Differential Diagnosis for Unexplained Weight Gain

The following differential diagnosis is organized into categories to help guide the thought process.

• Single Most Likely Diagnosis

  • Hypothyroidism: Although labs may initially appear normal, subtle thyroid dysfunction can lead to weight gain. Repeat thyroid function tests or assessing for thyroid antibodies might be necessary.
  • Insulin Resistance/Pre-diabetes: Early stages may not show abnormal labs, but the body's decreased ability to effectively use insulin can lead to weight gain.

• Other Likely Diagnoses

  • Polycystic Ovary Syndrome (PCOS): Weight gain, particularly in the abdominal area, is common in PCOS, which may not always present with abnormal labs initially.
  • Cushing's Syndrome: Early or mild cases might not have overtly abnormal labs but can cause significant weight gain, particularly in the central area.
  • Medication Side Effects: Certain medications, such as steroids, some antidepressants, and antipsychotics, can cause weight gain as a side effect.
  • Sleep Apnea: Poor sleep quality can disrupt hormones that regulate hunger and fullness, leading to weight gain.

• Do Not Miss Diagnoses

  • Pheochromocytoma: A rare tumor of the adrenal gland that can cause episodic hypertension and weight gain due to hormonal imbalances.
  • Acromegaly: Excess growth hormone production, often due to a pituitary tumor, can lead to weight gain among other symptoms.
  • Prader-Willi Syndrome: A genetic disorder that affects physical, mental, and behavioral development and is characterized by an insatiable appetite, leading to obesity.

• Rare Diagnoses

  • Hypothalamic Obesity: Damage to the hypothalamus, which can be due to various reasons including tumors, surgery, or inflammation, can lead to excessive hunger and weight gain.
  • Leptin Deficiency: A very rare condition where the body does not produce enough leptin, a hormone that helps regulate energy balance and body weight.
  • Bardet-Biedl Syndrome: A rare genetic disorder characterized by obesity, intellectual disability, and other systemic findings.