Yesterday, at the ongoing 2010 European Society of Cardiology, I attended as session focussing on the potential role of excess fat tissue that may surround blood vessels or the heart. Regular readers will recall, that the role of these fat depots have been a focus of my interest in past years.

A new study by Olga Lamacchia and colleagues from the University of Foggia, Italy, published online in Nephrology Dialysis and Transplantation, suggests that increased fat deposition around the kidneys may also pose a risk marker for the development of chronic kidney disease in patients with type 2 diabetes.

The researchers performed a cross-sectional study in 151 patients with type 2 diabetes that included measurements of kidney function, blood flow and ultrasound assessment of the fat surrounding their kidneys.

Despite adjustment for both BMI and waist circumference, the amount of para- and perirenal fat predicted increases in renal resistance index and reduced glomerular filtration rate.

Furthermore, in subjects with waist circumference above the diagnostic values of metabolic syndrome kidney function significantly and progressively declined across tertiles of para- and perirenal fat thickness.

As explanations for this phenomenon, the authors discuss the potential role of increased intra-abdominal pressure of visceral obesity, direct physical compression of the kidneys, or mechanisms related to the secretion of adipokines and other factors by the surrounding fat tissue that may affect kidney function.

For anyone familiar with kidney anatomy, it may also be of interest to recall that as fat deposition grows within the renal sinus, compression of various renal structures, especially of the inner medulla that, unlike the entire kidney, is not protected by the fibrous capsule, may occur. Increases in renal interstitial fluid hydrostatic pressure tends to compress the medullary vasa recta and tubules, reducing blood and tubular flow through the distensible loop of Henle, which could ultimately result in greater fluid, sodium and urate reabsorption.

As my colleagues and I have previously suggested for epicardial fat, the authors suggest that measurement and recording of peri-renal fat should perhaps also be part of routine renal ultrasound assessments.

Although this recommendation, may be a bit premature, the study nevertheless adds to the continuing literature demonstrating that in obesity and the accumulation of excess fat it is not just the “how much” but rather the “exactly where”, that ultimately determines the development of certain weight-related health problems.

AMS
Stockholm, Sweden

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Lamacchia O, Nicastro V, Camarchio D, Valente U, Grisorio R, Gesualdo L, & Cignarelli M (2010). Para- and perirenal fat thickness is an independent predictor of chronic kidney disease, increased renal resistance index and hyperuricaemia in type-2 diabetic patients. Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association PMID: 20798120

I am currently attending the 2010 Scientific Meeting of the European Society of Cardiology, here in Stockholm.

In a session on diabetes and heart disease, Mamas Mamas from the University of Manchester, UK, reported that abnormal glucose tolerance (pre-diabetes or diabetes) is found in about 50% of unselected heart failure patients.

Importantly, only a small fraction of patients will have abnormal fastng glucose, suggesting that glucose tolerance tests are essential to determine abnormal glucose disposition in patients with heart disease.

Insulin resistance, in part due to decreased exercise capacity, may also be exacerbated in heart failure patients.

Longitudinal studies confirm the negative prognostic relevance of abnormal glucose tolerance in with a 35% increased risk in cardiovascular death with each 1% increase in HbA1c levels.

However, Mamas also noted that while the Diabetes Prevention Program, showed a marked reduction in the progression to diabetes with lifesyle intervention in individuals with pre-diabetes, the findings from this study did not suggest any reduction in heart failure or cardiovascular deaths.

Indeed, despite the wide recognition that diabetes is an important risk factor for heart disease, data on the prevention or improvement in cardiac function with diabetes treatment remains rather disappointing.

On a similar note, Clyde Yancy, Baylor University Medical Center, Dallas, TX, spoke on the issue of diabetic cardiomyopathy.

As Yancy pointed out, diabetic cardiomyopathy defined as significantly impaired cardiac function in diabetic patients in the absence of epicardial vascular disease, left-ventricular hypertrophy, valvular disease, or other causes of cardiomyopathy, makes it largely a diagnosis of exclusion.

The association between diabetic cardiomyopathy and diabetic retinopathy suggests that microvascular abnormalities may play a role.

However, there may also be direct metabolic effects of dysglycemia and hyperinsulinemia, resulting in lipotoxicity and generation of oxidative stress leading to apoptosis and fibrosis. This may well explain the findings of left-ventricular remodeling, myocardial fibrosis, collagen and lipid deposition with altered compliance and diastolic dysfunction, seen in patients with diabetic cardiomyopathy.

Animal studies show that increased glucose levels can increase expression of box-1 protein, involved in pro-inflammatory defense mechanisms. Blocking this response may, thus, prove a novel approach to preventing and treating cardiomyopathy.

This is important because, as noted previously by Mamas (and other speakers in this session), current anti-diabetic treatments do not appear to have the expected beneficial effects on heart function or macrovascular disease in patients with diabetes.

In the context of obesity management it is therefore perhaps important to recall the fact that one of the most impressive findings from bariatric surgery studies, is the remarkable reduction (upto 80%) of diabetes related mortality - something conventional diabetes treatments have yet to demonstrate.

Whether similar benefits can be seen with more moderate weight loss of course remains to be seen, nevertheless, it is certainly increasingly apparent that simply controlling blood glucose levels in patients with diabetes may not be the answer.

AMS,
Stockholm, Sweden

Psoriasis is a chronic, autoimmune disease that causes red, scaly patches to appear on the skin, and affects 2-3% of the population in Western countries.

Several previous reports have linked an association between obesity and psoriasis and studies indicate that obese patients with psoriasis are more difficult to treat.

This complex relationship between posoriasis and excess weight is now reviewed by Bremmer and colleauges from the University of Portland, Oregon, in an article released online by the Journal of the American Academy of Dermatology.

The authors performed a literature review and identified numerous studies that support an association between obesity and psoriasis.

As the authors note in their discussion:

“Several mechanisms by which psoriasis could lead to obesity have been proposed, including increased social isolation, increased unhealthy dietary habits, increased depression, increased alcohol consumption, and decreased physical activity, particularly secondary to psoriatic arthritis. In fact, one case-control study found that both males and females with psoriasis report consuming significantly more total fat, saturated fat, and alcohol than their respective healthy controls.”

While weight gain has been associated with increase in psoriasis prevalence and symptoms, weight loss has been described to substantially reduce skin lesions and other symptoms of psoriasis, suggesting a causative link in the association between excess weight and psoriasis.

Not only are obese patients with psoriasis more difficult to treat, they also appear to be more likely to experience adverse effects to medications and are less likely to respond favorably to systemic therapies.

Unfortunately, as the authors point out, there is currently little evidence to guide clinicians to the best treatment choices for obese patients with psoriasis.

Given the frequency of psoriasis that I see in my obesity clinic, I can only confirm that this certainly appears to be an area that would warrant further study.

AMS
Edmonton, Alberta

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Bremmer S, Van Voorhees AS, Hsu S, Korman NJ, Lebwohl MG, Young M, Bebo BF Jr, Blauvelt A, & National Psoriasis Foundation (2010). Obesity and psoriasis: From the Medical Board of the National Psoriasis Foundation. Journal of the American Academy of Dermatology PMID: 20692722

As blogged before, any medical condition that affects mobility, can potentially promote weight gain and the development of obesity with all its mental, physical and socioeconomic sequelae.

This of course also applies to patients diagnosed with multiple sclerosis (MS), a progressively disabling disease of the central nervous system currently affecting an estimated 2·5 million people worldwide. Multiple sclerosis is also the most common non-traumatic cause of disability in young adults.

In addition, patients with multiple sclerosis also often have psychiatric comorbidities ranging from depression, anxiety and social phobias to sleep disorders and chronic pain, which can all further adversely affect ingestive behaviour.

In a paper by Ruth Ann Marrie and Ralph Horowitz from the University of Manitoba, Winnipeg, Canada, just published in Lancet Neurology, the authors discuss why recognising obesity and other chronic illnesses in patients with multiples sclerosis is so important.

Apart from promoting the obvious sequelae of hypertension, diabetes and heart disease, obesity is also associated with delayed diagnosis of multiple sclerosis and obese patients tend to have higher levels of immobility and disability at the time of diagnosis.

Conversely, the diagnosis of comorbidities could be delayed by mistakenly attributing neurological symptoms such as progressive inability to walk, pain, or seizures to the pre-existing diagnosis of MS.

Corticosteroids used for relapses, may also contribute to weight gain and worsening of diabetes.

As the authors point out in the discussion:

“Further work is needed to establish whether pre-existing comorbidities affect the risk and phenotype of multiples sclerosis and, if so, how. Data from some studies indicate that comorbidities and health behaviours also affect disease progression. These findings need to be verified, and a broader range of disability outcomes, such as upper extremity and cognitive function, need to be taken into account. From a therapeutic perspective, important questions include whether comorbidities affect treatment choice, response, tolerability, and adherence, and whether we should use different treatment strategies in the presence of a comorbidity.”

As in all patients with impaired mobility and other physical or mental comorbidities, weight management can be challenging and should probably start well before weight gain sets in.

AMS
Edmonton, Alberta

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Marrie RA, & Horwitz RI (2010). Emerging effects of comorbidities on multiple sclerosis. Lancet neurology, 9 (8), 820-8 PMID: 20650403

Male hypogonadism with low testosterone levels can negatively affect muscle mass and has been associated with the increased accumulation of visceral fat. Thus, in clinical practice it may be important to assess older men presenting with weight gain for testosterone deficiency.

The latest issue of the New England Journal of Medicine features two articles relevant to this issue.

In the first article, Frederick Wu and colleagues (for the EMAS group) surveyed a random population sample of 3369 men between the ages of 40 and 79 years at eight European centers regarding general, sexual, physical, and psychological health. Levels of total testosterone were measured in morning blood samples.

Symptoms of poor morning erection, low sexual desire, erectile dysfunction, inability to perform vigorous activity, depression, and fatigue were significantly (inversely) related to the testosterone level. However, only the three sexual symptoms had a syndromic association with decreased testosterone levels diagnostic of hypogonadism.

Importantly, none of the non-sexual symptoms (decreased energy levels, depression, loss of strength, etc.) were specific enough to screen for or diagnose testosterone deficiency.

The authors conclude that late-onset hypogonadism can be defined by the presence of at least three sexual symptoms associated with a total testosterone level of less than 11 nmol per liter (3.2/mL) and a free testosterone level of less than 220 pmol/L (64 pg/mL).

In the second article, Shehzad Basaria and colleagues from Boston University, examine the efficacy and safety of testosterone supplementation in older men (Testosterone in Older Men with Mobility Limitations (TOM) trial).

A total of 209 Community-dwelling men (mean age, 74 years) with limitations in mobility and low serum testosterone levels were randomly assigned to receive placebo or testosterone gel for 6 months. Not surprisingly, participants had a high prevalence of hypertension, diabetes, hyperlipidemia, and obesity at the time of enrollment into the trial.

Just three years into the study, the data and safety monitoring board recommended that the trial be discontinued because there was a significantly higher rate of adverse cardiovascular events in the testosterone than in the placebo group.

During the course of the study, significantly more men in the testosterone group than in the placebo group had cardiac, respiratory, and dermatologic events.

Of particular concern to the data and safety monitoring board was the greater number of subjects with cardiovascular-related events (23 vs. 5) and atherosclerosis-related events (7 vs. 1).

On a positive note, the testosterone group did have significantly greater improvements in leg-press and chest-press strength and in stair climbing while carrying a load than the placebo group.

While the the study suggests that treating testosterone deficiency in older men with limitations in mobility and a high prevalence of chronic disease is not without risk, the authors raise some important caveats in interpreting this finding.

For one, the overall number of adverse events is rather small and there may have been some limitations with respect to the ascertainment of adverse events. Caution is also warranted in extrapolating these findings to other doses and formulations of testosterone or to other populations, particularly young men who have hypogonadism without cardiovascular disease or limitations in mobility.

I guess further studies will be needed to address the efficacy and safety of testosterone treatment for male hypogonadism. Clinicians will certainly have to carefully assess and discuss the risk/benefit ratio of testosterone substitution treatment with their patients.

AMS
Edmonton, Alberta

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Wu FC, Tajar A, Beynon JM, Pye SR, Silman AJ, Finn JD, O’Neill TW, Bartfai G, Casanueva FF, Forti G, Giwercman A, Han TS, Kula K, Lean ME, Pendleton N, Punab M, Boonen S, Vanderschueren D, Labrie F, Huhtaniemi IT, & the EMAS Group (2010). Identification of Late-Onset Hypogonadism in Middle-Aged and Elderly Men. The New England journal of medicine PMID: 20554979

Basaria S, Coviello AD, Travison TG, Storer TW, Farwell WR, Jette AM, Eder R, Tennstedt S, Ulloor J, Zhang A, Choong K, Lakshman KM, Mazer NA, Miciek R, Krasnoff J, Elmi A, Knapp PE, Brooks B, Appleman E, Aggarwal S, Bhasin G, Hede-Brierley L, Bhatia A, Collins L, Lebrasseur N, Fiore LD, & Bhasin S (2010). Adverse Events Associated with Testosterone Administration. The New England journal of medicine PMID: 20592293