This blog provides free general information for anyone who is seeking to understand the adverse impact of obesity on our health, not intended as a medical consult. Please seek proper medical advice for individual assessment and management.

The crucial learning points are:

• How to measure and categorize obesity
• The clinical consequence of obesity on our body system
• Understand what is metabolic syndrome
• The pathophysiology of obesity
• What is the benefit of bariatric/metabolic surgery

How to measure and define obesity

Traditionally obesity has been measured in quantitative terms by measuring total body weight (in kilograms or pounds) and calculating the body mass index using a mathematical formula (Quetelet index). The World Health Organization (WHO) classification system (listed below) has widely used around the world since the 1990s and recommendations for bariatric surgery has been based on BMI calculation (as established by the National Institutes of Health since 1991). However we now recognized the limitation of using this criteria because it does not take into account the non Caucasian population, which led to different Asian countries putting forward its own recommendations for bariatric surgery, and more importantly weight alone is insufficient to determine who is more at risk to develop adverse health problems and complications associated with morbid obesity.

More recently obesity is assessed in qualitative terms by measuring individual risk factors for metabolic syndrome. The emphasis here is to recognize central (also know as visceral, male pattern or Android) obesity, which is an essential component of metabolic syndrome.  Evaluations include measuring central fat distribution (waist circumference, neck diameter), biochemical markers (such as blood test for glucose intolerance, insulin resistance, Type 2 diabetes mellitus, hypercholesterolaemia, hyperlipidaemia, inflammatory markers (such as CRP), liver function test) and specialized investigations (eg. liver biopsies for liver cirrhosis, sleep studies for obstructive sleep apnoea).

Body weight measurements:

Body weight is calculated in kilograms, height in metres (the metric system)

Body mass index (BMI) is weight/height square (kg/m²)

BMI prime is actual BMI/BMI 25 (ratio)

Circumference measurements:

Waist circumference (cm) is the circumference around the widest waist line

Hip circumference is widest circumference (cm) around the buttocks or greater trochanter

Waist:hip ratio (WHR) can then be determined

Hence fat distribution is described as apple versus pear shape obesity (emphasizing that male apple shaped, visceral or central obesity is different from female pear shape obesity), recognizing the fact that android obesity may be a warning sign for those at a higher risk to develop metabolic complications.

Biochemical measurements:

Blood tests that are usually performed include:

Fasting cholesterol (LDL, HDL, total cholesterol) and triglycerides

Random blood glucose plus other test if diabetes is suspected (eg. oral glucose tolerance test)

Liver function test (to screen for fatty liver disease)

Serum or urine cortisol level (to exclude Cushing’s syndrome)

Thyroid function test (to exclude hypothyroidism) 

 

Tabulated below are different categories of obesity and the general recommendations for bariatric surgery.  The distinction between the Caucasian and Asian standard is also listed for comparison.

WHO BMI (1993) categories for Caucasian adults:

Description	BMI (kg/m2)	BMI prime
Normal weight	18.5-24.9	0.74-1.0
Overweight	25-29.9	1.0-1.2
Moderate obese (class 1)	30-34.9	1.2-1.4
Severely obese (class 2)	35-39.9	1.4-1.6
Very severely obese (class 3)	>40	>1.6

*For Caucasians the at risk waist circumference is above 102cm (male) or 88cm (female)

 

BMI categories for Asians (2010):

Description	BMI
Underweight	<18.5
Healthy weight	18.5-22.9
Overweight	23-24.9
Moderate obese (class 1)	25-29.9
Severely obese (class 2)	>30

*For Asians the at risk waist circumference is above 90cm (male) or 80cm (female)

 

Suggested recommendations for bariatric or metabolic surgery include:

Caucasian standard (NIH 1991)	IFSO-Asia Pacific (2010)
BMI >40	BMI >35 with or without co-morbidities
BMI>35 with co-morbidities	BMI >32 with co-morbidities (diabetes or 2 other co-morbidities)
Obesity with failed medical treatments	BMI>30 with waist circumference >80cm (female) or >90cm (male) along with metabolic syndrome (triglyceridaemia, hypertension, hyperglycemia or reduced HDL)

 

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The pathological consequences of visceral/central obesity

Morbid obesity and central visceral fat in particular results in extreme harmful damage to the body not just in terms of weight (the physical stress) but also in terms of metabolic and oxidative stress.

The physical stress

The physical effects of morbid obesity are more than just purely mechanical due to excessive stress/forces on weight bearing joints for example. Morbid obesity is also excess amount of visceral fat, subcutaneous fat, plasma volume and total body water with significant haemodynamic effects (to heart, blood vessels and kidney) and respiratory effects (poor oxygen exchange). Increases in blood volume, cardiac output, kidney and liver size results in systemic hypertension, increased renal plasma blood flow, glomerular filtration rate (GFR) and albumin excretion and hyperfiltration (potentially high output renal failure and nephrotic syndrome). Morbid obesity is associated with obstructive sleep apnoea, alveolar hypoventilation and respiratory depression.

The metabolic stress

The key to understanding the harmful effects of visceral obesity is to understand that adipose tissue is not just a reservoir of fat (resulting in poor body shape and physical appearance) but that it is an active endocrine organ that secretes harmful hormones and inflammatory cytokines (resulting in the multiple medical co-morbidities and complications). These have negative impact on metabolic profile and endothelial function.

The hormones produced by visceral fat contribute to insulin resistance, metabolic dysfunction and vascular disease. Visceral adipose tissue is regarded as an independent risk factor for obesity related co-morbidities (Type 2 diabetes mellitus, dyslipidaemia, cardiovascular diseases).

Ghrelin is an orexigenic peptide (appetite stimulating hormone) released when we are hungry from direct effects on the hypothalamus and indirect effects via growth hormone release. It is also a diabetogenic peptide which suppress insulin release and contribute to the development of insulin resistance and Type 2 diabetes.

After bariatric surgery such as the sleeve gastrectomy (by resecting the bulk of the gastric fundus and body), ghrelin levels has been found to be significantly decreased over the medium to long term resulting in reduced hunger, sustained weight loss, improvement in glucose homeostasis and have beneficial metabolic effects.

The oxidative stress

Morbid obesity is also regarded as a chronic inflammatory disease with elevated levels of C reactive protein (CRP) as well as interleukin 6 (IL-6) and tumour necrosis factor alpha (TNFa) from visceral fat stores and phagocytic macrophage activity respectively.

Morbidly obese patients have been found to have high levels of free fatty acids, low levels of adiponectin and elevated inflammatory markers. The free fatty acids induce insulin resistance. Adiponectin normally has an anti-inflammatory effect by inhibitory actions macrophage activity and reduces TNFa and IL-6.

Elevated CRP is associated with obesity, hypertension, diabetes, dyslipidaemia (all components of metabolic syndrome), cardiovascular risk and its complications. Although the relationship between elevated BMI and CRP is not linear, the consistent post op normalization of CRP within 1 year is a good testimony that bariatric/metabolic surgery produces beneficial effects in the treatment of morbid obesity (from a metabolic and inflammatory disease process point of view).

Cortisol levels have also been found to be elevated in obese individuals. Cortisol promotes differentiation and proliferation of adipocytes and its receptors are found abundantly in visceral central fat as dinstinct from peripheral subcutaneous fat. Cortisol redistributes adiposity from peripheral to central fat depots, which are more metabolically active resulting in lipolysis and release of free fatty acids into circulation. The result is oxidative damage, advanced atherosclerosis and associated cardiovascular complications (such as heart attacks and strokes). Within 6 months after bariatric surgery, serum cortisol is found to be reduced significantly and along with its cardiovascular risks.

After bariatric surgery elevated levels of adiponectin and reduced levels of CRP, IL-6 and TNFa have been discovered with the consequent beneficial results. The reduction in damaging effects from chronic inflammation and endothelial damage may occur with the bariatric/metabolic surgery in the early post operative phase before significant reduction in visceral fat and positive benefits is likely to be independent of weight loss.

After bariatric surgery adiponectin levels increase, insulin sensitivity is enhanced, it has anti-inflammatory and anti-atherogenic effects, improving endothelial dysfunction.

Endothelial dysfunction and inflammation

Increased fat deposition in the heart chambers and blood vessels has adverse consequences to normal structure and function. Obese patients have been reported to have left ventricle or septal hypertrophy with left and right ventricle dysfunction.

The arteries tend to be stiffer with increased pulse wave velocity, a disproportionately increase in blood flow and thickening of the arterial intima and media. There is sympathetic nervous system over activity or attenuated baroreflex sensitivity resulting in arterial hypertension and reduction in heart rate variability. With metabolic problems and chronic inflammation this leads to endothelial dysfunction and the development of accelerated atherosclerosis.

After bariatric/metabolic surgery there is significant improvement in arterial hypertension, lipid profiles (increase HDL, reduce total cholesterol, LDL and triglycerides) and significant decrease in chronic inflammation all contributes to the improvement in endothelial function. Blood flow through the coronary, carotid and renal arteries are improved. In the heart improvements in left ventricle structure (reduced epicardial fat thickness) and function has been noted.

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The clinical consequences of visceral/central obesity

Morbid obesity potentially leads to numerous organ system dysfunctions. It is well known that morbid obesity increases the risk for developing Type 2 diabetes mellitus and is an independent risk factor for cardiovascular disease. Some others are listed below:

Cardiovascular system

• Hypertension, coronary artery disease, premature adult mortality, peripheral arterial thrombosis, venous stasis

Metabolic/endocrine system

• Glucose intolerance, insulin resistance, Type 2 diabetes mellitus, dyslipidaemia

Respiratory system

• Obstructive sleep apnoea, reduced exercise tolerance

Central nervous system

• Stroke, intra cranial hypertension

Gastro-intestinal system

• Gallstones, gastro-oesophageal reflux, non alcoholic fatty liver disease (see below)

Reproductive system

• Polycystic ovary syndrome

Skeletal system

• Degenerative joint disease

Obesity may be associated with an increased risk for various cancers (breast, colon, gastro-oeosphageal, etc.).

Patients with morbid obesity are more difficult to manage should the patient require surgery and also increases the risk of post operative complications (such as incisional hernia, blood clots, respiratory complications).

Non alcoholic fatty liver disease (NAFLD) and non alcoholic steato-hepatitis (NASH)

Steatosis is fatty liver disease which is common in people with obesity, diabetes mellitus or heavy alcohol consumption.

Steato-hepatitis is a fatty liver with associated inflammation.

NASH is inflammation of liver cells, which may lead to hepatocyte cell death, fibrosis, cirrhosis and potentially primary liver tumours (eg. hepatocellular carcinoma).

Patients with morbid obesity and diabetes mellitus have an increased risk of developing NASH (of which ~25% of NASH patients is predicted to progress to liver cirrhosis and liver failure).

Patients with NASH more likely to have metabolic syndrome, cardiovascular disease and higher premature mortality rates.

Cardiovascular and metabolic damage

Less talk about even amongst the medical is the unknown side effects of obesity where the clinical impact may not be immediately apparent till later in the course of the disease. Hence we now recognized that obesity is a chronic disease.

Several well designed studies have indicated that obesity may permanently affect the structure of the heart chambers and blood vessels (eg. left ventricle hypertrophy, left dysfunction, diastolic dysfunction, abnormal conduction, stiff blood vessels, sympathetic nervous system over activity which leads to tachycardia and hypertension).

Visceral adipose tissue is now recognized as an endocrine organ which produces hormones and various cytokines. This sets up a perpetual cycle of chronic inflammation, tissue injury, further inflammation and end organ damage. This leads to cardiovascular complications such as heart attack, strokes and the microvascular complications of diabetes.

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Metabolic Syndrome

There have been difficulties in reaching a universal consensus for the definition of metabolic syndrome. Essentially the four elements necessary to diagnose the syndrome are:

• Central or visceral obesity
• Hyperglycemia or hyperinsulinaemia (impaired glucose tolerance, insulin resistance or Type 2 diabetes mellitus)
• Hypertension
• Dyslipidaemia

Several definitions exist to define metabolic syndrome, the most commonly used are as listed below.

American Heart Association revised National Cholesterol Educational Program Adult Treatment Panel 3 (NCEP ATP3) (2004) definition:

At least 3 criterias of the following:

Increased waist circumference >102cm (male) or 88cm (female)

Elevated triglyceride >1.7mmol/L

Reduced HDL choletsreol <1.03mmol/L (male) or <1.29 mmol/L (female)

Hypertension BP>130/85mmHg or on anti-hypertensive medications

Elevated fasting glucose >5.6mmol/L or on oral hypoglycemic medications

International Diabetes Federation (2006) definition:

Central obesity BMI>30 with 2 of the following:

Triglycerides >1.7mmol/L or on anti-triglyceride medications

HDL-cholesterol <1.03 mmol/L (male) or <1.29mmol/L (female) or on medications

Hypertension BP>135/85mmHg or on medications

Raised fasting blood glucose >5.6mmol/L or previously diagnosed Type 2 diabetes
 

WHO (1999) definition:

Type 2 diabetes, impaired glucose tolerance or insulin resistance with 2 of the following:

Hypertension:     BP>140/90 mmHg or on anti-hypertensive medications

Dyslipidaemia:    HDL cholesterol <0.9mmol/L (male) or <1.0 mmol/L (females)

Triglycerides > 1.7mmol/L

Central obesity:   BMI>30, WHR > 0.9 (male) or >0.85 (female)

Microalbuminuria: urine albumin>20mcg/min or alb:Cr ratio>30mg/g

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The patho-physiology of obesity

Obesity is now regarded as a chronic disease which consist of

• A pro-inflammatory state
• Dyslipidaemia and accelerated atherosclerosis state
• A pro-thrombotic state
• Metabolic (endocrine) state
• Excess cell proliferation

As alluded earlier it is important to make the distinction between central versus peripheral obesity. The visceral (android) obesity also known as central abdominal adiposity, conceptualize as male pattern apple shape obesity in our lay community, are those specifically targeted for therapeutic intervention.

This condition may predispose an individual to develop systemic inflammation, dyslipidaemia and insulin resistance which may progress and lead to various medical co-morbidities (such as hypertension, coronary artery disease, Type 2 diabetes, metabolic syndrome) and complications (such as acute myocardial event, stroke, peripheral arterial thrombosis).

Dyslipidaemia may be associated with accelerated lipolysis of visceral fat which leads to elevation of plasma free fatty acids, triglycerides, LDL and reduction of HDL cholesterol. The increased circulation of free fatty acids and inflammatory cytokines will cause toxic damage to cells for instance pancreatic beta cells (that leads to diabetes mellitus) or to the vascular system (that leads to endothelial dysfunction, accelerated atherosclerosis and associated cardiovacsular complications such as  haemorrhage into an atheromatous plaque and the risk of acute myocardial infarct or stroke).

Non visceral (gynoid or peripheral) obesity, female pear shape obesity in general refers to the excess subcutaneous fat deposition around the hips, lower limbs and extra-peritoneal areas. Peripheral fat is less metabolically active, associated with less lipolysis and release less adipokines, thus the risk for cardiovascular and metabolic complications are lower.

Also as alluded to earlier obesity is regarded as a chronic disease and a chronic inflammatory condition, the visceral fat is an active endocrine organ. When fat cells (adipocytes) increase in size and number with ectopic deposition in liver, muscle or pancreas, they secrete endocrine hormones (adipokines) and inflammatory hormones (cytokine) which in turn will affect food or caloric intake, regulation of energy metabolism, lipid storage, insulin sensitivity, blood pressure control, inflammatory and immune response, vascular haemostasis and blood vessel regeneration (angiogenesis), all of which will add to the complications of obesity.

• Research studies have shown that obesity is often associated with increased circulating levels of leptin (termed leptin resistance), ghrelin, insulin (termed insulin resistance) and resistin as well as reduced levels of adiponectin and peptide YY.
• Secondly obesity is associated with increased inflammatory mediators (IL-6, CRP, TNFa, PAI-1), increased lipolysis and circulating free fatty acids.

The above reveal an exciting area of discovery which in turn open up to a whole new area of research to decipher the complex interaction between gut hormones and fat cell hormones on how it affects the entero-insular axis, the vicious cycle of inflammation and organ damage.

 

An example of the chemical/hormonal effects from fat cells

Adipokines
Leptin	Leptin resistance associated with over eating, morbid obesity and insulin resistance
Adiponectin	Associated with insulin resistance, chronic inflammation, atherosclerosis and have an effect on metabolic rate
Resistin	Promotes insulin resistance and high blood sugar
Vistatin	Possibly contribute to insulin resistance
Cytokine
Tumour necrosis factor alpha (TNFa)	Has a role in inflammation, induce insulin resistance
Interleukin (IL-6,8,10)	Has a role in inflammation, induce insulin resistance
Plasminogen activator inhibitor (PAI-1)	Promote blood clot formation and its associated complications
Other hormones
Ghrelin	Stimulates hunger (orexigenic effect) and affect gastric motility/secretion
Peptide YY	Stimulate satiety and affect gastric motility
Insulin	Help to suppress appetite, control glucose uptake into muscle and fat cells
Amylin	Suppress appetite and help glucagon secretion
Glucagon like peptide (GLP-1)	Incretin effect

Ghrelin

There has been much talk about ghrelin, which is believed to be an important gut hormone in regulating appetite, controlling caloric intake and postulated to be one of the crucial mechanism of how bariatric surgery (such as the sleeve gastrectomy and gastric bypass) works. Ghrelin is predominantly secreted in the gastric fundus, smaller amounts in the pancreas and other parts of the gastro-intestinal tract.

• Acyl ghrelin is regarded as an orexigenic hormone which stimulates appetite to encourage us to eat.
• Acyl ghrelin also suppress insulin release, it has been termed a diabetogenic peptide. The imbalance between the acyl and deacyl isoforms of ghrelin is believed to be a possible pathogenesis for developing hyperglycemia and insulin resistance. Logically improvements in hyperglycemia may be attributed to an immediate reduction in ghrelin before caloric restriction or significant weight loss has been achieved in the early post op period.

After a sleeve gastrectomy, the levels of both acyl and deacyl ghrelin have been recorded to drop significantly and the effect is maintained in the short and medium term. This may partially explain how the sleeve operation works, not just appetite suppression leading to weight loss but also improvement in insulin sensitivity and hopefully for some patients remission of type 2 diabetes.

Glucagon-like peptide 1 (GLP-1)

GLP-1 are peptide hormones that is released from the distal small bowel in response to a meal. The incretin effect is characterized by improved pancreatic beta cell sensitivity to circulating glucose, which in turn increase insulin release, suppresses glucagon secretion and help pancreatic acinar cells to differentiate into new beta cells, all of which helps glucose homeostasis.

The rapid delivery of nutrients to the hind gut result in the release of GLP-1, has a direct action as described above (which leads to an in increase insulin secretion and improved insulin sensitivity) and an indirect indirect effect via reduction in glucagon (which results in reduced liver gluconeogenesis and a reduced fasting blood glucose level).

GLP-1 may have beneficial vascular effects such as reducing vascular tone and improve myocardial contractility.

 

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The benefits of bariatric and metabolic surgery

Initially the focus may be on total body weight, especially in our image conscious society that leads to patients seeking advice on weight loss (bariatric) surgery. When a thorough history is taken (especially family history of visceral obesity, type 2 diabetes, coronary artery disease or stroke) and various biochemical parameters have been assessed to confirmed metabolic syndrome, bariatric/metabolic surgery becomes necessary rather than just desirable.

After the above introduction, if visceral obesity is understood as a chronic disease (chronic metabolic, hormonal, inflammatory state) with serious health effects (especially type 2 diabetes, metabolic syndrome and coronary artery disease) and associated complications (heart attacks, stroke, blood clots, etc.) not just an overweight issue, it is easier to make sense of the benefits of metabolic surgery.  In other words surgery is not just for weight loss but to improve medical co-morbidities, to prevent cardiovascular and metabolic complications and prevent premature mortality associated with morbid obesity.

Bariatric surgery is the most effective treatment of morbid obesity with metabolic disorders (patients already in the higher risk group). Conservative measures with dieting, exercise, medications and lifestyle adjustments in this high risk group have been proven to be ineffective and possibly leads to deterioration in metabolic disorder.

Furthermore we stress that surgery is not just to reduce the body weight or improve the medical co-morbidities (such as high blood pressure and sugar, etc.) but also to reduce the chronic disease and chronic damage (pro-inflammatory state, the accelerated atherosclerosis state, the pro-thrombotic and endocrine/metabolic state).

Amongst the medical community it has been stated that the aims of bariatric and metabolic surgery are:

• To achieve long term sustained weight loss (aim for >50% excess weight loss, >5-15% decrease in BMI and reduced waist circumference)
• To help improve glycemic control (possibly resolution of type 2 diabetes for some patients) with marked metabolic benefits through improvement in lipid levels and metabolic/endocrine profiles, reduction of circulating toxic free fatty acids and damaging inflammatory cytokines
• Metabolic surgery specifically aim to reduce central/visceral obesity, reduce the pro-inflammatory, pro-thrombotic, pro-metabolic and accelerated atherosclerotic dyslipidaemic state
• Improve vascular endothelial state, improve arterial inflammation state (atherosclerosis) and reduce cardiovascular risk factors
• Bariatric and metabolic surgery has been proven to be an effective measure in treatment of severe/morbid obesity, in reducing medical co-morbidities, reduce complications and mortality and improve quality of life

Bariatric and metabolic surgery has been proven over other non-operative techniques to achieve:

• Sustained effective excess weight loss maintained over time
• Improvement in medical co-morbidities (especially diabetes and metabolic syndrome)
• Improved physiology states (vascular endothelial function, reduced inflammatory state, improve cardio-vascular risk factors)
• Decrease morbidity and mortality (from complications of diabetes, coronary artery disease, etc.)
• Reduced health care utilization and costs (either from outpatient medication cost or inpatient treatment for co-morbidities and complications of obesity)
• Improved sense of well being, confidence, body image and quality of life
• As well as multiple associated lifestyle benefits, such as social and employment opportunities which may never be affirmed

Summary points on visceral obesity and insulin resistance

In the past 50 years the global prevalence of obesity has tripled and adult diabetes mellitus has increased by 4 times. Morbid obesity causes accumulation of visceral fat which leads to insulin resistance (IR) and metabolic dysfunction.

In normal people visceral adipocytes can synthesise triglycerides and release free fatty acids (ffa) from triglycerides when energy is required.

Abnormal adipocyte cells have reduced ability to synthesize triglycerides, ffa overflow to other tissues, resulting in ectopic lipid deposition which interfere with insulin signalling and other tissue function. These visceral adipose tissue have strong metabolic activity and endocrine effects, producing a variety of cytokines.

Central obesity and visceral fat, hence IR is strongly associated with metabolic syndrome. Bariatric surgery has significant effect in both metabolism and weight loss in the short term. The reduction in lipid accumulation will occur much slower.

After metabolic surgery, eg. Roux Y gastric bypass fasting blood glucose and IR may improve 1 week after surgery before any significant weight loss is achieved. The proximal small bowel may be the core regulator of systemic IR and regulates insulin sensitivity, through liver gluconeogenesis and muscle insulin resistance.