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WHAT IS A HOT NODULE?

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A “hot” nodule – a.k.a. autonomous hyperfunctioning adenoma – is a growth on the thyroid gland that has escaped the body’s normal thyroid hormone regulation system and has literally gone rogue, manufacturing excess hormone as it pleases. It was first described in 1918 by American doctor Emil Goetsch, and for a time the hyperthyroidism resulting from a toxic adenoma was known as “Goetsch’s disease.”

Are they common?

Thyroid nodules themselves are actually very common, especially in women, who are six times as likely as men to grow them, and especially as we age, with about 30 percent of people under the age of 50 having at least one nodule (according to ultrasound results) (S1), and up to percent 65 percent of us sport nodular growths by the time we reach old age (according to autopsy results) (S2). Some nodules are stand alone and “solitary,” and many people who have nodules have more than one. Other nodules grow in groups as in multinodular goiter, basically a thyroid that has become enlarged due to iodine deficiency or disease.

Most people who have solitary nodules will never know they have them; first, because most are not “palpable” or can be felt by touch, and second, because endocrine experts say the majority (more than 90 percent) are harmless, causing no symptoms and posing no problems. Nodules tend to be stable after a time, but may grow and shrink or even occasionally disappear according to the rise and/or fall of iodine in the diet. Only about 5 percent of nodules turn out to be malignant growths and need to be removed. callout 1If discovered through routine exams or tests for other reasons, all nodules of a certain size should be biopsied by fine needle aspiration to rule out cancer. (Hot nodules are almost never malignant.)

The majority of nodules (85 percent) will show up as “cold” on an iodine uptake scan, according to endocrineweb, meaning they do not absorb iodine and do not produce thyroid hormone. About 10 percent are “warm;” the commony do absorb iodine and create hormone at roughly the same rate as the rest of the thyroid. About 5 percent of nodules show up as “hot,” revealing an increased rate of iodine uptake and likely increased thyroid hormone output.

Indeed, increased “iodine trapping” is the primary characteristics of a hot adenoma, along with a high level of sodium/iodide symporter gene expression that allows that iodine to flow freely into the nodule’s follicles. A nodule thus fueled with increased iodine can, and will, secrete higher amounts of thyroid hormone than the tissue around it. Furthermore, this secretion can be further enhanced by thyrotropin stimulating hormone (TSH). (It hardly seems fair that a drop in TSH can’t stop a hot nodule from manufacturing hormone, but a rise can definitely stimulate it to make even more.)

Why does a nodule become hot?

According to one medical review, “a toxic adenoma probably evolves gradually from a small autonomously hyperfunctioning adenoma that initially is only slightly more active” than the rest of the thyroid (S3). Basically, it begins as a warm compensated nodule, then at some point – depending on the age of the person, the size of the nodule and most importantly, iodine intake – the hormone output speeds up. “The rate of development of thyrotoxicosis” in people with hyperfunctioning adenomas who are euthyroid, or have normal TSH, is about 4 percent per year, says the review.

But why would a nodule grow to become hot rather than remain cold like most nodules? “Mutations of the TSH receptor are found in the majority of solitary hyperfunctioning thyroid adenomas,” says the same review. The mutation activates the intracellular regulator cAMP (cyclic Adenosine MonoPhosphate), causing an increase in the cells' function and growth. callout 1What causes this mutation is unknown, although because such adenomas are more common in places with lower dietary iodine intake, resulting in higher TSH levels, the chronic TSH stimulation is suspected to “create a mutagenic environment.” Sounds good in theory, but it doesn’t explain the problem for someone like me living in the United States, where iodine excess, and a resulting trend toward hypothyroidism, is more the norm.

Whatever the cause of the TSH receptor mutation, a single thyroid follicular cell with that mutation can replicate itself, literally cloning itself, again and again at an unusually accelerated rate in the beginning, proliferating into “clonal” tumors or nodules. Over time, however, the rate of growth slows, so that by the time the nodule becomes clinically detectable, it is near the end of its proliferation process and is likely to remain stationary in size. Thus, while a hyperfunctioning nodule can certainly become hotter and create more hormone due to increased iodine intake, it is comforting to know the nodule itself is not likely to grow bigger once it has been discovered. (One study that followed 287 patients with hyperfunctioning nodules up to 15 years found no change in nodule size in 86 percent of the patients, while 9 percent had a nodule that grew at least 1 cm.) It’s also comforting to know that cold nodules will not suddenly turn hot due to an iodine blast, say from iodinated contrast dye during medical testing, which was my worry when I was told at my first ultrasound that my thyroid was sporting seven nodules. Cold nodules are an entirely different species of tumor.

It is also not inevitable that a hot nodule will become toxic and result in full-blown hyperthyroidism. That was certainly my fear when I was first diagnosed. But in fact, a truly toxic adenoma is considered rare, as we will see below. Despite a hot nodule’s rogue nature, among all patients who have them, “more than 75 percent have normal TSH when their nodule is first detected,” or so says one review (S3). (While I personally question this statistic because a doctor is unlikely to order the iodine uptake scan by which a nodule is diagnosed as hot unless TSH is already abnormally low, perhaps this number reflects the growing trend of discovering nodules incidentally through other medical testing such as X-rays.)

From hot nodule to toxic nodule

Some hyperfunctioning nodules are small and only mildly overproducing, and the pituitary gland will compensate with a small decrease of Thyrotropin Stimulating Hormone (TSH) to keep hormones in balance and symptoms at bay. This is called a “compensated” adenoma and allows the rest of the thyroid to keep functioning normally.

One can go along for years with an overproducing nodule of this type, never realizing it is there because TSH stays in the low normal range, but perhaps experiencing intermittent mysterious symptoms due to occasional increased iodine intake, say a weeklong sushi binge or an experiment with kelp supplements. I myself experienced stretches of unexplained heart palpitations and anxiety over a period of four years, and even once had a doctor ask me if I took thyroid hormone because of a high-ish free T4. But because my TSH stayed in low normal range - although sometimes by only a hair - I was always told my thyroid was “fine.”

Over time, with enough iodine supply, a nodule can overproduce to the point that TSH drops below normal (generally .450 mIU/L), while still allowing the rest of the thyroid to compensate well enough to keep T3 and T4 in the normal range. This is considered “subclinical” hyperthyroidism, or simply an “overactive” thyroid. At this stage, a doctor may or may not decide to do anything about it, such as a referral to an endocrinologist or offering a small dose of thyroid-suppressing medication. Indeed, the official medical position on subclinical hyperthyroidism seems to be to “observe” the nodule and periodically check hormone levels. This can be a frustrating medical gray area to be in, especially if one is getting the equivalent of a medical shrug because of undramatic lab results while experiencing what feels like dramatic symptoms. (See Thyroid Lab Dilemma).

Indeed, individual sensitivity to thyroid hormones varies widely, and even the American Association of Clinical Endocrinologists notes, “while it might be anticipated that the severity of thyrotoxic symptoms is proportional to the elevation in the serum levels of free T4 and T3,” in one study “the Hyperthyroid Symptom Scale did not strongly correlate with free T4 or T3 estimates and was inversely correlated with age” (S7). callout 4In other words, the younger you are, the more keenly you may experience symptoms.

Many a patient with low TSH but supposed “normal” T4 and T3 hormone levels can attest to experiencing frightening symptoms like racing heartbeat and palpitations, panic attacks and insomnia. But with or without symptoms, studies also show “adverse consequences” to the body with a very low TSH. One 2012 paper found “subclinical hyperthyroidism associated with increased risks of total coronary heart disease mortality and incident atrial fibrillation,” with the highest risks seen when TSH was below 0.10 mIU/L (S4). Meanwhile, a 2013 review noted “long-term TSH suppression leads to decreased bone mineral density and an increased fracture rate in the hip and in the spine” (S6).

So treatment can definitely feel imperative for mind and body, yet treatment options at the subclinical stage are usually confined to medication like beta blockers, and/or thyroid hormone-blockers like PTU and methimazole, and medication is not without the risk of side effects, some possibly serious. This understandably poses a dilemma posed to the cautious physician faced with an upset patient desperate to feel normal again.

Now, if TSH drops down to zero, the rest of the thyroid can go dormant or “quiescent” and stop creating hormone altogether, leaving the nodule to run the show and raise T3 and T4 above normal ranges. That’s when the nodule officially becomes “toxic,” and true hyperthyroidism exists. That is the point at which an endocrinologist will hop to and start talking about treatments beyond medication.

Fortunately, most hot nodules will not progress that far, with estimates ranging from anywhere between 1 percent (S1), to 10 percent (S5) of all solitary nodules becoming toxic or presenting with hyperthyroidism. Those are good odds. And as long as a nodule is not too toxic, short-term medication can be effective at getting the nodule back under control, while occasional maintenance doses can keep hormone levels – and symptoms - manageable.

Perhaps even more fortunately, because we can control our iodine intake, we have at least some degree of control over how much hormone we produce.

What determines the rate of hormone production?

The amount of hormone produced by the nodule depends on two things: 1) The size of the nodule and the number of individual cells within it, and 2) the iodine supply.

The first can be looked at as the size of the factory: A smaller nodule or less density of the nodule means a smaller capacity to produce hormone, while a larger nodule with more density or more cells has the capacity to produce more hormone. As one medical review notes, “Thyrotoxicosis is rare in patients with adenoma less than 2.5 cm in diameter ... In contrast, about 80 percent of patients with adenomas more than 5cm in diameter” have hyperthyroidism (S3).

So size is definitely important, but it is not the only thing that matters. Even a big factory cannot produce a lot of hormone without the required building material. The availability of iodine also drives the amount of hormone produced, which means we can slow the rate of hormone production by controlling the amount of iodine in our diet, and avoiding medications or medical tests that include iodine, as in contrast dye. (See Iodine is Key)

Can hot nodules shrink or disappear?

Most hyperfunctioning adenomas, once developed, are known to be stationary in nature, unlikely to change size. Again, a study that followed patients with hot nodules for up to found that 86 of the nodules remained the same size. Nine percent did grow, but the remaining 5 percent of nodules actually shrunk or disappeared, which was attributed to “hemorrhagic infarction.”

So there is a small (tiny) chance that a hot nodule will resolve on its own through a hemorrhage. But should that happen, says one paper, the destruction of the nodule will release stored hormone into the system and can cause thyrotoxicosis lasting for several months. Not sure that’s something I’d want.

The question we are left with then - do we pursue medical treatment for the hot nodule? Or, do we learn how to better live with it?

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