature-mining techniques and pathway mapping. An independent dataset was used to validate our findings and we found that the top ten genes mapped onto this dataset gave a misclassification rate of 0.15. The described method allows us best to utilise the information available from small sample size microarray data in the context of ethnic minorities.

Circulating insulin-like growth factor (IGF)-I and IGF binding protein (IGFBP)-3 levels and postmenopausal breast cancer risk in the prostate, lung, colorectal, and ovarian cancer screening trial (PLCO) cohort.

Early prospective studies suggested circulating insulin-like growth factor (IGF)-I was positively associated with risk of premenopausal, but not postmenopausal, breast cancer; however, a recent, large analysis reported a statistically significant positive association with postmenopausal disease. Therefore, we conducted a large study nested within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort to assess the association between circulating IGF-I and IGF binding protein (IGFBP)-3 levels and subsequent postmenopausal breast cancer risk. We included 389 breast cancer cases and 470 controls, aged 55-74, not using exogenous hormones at blood draw, and matched by age at and date of serum collection. Mean follow-up was 8.5 years; mean time between serum collection and diagnosis was 4.0 years. We used Cox proportional hazards regression models to obtain hazard ratios (HRs) and 95% confidence intervals (95% CIs). Multivariate HRs for IGF-I, IGFBP-3, and the molar ratio IGF-I/IGFBP-3, comparing the highest quintile to the lowest, were 1.28 (95% CI, 0.67-2.44), 1.12 (95% 0.55-2.27), and 1.25 (95% 0.72-2.15), respectively. Multivariate HRs per one quintile increase were 1.07 (95% 0.92-1.25) for IGF-I, 1.01 (95% 0.86-1.18) for IGFBP-3, and 1.10 (95% 0.98-1.24) for the molar ratio. These models included accepted breast cancer risk factors and height, along with baseline BMI and serum estradiol, both of which increased the risk associated with IGF-I and the molar ratio. IGF-I and the IGF-I/IGFBP-3 molar ratio were positively, although not statistically significantly, associated with postmenopausal breast cancer risk. Further research should emphasize larger studies, including pooled analyses, analyses by cancer subtype, improved exposure assessment, and possible mechanisms.

Energy intake and risk of postmenopausal breast cancer: an expanded analysis in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (PLCO) cohort.

Although animal experiments have consistently shown a positive relationship between breast cancer and energy intake, evidence from human studies remains inconclusive. In the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial cohort, 29,170 women, ages 55 to 75 years, who successfully completed a food frequency questionnaire (FFQ) at entry (1993-2001), were followed through 2007, and 1,319 incident breast cancers were ascertained (median time from FFQ completion to diagnosis, 4.4 years). Women in the highest quartile of energy intake, relative to the lowest, had modestly, but significantly, increased breast cancer risk [multivariate relative risk (RR), 1.21; 95% confidence interval (95% CI), 1.03-1.42; P(trend) = 0.03]. The inclusion of body mass index and physical activity in the model reduced risk slightly (RR, 1.18; 95% CI, 1.00-1.39; P(trend) = 0.07). However, in similar analyses using energy intake from a FFQ administered approximately five years after entry (27,428 women; 806 incident breast cancers; median time from FFQ completion to diagnosis, 2.7 years), women in the highest and lowest quartiles of energy intake had similar risk. When follow-up time after the first FFQ was divided into three 4-year periods, the multivariate RRs for high versus low energy intake increased from 1.21 to 1.37 to 1.55 with increasing time since dietary assessment. Although the divergent results for the two FFQs could be due to subtle questionnaire differences, our findings suggest a modest positive association between energy intake and postmenopausal breast cancer that strengthens with time since dietary assessment.