What are the typical presentations of central hypothyroidism?

Clinical Presentation of Central Hypothyroidism

Central hypothyroidism typically presents with milder and less specific symptoms than primary hypothyroidism, characterized by low free T4 levels with low to normal TSH concentrations due to insufficient stimulation of the thyroid gland by the pituitary or hypothalamus. 1

Key Clinical Features

General Symptoms

• Fatigue and lethargy (often less severe than in primary hypothyroidism)
• Weight gain
• Cold intolerance
• Dry skin
• Constipation

These symptoms result from decreased metabolic rate, with weight gain occurring due to reduced fat-burning and cold intolerance from decreased heat production 2.

Distinguishing Features from Primary Hypothyroidism

• Symptoms are typically milder 1
• May be masked by other pituitary hormone deficiencies 3
• Often part of a constellation of other pituitary hormone deficiencies 4
• Hair loss may be present but is generally less pronounced 5

Laboratory Findings

• Low free T4 with low to normal TSH levels (key diagnostic finding) 1, 6
• May have concurrent deficiencies in other pituitary hormones:
  • ACTH (leading to adrenal insufficiency)
  • FSH/LH (causing hypogonadotropic hypogonadism)
  • Growth hormone deficiency 4

Etiology and Associated Conditions

Central hypothyroidism can be:

1. Isolated - affecting only the thyroid axis
2. Combined - part of multiple pituitary hormone deficiencies 1

Common causes include:

• Pituitary tumors (most common acquired cause)
• Hypothalamic disorders
• Post-surgical hypopituitarism
• Radiation therapy to the brain
• Immune checkpoint inhibitor therapy (particularly anti-CTLA-4 antibodies) 4
• Genetic causes (rare, mostly congenital) 6

Diagnostic Challenges

The diagnosis of central hypothyroidism is often challenging due to:

1. Subtle or nonspecific clinical presentation
2. Laboratory interference in free T4 or TSH measurements
3. Concurrent systemic illness that can mimic the biochemical profile
4. The common practice of "TSH-reflex" testing (measuring only TSH without free T4) 1

Critical Diagnostic Approach

• Morning testing of thyroid function (TSH, free T4) is essential
• Additional testing should include:
  • ACTH and cortisol levels (or 1 mcg cosyntropin stimulation test)
  • Gonadal hormones (testosterone in men, estradiol in women, FSH, LH)
  • MRI of the sella with pituitary cuts when hypophysitis is suspected 4

Special Considerations

Hypophysitis from Immune Checkpoint Inhibitors

Patients receiving immune checkpoint inhibitors (particularly ipilimumab) should be monitored closely as:

• Incidence of hypophysitis can be up to 17% with high-dose ipilimumab
• Typically occurs 8-9 weeks after starting treatment
• Often presents with headache (85%) and fatigue (66%)
• MRI may show pituitary enlargement that resolves within two months 4

Potential Complications if Untreated

• Cardiovascular risks
• Impaired quality of life
• Growth and developmental issues (in congenital cases)
• Metabolic alterations 6

Central hypothyroidism requires careful evaluation and diagnosis, as it can be easily missed due to its subtle presentation and the limitations of standard thyroid function testing approaches that focus primarily on TSH levels.