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Pathology 102: Define the Cause of Hypothyroidism to Treat It Skillfully
It is important to diagnose the cause of your patient’s thyroid problem—and as my Med-Mal anecdote suggests, skipping this step can be harmful. We should test for autoantibodies; here’s why:
We know that autoimmune thyroiditis (AIT) is the most common cause of hypothyroidism in the US. There are two main forms of AIT: Hashimoto’s disease, which we all understand to cause hypothyroidism and Graves’ disease—the most common cause of hyperthyroidism. Both can cause hypothyroidism, but they can respond very differently to our treatment efforts.
Hashimoto’s is a T-cell mediated, destructive process.81 Its hallmark autoantibodies react with the thyroid peroxidase enzyme that constructs thyroid hormone (TPO-Ab) and with thyroglobulin, the protein in which thyroid hormone is manufactured and stored (Tg-Ab).13 These antibodies are probably cytotoxic, though that has been debated.82
Graves’ disease involves both stimulating and destructive events: B-lymphocytes release antibodies that bind to thyroid cells’ TSH-receptors (TSH-R) and, by molecular mimicry, make the cells respond exactly as they do to TSH.4 Most Graves’ patients also make the destructive autoantibodies typical of Hashimoto’s disease.83
Always remember that any hypothyroid patient could have end-stage, “burned-out” Graves’ disease.24 This can affect your therapy: As long as a Graves’ patient has a shred of functioning thyroid tissue, the TSH-receptor-stimulating antibodies (TRs-Ab or TSI, formerly LATS) can drive that residual thyroid to produce hormones unpredictably. We’ll discuss this and other types of “autonomous function” presently.
Test Thyroid Autoantibodies
When a patient’s thyroid gland is palpably abnormal, I test for both TPO-Ab and Tg-Ab. Yes, the medical literature now supports the value of testing Tg-Ab.84 Various other anti-thyroid antibodies exist for which no commercial tests are available.85
If the history and examination raise a question of prior Graves’ or give a hint of autonomous function, order either TSI (a biological assay) or the faster, less-expensive immunoassay for TR-Ab (which does not differentiate between stimulating and blocking antibody).86 This complements your comparison of TSH and thyroid hormone levels and helps to predict autonomous function or unreliable TSH values. Identifying or anticipating such problems can improve treatment outcomes.
Disappointingly, not every case of AIT can be proven by these antibody tests. Probably because Hashimoto’s is primarily a T-cell mediated disease, autopsy series have found up to 10% of glands with histological AIT are antibody-negative.87 Ultrasound can help,88 and I’ve learned to trust palpation.
Tests for Less-Common Causes of Hypothyroidism
Most post-ablative hypothyroid patients report their status; sometimes a surgical scar is the tip-off. Nutritional issues can be more challenging. As above, low iodine can cause goiters but less often hypothyroidism. In the US, we are more likely to see pseudo-hypothyroidism due to iodine toxicity,32, 89 often from people following ill-considered internet suggestions.
For iodine, test overnight-fasting blood or get a first-voided morning urine specimen—it is routinely used by the WHO, which considers 100 mcg of iodine/ L “replete.”90 Others prefer a 24-hour urine collection. I will not use the “iodine-loading test,”91 which I believe is bogus – and not wholly safe.92
Pharmacological doses of lithium can cause hypothyroidism in up to 20% of chronic users.34, 35 More often, lithium in the amounts used to treat type-I bipolar disorder will produce a marked multinodular goiter. If you test, know that “therapeutic” blood values are actually thyroid-toxic, with cumulative effects.93
Basal Temperatures
It is tempting to measure basal axillary temperatures on waking in the morning. I believe low axillary temperatures imply low metabolic rate and may support laboratory testing,94,95 but they do not prove low thyroid function. I have tried and will testify: Basal temperatures cannot be used to safely guide doses of thyroid hormone replacement.
Therapeutics 101: Treat Hypothyroidism…Successfully.
It is unlikely that any practitioner in the US will need to treat iodine-deficient hypothyroidism. To the many clinicians who give supplementary iodine, a caution: The iodine-depleted thyroid gland enlarges and up-regulates all of its mechanisms for taking up iodine and incorporating it into thyroid hormone. Therefore, hyperthyroidism can occur if iodine is rapidly or excessively replaced; it is not uncommon and is sometimes severe.96-97
The amount of iodine supplementation should be moderate.98 NHANES-III found elevated urinary iodine (>401 mcg/L) is associated with higher risk of all-cause mortality, whereas low iodine was not.99 Some patients arrive for consultation with first-voided urine iodine values in the thousands of micrograms per liter.
Thyroid Hormone Replacement
It is important to ask if your patient has a preference for any particular form of thyroid treatment. For the sake of an orderly presentation, let’s begin with a patient who prefers “orthodox” replacement with levothyroxine (T4).100 Levothyroxine is synthetic but biologically identical. Proponents have touted the fact that T4 is a pre-hormone as evidence of its safety: They state that only the required amount of T3 will be made.101 Critics ask if it can be…but that’s for later.
Current guidelines encourage us to treat patients whose TSH value is >10 µIU.100 Those patients with TSH between 5 and 10 may have “subclinical hypothyroidism,”102 so treatment is recommended only if TSH is consistently elevated and freeT4 is low, regardless of their symptoms. Semantically, perhaps sub-laboratory is a more correct term. We’ll re-visit this, at which time the truth of this statement will be validated: “(Our) needs include the development of superior biomarkers of euthyroidism to supplement thyrotropin (TSH) measurements.”100
Pre-Treatment Considerations
Before starting treatment with levothyroxine (T4), always assess the patient’s overall health, the nature of the thyroid disease, and the adequacy of other endocrine systems. For example, patients with no gland whatsoever—whether congenitally absent or ablated by operation or iodine 131*–are often said to be the most difficult: They have no endogenous production to “back them-up”100 when they miss a dose or if our treatment efforts go off-target.
The adrenal glands are essential to our metabolism; if thyroid sets the thermostat of the metabolism, the adrenal is the furnace. The entire spectrum of adrenal dysfunction, from Addison’s to the lightly regarded “adrenal fatigue” should be addressed.103 Decreased adrenal mass is associated with long-term hypothyroidism, following experimental abnormalities of all three components of the hypothalamic-pituitary-adrenal axis.104 Correcting the thyroid deficiency can create increased demands for adrenal steroids.105 Thus, adrenal issues should be addressed before or concurrently with thyroid hormone replacement—not deferred to afterwards.
Steroid sex hormones also can be important: Postmenopausal women have complained that thyroid treatment provokes symptoms of estrogen deficiency. These included vasomotor flashes, mood swings and insomnia – none of which correlated to peak-and-trough fluctuations of thyroid hormone. This may be mediated by crosstalk at receptors in the nuclei106-108 or perhaps simply by increasing the hepatic metabolism of estradiol.
Give Informed-Consent Talk Before Starting Treatment
The goal of treatment is to restore normal thyroid hormone effect at the cellular level, resolving the symptoms and signs of hypothyroidism. The coincidental restoration of desirable blood levels is both a goal and our guide, for we use the laboratory to monitor therapy.100 In certain cases, slightly more thyroid hormone replacement is given to suppress TSH, as after thyroid cancer treatment109 or to shrink a goiter.110
Risks should be discussed. Treatment can harm patients if we give too much hormone, or too little—or if a patient disregards our instructions and self-medicates according to whim. In IC-talk, emphasize that provider and patient are jointly responsible and both must cooperate. As above, age and other health issues influence risk. Otherwise, harm is possible only if the patient is allergic to some “inert” component of the tablet or if he chokes on a pill. Fertility can be increased, menstrual cycles may resume, and rarely, allergies might get stronger as this unwanted portion of the immune system is strengthened.
Explain the therapeutic dose-response curve: Too little treatment does nothing; just the right amount achieves all that T4 can—and too much makes things worse. Make sure the patient hears these words: “If you feel worse with treatment, we may have increased the dose too quickly, or the dose is incorrect, either in the amount or its timing111,112 or there is an unsuspected problem.”
Trusting our history, physical and lab findings, we expect treatment to do good things. Importantly though, every new thyroid prescription begins a treatment-trial. If it does not help, the reason must be determined.
