Unexplained weight gain

Unexplained weight gain is an increase in body weight that is not accounted for by intentional change in diet or activity, pregnancy or growth. Its clinical meaning depends on the composition of the gain: fat, fluid, muscle or a mass. Rapid gain over days is nearly always fluid. Gain over weeks to months is most often drug induced, endocrine or related to lifestyle and sleep.

Clinical relevance. Fluid gain signals heart failure, nephrotic syndrome, cirrhosis or kidney disease and can threaten life. Fat gain with specific features may indicate Cushing syndrome or hypothyroidism. Most chronic weight gain is multifactorial, and weight stigma needs to be avoided during assessment.

Classification by composition and tempo.

• Fluid retention (days to weeks): heart failure, nephrotic syndrome, cirrhosis with ascites, chronic kidney disease, protein losing states, drugs, pregnancy and pre-eclampsia, capillary leak.
• Fat gain (weeks to months): energy imbalance, drugs, endocrine disease, sleep loss, psychological causes, smoking cessation.
• Mass: ovarian or other tumour, fibroids, organomegaly, large cysts, ascites from malignancy.
• Muscle: anabolic steroids, growth hormone, exercise.

Mechanisms. Weight gain follows a positive energy balance (increased intake, reduced expenditure, reduced satiety signalling, metabolic slowing), sodium and water retention (reduced cardiac output, hypoalbuminaemia, renal sodium retention), cortisol excess, thyroid hormone deficiency, insulin excess, and hypothalamic dysregulation.

Measures. Body mass index (25 to 29.9 overweight; 30 or more obesity; ethnicity specific lower thresholds apply in some populations). Waist circumference (abdominal obesity at 94 cm or more in men and 80 cm or more in women for many populations; high risk at 102 cm and 88 cm). Waist to height ratio (over 0.5).

History.

• Amount and rate of gain, time course, distribution (central, generalised, face and neck), oedema, abdominal distension, breathlessness lying flat, nocturia, reduced urine, foamy urine.
• Diet and portion size, snacking, sugar sweetened drinks, alcohol, binge episodes, night eating, physical activity, sleep duration, shift work, smoking cessation, stress and mood, menopause.
• Endocrine features: cold intolerance, constipation, dry skin, slowed thinking (hypothyroidism); easy bruising, striae, proximal weakness, thin skin, hypertension, diabetes (Cushing syndrome); menstrual irregularity, hirsutism, acne, subfertility (polycystic ovary syndrome); headache, visual change, galactorrhoea (pituitary); episodic sweating, tremor and hunger (insulinoma).
• Drugs: antipsychotics (olanzapine, clozapine, risperidone), mirtazapine, paroxetine, tricyclics, valproate, carbamazepine, gabapentin, pregabalin, lithium, corticosteroids, insulin, sulphonylureas, pioglitazone, medroxyprogesterone acetate injection, beta blockers, calcium channel blockers (oedema), NSAIDs, antihistamines, dolutegravir and other integrase inhibitors, tamoxifen, aromatase inhibitors, oestrogen and progestogen contraceptives.
• Family history of obesity, early onset obesity, diabetes, thyroid disease. Childhood onset suggests genetic or hypothalamic causes.
• Mental health: depression, binge eating disorder, bulimia, trauma, medicated mood disorder.

Examination.

• Weight, height, body mass index, waist circumference, blood pressure.
• Face and neck (moon face, plethora, supraclavicular and dorsocervical fat pads), skin (striae over 1 cm wide and purple, bruising, acanthosis nigricans, hirsutism, acne, dry skin), hair, goitre.
• Heart and fluid: jugular venous pressure, oedema, ascites, pleural effusion, hepatomegaly, third heart sound.
• Abdominal or pelvic mass. Proximal muscle strength (stand from squat).
• Neck circumference, Mallampati class and features of sleep apnoea.
• Reflexes (slow relaxation), visual fields.
• Mental state and eating behaviour screen.

Red flags.

• Weight gain over 2 kg in a week or 5 kg in a month with oedema, breathlessness or reduced urine.
• Orthopnoea, paroxysmal nocturnal dyspnoea, ascites, jaundice, frothy urine, facial puffiness.
• Features of Cushing syndrome (striae, bruising, proximal weakness, new hypertension or diabetes).
• Headache, visual field loss, galactorrhoea, amenorrhoea.
• Pelvic or abdominal mass, abdominal distension, early satiety.
• Pregnancy with swelling, headache or hypertension.
• Hypoglycaemic episodes, suicidal thoughts, severe binge eating.

Energy imbalance and lifestyle. High energy diet, sugar sweetened drinks, alcohol, reduced physical activity, inadequate sleep, shift work, smoking cessation, pregnancy and postpartum weight retention, menopause.

Drugs. Antipsychotics, mirtazapine, tricyclic antidepressants, paroxetine, valproate, carbamazepine, gabapentin and pregabalin, lithium, corticosteroids, insulin, sulphonylureas, pioglitazone, depot medroxyprogesterone, beta blockers, antihistamines, integrase inhibitors, tamoxifen, aromatase inhibitors.

Endocrine and metabolic. Hypothyroidism, Cushing syndrome (endogenous or exogenous), polycystic ovary syndrome, hypogonadism, growth hormone deficiency, hypothalamic and pituitary disease (craniopharyngioma, injury, irradiation), insulinoma, hyperinsulinism, prolactinoma, type 2 diabetes with insulin treatment, menopause.

Fluid retention.

• Cardiac: heart failure (reduced or preserved ejection fraction), constrictive pericarditis, restrictive cardiomyopathy, right heart failure from pulmonary hypertension, valvular disease.
• Renal: nephrotic syndrome (minimal change disease, focal segmental glomerulosclerosis, membranous nephropathy, diabetic nephropathy, amyloidosis), nephritic syndrome, chronic kidney disease, acute kidney injury.
• Hepatic and protein: cirrhosis with ascites, protein losing enteropathy, severe malnutrition (kwashiorkor), hypoalbuminaemia.
• Vascular and lymphatic: chronic venous insufficiency, lymphoedema, lipoedema, obstruction of the inferior vena cava, deep vein thrombosis.
• Others: idiopathic cyclical oedema, drug induced oedema (amlodipine, NSAIDs, pioglitazone, corticosteroids, minoxidil), pre-eclampsia, ovarian hyperstimulation, capillary leak syndrome, myxoedema.

Mass. Ovarian tumour, fibroid, ascites from malignancy, hepatosplenomegaly, retroperitoneal tumour, large cyst.

Psychological and behavioural. Binge eating disorder, night eating syndrome, depression with hyperphagia, emotional eating, bulimia nervosa, trauma, medicated mood disorder.

Genetic and sleep related. Prader-Willi syndrome, Bardet-Biedl syndrome, melanocortin 4 receptor deficiency, obstructive sleep apnoea.

1. Measure weight, height, body mass index, waist circumference and blood pressure. Compare with previous records. Distinguish fluid, fat and mass by examination.
2. Urinalysis with albumin to creatinine ratio (or protein to creatinine ratio; nephrotic range is protein to creatinine ratio over 300 to 350 mg/mmol or albuminuria with serum albumin under 25 g/L and oedema).
3. Urea, creatinine and eGFR, electrolytes, liver function tests, albumin, glucose and HbA1c, lipid profile, thyroid stimulating hormone, full blood count, and pregnancy test in women of reproductive age.
4. Cardiac tests when fluid overload is possible: NT-proBNP (under 125 pg/mL makes chronic heart failure unlikely), ECG, chest radiograph and echocardiography.
5. Hypothyroidism: raised thyroid stimulating hormone with low free thyroxine; treat after confirming. Subclinical elevation seldom explains weight gain.
6. Cushing syndrome screening in patients with suggestive features: 1 mg overnight dexamethasone suppression test (dexamethasone 1 mg orally at 23:00; 08:00 cortisol under 50 nmol/L, 1.8 microgram/dL, excludes it).
7. Or late night salivary cortisol on 2 occasions, or 24 hour urinary free cortisol on 2 collections. Exclude exogenous steroids, alcohol use and depression as causes of false positives. Abnormal tests need endocrine review with ACTH and imaging.
8. Polycystic ovary syndrome: after excluding other causes, 2 of 3 features (oligo or anovulation, clinical or biochemical hyperandrogenism, polycystic ovarian morphology on ultrasound). Check total and free testosterone, SHBG, 17 hydroxyprogesterone, prolactin, thyroid stimulating hormone and glucose.
9. Pituitary and hypothalamic: prolactin, LH, FSH, oestradiol or testosterone, IGF-1, 08:00 cortisol, and MRI of the pituitary when indicated.
10. Fluid causes: 24 hour urine protein or ratio, serum albumin, abdominal ultrasound with Doppler, liver ultrasound, paracentesis and ascitic fluid analysis (serum ascites albumin gradient 11 g/L or more indicates portal hypertension), renal ultrasound, and biopsy for glomerular disease by specialists.
11. Mass: pelvic and abdominal ultrasound, CA-125 and CT when ovarian tumour is suspected.
12. Sleep study when snoring or daytime sleepiness. Eating behaviour questionnaires for binge eating.
13. Insulinoma: supervised fast with glucose, insulin, C peptide and proinsulin during hypoglycaemia.

Limits. Weight alone cannot distinguish fat from fluid. Screening tests for Cushing syndrome have false positives in obesity, alcohol use, depression and oestrogen therapy. Subclinical thyroid abnormalities are common and rarely cause large weight gain.

Fluid overload. Treat the cause.

• Heart failure: furosemide 40 mg orally once daily (or 20 to 40 mg intravenously in decompensation) titrated to weight loss of 0.5 to 1 kg daily, with disease modifying therapy directed by cardiology and monitoring of potassium, sodium and creatinine.
• Nephrotic syndrome: sodium restriction under 2 g daily, furosemide 40 mg orally once or twice daily, ACE inhibitor or angiotensin receptor blocker at the lowest effective dose for proteinuria, statin, thromboprophylaxis when albumin is under 20 to 25 g/L, and nephrology for biopsy.
• Cirrhotic ascites: sodium restriction 2 g daily, spironolactone 100 mg orally once daily with furosemide 40 mg (maintaining the 100:40 ratio), increasing every 3 to 5 days to a maximum of spironolactone 400 mg and furosemide 160 mg daily; monitor sodium, potassium and creatinine.
• Large volume paracentesis with albumin 8 g for each litre removed when more than 5 litres are drained.
• Drug induced oedema: stop or change the offending drug where possible.
• Venous insufficiency and lymphoedema: compression, leg elevation and skin care.

Endocrine causes.

• Hypothyroidism: levothyroxine 1.6 micrograms/kg orally once daily on an empty stomach (start 25 micrograms daily in older adults or coronary disease and increase by 25 micrograms every 4 to 6 weeks). Check thyroid stimulating hormone at 6 to 8 weeks.
• Cushing syndrome: endocrinology review for surgery or medical therapy; stop avoidable exogenous glucocorticoids slowly (abrupt withdrawal risks adrenal crisis).
• Polycystic ovary syndrome: lifestyle, metformin 500 mg orally daily increasing to 1 g twice daily with meals, combined oral contraceptive for cycle control and androgen symptoms, and fertility support as needed.
• Hypogonadism: testosterone replacement under specialist direction after confirming low morning testosterone on 2 occasions.
• Pituitary disease: specialist care.

Drug induced weight gain. Review necessity, dose and alternatives (for example aripiprazole or lurasidone rather than olanzapine; bupropion rather than paroxetine; topiramate or lamotrigine rather than valproate), without stopping essential psychiatric or antiepileptic therapy abruptly. For antipsychotic related weight gain, metformin 500 mg orally twice daily increasing to 1 g twice daily has modest benefit.

Lifestyle and obesity management.

• Aim for 5% to 10% weight loss with an energy deficit of 500 to 750 kcal daily.
• Use a balanced diet with reduced refined carbohydrate and sugar sweetened drinks, 150 to 300 minutes of moderate activity weekly with resistance training, behaviour change support, sleep of 7 to 9 hours, and alcohol reduction.
• Pharmacotherapy for body mass index of 30 or more, or 27 or more with weight related comorbidity: semaglutide 2.4 mg subcutaneously once weekly (start 0.25 mg weekly, increase every 4 weeks to 0.5, 1.0, 1.7 and then 2.4 mg).
• Or tirzepatide (start 2.5 mg weekly for 4 weeks, increase in 2.5 mg steps at 4 week intervals to a maintenance dose of 5, 10 or 15 mg).
• Counsel on nausea, gallstones, pancreatitis, thyroid C cell tumour warning, and avoid in pregnancy. Stop at least 1 week before elective procedures where aspiration risk applies.
• Orlistat 120 mg orally with each main meal (up to three times daily) is an alternative with gastrointestinal effects and reduced fat soluble vitamin absorption.
• Bariatric surgery for body mass index of 40 or more, or 35 or more with comorbidity (lower thresholds in type 2 diabetes and some ethnic groups).
• Binge eating disorder: psychological therapy (cognitive behavioural therapy), and lisdexamfetamine under specialist direction.
• Sleep apnoea: continuous positive airway pressure.

Monitoring. Weigh at each visit. Review fluid weight daily in heart failure and cirrhosis. Recheck thyroid function at 6 to 8 weeks, renal function and electrolytes within 1 week of starting or changing diuretics, and HbA1c at 3 months.

Referral and escalation. Same day assessment for rapid fluid gain with breathlessness or reduced urine. Cardiology, nephrology or hepatology for fluid overload. Endocrinology for suspected Cushing syndrome, pituitary disease or complex thyroid disease. Gynaecology for pelvic mass or polycystic ovary syndrome with fertility needs. Weight management services, bariatric services and mental health teams as indicated.

Admission. Decompensated heart failure, anasarca, tense ascites, acute kidney injury, nephrotic syndrome with complications, severe hypoalbuminaemia, pre-eclampsia, suspected adrenal or pituitary crisis, suicidal risk.

Safety netting. Return for sudden breathlessness, reduced urine, abdominal swelling, severe headache, visual change, fits, chest pain, or leg swelling on one side.

Special groups. Pregnancy: excess gestational weight gain with swelling, headache or hypertension needs urgent assessment for pre-eclampsia. Children and adolescents: weight gain with short stature or slowed growth suggests hypothyroidism, Cushing syndrome or hypothalamic disease. Older adults: fluid retention and drugs dominate. HIV: weight gain on dolutegravir based regimens; advice and monitoring of glucose and lipids. Postmenopausal women: central redistribution; review hormone therapy and metabolic risk.