Endocrine JC035: I Am Overweight, Doctor: Obesity, Hyperlipidaemia Flashcards
Obesity
- Multifactorial chronic disorder characterised by an excess of adipose tissue
- Prevalence increasing worldwide
- 2014: slightly more obese men in China (43 million) than USA (41 million)
- China: moved from 60th place (41th place for women) in 1975 to 2nd rank in 2014 for men with severe obesity
- Similar trend for women (46 million)
- HK men mean BMI: 24.3
- HK women mean BMI: 24.0
Measurements to quantify obesity
- Weight
- BMI
- does not provide any indication of distribution of fat
- adipose tissue in **truncal distribution around + in **abdomen has a particularly strong relationship with adverse metabolic and vascular effects of obesity - WHR
- Men >=0.9, Women >=0.85
- assess distribution of fat (central obesity (SpC FM)) - Waist circumference (WC)
- assess distribution of fat
- increasingly used as measure of central obesity
- ethnic differences recognised
—> Chinese: Men >=90 cm, Women >=80 cm
—> Caucasians: Men >=94 cm, Women >=80 cm - ***Skin-fold thickness
- Estimates of total body fat (by ***bioimpedence, cytometry)
WHO expert consultation 2004
- Caucasian-based BMI cut off values are not directly applicable to other ethic groups
- BMI of Asian populations:
—> <18.5: Underweight
—> **18.5-23: Normal, Acceptable risk
—> **23-27.5: Increased risk (of developing comorbidities associated with obesity)
—> >27.5: High risk
(23-25: Overweight
25-30: Obese class 1
>=30: Obese class 2)
Caucasians:
18.5-25: Normal
25-30: Overweight
30-35: Obese class 1
35-40: Obese class 2
>=40: Obese class 3
HK population health survey 2014/15
15-84 yo BMI:
- 30% obese, 20% overweight
Male:
- BMI: 36% obese, 21% overweight
- WC: 28% central obesity
Female:
- BMI: 24% obese, 19% overweight
- WC: 37% central obesity
Analysed by household income:
- % of people overweight / obese ↓ with ↑ household income (∵ more health conscious)
Prevalence of central obesity generally ↑ with age
Etiology of obesity
- Multiple influences: **Genetic + **Environmental + ***Behavioural
- Mismatch between energy intake vs expenditure
- Only very few cases of obesity solely due to single-gene defect (i.e. Monogenic cause of obesity very rare)
- Genetic influences: generally ***Polygenic
- Adoption studies, Complex segregation analysis: Heritability ~33%
- Environmental factors
- food intake, content of fat in diet
- sedentary lifestyle, lack of exercise
- inverse relationship between socio-economic status and prevalence of obesity
Health costs of obesity
- Associated with many co-morbid conditions
- Risk of morbidity + mortality ↑ with ↑ body weight
—> e.g. risk of CHD doubled if BMI >25 and 4x if BMI >=29
—> DM, HT - As weight reduction can alleviate obesity-associated co-morbidities
—> Goal of obesity treatment should be ***Reduction of co-morbidity rather than for cosmetic reasons
Diseases and Morbidity attributable to obesity
- CVS
- HT
- CHD
- Stroke - Metabolic
- Type 2 DM
- Dyslipidaemia
- Insulin resistance
- ***PCOS - ***GI
- Hiatus hernia
- Gallstones
- CRC
- Non-alcoholic hepatic steatosis - Respiratory
- Breathlessness
- ***OSA
- Hypoventilation syndrome (Pickwickian syndrome) - Neurological
- Nerve entrapment
- Sciatica - Breast
- Breast cancer
- Gynaecomastia - ***Genitourinary
- Stress incontinence
- Reduced fertility (PCOS)
- Pregnancy complications - O/T
- OA of weight-bearing joints - Psychological
- Poor self-esteem
- Depression
Conditions associated with obesity
- Hypothyroidism
- Cushing’s syndrome
- Hypothalamic tumours
- GH deficiency (associated with ↑ in abdominal, visceral fat)
- Hypogonadism in male (associated with ↑ in abdominal, visceral fat)
- PCOS
Common medications causing weight gain
- ***Antidepressants
- MAOIs
- TCAs (Nortriptyline, Amitriptyline, Doxepin)
- Paroxetine, Citalopram, Escitalopram, Imipramine, Mirtazapine - ***Antipsychotics
- Thioridazine, Olanzapine, Risperidone, Clozapine, Quetiapine - DM medications
- Insulin
- ***Sulfonylurea, Meglitinide, TZD - ***Glucocorticoids
- Prednisone - Anticonvulsants
- Valproate, Carbamazepine
Control of body weight, energy homeostasis
Peripheral signals from Adipose tissue, GI tract, Pancreas
1. Adipose tissue: **Leptin
2. GI tract: **Ghrelin, GLP-1, OXM, PYY, CCK
3. Pancreas: ***Insulin
—> via Blood (Leptin, Insulin, Ghrelin), Vagus nerve
—> CNS (Brain systems) receive + integrate peripheral + other CNS signals
—> regulate appetite
—> regulate body weight, maintain energy homeostasis
Leptin, Insulin, Ghrelin:
- integrated directly into ***Hypothalamus
Hypothalamus:
- centre for regulation of energy balance
- integrates neural, hormonal, nutrient messages from the body —> send signals to higher centres —> feeling of hunger / satiety
- control energy expenditure via **ANS + **Pituitary hormones
- large number of hypothalamic neurotransmitter affect both food intake + thermogenesis
Neurotransmitter (X hormone) affecting energy balance
X rmb
↑ food intake:
- Neuropeptide Y
- Melanin-concentrating hormone
- Galanin
- Orexin A + B
- Opioids
- GH-releasing hormone
↓ food intake:
- **Serotonin / 5HT —> now used as therapy
- **Glucagon-like peptide 1 (GLP1) —> now used as therapy
- Dopamine
- Cholecystokinin (CCK)
- Corticotrophin-releasing factor
- Neurotensin
- Bombesin
- MSH
Leptin
- Peptide **hormone (x neurotransmitter) synthesised by **adipocyte
- act in Hypothalamus to ***suppress food intake + ↑ energy expenditure
- mutation in Leptin gene —> ob/ob mice (obese)
- mutation in Leptin receptor gene —> db/db mice (obese), fa/fa rat
- mutation in Leptin / Leptin receptor as a cause of obesity are ***extremely rare in humans
Human:
- Leptin level ↑ in parallel with fat mass
- Leptin serum concentration ↑ in obese subjects
—> Human obesity is not a state of Leptin deficiency / Extreme Leptin insensitivity
—> Partial resistance to Leptin?
A new perspective on Adipose tissue
- Adipose tissue is not inert tissue
- A major endocrine + secretory organ
- Release a wide range of protein factors + signals —> ***Adipokines (in addition to fatty acids / other lipid moieties) —> Regulate appetite + energy homeostasis
Adipokines:
- Adiponectin
- TNFα
- IL-1β, IL-6, IL-8, IL-10
- Monocyte chemoattractant protein-1 etc.
Why is sustained weight loss difficult?
- Long-term signals energy stores + Short-term fluctuations in food intake —> released from Adipose tissue + Gut endocrine system to CNS
—> integrated in Hypothalamus + Brainstem
—> CNS release neuropeptide
—> changes in appetite, behaviour, energy expenditure to maintain a stable weight - Physiological adaptations
—> ↑ in appetite-stimulating hormones (e.g. **Ghrelin) + ↓ in appetite-suppressing hormones
—> **defend against weight loss / negative energy balance
Management of obesity
Aims:
1. Weight reduction
2. Maintenance of weight loss
3. Modification of concurrent risk factors for mortality and morbidity e.g. smoking, DM, HT, HL
4. Be realistic —> treatment directed towards health rather than cosmetic goals (1-2 lb per week (web, SpC FM))
5. Weight loss of ***5-10% of total body weight already associated with health benefit
Suggested CVS benefits of 10kg weight loss
- > 20% ↓ in total mortality
- ↓ 10 mmHg of SBP
- ↓ 20 mmHg of DBP
- ↓ 50% in fasting glucose in DM
- ↓ 10% in total cholesterol
—> ↓ 15% LDL
—> ↓ 30% TG
—> ↑ 8% HDL
Strategies for weight reduction
- Lifestyle modification
- diet
- exercise - Drug therapy
- BMI **>30
- BMI **27-29 if have comorbidities - Surgery
- BMI **>=40
- BMI **>=35 if have comorbidities
Diet therapy
- Cornerstone of any treatment programme for obesity
- Low Calorie Diet (LCD): ***>=800 kcal/day, typically 800-1500
- Very LCD: <800 kcal/day
- Weight loss of around **0.5 kg/week is optimal —> **600 kcal/day deficit —> faster rate of weight loss lose not only fat but also lean body mass
- Very LCD leads to faster rate in weight reduction in first 2-3 months but ***NOT superiorly in maintenance weight loss after 1 year —> ONLY used under medical supervision
- Long-term weight loss in most trials (FU 2-7 years) show weight loss ***2-6 kg
- Effective in promoting significant weight loss (max 4-7%)
- ***Low carb diets: somewhat more effective in short terms (3-6 months)
- ***All diets appear equivalent over long term (>=1 year)
Physical activity
- Dietary modification + Adequate physical activity —> repeatedly shown to be important for initial weight loss + long-term weight maintenance
- Gradual ↑ physical activity until energy expenditure of ***1000-1500 kcal/week
Benefits of Lifestyle modifications:
e.g. DM
- significant weight loss (compared with medication)
- ↓ type 2 DM incidence by 58% (compared to Metformin 31%)
Problem with Lifestyle modification
Difficult to maintain long-term compliance
- **Behavioural treatment
- **Relapse-prevention treatment
- Problem-solving therapy
- **Social support
- Telephone contact
- **Structured meal + meal replacement
- ***Home-based exercise
Drug treatment
- Only appropriate in individuals who are at **medical risk from their level of obesity + have **not responded to more traditional / conservative treatment
- Consider in:
—> BMI **>30
—> BMI **27-29 if have comorbidities - Treatment should be discontinued if patient does not get medical benefit
Drugs:
1. **GI lipase inhibitor (Orlistat)
2. **Phentermine / Topiramate (Qsymia)
3. **Bupropion / Naltrexone (Contrave)
4. **Liraglutide (Saxenda)
5. Rimonabant (endocannabinoid receptor antagonist, withdrawn)
6. Sibutramine (serotonergic agent, withdrawn)
7. Lorcaserin (selective serotonin 2C receptor agonist, withdrawn)
- Currently available agents have limited efficacy
- complex + redundant physiological pathways that defend body against negative energy balance —> make it impossible to treat human obesity effectively with any single pharmacological approach
Comparative efficacy of weight loss medications
- average 5-7% weight reduction
- Phentermine/Topiramate > Liraglutide ~ Bupropion/Naltrexone > Orlistat
- ***none available in HA, all self-financed items
Orlistat
MOA:
- Inhibit GI lipase —> ↓ absorption of dietary fat —> promote weight loss
Effect:
- ↓ dietary fat by 30% with a dose of 120mg TDS —> ↓ weight by ~3kg
- ↓ progression to DM
PK:
- systemic absorption negligible
- potential for systemic adverse effects is small
SE:
- GI upset
- ***Steatorrhoea
- Faecal urgency
- Oily spotting
- ↓ Absorption of fat soluble vitamins
Phentermine / Topiramate (Qsymia)
Phentermine:
- **Anorexigenic agent
- act via **enhancement of NE release + possibly via ***blockade of NE reuptake as well
Topiramate:
- ***Neurostabiliser for treatment of seizure disorder + migraine prophylaxis
- Exact MOA for weight loss unknown
- Amount of weight loss achieved with combination therapy > either agent alone
SE:
- **Teratogenicity
- Slight ↑ HR
- **Psychiatric + Cognitive adverse effects
- Metabolic acidosis
Bupropion / Naltrexone (Contrave)
Bupropion:
- **Inhibitor of neuronal reuptake of Dopamine + NE
- antidepressant to treat **depression + ***smoking cessation
Naltrexone:
- **Opioid antagonist
- treat **alcohol + ***opioid dependence
Effect:
- ↓ appetite + cravings for food
SE:
- N+V
- constipation
- headache
- dizziness
- insomnia
- dry mouth
- diarrhoea
Monitor:
- Mood changes
- Suicidal thoughts / actions
Liraglutide (Saxenda)
- GLP-1 agonist used in type 2 DM (1.8 mg / day)
- Higher dose formulation (3mg / day) developed specifically for treatment of obesity
- SC injection
MOA:
1. ↑ Glucose-stimulated Insulin secretion + ↓ Glucagon secretion
2. Delays gastric emptying
3. ***↑ Satiety by central effects on hypothalamus
SE:
- mainly GI
Surgery
Patients considered eligible for surgery if
- BMI >=40
- BMI >=35 with comorbidity (e.g. DM, respiratory insufficiency)
Principles:
- ↓ size of reservoir / intake
- ↓ efficacy of absorption
Bariatric surgery:
1. ***Gastric restrictive surgery (↓ size of reservoir / intake)
- Adjustable gastric banding
- Roux-en-Y gastric bypass
- Vertical sleeve gastrectomy
- ***Jejunoileal bypass, Biliopancreatic bypass (↓ efficacy of absorption)
- Biliopancreatic diversion with a duodenal switch
- Not commonly performed
- Malabsorption, diarrhoea, oxalate kidney stones, cirrhosis
Comparisons:
- Gastric bypass (GB): more effective in weight loss but more complications
- Adjustable gastric banding (AGB): lower mortality + complication rates, but higher reoperation rate + less substantial weight loss than GB
- Sleeve gastrectomy: more effective in weight loss than AGB, ~ to GB
Complications:
- 5% adverse intraoperative events
- late complications:
—> AGB: **band slippage, leakage, erosion
—> GB: **anastomotic strictures, marginal ulcers, bowel obstructions
—> All: Macro/Micronutrient deficiency e.g. Fe, Ca, Vit B12, Vit D
Efficacy of BMI change:
- Overall: significant weight reduction, reduce mortality on long-term FU
- Mean 20 years weight reduction: Roux-en-Y GB 25%, AGB 15%
- an effective mean to achieve lasting weight loss + improving metabolic disease + reducing CVS risk
- pre-op multidisciplinary assessment needed to select appropriate candidates
- choice of surgical modality should consider **individual goals + **existing comorbidities + ***experience of centre
- long-term FU + monitoring mandatory to support safe outcome
Roux-en-Y gastric bypass
- Formation of small gastric pouch (proximal portion of gastric body)
- Roux-en-Y anastomosis to allow gastric, pancreatic, biliary, duodenal secretions to enter distal intestine
Vertical sleeve gastrectomy / Laparoscopic sleeve gastrectomy
- Greater curvature of stomach excised by staples —> create a new 150ml banana-shaped gastric pouch
- Restrict amount of food that can be eaten ***without any bypass of intestines / problems of malabsorption
Laparoscopic Adjustable gastric banding
- Small inflatable belt placed around upper portions of stomach —> restrict amount of food consumed + provides a constant feeling of being “full”
- SC injection port —> inject fluid to adjust size of band
- Least invasive form of bariatric surgery
Bioenterics intragastric balloon
- Non-surgical procedure
- Placed inside stomach by endoscope —> act as a bezoar partially to fill stomach —> induce early satiety
- Non-permanent + Reversible —> remove after 6-9 months
- A kind of behaviour therapy (aim to change eating habit + dietary pattern)
