Alan N. Peiris

Insulin: A Novel Factor in Carcinogenesis

Cancer is a leading cause of mortality in the United States. Despite much research on specific carcinogens, the cause of many cancers remains unclear. The identification of novel causative agents offers the potential for cancer prevention. Diseases such as obesity and diabetes mellitus, characterized by hyperinsulinemia, are associated with increased risk of endometrial, colorectal, and breast carcinomas. There is increasing evidence that insulin is a growth factor for tumor formation. The mechanisms underlying insulin-mediated neoplasia may include enhanced DNA synthesis with resultant tumor cell growth, inhibition of apoptosis, and altered sex hormone milieu. The reduced insulin levels seen with physical activity, weight loss, and a high fiber diet may account for decreased cancer risk. The role of newer drugs that restore sensitivity to insulin, thereby reducing hyperinsulinemia, is an exciting potential area of cancer prevention. In this review, we discuss the potential role of insulin as a tumor growth factor.

Possible Role of Serum 25-Hydroxyvitamin D in Black–White Health Disparities in the United States

Significant health disparities exist between African Americans (AAs) and White Americans (WAs). The all-cause mortality rate for AAs in 2006 was 26% higher than for non-Hispanic WAs. Explanations for the disparities usually include socioeconomic status, lifestyle behaviors, social environment, and access to preventive health care services. However, several studies indicate that these factors do not account for the observed disparities. Many studies report that vitamin D has important health benefits through paracrine and autocrine mechanisms and that higher serum 25-hydroxyvitamin D (25[OH]D) levels are associated with better health outcomes. AAs have a population mean serum 25(OH)D level of 16 ng/mL, whereas WAs have a level of 26 ng/mL. From preliminary meta-analyses of serum 25(OH)D level-disease outcome from observational studies, differences in serum 25(OH)D level for AAs and WAs can explain many of the health disparities. The ratios of mortality rates for AAs to WAs for female breast cancer, colorectal cancer, cardiovascular disease, and all-cause mortality rate in 2006 were 1.34, 1.43, 1.29, and 1.26, respectively. The 25(OH)D level-disease outcome ratios for 16 ng/mL versus 26 ng/mL for the same diseases were 1.26, 1.44, 1.27, and 1.26, respectively. The close agreement between these 2 sets of numbers suggests that low serum 25(OH)D level is an important health risk for AAs. Given the widespread vitamin D deficiency in the AA population and the potential widespread health benefits that accompany adequate replacement, we believe that addressing this issue may be the single most important public health measure that can be undertaken.

Relationship Between Vitamin D Status and ICU Outcomes in Veterans

OBJECTIVE Vitamin D deficiency remains a poorly recognized pandemic and is closely linked to increased health care costs in veterans. Projected health care needs in veterans are expected to increase over the next decade. Intensive care unit (ICU) costs contribute significantly to hospital costs and stem from intervention services and management of sepsis including nosocomial infections. Vitamin D has immunomodulating and antimicrobial properties through antimicrobial peptides such as cathelicidin. DESIGN/METHODS A retrospective study was undertaken to evaluate if vitamin D deficiency was associated with less than optimal ICU outcomes in veterans. The study included 136 veterans with 25(OH)D levels drawn within a month of admission to ICU. RESULTS The average 25(OH)D level was 24.6 ng/mL (normal range 30-100) with 38% of patients falling in the vitamin D-deficient category (<20 ng/mL). ICU survivors had a significantly lower rate of vitamin D deficiency compared with nonsurvivors (28% versus 53%). Twenty-nine percent of vitamin D-replete patients were in ICU 3 days or more, whereas 58% of patients with vitamin D deficiency stayed in ICU 3 days or longer. This difference was highly significant translating to twofold increased risk (2.0 Relative Risk [RR]) for 3-day or longer stay in ICU for patients with vitamin D deficiency. Moreover, the risk of death was significantly higher in ICU patients with vitamin D deficiency (RR 1.81). CONCLUSION A vitamin D-replete state may reduce costs and confer survival advantages in critical illness. We recommend that 25(OH)D levels be routinely checked and deficiencies treated in ICU patients.

Antimicrobial implications of vitamin D

Evidence exists that vitamin D has a potential antimicrobial activity and its deficiency has deleterious effects on general well-being and longevity. Vitamin D may reduce the risk of infection through multiple mechanisms. Vitamin D boosts innate immunity by modulating production of anti-microbial peptides (AMPs) and cytokine response. Vitamin D and its analogues via these mechanisms are playing an increasing role in the management of atopic dermatitis, psoriasis, vitiligo, acne and rosacea. Vitamin D may reduce susceptibility to infection in patients with atopic dermatitis and the ability to regulate local immune and inflammatory responses offers exciting potential for understanding and treating chronic inflammatory dermatitides. Moreover, B and T cell activation as well as boosting the activity of monocytes and macrophages also contribute to a potent systemic anti-microbial effect. The direct invasion by pathogenic organisms may be minimized at sites such as the respiratory tract by enhancing clearance of invading organisms. A vitamin D replete state appears to benefit most infections, with the possible noteworthy exception of Leishmaniasis. Antibiotics remain an expensive option, and misuse of these agents results in significant antibiotic resistance and contributes to escalating health care costs. Vitamin D constitutes an inexpensive prophylactic option and possibly therapeutic product either by itself or as a synergistic agent to traditional antimicrobial agents. This review outlines the specific antimicrobial properties of vitamin D in combating a wide range of organisms. We discuss the possible mechanisms by which vitamin D may have a therapeutic role in managing a variety of infections.

Differences in vitamin D status may account for unexplained disparities in cancer survival rates between African and white Americans

Considerable disparities in cancer survival rates exist between African Americans (AAs) and white Americans (WAs). Various factors such as differences in socioeconomic status (SES), cancer stage at time of diagnosis, and treatment—which this analysis considers primary explanatory factors—have accounted for many of these differences. An additional factor not usually considered is vitamin D. Previous studies have inversely correlated higher solar ultraviolet-B (UVB) doses and serum 25-hydroxyvitamin D (25(OH)D) concentrations with incidence and/or mortality rates for about 20 types of cancer and improved survival rates for eight types of cancer. Because of darker skin pigmentation, AAs have 40% lower serum 25(OH)D concentrations than WAs. This study reviews the literature on disparities in cancer survival between AAs and WAs. The journal literature indicates that there are disparities for 13 types of cancer after consideration of SES, stage at diagnosis and treatment: bladder, breast, colon, endometrial, lung, ovarian, pancreatic, prostate, rectal, testicular, and vaginal cancer; Hodgkin lymphoma and melanoma. Solar UVB doses and/or serum 25(OH)D concentrations have been reported inversely correlated with incidence and/or mortality rates for all of these cancers. This finding suggests that future studies should consider serum 25(OH)D concentrations in addressing cancer survival disparities through both measurements of serum 25(OH)D concentrations and increasing serum 25(OH)D concentrations of those diagnosed with cancer, leading to improved survival rates and reduced disparities.

Healthcare costs of Staphylococcus aureus and Clostridium difficile infections in Veterans: role of vitamin D deficiency

Clostridium difficile and staphylococcal infections are associated with increased morbidity, mortality and healthcare costs. Vitamin D deficiency may also contribute to increased healthcare costs. There is increasing evidence that vitamin D may have an antimicrobial role. We examined the relationship of serum 25(OH)D levels to staphylococcal and C. difficile infections to determine if vitamin D deficiency was associated with adverse outcomes. In the outpatient setting, vitamin D deficiency in patients with C. difficile and staphylococcal infections were associated with significantly increased total outpatients costs and fee-based consultation. Laboratory expenses had a trend towards higher costs in the vitamin D-deficient group but did not reach statistical significance. The differences were most clearly seen in the in-patient group with enhanced laboratory, pharmacy and radiology costs. These differences resulted in vitamin D-deficient patients with C. difficile or staphylococcal infections having costs more than five times higher than the non-deficient patients. The total length of hospital stay was four times greater in the vitamin D-deficient group. In addition, the total number of hospitalizations was also significantly greater in the vitamin D-deficient group. Surgery costs demonstrated a tendency to be higher in the vitamin D-deficient group but failed to reach statistical significance. Vitamin D deficiency is intimately linked to adverse health outcomes and costs in Veterans with staphylococcal and C. difficile infections in North East Tennessee. We recommend that vitamin D status be checked in patients with these infections and appropriate therapy be instituted to restore vitamin D level to normal in an expeditious manner.

Infectious causes of adrenal insufficiency.

More than 150 years ago, Thomas Addison first described the clinical features and pathogenesis of adrenal insufficiency. At that time, tuberculosis was the most common cause of this disease. The pathway to diagnosis and treatment of Addisons disease has been well described. However, determining the cause of the disorder remains a challenge. It is important to consider recently described infectious agents in the pathogenesis of Addisons disease. Mycobacterial, bacterial, viral, and fungal infections may lead to the development of adrenal insufficiency. Skin, pulmonary, and imaging findings can aid the clinician in making a prompt diagnosis of specific infections, which is crucial because early identification of infectious causes of Addisons disease may enable recovery of adrenal function. This review describes the clinical presentations of the multiple infectious causes of adrenal insufficiency.

The Relationship of Vitamin D Status to Cardiovascular Risk Factors and Amputation Risk in Veterans With Peripheral Arterial Disease

OBJECTIVES Peripheral arterial disease (PAD) is a common and often overlooked entity responsible for considerable morbidity and mortality. Recent evidence suggests that nontraditional risk factors such as vitamin D may contribute to atherosclerosis. We hypothesized that vitamin D status was associated with cardiovascular risk factors and that vitamin D deficiency (25(OH)D <20 ng/mL) enhanced the risk of amputation. DESIGN We reviewed medical records of 1435 veterans between 2000 and 2008 in Tennessee via retrospective chart analysis using correlations, logistic regressions, t tests, and χ(2) analyses. RESULTS Vitamin D status was significantly and inversely correlated with body mass index (BMI), glucose, and triglyceride values. Hypertension and diabetes but not smoking also emerged as significantly associated. Of the sample population, 5.2% (n = 75) had an amputation performed. Those individuals who were vitamin D deficient had a significantly higher amputation rate (6.7%) compared with patients who were nondeficient (4.2%). BMI, triglyceride, total cholesterol, hypertension, and diabetes were found to account for 5.7% of the variation in amputation status. Vitamin D concentration and deficiency status accounted for a nonsignificant amount of additional variance. CONCLUSIONS We conclude that vitamin D deficiency is closely linked to increased adiposity, triglyceride, and glucose measurements. Vitamin D deficiency was associated with an increased amputation risk in veterans with PAD and appears to mediate its effects through traditional risk factors.

The Association Between Obstructive Sleep Apnea Syndrome and Microvascular Complications in Well-Controlled Diabetic Patients

BACKGROUND Obstructive sleep apnea syndrome (OSAS) may promote hyperglycemia and insulin resistance. OBJECTIVE We studied the link between sleep apnea and microvascular diabetic complications in veterans with type 2 diabetes mellitus (DM-2). DESIGN A retrospective electronic chart of all veterans referred for sleep studies over a 1-year period was reviewed. Ninety-eight patients with a glycosylated hemoglobin < 6.5% were included in the study. The degree of glycemia (HbA1c) and presence of macro- and microvascular complications were compared with OSAS variables. METHOD Statistical analysis examined bivariate associations between OSAS variables and metabolic syndrome parameters. RESULTS The apnea hypopnea index was significantly related to diabetic microvascular complications, particularly retinopathy. Oxygen desaturation was significantly and inversely related to microalbuminuria, microvascular complications, retinopathy, and HbA1c. CONCLUSIONS Sleep apnea is associated with microvascular complications even in well-controlled DM-2 veterans. CLINICAL IMPLICATIONS Screening for OSAS should be considered in patients with DM-2.

The Relationship of Vitamin D Deficiency to Health Care Costs in Veterans

Vitamin D deficiency is often unrecognized and has been linked to many chronic diseases. Vitamin D supplementation has been shown to ameliorate these chronic diseases and may reduce the prevalence of some cancers. We analyzed the health care costs associated with vitamin D deficiency in Veterans in Northeast Tennessee. A retrospective electronic chart analysis of the relationship of 25-hydroxyvitamin D [25(OH)D] status to health care costs, services, and utilization was done in 886 veterans. The overall costs were higher by 39% in the vitamin D-deficient group. Vitamin D deficiency was associated with increased service utilization in many areas including more frequent emergency room and clinic visits as well as increased inpatient stay and inpatient services. The serum level of vitamin D was also related to health care costs, although to a lesser extent. Vitamin D deficiency is closely linked to increased health care costs in veterans.