Health consequences of obesity

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Physiological Consequences of Obesity

Endocrine Changes in Obesity

It is well documented that obesity is associated with changes in the normal endocrine profile. Many studies have focused particularly on the alterations in the sex steroid profile of obese individuals. This section of the article will briefly discuss the types of changes observed and their consequences on the health of the individual.

Oestrogens

Oestrogens are synthesized by aromatization of circulating testosterones. This conversion reaction is catalysed by the enzyme aromatase (Ali,) which is expressed at many sites throughout the body, including adipose tissue. Therefore, an increase in adipose tissue mass, results in a greater capacity for aromatization, and oestrogen levels rise.

The effects of obesity on oestrogen concentrations are augmented in postmenopausal women. In premenopausal, non-pregnant women, the principal site at which this takes place is the ovaries (Simpsom 2000) and so the contribution of adipose tissue to overall oestrogen synthesis is minor. However, after the menopause, adipose tissue becomes the main source of oestrogens (Simpson.)

Androgens

The increased capacity for aromatization results in hypoandrogenism in males, as a higher proportion of circulating testosterone is converted to oestrogen (Hammoud et al.) Other factors contributing to the decrease in circulating testoerone include insulin resistance and the suppression of the hypothalamic pituitary testicular axis (Hammoud.)

Most studies in premenopausal women have demonstrated that the concentration of free testosterone in the circulation increases with body weight. It has been proposed that the relationship between body weight and androgens is mediated by insulin and IGF-1, which are both increased in obese subjects.

Furthermore, as is the case for oestrogen, adipose tissue is an important site of peripheral testosterone production, due to local expression of 17 beta hydroxysteroid dehydroenase. Therefore there is a positive association between adipose tissue mass and androgen concentration.

SHBG

Sex steroids are highly lipophilic and are therefore carried in the circulation bound to proteins – sex hormone binding globulins (SHBG.) It is well documented that obesity results in a decreased concentration of SHBG. This is thought to be associated with the rise in insulin levels associated with obesity, as insulin inhibits hepatic synthesis of SHBG. The decreased concentration of binding protein results in an increase in the free fraction of sex steroids. (2)

Obesity and Cancer

It is estimated that 10% of all cancer deaths among non-smokers are related to obesity. Many hypotheses have been proposed to explain this, the most convincing of which is that alterations in endogenous hormone metabolism mediate the effects of obesity on cancer risk Kalle et al. This in part thought to be true due to the fact that sex steroids regulate the balance between cell proliferation, differentiation and apoptosis. 3

Many types of cancer are more prevalent in obese subjects, the most widely studied of which are breast and endometrial cancer. It has been observed that these types of cancer are associated with an increase in oestrogen concentration, decrease in plasma SHBG and an increase in androgen levels. (3, 2) These observations have led to the establishment of the unopposed oestrogen hypothesis. This hypothesis suggests that risk of cancer is due to increased exposure to oestrogen, which is unopposed by progestagens. This results in increased mitotic activity of cells. (Key et al) Increased mitosis, increases the risk of mutation accumulation, and thus the development of cancer.

Infertility

Obesity is thought to account for around 6% of primary infertiliy. (1)

Women

Many studies have observed increased number of atretic follicles in obese women. This reflects the increased risk of anovulatory infertility in obese women. * The anovulation is mainly due to hyperandrogenism. High androgen levels cause increased apoptosis of the granulosa cells, damage to the endometrium and developing oocytes. Excess oestrogen also contributes to infertility. This is partly due to increased negative feedback causing decreased gonadotrophin secretion (1,

There is a well established link between PCOS and obesity. This syndrome is characterized by anovulatory infertility, obesity, hirsutism, multiple ovarian cysts and insulin resistance. ? It is unkown whether PCOS is a cause or effect of obesity (*.)

Men

Obese men generally express “hyperoestrogenic hypogonadotropic hypogonadism.” (hAMMOUD, one of other first ref) Essentially the high oestrogen levels, combined with low testosterone levels result in subfertility.

Many studies have reported a negative association between spermatogenesis and increasing BMI. The mechanism mediating this association is yet to be identified. However, it has been suggested that the gerneral hypoandrogenism observed in obese males, may reflect a reduced concentration of testosterone within the testes, which would cause a reduction in sperm count. Furthermore, the observed hyperoestrogenism causes inappropriate suppression of the hypothalamic-pituitary-gonadal axis, resulting in reduced spermatogenesis. The effects of obesity on spermatogenesis is thought to be qualitiative as well as quantitative. For example, .Ghanayem et al . . showed reduced sperm motlity and hyperactivated progression.

Obesity has also been associated with erectile dysfunction (hammoud, first). Feldman et al found that 79% of men suffering erectile dysunction were overweight or obese. Although erectile dysfunction is hought to be in part a result of hypoandrogenism, the main cause is thought to be related to endothelial dysfunction and disruption of the nitric oxide pathway.

In summary, alterations in sex steroid profiles as a result of obesity have many adverse effects on health. The most well documented health consequences are cancer and infertility.

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Psychosocial Consequences of Obesity

The relationship between obesity and mental health has been the subject of continuous debate over the past 30 years and remains a topic of extensive deliberation . Early studies exploring the relationship were consistent with the “jolly fat” hypothesis, suggesting that obesity confers a protective role against anxiety and depressive disorders;1 however, the weight of more recent studies contradict the “jolly fat” hypothesis and suggest that the increasing global prevalence of both depression and obesity are functionally linked.2,3 The underlying mechanisms and direction of this link remain largely unknown,3 although recent research has indicated that gender, obesity severity, comorbid physical illness, stress and abdominal fat distribution are important mediating risk factors for the development of an obesity-mental disorder link.1,2,4,5, These newly discovered mediators give rise to new hypotheses, involving over-activity of the hypothalamic-pituitary-adrenocortical axis,1,2 side-effects of medication for depression, and the social stigmatization of obesity.2

A recent nationally representative Canadian study, whose methodology controlled for sociodemographic factors and comorbid physical health problems, found significant positive relationships between obesity and an array of lifetime psychiatric disorders and past-year mood and anxiety disorders.2 These conclusions are consistent with current literature.6,5,7,8 Further subgroup analyses revealed that obese women had a greater susceptibility to specific mental disorders compared to men, including depression, mania, panic attacks, panic disorder, social phobia and agoraphobia (with and without panic).3 These findings are consistent with previous research, and thus reinforce the notion that obese women have an enhanced vulnerability towards mental disorders.2,4,5,7,9 This result may be explained in terms of the increased consciousness amongst women to conform to a socially desirable image and weight.3 The study also positively linked obesity to suicidal behaviours and negatively linked obesity with past-year drug dependence3; both these findings are supportive of existing literature.6,7,10 Mather et al. (2009) suggest that the former may be attributed to the social stigmatization attached to obesity, inducing feelings of decreased self-worth and decreased self-esteem that fuel suicidal thoughts; and the latter due to protective effects of obesity, arising through food and addictive drugs competing for the same reward sites in the brain.3,11 At face value, this data appears convincing, however, it is important to note that some studies fail to identify mental disorders as a psychosocial consequence of obesity.12,13 Similarly, whilst much research is indicative of sex differences between obesity and mental disorders,1,5 this is not a unanimous conclusion.6,7,14 In addition, some research only identifies associations amongst the severely obese, who illustrate a BMI of >35kg/m2.5 These variable conclusions may in part be attributed to methodological differences between studies.5

1 Rivenes, A.C., Harvey, S.B., and Mykltun, A. (2009). The relationship between abdominal fat, obesity, and common mental disorders: Results from the HUNT Study. Journal of Psychosomatic Research, 66: 269-275.

2 Stunkard, A.J., Faith, M.S. and Allison, K.C. (2003). Depression and Obesity. Society of Biological Psychiatry, 54: 330-337.

3 Mather, A.A., Brian, J.C., Enns, M.W. and Sareen, J. (2009). Association of obesity with psychiatric disorders and suicidal behaviours in a nationally representative sample. Journal of Psychosomatic Research, 66: 277-285.

4 Simon, G.E., Ludman, E.J., Linde, J.A., Operskalski, B.H., Ichikawa, L., Rohde, P., Finch, E.A. and Jeffery, R.W. (2008). Association between obesity and depression in middle-aged women. Gen Hosp Psychiatry, 30(1): 32-39.

5 Scott, K.M., Bruffaerts, R., Simon, G.E., Alonso, J., Angermeyer, M., de Girolamo, G., Demyttenaere, K., Gasquet, I., Haro, J.M., Karam, E., Kessler, R.C., Levinson, D., Mora, M.E.M., Browne, M.O., Ormel, J.H., Villa, J.P., Uda, H. and von Korff, M. (2008). Obesity and Mental Disorders in the General Population: Results from the World Mental Health Surveys. Int J Obes, 32(1):192-200.

6 Simon, G.E., Von Korff, M., Saunders, K., Miglioretti, D.L., Crane, P.K., van Belle, G. and Kessler, R.C. (2006). Association Between Obesity and Psychiatric Disorders in the US Adult Population. Arch Gen Psychiatry, 63: 824-830.

7 Carpenter, K.M., Hasin, D.S., Allison, D.B. and Faith, M.S. (2000) Relationships between obesity and DSM-IV major depressive disorder, suicide ideation, and suicide attempts: results from a general population study. Am J Public Health, 90:251–257.

8 Onyike, C.U., Crum R.M. and Lee H.B. (2003). Is obesity associated with major depression? Results from the third National Health and Nutrition Examination Survey. Am J Epidemiol, 158:1139–1147.

9 Scott, K.M., Oakley Browne, M.A., McGee, M.A. and Wells, J.E. (2006). Mental-physical comorbidity in Te Rau Hinengaro: the New Zealand Mental Health Survey (NZMHS). Australian and New Zealand Journal of Psychiatry, 40:882–888. 10 Dong, C., Li, W.D. and Li, D. (2006). Extreme obesity is associated with suicide attempts: results from a family study. Int J Obes, 30: 388-390.

11 Kleiner, K.D., Gold, M.S., Frost-Pineda, K. (2004). Body mass index and alcohol use. J Addict Dis, 23:105-118.

12 Hasler, G., Pine, D.S. and Gamma, A. (2004). The associations between psychopathology and being overweight: A 20-year prospective study. Psychol Med, 34:1047–157.

13 Faith, M.S., Matz, P.E. and Jorge, M.A. (2002). Obesity-depression associations in the population. J Psychosom Res, 53:935–942.

14 Onyike, C.U., Crum, R.M., Lee, H.B., Lyketsos, C.G. and Eaton, W.W. (2003). Is obesity associated with major depression? Results from the Third National Health and Nutrition Examination Survey. American Journal of Epidemiology. 158(12):1139–1147. Rachael White 15:09, 23 October 2009 (UTC)

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Cardiovascular Disease in Obesity

Obesity is well known for its association with many serious of diseases, including type 2 diabetes mellitus, coronary heart disease (CHD) amongst many others . BMI has a close correlation with the incidence of several chronic conditions caused by excess fat, and waist circumference correlates with the measure of risk for CHD such as hypertension or blood lipid levels(1).

Obesity increases the risk of cardiovascular disease and premature death which may be indirectly mediated through risk factors associated with the metabolic syndrome . [PICTURE]. Central deposition of adipose tissue increases the risk of cardiovascular morbidity and mortality, including stroke, congestive heart failure, myocardial infarction and cardiovascular death(2). Waist-hip ratios are commonly used to assess this type of body fat distribution. Obesity causes an increase in total body oxygen consumption due to excess lean tissue mass as well as the oxidative demands of metabolically active adipose tissue. This results in an increase in cardiac output1. The left ventricle dilates to accommodate the increased venous return with subsequent development of eccentric hypertrophy to keep the wall stress normal(3). Eventually the ventricle can no longer adapt to volume overload and the dilation of LV results in decreased ventricular contractility(1). With LV hypertrophy, reduced ventricular compliance alters ability of the chamber to accommodate an increased volume during diastole and this results in diastolic dysfunction. A combination of systolic and diastolic dysfunction leads to clinically significant heart failure(1). [PICTURE] Hypertension also becomes more prevalent with increasing severity of obesity(3). In men a BMI of <25 or >30 shows a prevalence of hypertension of 15% and 42%, respectively; in women these are 15% and 38%, respectively(3). Fatal arrhythmias may be the most frequent cause of death among obese people as increased catecholamine and free fatty acid levels may affect repolarization(3). The Framingham Study shows that sudden cardiac death was 40 times higher in obese men and women. In the NHANES III study, 30% of obese patients with glucose intolerance had a prolonged corrected QT (QTc) interval(3). A QTc of more than 0.42 seconds was associated with increased mortality in “healthy” obese patients(3). Schouten et al found that 8% of obese individuals had QTc interval of more than 0.44 seconds and in 2% it was more than 0.46 seconds.

Increased adiposity and reduced physical activity are strong and independent predictors of CHD and death. For each unit increase in BMI, the risk of CHD increases by 8%. However each 1 hour metabolic equivalent increase in activity score decrease CHD risk by 8%(2). Physical activity attenuates the risks of obesity on coronary health and also increases myocardial oxygen supply, improving myocardial contraction and electrical stability(2). Various studies have shown that obesity is an independent predictor of coronary artery disease and this is also linked to BMI(3) and that obesity accelerates atherosclerosis many years before the clinical signs become obvious. In autopsies among 15-35 year olds who died from accidental causes, plaques and ulceration in the coronary arteries and abdominal aorta were found and the extent of damage related to the amount of abdominal fat and BMI(3).

The risk of stroke increases with increased BMI and waist-hip ratio. In the prospective Physician’s Health study, results showed that an increase of 1 BMI unit, increased the rate of ischemic stroke by 4% and 6% for haemorrhagic stroke. The underlying mechanisms linking increased BMI to increased stroke risk are not clear but it is thought that it could be mediated by the prothrombotic and proinflammatory state in obesity(3). Adipose tissue is considered as an active endocrine organ(2). Release of adipokines (e.g. leptin and adiponectin), proinflammatory cytokines (IL-6 and CRP) and hypofibrinolytic factors (PAI-1) might, together, lead to increased oxidative stress and endothelial dysfunction, finally promoting atherosclerosis which then leads to stroke(2). Terao et al (2008) investigated the effect of inflammatory and injury reposonse to ischaemic stroke in obese mice, and discovered that when the middle cerebral artery (MCA) was occluded and reperfused, the inflammatory and injury responses were worse in obese mice (ob/ob) than in wild type mice(4). Monoctye chemoattractant protein-1 appears to be involved in the exaggerated responses to ischaemic stroke in obese mice.

1. Kopelman P.G. (2000) Obesity as a medical problem. Nature. 404:635-642.

2. Gaal L.F.V. et al. (2006) Mechanisms linking obesity with cardiovascular disease. Nature. 444:875-879.

3. Mathew B. et al. (2008) Obesity: effects on cardiovascular disease and its diagnosis. J Am Board Fam Med. 21:562-568.

4. Terao S. et al. (2008) Inflammatory and injury responses to ischemic stroke in obese mice. Stroke. 39:943-950

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References

Obesity and non-alcoholic fatty liver disease

Disease Definition NAFLD, refers to the accumulation of fat, mainly triglycerides, in hepatocytes that exceeds 5% of the liver weight.(1)

NAFLD primarily results from insulin resistance, and thus frequently occurs as part of the metabolic changes that accompany obesity.(1)

NAFLD is an increasingly recognized condition that may progress to end stage liver disease(2)

NAFLD refers to a wide spectrum of liver damage ranging from simple steatosis to steatohepatitis, advanced fibrosis and cirrhosis. (2) Clinical presentation Patients may complain of fatigue or malaise and a sensation of fullness or discomfort in the right upper abdomen(1)

Insulin resistance and oxidative stress play a key role in the development and progression of NAFLD. Mild to moderate elevation of serum aminotransferases is the most common and often the only laboratory abnormality.(1)

Histological features include steatosis alone or in combination with mixed inflammatory cell infiltration, hepatocyte ballooning and necrosis, Mallory’s hyaline and fibrosis. These histalogical features are mostly seen in acinar zone 3…(1) NAFLD is histologically indistinguishable from the liver damage resulting from alcohol abuse. Liver biopsy features include steatosis, mixed inflammatory-cell infiltration, hepatocyte ballooning and necrosis, glycogen nuclei, Mallory’s hyaline and fibrosis. The presence of these features, alone, or in combination, accounts for the wide spectrum of NAFLD.(2) A finding of fibrosis in NAFLD suggests more advanced and severe liver injury. According to a number of cross sectional studies including a total of 673 liver biopsies, some degree of fibrosis is found in up to 66% of patients at the time of diagnosis, whereas severe fibrosis is found in 25% and well established cirrhosis in 14%.(2) The combination of steatosis, infiltration by mono-nuclear cells or polymorphonuclear cells and hepatocyte ballooning and spotty necrosis is known as non-alcoholic steatohepatitis. Most patients with this type of non-alcoholic fatty liver disease have some degree of fibrosis, whereas Mallory’s hyaline may or may not be present. The severity of steatosis can be graded on the basis of the extent of involved parenchyma. (2) Treatment of patients with NAFLD should focus on the management of associated conditions including obesity and glucose and lipid abnormalities. Lifestyle intervention with diet and increased physical activity are the cornerstone in the management of NAFLD. Medications including insulin sensitizers and antioxidants are being evaluated in placebo-controlled trials. (1)

Patients with NAFLD with simple steatosis seem to follow a relatively benign course, whereas in others, NAFLD progresses to advanced fibrosis and cirrhosis with its consequent complications of portal hypertension and liver failure. Cirrhotic stage NAFLD constitutes a common indication for liver transplantation. As in other types of cirrhosis, cirrhotic stage NAFLD may be complicated by hepatocellular carcinoma (HCC). (1)

Most patients with NAFLD have no symptoms or signs of liver disease at the time of diagnosis, although many patients report fatigue or malaise and a sensation of fullness or discomfort on the right side of the upper abdomen. Hepatomegaly is the only physical finding in most patients. Acanthosis nigricans may be found in children with NAFLD.(2)

Mildly to moderate elevated serum levels of aspartate aminotransferase, alanine aminotransferase, or both are the most common and often the only laboratory abnormality found in patients with NAFLD. (2)

The ratio of aspartate aminotransferase to alanine aminotransferase is usually less than 1, but this ratio increases as fibrosis advances, leading to a loss of its diagnostic accuracy in patients with cirrhotic NAFLD. (2)

Other abnormalities including hypoalbuminaemia, a prolonged prothrombin time, and hyperbilirubinaemia, may be found in patients with cirrhotic stage NAFLD.

Elevated serum ferritin levels are found in half the patients, and increased transferring saturation is found in 6 to 11% of patients. Hepatic Iron index and hepatic Iron level, however are usually in the normal range. It has been suggested that heterozygosity for the hemachromatosis gene may ne increased in NAFLD and that hepatic iron overload may be associated with more severe liver disease. (2) Diagnosis The diagnosis of NAFLD is usually suspected in persons with asymptomatic elevation of aminotransferase levels, radiological findings of fatty liver, or unexplained persistent hepatomegaly. The clinical suspicion of NAFLD and its severity can only be confirmed with a liver biopsy.(2) The diagnosis of NAFLD requires the exclusion of alcohol abuse as the cause of liver disease, a daily intake as low as 20g in females and 30g in males may be sufficient to cause alcohol induced liver disease in some patients. (2)

Risk Factors The central obesity phenotype is associated with increased intraabdominal (or visceral) fat. Visceral adipose tissue has greater lipolytic potential than subcutaneous adipose tissue, and the release of free fatty acids from visceral fat into the portal circulation creates a “first pass effect”. Increased free fatty acid concentrations, in turn, are considered a major mediator of insulin resistance. In contrast free fatty acid flux and concentrations in individuals with predominantly lower body obesity tend to be normal, regardless of BMI. Therefore, patients with central obesity are characteristically insulin resistant, and more commonly present with NAFLD than patients with lower-body obesity. (1) Obesity… coexisting conditions frequently associated with NAFLD. (2) The reported prevalence of obesity in several series of patients with non alcoholoic fatty liver disease varied between 30 and 100 %.(2) The prevalence of NAFLD increases by a factor of 4.6 in obese people.(2) Truncal obesity seems to be an important risk factor for NAFLD, even in patients with a normal BMI.

Pathogenesis The pathogenesis of NAFLD has remained poorly understood since the earliest description of the disease. Much current thinking remains hypothetical, since the mechanism or mechanisms are still being worked out. It is not yet understood why simple steatosis develops in some patients, whereas steatohepatitis and progressive disease develops in others; differences in body fat distribution or antioxidant systems , possibly in the context of genetic pre-disposition, may be among the explanations.(2) A net retention of lipids within hepatocytes, mostly in the form of triglycerides, is a prerequisite for the development of NAFLD. The primary metabolic abnormalities leading to lipid accumulation are not well understood, but they could consist of alterations to the pathways of uptake, synthesis, degredation, or secretion in hepatic lipid metabolism resulting from insulin resistance. Insulin resistance is the most reproducible factor in the development of NAFLD. The molecular pathogenesis of insulin resistance seems to be multi-factorial, and several molecular targets involved in the inhibition if insulin action have been identified. These include Rad (ras associated with diabetes), which interferes with essential cell functions (growth, differentiation, vesicular transport, and signal transduction); PC-1 (a membrane glycoprotein that has a role in insulin resistance), which reduces insulin stimulated tyrosine kinase activity; leptin, which induces dephosphorylation of insulin receptor substrate-1; fatty acids, which inhibit insulin induced phosphorylation of insulin receptor substrate-1 snf reduced the expression of the insulin dependant transport molecule Glut-4. Insulin resistance leads to fat accumulation in hepatocytes by two main mechanisms: lipolysis nad hyperinsulinaemia.(2) Prevalence NAFLD affects 10 to 24% of the general population in various countries. This prevalence increases to 57.5% to 74% in obese persons. NAFLD affects 2.6% of children and 22.5% to 52.8% of obese children(2). NAFLD is the most common cause of abnormal liver test results among adults in the United States.(2) Prognosis Changes in fibrosis stages have been specifically evaluated in four independent studies. Overall fibrosis progresses over time but remains stable for a number of years in many cases, and may actually improve spontaneously in some. Higher BMI and more insulin resistance or he presence of type 2 diabetes are risk factors for a higher rate of fibrosis progression.(1) It is the thirteenth most common cause of death in the common population. (1) Prevention Preventing the development of insulin resistance and its clinical manifestations is expected to prevent NAFLD development. Weight gain and obesity resulting from increasingly sedentary lifestyles and high fat diets seem to be a key factor in the development of insulin resistance and NAFLD. Thus achieving and maintaining appropriate weight control would be expected to prevent the development of NAFLD, as would the treatment of glucose and lipid abnormalities.(1) Improvement of liver test results is almost universal in obese adults and children after weight reduction. The degree of fatty infiltration usually decreaseswith weight loss in most patients, although the degree of necroinflammation and fibrosis may worsen. The rate of weight loss is important and may have a critical role in determining whether liver histological findings will improve or worsen. In patients with high degree of fatty infiltration, rapid weight loss may promote necroinflammation, portal fibrosis and bile stasis. A weight loss of about 500g a week in children and 1600g per week in adults has been advocated. . Nevertheless, the most effective rate and degree of weight loss still have to be established. (2) An attempt at gradual weight loss along with appropriate control of serum glucose and lipid levels is a useful first step. Perhaps these should be the only treatment recommendations for patients with NAFLD with pure steatosis and no evidence of necroinflammation or fibrosis. Since most patients who have problems form NAFLD have steatohepatitis, treatment is more likely to be aimed at those with steatohepatitis, Patients with steatohepatitis, particularly those with fibrosis on liver biopsy, should be monitored closely, with more careful metabolic control, and be offered enrolment in clinical trials. Many patients with cirrhotic stage NAFLD have coexisting conditions which reduce the usefulness of liver transplantation. Nevertheless, for the patient with decompensatied cirrhosis, liver transplantation is a potential therapeutic alternative. NAFLD, however, may recur in the allograft or develop after liver transplantation for cryptogenic cirrhosis. (2)