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Endocrine Review Course Learning Objectives:
- Discuss the differential diagnosis of a High TSH
- Identify physiological mild TSH elevation with advanced age that does not require treatment 
- Be able to pick up on exam question clues of high TSH scenarios 



Text: 
A 20-year-old female presents to her primary care physician for a wellness check. She reports fatigue and sleepiness. Family history includes hypothyroidism in her mother.  Her physical exam reveals slightly enlarged thyroid gland. Her vital signs within normal reference ranges. Her TSH was measured and was elevated at 7.5.  What’s the best next step:

·       
Check FT4·    
 Start levothyroxine·       
Perform thyroid US·       
Check Thyroid peroxidase antibody 

And the answer is Check FT4. This would be needed to confirm and characterize hypothyroidism (overt vs subclinical). Starting levothyroxine at this point is premature. Although this patient has enlarged thyroid, however thyroid ultrasound is not a routine part of hypothyroidism evaluation and would not be the best next step. While measuring TPO may help explain the etiology, it would not be the best next step. Reference range can vary widely depending on the assay measurement. With that caveat for serum TSH, normal reference range is typically between 0.4 – 4.0 mU/l. Above 2mU/l the risk of developing hypothyroidism increases especially in the presence of TPO antibodies.  ­­­­ 

When encountering high TSH, you should immediately have 3 differential categories:o   
First category is Appropriate pituitary response to low levels of thyroid hormone, in this case, the pituitary is attempting to increase thyroid hormone production§  Such as in primary clinical and subclinical hypothyroidism, from Hashimoto’s, thyroid radiation, previous thyroid surgery, and drug induced hypothyroidism like amiodarone, lithium, interferon-alpha, and immune checkpoint inhibitors, TKI, physiological increase with later age, morbid obesity Second category is Inappropriate pituitary response, in this case, thyroid levels are high, but the pituitary continued to provide stimulation to the thyroid due to pituitary pathology or resistance (TSHoma or thyroid hormone resistance) which will be discussed in detail in a future episode. Briefly TSHoma or thyrotropinoma is rare TSH-secreting pituitary tumor. Thyroid hormone resistance is due to mutation in TSH receptor.  This can also be seen in the late recovery phase of thyroiditis and in recovery of sick euthyroid syndrome.     
Third category is lab assay abnormalities such as Macro-TSH. We previously mentioned assay interference with antibodies but also Macro-TSH can cause interference. TSH is elevated usually VERY HIGH like 100 mIU/L and thyroid hormone levels here are typically normal. Macro-TSH is a macromolecule made from the autoimmune anti-TSH immunoglobulin and TSH molecule. It is biologically inactive. The gold standard method to detect macro-TSH is chromatography. It is also important to keep in mind macro-TSH for persistent TSH elevation.

 Exam Clues-       In each Clinical scenario, you should screen the question for specific supportive clues, for example:o   Family or personal history of autoimmune disease could support primary hypothyroidism/Hashimoto’s diseaseo   Strong multigenerational Family history of thyroid disorder (autosomal dominant pattern) could support TSH resistance, genetic testing for THR-B is possibleo   Recent critical illness could indicate sick euthyroid in recovery phaseo   Unusual diet such as kelp/seaweed/seamoss diet or recent IV contrast may s

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