Medicine chapters
Obesity and lipid disorders
How obesity develops and harms health, how it is measured and treated (diet, activity, drugs, bariatric surgery), and the types, screening and treatment of lipid disorders including familial hypercholesterolaemia.
- Obesity is a BMI of 30 or more (lower cut-offs for South Asians); central (waist) fat carries the most risk of diabetes, heart disease, sleep apnoea, fatty liver and cancer. Treat with diet, activity and behaviour change, then drugs (orlistat, GLP-1 agonists), then bariatric surgery (BMI over 40, or over 35 with complications).
- Lipid disorders are primary (genetic) or secondary (hypothyroidism, diabetes, nephrotic syndrome, cholestasis, alcohol, drugs); familial hypercholesterolaemia (autosomal dominant LDL-receptor defect) gives very high LDL, tendon xanthomas and early heart disease.
- Statins are first line for cholesterol and cardiovascular risk; add ezetimibe, then PCSK9 inhibitors; fibrates for very high triglycerides (pancreatitis risk).
On this page
Overview
Obesity is an excess of body fat large enough to harm health. It is rising fast in Pakistan and other developing countries, along with type 2 diabetes and heart disease.
Lipid disorders (dyslipidaemias) are abnormal levels of cholesterol and triglycerides. Raised LDL and non-HDL cholesterol drive atherosclerosis; very high triglycerides cause pancreatitis.
Both are major, treatable cardiovascular risk factors and often occur together in the metabolic syndrome.
Obesity: measurement
BMI = weight (kg) ÷ height (m)²
| Category (WHO) | BMI (kg/m²) | Risk of related disease |
|---|---|---|
| Underweight | Below 18.5 | Other problems |
| Normal | 18.5–24.9 | Average |
| Overweight | 25–29.9 | Mildly raised |
| Obese class I | 30–34.9 | Moderate |
| Obese class II | 35–39.9 | Severe |
| Obese class III (morbid) | 40 or more | Very severe |
For South Asians, who carry more visceral fat at a lower BMI, lower action points are widely used: overweight from 23 and obese from 27.5. Check the current national guidance, as cut-offs vary.
Weight 81 kg, height 1.80 m
BMI = 81 ÷ (1.80 × 1.80) = 81 ÷ 3.24 = 25.0 kg/m²
WHO: overweight. South Asian cut-offs: overweight (above 23, below 27.5)
Central (abdominal) obesity matters more than BMI alone. Measure waist circumference: for Europeans, above about 102 cm in men and 88 cm in women is high risk (ATP III); the IDF uses lower values (94 cm and 80 cm), and lower values again are used for South Asians. A high waist-to-hip ratio also shows central fat.
Central (visceral) fat predicts diabetes and cardiovascular disease better than BMI, so always measure the waist.
BMI does not separate fat from muscle. A muscular athlete may have a "high" BMI, and an older person may have a "normal" BMI with too much fat.
Obesity: pathophysiology
Obesity results from energy intake exceeding energy expenditure over a long time. The recent epidemic is due mainly to lifestyle change (calorie-dense food, sugary drinks, inactivity), acting on a polygenic background.
Control of appetite
| Signal | Source | Effect |
|---|---|---|
| Leptin | Adipose tissue (ob gene) | Suppresses appetite; levels rise with fat mass. Most obese people have high leptin with leptin resistance; congenital leptin lack is very rare |
| Ghrelin | Stomach fundus | Stimulates appetite; high before meals, falls after eating |
| Insulin | Pancreas | Long-term satiety signal |
| PYY, GLP-1, CCK | Gut after meals | Satiety |
- In the arcuate nucleus of the hypothalamus, NPY/AgRP neurones increase hunger, while POMC neurones (via α-MSH and the melanocortin-4 receptor) reduce it.
- MC4R mutations are the commonest single-gene cause of human obesity, but monogenic obesity is rare overall.
- Damage to the ventromedial hypothalamus (satiety area) causes overeating and obesity.
Secondary causes (rare)
Hypothyroidism, Cushing syndrome, polycystic ovary syndrome, hypothalamic damage (tumour, trauma), drugs (corticosteroids, antipsychotics, insulin, sulphonylureas, some antidepressants and anticonvulsants), and genetic syndromes such as Prader–Willi (hyperphagia, hypotonia, hypogonadism, paternal 15q11–13 deletion) and Laurence–Moon–Biedl.
Obesity: complications
| System | Complications |
|---|---|
| Metabolic | Type 2 diabetes (strongest link), dyslipidaemia, gout, non-alcoholic fatty liver disease |
| Cardiovascular | Hypertension, coronary disease, stroke, heart failure, varicose veins, venous thromboembolism |
| Respiratory | Obstructive sleep apnoea, obesity hypoventilation, breathlessness |
| Musculoskeletal | Osteoarthritis of knees and hips, back pain |
| Gut | Gallstones, gastro-oesophageal reflux, hiatus hernia |
| Reproductive | PCOS, menstrual problems, infertility, pregnancy complications (gestational diabetes, pre-eclampsia) |
| Cancer | Endometrial, breast (postmenopausal), large bowel, oesophageal adenocarcinoma, kidney |
| Psychosocial | Depression, low self-esteem, stigma |
| Surgical | Higher anaesthetic and wound complications |
Metabolic syndrome
A cluster of risk factors built on central obesity and insulin resistance.
| Feature | ATP III (any 3 of 5) | IDF (large waist + any 2) |
|---|---|---|
| Waist | Men above 102 cm, women above 88 cm | Lower, ethnic-specific (Europeans 94 / 80 cm) |
| Triglycerides | 1.7 mmol/L or more (150 mg/dL) | Same |
| HDL | Men below 1.03 (40 mg/dL), women below 1.29 mmol/L (50 mg/dL) | Same |
| Blood pressure | 130/85 mmHg or more | Same |
| Fasting glucose | 6.1 mmol/L or more (Kumar's table) | 5.6 mmol/L or more |
Obesity: management
Aim: a realistic first goal of about 10% weight loss, which brings worthwhile falls in blood pressure, glucose and lipids.
1. Lifestyle (always first)
- Diet: a calorie deficit (for example about 1000–1500 kcal a day) with adequate protein, complex carbohydrates, fruit and vegetables; fewer sugary drinks, fried and processed foods; less alcohol. Any calorie-reduced diet works if it can be kept up; aim for about 0.5–1 kg loss a week.
- Physical activity: about 30 minutes a day of moderate activity; mainly helps keep weight off.
- Behaviour change: goal setting, self-monitoring, family involvement, support groups.
2. Drugs (adjunct to lifestyle, review after about 3 months)
| Drug | Action | Main problems |
|---|---|---|
| Orlistat | Blocks pancreatic and gastric lipase, so less dietary fat is absorbed | Oily, loose stools and faecal urgency (worse with fatty meals); low fat-soluble vitamins |
| GLP-1 receptor agonists (liraglutide, semaglutide) | Slow gastric emptying and reduce appetite centrally | Nausea, vomiting; injection; cost |
| SGLT2 inhibitors (in diabetes) | Glucose loss in urine | Modest weight loss; genital infections |
Several older appetite suppressants (sibutramine, rimonabant) were withdrawn for cardiovascular or psychiatric harm.
3. Bariatric (metabolic) surgery
Indications: BMI over 40, or BMI over 35 with an obesity-related disease (e.g. type 2 diabetes, sleep apnoea), after proper non-surgical attempts, in a patient fit for surgery and committed to follow-up.
| Type | Examples |
|---|---|
| Restrictive | Sleeve gastrectomy, adjustable gastric band |
| Restrictive + malabsorptive | Roux-en-Y gastric bypass, duodenal switch |
Surgery gives the largest and most lasting weight loss, often remission of type 2 diabetes, and fewer cardiovascular events and deaths. Problems: leaks, dumping syndrome, deficiencies of iron, B12, folate, calcium and vitamin D (lifelong supplements and monitoring), gallstones, weight regain. Women should delay pregnancy for about a year after surgery.
Liposuction removes fat but does not improve cardiovascular risk factors.
Lipid disorders: lipoproteins in brief
| Particle | Main lipid | Made in | Notes |
|---|---|---|---|
| Chylomicrons | Triglyceride (dietary) | Gut | Cleared by lipoprotein lipase (needs apo C-II); cause milky plasma |
| VLDL | Triglyceride (made by liver) | Liver | Main triglyceride in fasting blood |
| LDL | Cholesterol | From VLDL | Taken up by LDL receptors (apo B-100); most atherogenic |
| HDL | Cholesterol (reverse transport) | Liver, gut | Protective; LCAT esterifies its cholesterol |
| Lipoprotein(a) | Cholesterol | Liver | Genetically determined, raises risk |
PCSK9 is a protein that destroys LDL receptors; blocking it raises receptor numbers and lowers LDL.
Calculating LDL (Friedewald)
LDL = total cholesterol − HDL − (triglyceride ÷ 2.2) (mmol/L; valid only if triglyceride is below about 4.5 mmol/L)
Total cholesterol 6.2, HDL 1.0, triglyceride 2.2 mmol/L
LDL = 6.2 − 1.0 − (2.2 ÷ 2.2) = 6.2 − 1.0 − 1.0 = 4.2 mmol/L
Non-HDL cholesterol = 6.2 − 1.0 = 5.2 mmol/L
Lipid disorders: types
Secondary hyperlipidaemia (always exclude first)
Hypothyroidism, poorly controlled diabetes, obesity, nephrotic syndrome, chronic kidney disease, cholestasis (e.g. primary biliary cholangitis), alcohol, anorexia nervosa, pregnancy and drugs (thiazides, beta-blockers, corticosteroids, oestrogens, retinoids, ciclosporin, antiretrovirals).
Primary (genetic) disorders
| Disorder | Defect and inheritance | Lipids | Clinical clues |
|---|---|---|---|
| Heterozygous familial hypercholesterolaemia | LDL-receptor mutation (most), apo B-100 or PCSK9 gain; autosomal dominant; about 1 in 350 (Kumar) | Very high LDL, normal triglyceride | Tendon xanthomas (Achilles, finger extensors), corneal arcus before 40, premature coronary disease, family history |
| Homozygous FH | Both alleles | LDL above 13 mmol/L | Tuberous xanthomas in childhood, coronary disease or aortic stenosis by early adult life |
| Familial combined hyperlipidaemia | Polygenic; common | Raised cholesterol and/or triglyceride, varies over time | No specific signs; premature CVD in family |
| Remnant (type III) hyperlipidaemia | Apo E2/E2 plus another factor | Cholesterol and triglyceride about equal | Palmar crease (planar) xanthomas, tuberous xanthomas on elbows and knees |
| Lipoprotein lipase or apo C-II deficiency (familial chylomicronaemia) | Autosomal recessive | Triglyceride very high (often above 20 mmol/L) | Recurrent pancreatitis, eruptive xanthomas, lipaemia retinalis, hepatosplenomegaly, creamy layer on plasma |
| Tangier disease | ABCA1 defect | Very low HDL | Orange tonsils, neuropathy |
Xanthomas: what they point to
| Sign | Suggests |
|---|---|
| Tendon xanthomas | Familial hypercholesterolaemia |
| Palmar crease (planar) xanthomas | Remnant hyperlipidaemia; also cholestasis (PBC) |
| Eruptive xanthomas (buttocks, extensor surfaces) | Severe hypertriglyceridaemia |
| Tuberous xanthomas (elbows, knees) | Remnant hyperlipidaemia, homozygous FH |
| Xanthelasma (eyelids) | Non-specific; lipids are often normal |
| Corneal arcus before 40 | Hypercholesterolaemia |
Lipid disorders: screening
- Screening practice differs between countries; many check lipids in adults over 40 as part of cardiovascular risk assessment (e.g. QRISK in the UK).
- Test at any age if there is: family history of premature coronary disease (before 60) or of a lipid disorder, xanthomas or xanthelasma, corneal arcus before 40, diabetes, hypertension, obesity, acute pancreatitis, chronic kidney disease.
- Cascade testing: first-degree relatives (including children) of anyone with FH.
- A non-fasting sample is fine for total and HDL cholesterol; repeat fasting if triglycerides are raised.
- After an acute myocardial infarction, lipids fall for up to 3 months; measure within 48 hours or wait 3 months.
Lipid disorders: management
Lifestyle
Less saturated and trans fat, more fibre, plant stanols, weight loss, more exercise, stop smoking, cut alcohol (especially for high triglycerides), and good diabetes control.
Drugs
| Drug | How it works | Effect | Key side effects and cautions |
|---|---|---|---|
| Statins (atorvastatin, rosuvastatin, simvastatin) | Inhibit HMG-CoA reductase (rate-limiting step of cholesterol synthesis) → more hepatic LDL receptors | LDL down by about 30–60%; triglycerides down modestly | Myalgia, myositis, rhabdomyolysis (check CK), raised liver enzymes; interactions with CYP3A4 inhibitors (clarithromycin, some antifungals) for simvastatin; avoid in pregnancy and breast-feeding |
| Ezetimibe | Blocks NPC1L1 cholesterol transporter in the gut | LDL down about 20% | Well tolerated; added to a statin |
| PCSK9 inhibitors (alirocumab, evolocumab) | Antibodies to PCSK9 → more LDL receptors | LDL down about 40–60% | Injection; for FH, very high risk or statin intolerance |
| Fibrates (fenofibrate, bezafibrate) | Activate PPAR-α → more lipoprotein lipase | Triglycerides down sharply; HDL up | Myositis (especially gemfibrozil with a statin), gallstones |
| Bile acid sequestrants (colestyramine, colesevelam) | Bind bile acids in gut | LDL down; triglycerides may rise | Bloating, constipation; block absorption of other drugs; safe in pregnancy |
| Nicotinic acid | Reduces VLDL production | LDL and triglycerides down, HDL up | Flushing (prostaglandin; reduced by aspirin), gout, high glucose; little used |
| Omega-3 fatty acids | Reduce VLDL | Triglycerides down | Mild gut upset |
Who to treat
- Secondary prevention (known coronary disease, stroke/TIA, peripheral arterial disease): high-intensity statin for everyone, whatever the cholesterol, aiming for a low LDL (Kumar suggests LDL below 2 mmol/L); add ezetimibe or PCSK9 inhibitor if needed.
- Type 2 diabetes over 40: usually a statin.
- Primary prevention: calculate 10-year cardiovascular risk; offer a statin when the risk exceeds the local threshold (commonly 10% in UK practice) after lifestyle advice.
- Familial hypercholesterolaemia: treat from youth; often statin plus ezetimibe, then PCSK9 inhibitor; lipid apheresis in homozygotes.
- Triglycerides: below 2 mmol/L is normal; above about 10 mmol/L carries pancreatitis risk. Treat secondary causes and alcohol; use a fibrate first when triglycerides are very high, otherwise a statin first in mixed disease.
Statins reduce cardiovascular events in proportion to the absolute LDL reduction achieved.
"Statins stop synthesis, Ezetimibe stops entry, fibrates fight fat (triglyceride)."
Hypothyroidism must be excluded before starting a statin for high cholesterol; it raises LDL and also increases the risk of statin myopathy.
Expect: BMI calculation and WHO and South Asian cut-offs; waist circumference; leptin and ghrelin; secondary causes of obesity (hypothyroidism, Cushing, PCOS, Prader–Willi); metabolic syndrome criteria; orlistat (lipase inhibitor, oily stools); bariatric surgery indications and nutritional deficiencies; secondary causes of hyperlipidaemia; FH inheritance, LDL-receptor defect and tendon xanthomas; palmar xanthomas in remnant disease and PBC; eruptive xanthomas, lipaemia retinalis and pancreatitis with lipoprotein lipase deficiency; Friedewald formula; statin mechanism, myopathy and drug interactions; ezetimibe, PCSK9 inhibitors, fibrates and niacin flushing.
Quick revision
- BMI = kg ÷ m²; obese 30+ (WHO), 27.5+ (commonly used for South Asians); waist matters most.
- Leptin from fat suppresses appetite (resistance in obesity); ghrelin from stomach stimulates it.
- Obesity → diabetes, hypertension, OSA, NAFLD, OA, gallstones, cancers.
- Treatment ladder: lifestyle → orlistat or GLP-1 agonist → bariatric surgery (BMI over 40, or over 35 plus disease).
- Exclude secondary hyperlipidaemia: hypothyroid, diabetes, nephrotic, cholestasis, alcohol, drugs.
- FH: autosomal dominant LDL-receptor defect, tendon xanthomas, early MI; screen relatives.
- Very high triglycerides → pancreatitis, eruptive xanthomas, lipaemia retinalis; fibrate.
- Statins first line (check CK for myopathy); then ezetimibe; then PCSK9 inhibitors.
Written by The House Job from standard references (Kumar and Clark's Clinical Medicine; Park's Textbook of Preventive and Social Medicine).
FAQ
Why do most obese people have high leptin levels?
Fat cells make leptin in proportion to fat mass, but the brain becomes resistant to it, so the high level fails to curb appetite.
Which is more dangerous, a large waist or a high BMI?
A large waist, because it reflects visceral fat, which is most closely tied to insulin resistance, diabetes and heart disease.
What causes tendon xanthomas?
Long-standing very high LDL cholesterol, most typically familial hypercholesterolaemia, deposits cholesterol in tendons such as the Achilles and finger extensors.
Why is gemfibrozil avoided with statins?
It raises statin levels and adds its own muscle toxicity, so the risk of myositis and rhabdomyolysis rises sharply.
Can lipids be checked without fasting?
Yes for cholesterol and HDL; a fasting sample is needed only when triglycerides are high or the LDL calculation is unreliable.