What conditions could cause symptoms of facial puffiness, hair loss, fatigue, and brain fog in a middle-aged adult with a potential history of autoimmune disorders or endocrine issues?

Differential Diagnosis: Facial Puffiness, Hair Loss, Fatigue, and Brain Fog

Hypothyroidism is the most likely diagnosis and should be evaluated immediately with TSH and free T4 testing, as this constellation of symptoms—facial puffiness (periorbital), hair loss, fatigue, and brain fog—represents classic manifestations of thyroid hormone deficiency. 1

Primary Diagnostic Consideration: Hypothyroidism

Clinical Presentation

The symptom cluster you describe is pathognomonic for hypothyroidism 1:

• Periorbital puffiness is a characteristic physical finding in hypothyroidism, resulting from myxedematous changes 1
• Hair loss is a cardinal symptom that typically improves within 3-4 months of adequate levothyroxine replacement 2
• Fatigue is one of the most common presenting complaints in hypothyroid patients 1, 2
• Brain fog (cognitive impairment, poor memory, and concentration difficulties) is well-documented in hypothyroidism and represents a recognizable symptom complex 3, 4

Autoimmune Etiology

Given the history suggesting autoimmune disorders, Hashimoto's thyroiditis is the most probable underlying cause 2, 5. Patients with positive anti-TPO antibodies have a 4.3% annual risk of developing overt hypothyroidism versus 2.6% in antibody-negative individuals 2, 5.

Diagnostic Workup

Measure TSH and free T4 simultaneously as the initial screening tests 6:

• TSH has sensitivity above 98% and specificity greater than 92% for detecting thyroid dysfunction 2, 6
• Free T4 distinguishes subclinical from overt hypothyroidism 6
• Consider anti-TPO antibodies to confirm autoimmune etiology 5, 6

Secondary Considerations: Other Autoimmune/Endocrine Conditions

Cushing's Syndrome

While less likely than hypothyroidism, Cushing's can present with 1:

• Facial puffiness ("moon face")
• Fatigue and proximal muscle weakness
• Weight gain with central distribution
• Screen with overnight 1-mg dexamethasone suppression test or 24-hour urinary free cortisol 1

Adrenal Insufficiency

Critical to exclude before treating hypothyroidism, as thyroid hormone can precipitate adrenal crisis 2, 6:

• Presents with fatigue, weight loss (not gain), hypotension
• More common in patients with autoimmune thyroid disease 2
• Screen with morning cortisol and ACTH if suspected 6

Primary Biliary Cholangitis (PBC)

Can cause fatigue and is associated with autoimmune conditions 1:

• Fatigue has both peripheral and central components, frequently associated with cognitive impairment 1
• Associated autoimmune conditions include hypothyroidism, Sjögren's syndrome 1
• Screen with antimitochondrial antibodies if liver enzymes elevated 1

Conditions Associated with Brain Fog

Long COVID

If there is recent COVID-19 history 1, 4:

• Brain fog characterized by fatigue, dizziness, myalgia, word-finding difficulties, and memory impairment 4
• Low cortisol levels documented more than 1 year into symptom duration, suggesting hypothalamus-pituitary-adrenal axis dysfunction 1
• Neuroinflammation, reduced cerebral blood flow, and brainstem abnormalities observed 1

ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome)

Consider if symptoms include 1:

• Profound fatigue not alleviated by rest
• Postexertional malaise (cardinal symptom)
• Cognitive impairment and orthostatic intolerance
• Can follow viral infections; up to 75% cannot work full-time 1

Neuroinflammatory Processes

Brain fog represents cognitive dysfunction related to underlying neuronal dysfunction 7, 8:

• Chronic low-level inflammation is most detrimental to mind and body 8
• Associated with diminished natural killer cell function, T cell abnormalities, mitochondrial dysfunction 1

Less Common Endocrine Causes

Hypopituitarism/Central Hypothyroidism

Consider if 1, 2:

• Multiple pituitary hormone deficiencies present
• History of head trauma, pituitary surgery, or radiation
• Always rule out adrenal insufficiency first before treating thyroid dysfunction 2, 6

Hypoparathyroidism (22q11.2 Deletion Syndrome)

Can present in adults with 1:

• Fatigue and emotional irritability from hypocalcemia 1
• Hypothyroidism (>25% develop it) 1
• Requires calcium, magnesium, and parathyroid hormone measurements 1

Critical Diagnostic Algorithm

1. First-line testing 6:

   • TSH and free T4 (simultaneously)
   • Complete metabolic panel
   • Complete blood count

2. If TSH elevated 2, 6:

   • Confirm with repeat testing after 3-6 weeks (30-60% normalize spontaneously) 2
   • Measure anti-TPO antibodies to confirm autoimmune etiology 5, 6
   • Screen for adrenal insufficiency before starting levothyroxine 2, 6

3. If TSH normal but symptoms persist 6:

   • Consider free T3 measurement
   • Evaluate for other autoimmune conditions (celiac disease, type 1 diabetes, adrenal insufficiency) 5, 6
   • Screen for vitamin B12 deficiency 2

4. Additional testing based on clinical context 1:

   • Morning cortisol and ACTH if adrenal insufficiency suspected
   • Antimitochondrial antibodies if liver dysfunction present
   • Consider sleep study if obstructive sleep apnea suspected 1

Common Pitfalls to Avoid

• Never start thyroid hormone before ruling out adrenal insufficiency in patients with suspected central hypothyroidism or multiple autoimmune conditions, as this can precipitate life-threatening adrenal crisis 2, 6
• Do not treat based on a single elevated TSH value—30-60% normalize on repeat testing 2
• Avoid missing transient causes of TSH elevation such as acute illness, recovery from thyroiditis, or recent iodine exposure 2
• Do not overlook associated autoimmune conditions in patients with confirmed autoimmune thyroid disease—screen for celiac disease, type 1 diabetes, pernicious anemia, and adrenal insufficiency 5, 6