Jerry R. Greenfield

Obesity Is an Important Determinant of Baseline Serum C-Reactive Protein Concentration in Monozygotic Twins, Independent of Genetic Influences

Background—C-reactive protein (CRP) values predict atherothrombotic cardiovascular disease and type 2 diabetes mellitus. Associations between CRP and obesity, predominantly assessed anthropometrically, may partly explain these observations. Previous studies have been unable to control for genetic influences on CRP and obesity. The aim of this study was to examine the relationship between CRP and accurately measured body fat, lipids, apolipoproteins, blood pressure, and environmental and behavioral factors, independent of genetic influences. Methods and Results—One hundred ninety-four healthy female twins (age 57.2±7 years) were studied after excluding pairs with CRP values >10 mg/L. Total body fat and central abdominal fat (CAF) were measured by dual-energy x-ray absorptiometry. CRP concentration was strongly related to surrogate and direct measures of body fat (r =0.31 to 0.54, P <0.001), diastolic blood pressure (r =0.20, P =0.003), and lipid and apolipoprotein levels (r =0.21 to 0.51, P <0.008). Light-to-moderate alcohol consumers and nonusers of hormone replacement therapy (HRT) had lower CRP levels than abstainers and HRT users, respectively. In stepwise multiple regression analysis, CAF, triglycerides, apolipoprotein B, and HRT use explained 46% of the variance in circulating CRP. In analyses controlling for genetic influences in monozygotic twins, within-pair differences in CRP were associated with within-pair differences in total body fat (r =0.39, P <0.001), CAF (r =0.34, P =0.002), diastolic blood pressure (r =0.24, P =0.03), apolipoprotein AI (r =−0.33, P =0.01), HDL cholesterol (r =−0.42, P =0.001), and triglycerides (r =0.35, P =0.007). Conclusions—CRP was strongly related to total and central abdominal obesity, blood pressure, and lipid levels, independent of genetic influences. These relationships are likely to contribute significantly to prospective associations between CRP and type 2 diabetes and coronary events.

Physical activity reduces genetic susceptibility to increased central systolic pressure augmentation: a study of female twins ☆

OBJECTIVES We sought to examine associations between the augmentation index (AI) and metabolic, adiposity, and lifestyle factors, independent of genetic influences, and to determine whether gene-environment interactions modulate these relationships. BACKGROUND Reported associations between AI, an index of systemic arterial stiffness, and metabolic, adiposity, and lifestyle factors remain contradictory. The modulating effect of genetic risk is unknown. METHODS We studied 684 female twins (age 18 to 71 years); AI was derived from the pressure waveform measured at the radial artery by applanation tonometry. Percentage of total body fat (TBF) and percentage of central abdominal fat (CAF) were assessed by dual-energy X-ray absorptiometry. RESULTS In univariate analysis, age-adjusted AI was significantly associated with fasting triglyceride levels (r = 0.1, P = 0.03), apolipoprotein-B/A1 (r = 0.1, P = 0.04), percentage of TBF (r = 0.11, P = 0.006), and percentage of CAF (r = 0.11, P = 0.004). In co-twin case-control (monozygotic twin) analysis, a 3.1% absolute within-pair difference in percentage of CAF accounted for a 6% within-pair difference in AI, independent of genetic effects. Smokers and subjects with alcohol intakes >15 U/week had higher AI than nonsmokers (p = 0.01) and nondrinkers (p = 0.02), respectively. Forty percent of the variance in AI was explained by age, central mean arterial pressure, heart rate, height, percentage of CAF, and smoking. In gene-environment interaction analysis, subjects at high genetic risk of increased AI participating in regular leisure-time physical activity had AI values similar to low genetic risk subjects. CONCLUSIONS Central abdominal adiposity is a significant determinant of AI in female twins, independent of hemodynamic, lifestyle, and, importantly, genetic effects. Smoking is associated with increased AI, even after controlling for abdominal obesity and other AI determinants. Physical activity reduces genetic predisposition to increased AI.

Suppression of HPA axis in adults taking inhaled corticosteroids

Fluticasone propionate, a frequently prescribed potent inhaled corticosteroid, is an effective and generally safe treatment for chronic asthma. However, rare cases of dose related systemic absorption of inhaled corticosteroids leading to suppression of the hypothalamic-pituitary-adrenal (HPA) axis have been reported, particularly in children.1,2 Using the insulin tolerance test (ITT), we report two cases of symptomatic adrenocortical suppression in asthmatic adults taking inhaled fluticasone. The two patients reported here were selected from a review of 59 patients undergoing ITTs for investigation of suspected HPA dysfunction.3 Patient 1, a 38 year old woman (weight 49.9 kg) with a history of chronic asthma and allergic rhinitis, was referred for investigation of a 2 year history of fatigue, presyncope, and reduced libido. She denied symptoms of neuroglycopenia, thyroid dysfunction, headaches, arthralgia, myalgia, weight change, constipation, and diarrhoea. Past history included depression (in remission, on no current treatment) and bulimia nervosa. Menses were regular. There was no history of postpartum haemorrhage. Medications included fluticasone propionate/salmeterol xinafoate (Seretide) 250/25 µg one inhalation twice daily and mometasone …

Do gene-environment interactions influence fasting plasma lipids? A study of twins.

Background  The aims of this study were to determine the influence of smoking, alcohol consumption, physical activity and hormone replacement therapy (HRT) on lipids, independently of genetic factors, and to detect whether gene–environment interactions influence these associations.

ANCA-positive vasculitis induced by thioridazine: confirmed by rechallenge

SIR, Seborrhoeic keratosis, histologically described as a basal cell papilloma, is an easily recognized common benign tumour. It is commonly treated with cryotherapy, electrocautery, shave excision or curettage and cautery, and histology is usually not arranged unless the lesion looks atypical. In contrast, mycosis fungoides (MF), a fairly typical presentation of a cutaneous T-cell lymphoma, can be difficult to differentiate clinically and sometimes histologically from very common skin conditions such as eczema and psoriasis, and from other less common dermatoses such as chronic superficial dermatitis. We report here the first case of a solitary plaque of MF clinically mimicking seborrheic keratosis and examine the frequency of this observation in the literature. Indeed, a retrospective study of 577 specimens, clinically diagnosed and submitted as seborrheic keratosis, revealed that 37 (6Æ4%) were histologically diagnosed as malignant tumours, an occurrence seen more commonly than with melanocytic naevi. A 65-year-old male presented with a 3-year history of an asymptomatic warty lesion over the left temple. It had enlarged very gradually over this period but had not bled, ulcerated, changed colour or developed a sensory change, and examination revealed no other similar lesions elsewhere. He had a myocardial infarct in 1981, and had a history of diverticulitis and hyperlipidaemia, which were currently being treated with low dose aspirin, enalapril maleate and simvastatin. There was no family history of ischaemic heart disease, hyperlipidaemia or skin tumours. Examination revealed a 12 · 9-mm raised, pigmented, warty, crusted lesion over the left temple with some underlying induration (Fig. 1). No other similar lesions were noted elsewhere and there was no lymphadenopathy or organomegaly. A clinical diagnosis of a benign basal cell papilloma was made and a 4mm punch biopsy was taken because of the slight underlying induration of the base. After the initial histology report the residual lesion was completely excised. Both samples showed epidermal acanthosis with focal hyperkeratosis and parakeratosis, and dense lymphoid infiltrate in the superficial dermis with quite marked epidermotropism (Fig. 2a). The lymphoid cells were small, with some nuclear atypia, cerebriform nuclei and scattered mitotic activity (Fig. 2b). Immunohistochemistry confirmed these lymphoid cells to be of T-cell lineage (CD3 positive) (Fig. 3), with some cells expressing CD30 positive staining. Routine investigations, including full blood count and differential, liver function tests, urea and electrolytes and immunoglobulins and chest X-ray were normal. Computed tomography scan of chest and abdomen showed a 4Æ9 · 5-cm benign cyst in the left kidney. No further treatment was given as the original skin lesion was completely excised. The patient remains well, with no recurrence of the original lesion or development of another lesion at 3 years after initial presentation. This appears to be the first case of a clinically diagnosed seborrheic keratosis turning out to be a cutaneous T-cell lymphoma on histology, although it has been mistaken for squamous cell carcinoma, Bowen’s disease, basal cell carcinoma and malignant melanoma. Clinically atypical presentation as in our case, with the lesion being indurated, inflamed, irritated and lacking the stuck-on appearance is more likely to turn out to be malignant histologically. Goslen’s description of such lesions as a wolf in sheep s clothing’ is indeed very apposite and may sway us to biopsy slightly atypical lesions more often to avoid such mistakes. Unlike malignant melanoma, basal cell carcinoma and Bowen’s disease, seborrhoeic keratosis has not often been the subject of a study examining our diagnostic acumen or accuracy. However, 1Æ4% of 4310 clinically diagnosed seborrhoeic keratoses in a recent study were found to be squamous cell carcinomata histologically. So the question is, is it always worth it and cost-effective to send all clinically diagnosed seborrheic keratoses for histological assessment? , and for this, we do not think there is yet an answer. Adding to this is the fact that most patients have too many lesions (some more than 100) and this certainly will increase the workload on histopathologists and divert them from looking for something more urgent and sinister. So how can we avoid the sting in the tail? Field described cases of seborrheic keratosis he curetted from the back of patients where the lesions came away from the underlying skin as easily as did other lesions and all left more bleeding and a Figure 1. A 12 · 9 mm pigmented, crusted and slightly indurated warty lesion over the left temple. British Journal of Dermatology 2002; 147: 1264–1281.

How Sweet It Is: Intestinal Sweet Taste Receptors in Type 2 Diabetes

In humans, there are a number of taste receptors on the tongue. These include G protein–coupled receptors (GPRs) for sweet, bitter, and umami (savory) tastes and ion channel–based receptors for salt and sour. In recent years, there has been increasing interest in the distribution and function of these receptors elsewhere in the body (1). This has led to interesting and occasionally surprising findings, some with potential therapeutic implications (e.g., activation of bitter taste receptors in the airway’s smooth muscle causes bronchodilation, suggesting a novel target for asthma therapy) (2). Of particular interest in the area of diabetes and obesity is the role of sweet taste receptors (STRs) in the intestine (3,4). The upper gastrointestinal tract is well-endowed with taste and fat receptors, with sweet taste being detected, as elsewhere, by a heterodimer of the taste 1 receptor (T1R) family, T1R2/T1R3. These receptors have been localized to intestinal brush and enteroendocrine cells, and are coupled with α-gustducin as the α-subunit of the G protein (Fig. 1). They recognize sugars, d-amino acids, sweet proteins, and artificial sweeteners. Of importance to a possible role in the incretin response, these receptors are colocalized with glucagon-like peptide 1 (GLP-1) and L cells containing peptide YY (PYY) and K cells containing glucose-dependent insulinotropic polypeptide (GIP) (3). Incidentally, fatty acid responsive GPRs are also coupled to GLP-1 release, but are found predominantly …

Could metformin be used in patients with advanced chronic kidney disease

To the Editor: We read with great interest the review article by Chowdhury et al. Over the last 5 years there has been great interest in relaxing the contraindication of renal impairment for prescribing metformin. We have examined the use of metformin in patients with advanced chronic kidney disease (CKD). Chowdhury et al. referenced our publication of a population pharmacokinetic model, which we used to simulate possible dosing regimens for patients with all grades of renal function (down to creatinine clearances of 15 mL/min). The goal of this analysis was to ensure that the 95th percentile peak plasma concentrations of metformin did not exceed 5 mg/L. These dosing regimens have been assessed by MedSafe (the New Zealand medicines regulatory agency) and have been incorporated into their metformin product label. We encourage other regulatory bodies to consider making similar changes. Metformin is largely eliminated unchanged by the kidneys and, consequently, a major concern is that patients with renal impairment will accumulate metformin and this could lead to the development of lactic acidosis, a serious adverse effect of metformin. A putative metformin plasma concentration of 5 mg/L has been suggested as being indicative of significant risk of metformin-associated lactic acidosis (MALA). We and others have suggested that metformin at therapeutic dosages is not a causative agent, even at concentrations >5 mg/L, but rather is an innocent by-stander. Many patients on metformin have comorbidities that increase the risk of lactic acidosis. Indeed, a recent retrospective study showed that, while metformin was significantly associated with an increased risk of the need for acute dialysis, this risk was conditional upon concomitant “patient frailty.” This implies that secondary characteristics that predispose a patient to enhanced lactate concentrations, such as age, renal function and cardiac failure, work in conjunction with metformin concentrations to induce damage. Our metformin dosing regimen in acute kidney injury has also been supported by Hung et al. Their study showed the adverse effects of “over-dosing” of metformin in the setting of advanced chronic kidney disease, showing that metformin increased all-cause mortality in a dose-dependent manner in patients with CKD stage 5. The design of novel formulations of metformin that reduce systemic exposure to metformin, such as a delayed release form absorbed from the distal small intestine, could further increase the safety of metformin in renally compromised patients. In addition to monitoring metformin plasma concentrations and renal function, a practice we and others encourage, we agree with the authors’ guidance on counselling patients with advanced CKD for “sick day rules.” One of the common signs patients reference prior to the onset of MALA is severe gastrointestinal symptoms (vomiting, diarrhoea). This should be a red-light warning for patients to cease metformin use and seek medical attention. Chowdhury et al. conclude that more studies examining the safety and efficacy of metformin in patients with advanced CKD are required. We have recently completed a small pharmacokinetic study on metformin in patients on chronic haemofiltration over 12 weeks. Furthermore, we propose to study metformin in a larger haemofiltration patient cohort, for a longer duration, our aim being to determine the optimum metformin dosing regimen required in this high-risk patient group (www.anzctr.org.au, ACTRN12616000675426). We, too, believe that the cardiovascular benefits associated with metformin use far outweigh the risks of MALA, particularly if the patients are monitored carefully.

Ectopic Cushing syndrome due to neuroendocrine prostatic cancer

2008; 3: 54–60. 21 Holtkamp FA, de Zeeuw D, Thomas MC, Cooper ME, de Graeff PA, Hillege HJ et al. An acute fall in estimated glomerular filtration rate during treatment with losartan predicts a slower decrease in long-term renal function. Kidney Int 2011; 80: 282–7. 22 Apperloo AJ, de Zeeuw D, de Jong PE. A short-term antihypertensive treatment-induced fall in glomerular filtration rate predicts long-term stability of renal function. Kidney Int 1997; 51: 793–7. 23 Ahmed AK, Kamath NS, El Kossi M, El Nahas AM. The impact of stopping inhibitors of the reninangiotensin system in patients with advanced chronic kidney disease. Nephrol Dial Transplant 2010; 25: 3977–82. 24 Einhorn LM, Zhan M, Hsu VD, Walker LD, Moen MF, Seliger SL et al. The frequency of hyperkalemia and its significance in chronic kidney disease. Arch Intern Med 2009; 169: 1156–62. 25 Adam WR. Hypothesis: a simple algorithm to distinguish between hypoaldosteronism and renal aldosterone resistance in patients with persistent hyperkalemia. Nephrology (Carlton) 2008; 13: 459–63.

Treatment of an atraumatic fracture: the importance of establishing a definitive diagnosis.

WE DESCRIBEa patient with the adult form of osteopetrosis who presented with a hip fracture. Osteopetrosis is a rare inherited disease of bone characterized by osteoclast dysfunction and failure of bone resorption. (1,2) This results in dense, deformed, sclerotic bone, which despite increased radiographic bone mineral density (BMD), (3,4) has an increased propensity to fracture. (5) Although osteopetro sis was suspected at surgery, a subsequent radiological report suggested a diagnosis of Paget’s disease. Bisphosphonate therapy was initiated, which may have exacerbated the clinical condition. This unusual case stresses the importance of making a definitive diagnosis in the setting of an atraumatic fracture. An early postmenopausal 48-year-old woman presented to our institution in March 2000 for an opinion regarding management of chronic lower back, bilateral upper thigh, and shoulder girdle discomfort. In 1997, a diagnosis of osteopetrosis was suggested at the time of internal fixation of a minimal trauma subtrochanteric fracture of the left femur. Because the fracture was slow to unite, 10 mg of alendronate was started. This was increased to 40 mg when progress X-rays were thought to show Paget’s disease. The bisphosphonate was stopped in January 2000 because of dyspepsia in the presence of a hiatus hernia. After this, the patient was referred to the Bone and Calcium Clinic at our institution for a further opinion. Symptomatic estrogen deficiency had developed at the age of 46 years, 14 years after a hysterectomy for menorrhagia. This was managed successfully with transdermal estrogen. The patient’s maternal uncle had sustained consecutive bilateral hip fractures and had been informed that he had “chalky bones.” Neither of the patient’s parents nor any of her grandparents or three siblings had sustained any fractures. Dietary calcium intake was adequate and she denied smoking or excessive alcohol consumption. There was no history of fluoride treatment or exposure. Examination revealed a body mass index (BMI) of 38 kg/m (weight, 96 kg; height 1.59 m). There was no hepa tosplenomegaly. Despite an antalgic gait, there were no long bone deformities and no focal neurological or cranial nerve abnormalities. Audiometry was normal. Serum alkaline phosphatase was normal (58 U/liter; reference range [RR], 30–100), and apart from a mildly elevated g-glutamyl transf rase (54 U/liter; RR, 35), the remainder of the liver function tests was unremarkable. Serum calcium, intact parathyroid hormone, and 25and 1,25-hydroxyvitamin D were all normal. Urinary hydroxyproline excretion was 16 mM/mMC (RR, 3.3–15) and serum osteocalcin was 11.4 mg/liter (RR, 3–18). Total creatine kinase was 164 U/liter (RR, 0–175), but the BB isoenzyme was elevated to .20% (RR, 0–1%). Total acid phosphatase was 8.4 U/liter (RR , 6.5). The full blood count, urea, creatinine, and serum and urine electrophoretograms were unremarkable. Hepatitis B and C serology was negative. A lateral plain X-ray of the thoracic spine showed bands of dense bone adjacent to the vertebral end plates (Fig. 1). A radionuclide bone scan (Fig. 2) revealed postsurgical changes in the left femoral neck consistent with previous f acture. In addition, there were typical features of osteopetrosis with splaying in the proximal and distal femoral metaphyses as well as the proximal tibial, fibular, and humeral metaphyses bilaterally. Facial bone uptake was prominent; arthritic changes were noted in the sacroiliac joints, hands, and spine. Bone densitometry revealed very high values in the lumbar spine (L2–L4, 2.5 g/cm ; T score, 111) and right femur (total hip, 2.1 g/cm ; T score,19).