What other factors could be maintaining an elevated thyroid‑stimulating hormone in an elderly patient whose levothyroxine dose was increased to 137 µg and free thyroxine rose, yet TSH remains high?

Causes of Persistent TSH Elevation Despite Adequate Levothyroxine Dosing

Medication Adherence and Administration Issues

The most common cause of persistent TSH elevation in patients on levothyroxine is poor medication adherence. 1 Before investigating other causes, directly assess whether the patient is taking their medication consistently.

Beyond simple non-compliance, several administration errors can prevent adequate absorption:

• Timing with food: Levothyroxine must be taken on an empty stomach, 30-60 minutes before breakfast, as food significantly reduces absorption 2, 3
• Drug interactions: Iron supplements, calcium supplements, proton pump inhibitors, and antacids taken within 4 hours of levothyroxine will block absorption 2, 4
• Gastrointestinal disorders: Celiac disease, inflammatory bowel disease, atrophic gastritis, or any malabsorptive condition can prevent adequate levothyroxine uptake 1

Medication and Supplement Interference

Several medications increase levothyroxine metabolism or interfere with its action:

• Enzyme inducers: Phenytoin, carbamazepine, rifampin, and phenobarbital accelerate levothyroxine clearance 5
• Estrogen therapy: Oral contraceptives or hormone replacement therapy increase thyroid-binding globulin, requiring higher levothyroxine doses 1
• Tyrosine kinase inhibitors: These cancer medications can cause thyroid dysfunction 2

Age-Related TSH Elevation

In elderly patients, TSH naturally increases with age, and what appears as "elevated" TSH may actually represent a normal age-adjusted value. 6, 7, 4 Specifically:

• 12% of persons aged 80+ with no thyroid disease have TSH levels >4.5 mIU/L 2
• The median TSH level increases with advancing age, with upper limits reaching 7.5 mIU/L in patients over 80 2
• Standard population reference ranges (0.45-4.5 mIU/L) may be inappropriate for elderly patients 6, 8

For an elderly patient with TSH remaining elevated despite dose increases, consider that this may represent normal aging rather than inadequate treatment. 6, 7 The key question becomes whether the free T4 is in the upper half of normal—if so, further dose increases may cause harm rather than benefit 2.

Transient vs. Permanent Hypothyroidism

30-60% of elevated TSH levels normalize spontaneously on repeat testing, indicating transient thyroid dysfunction. 2, 6, 5 Causes of transient TSH elevation include:

• Recovery phase from thyroiditis (including viral or autoimmune) 2
• Recent acute illness or hospitalization 2, 6
• Recent iodine exposure from CT contrast 2
• Immune checkpoint inhibitor-induced thyroiditis 2

If the patient had a recent illness or medication change, recheck TSH in 4-6 weeks before increasing the dose 2.

Assay Interference

Heterophilic antibodies can cause falsely elevated TSH measurements 2. If TSH remains elevated despite free T4 in the upper-normal range and good medication adherence, consider sending the sample to a different laboratory using an alternative assay method 1.

Central Hypothyroidism Masquerading as Primary

In rare cases, what appears as inadequately treated primary hypothyroidism is actually central (secondary or tertiary) hypothyroidism with inappropriately normal or mildly elevated TSH 2. Clues include:

• History of pituitary disease, head trauma, or pituitary surgery
• Other pituitary hormone deficiencies
• TSH that is normal or only mildly elevated despite low free T4

In central hypothyroidism, TSH cannot be used to guide therapy—free T4 should be maintained in the upper half of normal. 2

Concurrent Adrenal Insufficiency

Before increasing levothyroxine in a patient with persistently elevated TSH, rule out adrenal insufficiency, as increasing thyroid hormone can precipitate adrenal crisis. 2, 3, 4 This is particularly important in patients with:

• Autoimmune hypothyroidism (increased risk of concurrent autoimmune adrenal insufficiency) 2
• History of pituitary disease
• Unexplained hypotension, hyponatremia, or hypoglycemia 2

Critical Monitoring Approach

After any dose adjustment, wait 6-8 weeks before rechecking TSH, as this represents the time needed to reach steady state. 2, 3, 4 Adjusting doses more frequently leads to inappropriate titration 2.

When TSH remains elevated despite apparent adequate dosing:

1. First: Verify medication adherence and proper administration technique
2. Second: Review all medications and supplements for interactions
3. Third: Consider age-adjusted reference ranges in elderly patients
4. Fourth: Rule out malabsorption or assay interference
5. Fifth: Ensure adequate time (6-8 weeks) has passed since last dose change

The target is TSH within 0.5-4.5 mIU/L with free T4 in the normal range, but in elderly patients, slightly higher TSH values (up to 6-7 mIU/L) may be acceptable to avoid overtreatment risks. 2, 6, 7