Obesity FCA part 1 Flashcards
Classify obesity according to BMI
BMI Classification 25 - 30 Overweight 30 - 35 Class 1 obesity 35 - 40 Class 2 obesity > 40 Class 3 obesity (morbid)
Classify the causes of obesity
LIFESTYLE
Caloric intake > Caloric expenditure
Sedentary work and leisure habits
ENDOCIRNE
1. GH deficiency: more fat than muscle
- Cushing syndrome
- Deposition of fat in face/neck/abdomen/mediastinum - Thyroid
- Hypothyroidism: slowed metabolism
- Hyperthyroidism (rarely): hyperphagia with static BMR - Hypothalamic disorders (RARE)
MEDICATION
- Antipsychotics (affect appetite control)
- Hypoglycaemic drugs
- Protease inhibitors
- Corticosteroids
- Beta-blockers
HEREDITY
- Leptin gene mutations
- Prader-Wili syndrome (chr. 15) FTT 2 yrs then hyperphagia and obesity
Summarise the pathophysiology of obesity
A. Increased visceral adipose tissue and ectopic fat deposition: lead to release ADIPOKINES: IL-6, TNF - a, CRP, leptin, resistin
B. Reduced subcutaneous adipogenesis leads to reduced levels of adiponectin.
Ectopic fat = fat in liver/pancreas/muscle)
All off the above lead to:
- Insulin resistance
- Dyslipidaemia
- Prothrombosis
- Proinflammation
- Cellular proliferation
What is adiponectin, what is its function and what are the consequences of its deficiency
Adiponectin
- Improves insulin sensitivity
- Reduce inflammation
- Modulates glucose and FFA metabolism
Low levels of adiponectin lead to:
- Insulin resistance
- T2DM
- Atherosclerosis
- Malignancies
Chronic caloric restriction –> rise in adiponectin levels
What is leptin
Leptin is a hormone released by adipose tissue that plays a role in the long term regulation of energy balance by suppressing appetite.
Higher levels of leptin are found in obese patients as it is believed that obese patients are leptin resistant.
Structurally similar to cytokines: IL-6 and can regulate T-cell proliferation and activation.
What are the consequences of increased circulating levels of IL-6 in obesity
IL-6 is implicated in the pathogenesis of:
- Asthma
- Sleep apnoea
- Malignancies
- Metabolic syndrome
- CVS disease
What is the mechanism for insulin resistance in obesity?
Increased visceral adipose tissue and ectopic adipocyte development leads to defective oxidation of FFA’s. Increased FFA’s in circulation and accumulation in organs leads to dyslipidaemia and insulin resistance
Visceral/Ectopic adiposity –> defective FFA oxidation –> accumulation FFAs –> dyslipidaemia and insulin resistance
What are the other names for the metabolic syndrome
Syndrome X
Insulin resistance syndrome
What is the metabolic syndrome and what are the criteria required for its diagnosis
Metabolic Syndrome is the co-occurence of metabolic risk factors for T2DM and CVS disease (abdominal obesity, hyperglycaemia, hypertension).
NCEP ATP III
National Cholesterol Education Program (NCEP) Adult Treatment Program (ATP III)
3 or more of the following
- Waist circumference > 94 cm
- TG > 1.7 mmol/L
- HDL < 1.03 mmol/L M & < 1.29 mmol/L F
- HPT SBP > 130 / DBP > 85 / Rx
- Glucose (fasting) > 5.6 mmol/L (or T2DM)
Via what mechanisms does visceral obesity lead to the development of cardiovascular disease?
Visceral obesity (and ectopic adipose tissue) –>
- Hypertension
- Increased TG
- Decreased HDL
- Increased LDL
- Inflammation CRP
- Metabolic syndrome
- Diabetes
- RAAS/SNS activation
Obesity is positioned as the only central and reversible cardiovascular risk factor that favourably influences all the other factors of the metabolic syndrome.
The above leads to micro and macrovascular complications associated with the above conditions
How does obesity accelerate atherosclerosis
Visceral and ectopic adipocytes –> reduced adiponectin and increased adipokines (IL-6, TNFa, leptin, resistin) –> defective oxidation of FFAs. Increased exposure of hepatocytes to FFAs –> dyslipidaemia (high LDL and TG, Low HDL) + pro-inflammatory adipokines –> accelerated atherosclerotic plaque development together with elevated glucose levels + prothrombotic effects –> larger plaques that are more likely to rupture, thrombose and occlude.
How does obesity affect cardiac structure
Unclear if obesity vs. comorbid conditions is the causal mechanism for remodelling of the myocardium.
(co-morbid conditions: OSA/DM/HPT) or is the remodelling a direct effect of obesity mediated by leptin and adiponectin???
How do cardiac dysrhythmias occur in obese patients
Most commonly due to OSA or LV hypertrophy
List the respiratory manifestations of pathogenic obesity
- Excess chest wall mass
- Fatty infiltration chest wall muscles
- Increased pulmonary blood volume
- –> Decrease chest wall compliance
- –> Decrease FRC
- –> Decrease total lung volume
- –> Decrease peripheral airway diameter
- –> Changes in pulm. blood volume with VQ mismatch
What is obstructive sleep apnoea and how is its pathophysiology related to obesity
Repetitive airway collapse during sleep leading to: hypoxia, SNS surges, airway oedema and inflammation.
IL-6, TNF-alpha, leptin and reduced adiponectin levels are similar to those in obese patients.
Vicious cycle can ensue: changes in sleep patterns during OSA can promote weight gain by modulating appetite regulating hormones
How does obesity contribute to the development of asthma
GORD and OSA are often associated with obesity and asthma and seem to have overlapping aspects of their pathophysiology.
E.g. leptin –> stimulates increased eotaxin (eosinophil chemoattractant). I.e. leptin appears to have an immunomodulatory role.
What is the relationship between BMI and GORD
Linear.
GORD affects 20% of population
GORD affects 30% of obese patients
(particularly abdominal obesity)
How are obese patients with GORD different to non-obese patients with GORD
Obese patients with GORD are more likely to have complications of GORD
- Erosive GORD
- Barrett (IL6, TNFa) / oes. adenoCa
- Hiatal hernia and reduced LOS tone
How can obesity affect the liver
NAFLD and steatohepatitis
Nonalcoholic fatty liver disease
- hepatic manifestation of metabolic syndrome
- TG accumulation in liver with possible inflammation –> fibrosis –> cirrhosis.
Describe the pathophysiology of NFLD
Visceral obesity –> defective fatty acid oxidation –> accumulation TG –> ectopic fat deposits in the liver + hyperinsulinaemia promotes hepatic triglyceride and FFA production.
FFAs travel between adipocytes and hepatocytes and bring adiponectin and TNFa. TNFa antagonizes adiponectin to promote steatosis and insulin resistance
How does cirrhosis result from NAFLD
Poorly opposed TNF alpha –> oxidant stress and high levels of inflammatory mediators in the liver, cell death, insulin resistance –> activation of hepatic stellate cells to repair cells (modulated by leptin, adiponectin, angiotensin, norepinephrine) –> when the liver is unable to adequately repair hepatocytes, cirrhosis develops.
What is the treatment of NAFLD
Diet and exercise Slow weight reduction (rapid weight loss can worsen inflammation) Rx: Insulin sensitizing agents: 1. Metformin 2. Thiazolidinediones
Are lipid lowering agents indicated in NAFLD
No. No proven benefit
What are the three factors that promote the formation of gallstones and how does obesity relate to these three factors
- Gallbladder hypo-motility
- Bile supersaturation with CHOL
- Bile destabilization with kinetic protein factors
Obesity
CHOL supersaturation
Visceral adiposity strongly associated with gallstone formation
What is the likely cause for increased gallstones in patients who have undergone gastric bypass or banding
Bile stasis
How is obesity related to malignancy
The same cytokines that cause insulin resistance: leptin, IL-6, TNFa, FFAs are involved in the promotion of cellular proliferation and the inhibition of apoptosis.
Adiponectin receptors are also expressed on a number of cancer cells and may supress growth. Therefore low levels of adiponectin is associated with cancer.
Which cancers have been associated with obesity
- Breast Cancer
- Endometrial cancer
- Colon Ca in men
- Renal Cell carcinoma
How is the volume of distribution of many drugs altered in obese patients
Vd depends on:
- Plasma protein binding
- Body composition
- Regional blood flow
Plasma protein binding does not differ in obese patients
Body composition:
Less lean body mass per kg
More fat mass per kg
Obesity –> vessel rich group of organs is VERY well perfused due to:
- Increased blood volume in obesity
- Increased Cardiac output in obesity
How should propofol be dosed ideal body weight or total body weight/lean body mass and why?
When propofol was compared between obese patients and normal weight controls –> dosing propofol using total body weight gave acceptable clinical results
- Unchanged initial volume of distribution
- Clearance related to body weight
- Vd at steady state related to body weight
No evidence of accumulation when dosing schemes are based on mg/kg TBW
