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This is an endocrine disease that results in a deficiency of thyroid hormone. We can categorize this as primary, secondary, or tertiary hypothyroidism.
Primary: the thyroid gland isn’t functioning (most common type).
Secondary: the pituitary gland doesn’t secrete enough thyrotropin (TSH) resulting in an underproduction of the thyroid hormone.
Tertiary: the hypothalamus doesn’t secrete enough TRH (thyrotropin releasing hormone) resulting in underproduction of TSH and ultimately thyroid hormone.
Central hypothyroidism encompasses both secondary and tertiary causes.
The most common cause worldwide is iodine deficiency. The most common cause in the US is from autoimmune dysfunction (Hashimotos disease).
Cretinism is severe hypothyroidism in an infant usually from the mother suffering from iodine deficiency.
Epidemiology of hypothyroidism
Congenital hypothyroidism affects 1 of every 4,000 newborns and is due to maldevelopment of the thyroid gland. It’s thought that about 4% of the population suffers from hypothyroidism and is more common in women (up to 8 times higher). The risk of hypothyroidism increases with age and found in up to 6% of women over 60 (TSH over 10 – TSH levels naturally increase with age).
Let’s start with the hypothalamic-pituitary-thyroid axis. This is a feedback loop which stimulates or decreases the amount of thyroid hormone released into circulation.
TRH is released from the hypothalamus and stimulates the release of TSH. TSH is secreted by thyrotrope cells of the anterior pituitary gland. TSH is is made up of alpha and beta subunits. The beta subunit is specific to TSH but the alpha subunit is seen in other hormones such as HCG (which is why this can be tricky in pregnancy). TSH has a diurnal rhythm and is highest at night.
TSH in turn stimulates the thyroid gland to release T4 (mostly) and small amounts of T3. These two hormones are responsible for metabolic homeostasis. T4 is a prohormone which then gets converted to T3 (active hormone) in the peripheral tissues by 5’-deiodination.
When enough T4 is produced, this leads to a negative feedback loop and signals the hypothalamus and anterior pituitary gland to decrease TRH and TSH production – which ultimately decreases T4 production. This way, the body remains in constant homeostasis.
Dopamine, glucocorticoids, and somatostatin suppress TSH – but only when given at pharmacological doses.
Let’s say there isn’t enough T4 in circulation. This triggers the production of TRH and TSH to stimulate the thyroid gland to produce more T4.
Etiology of Hypothyroidism
Hashimotos thyroiditis is the most common etiology of hypothyroidism. The body feels as if the thyroid antigens are foreign and lymphocytic infiltration of the thyroid gland occurs, resulting in destruction of the gland. Most patients have anti-thyroid peroxidase antibodies.
Up to 10% of women can develop postpartum hypothyroidism up to one year after conception and typically resolves after a few months.
Subacute thyroiditis is a rare presentation that typically occurs in middle aged women who present with thyroid pain, low grade fever, dysphagia, and an elevated ESR. It is thought to be viral in nature and is self limiting (1-6 months).
Drug induced hypothyroidism can also occur. Common medications to look out for include: tyrosine kinase inhibitors (used to treat many cancers), amiodarone, lithium, rifampin, phenytoin, carbamazepine, and phenobarbital. It can also be secondary to neck radiation following treatment of head/neck cancer, breast cancer, and/or Hodgkin lymphoma.
Central hypothyroidism can occur from pituitary tumor, tumors impinging the hypothalamus, trauma, Sheehan syndrome (postpartum pituitary necrosis), drugs (dopamine and corticosteroids decrease TSH production), and from TRH deficiency/resistance (mutation ofTRHR gene).
Clinical Features of the Newborn with Hypothyroidism
Most newborns appear normal at birth. Newborns may have certain clinical manifestations such as prolonged jaundice, feeding problems, hypotonia, enlarged tongue, delayed bone maturation, and umbilical hernia (which is common in healthy newborns). Congenital malformations, especially cardiac, are four times more common in congenital hypothyroidism.
But, children will be universally screened prior to discharge.
Clinical Features of the Adult with Hypothyroidism
There are two main changes that occur: slowing of the metabolic process and/or accumulation of matrix glycosaminoglycans (long unbranched polysaccharides).
Metabolic changes: fatigue, slow movement and slow speech, cold intolerance, constipation, weight gain (but not morbid obesity), delayed relaxation of deep tendon reflexes, and bradycardia.
Accumulation of glycosaminoglycans: coarse hair and skin, puffy faces, non-pitting edema, enlargement of the tongue (sleep apnea), and hoarseness.
Patients have a decreased cardiac output leading to DOE. Hypertension may also be seen because of increased vascular resistance. Hypercholesterolemia occurs because of decreased rate of metabolism.
Women often present with oligomenorrhea/amenorrhea or hypermenorrhea-menorrhagia. There is a decrease in fertility and an increased risk for abortion. This may also be a cause of hyperprolactinemia.
Men often report decreased libido, erectile dysfunction, and delayed ejaculation
Carpal tunnel syndrome is common in patients with hypothyroidism (up to 35%) – typically bilateral. Sensory loss in the feet and in a stocking-glove pattern are also common.
Muscle weakness, myalgias, cramps, and joint pain can all be seen as well.
You’ll first want to look at the thyroid for any scars, goiter, or even distended neck veins. It’s important to palpate the thyroid gland – which can be done in front of the patient or from behind. Have the patient flex the neck just a little to relax the neck muscles.
You can also ask the patient to swallow – as they do so, the thyroid gland will move up and down underneath your fingers.
If the lower borders of the thyroid lobes are not clearly felt, a goiter may be retrosternal. Large retrosternal goiters can cause distended neck veins and difficulty breathing, especially when the arms are raised (Pemberton’s sign)It may be difficult to estimate the size of the thyroid gland. If there is doubt – an ultrasound can reliably provide an accurate size.
Finally, palpate the cervical and supraclavicular lymph nodes.
You may notice a puffy face and non pitting pre-tibial edema due to skin thickening. Pallor with a yellowish hue may be seen due to carotene accumulation.
Lastly, ophthalmopathy, (usually seen in Graves’ disease) occurs in about 5% of patients with autoimmune hypothyroidism.
Patients may also have a hypocoagulable state which increases the risk for bleeding. Patients also have a decrease in red blood cell production resulting a normocytic normochromic anemia. About 10% have pernicious anemia which presents as a macrocytic anemia.
Hyponatremia can be noted because of the reduction in free water clearance. Elevated levels of creatinine and homocysteine are seen which often return to normal after treatment with T4.
In primary hypothyroidism, this stimulates increased TRH production which can lead to hyperprolactinemia (usually 150 and under) and is corrected when the thyroid dysfunction is corrected.
This is not going to be a clinical diagnosis. A lot of the symptoms present in hypothyroidism are not specific to the disease. The diagnosis really lies in laboratory testing: TSH and Free T4. You don’t want to order total T4 or T3.
It’s important not to order T3 because early in the disease process there will be an increased conversion of T4 to T3 in an attempt to maintain T3 levels. You also want to stay away from total T4 measurements because this indicates the amount of T4 which is bound to thyroid-binding globulin (80%), transthyretin, and albumin (10%). These binding proteins vary based on factors such as hormonal status (pregnancy), medications (OCP, NSAIDs, salicylates, phenytoid etc), inheritance, and comorbidities (inflammatory liver disease, nephrotic syndrome, etc).
The free (unbound) portion of these two hormones are what is considered to be biologically active – this is why free T4 (unbound T4) is the test of choice.
Primary hypothyroidism: HIGH TSH and LOW free T4.
Central hypothyroidism: inappropriately elevated TSH (low or low normal) and LOW free T4 Subclinical: High TSH and normal free T4.
95% of all hypothyroid cases will be primary hypothyroid. If you suspect this disease, the first test should be a TSH (such as a patient coming in with fatigue as we discussed in the fatigue lecture). If the TSH is elevated, the next step is to order both the TSH (again) and free T4.
Be careful here – because central hypothyroidism can present with a normal TSH. So, if you really suspect this disease, but have an initially normal TSH, you should repeat the TSH with a free T4 measurement.
Things that might clue you into central hypothyroidism include: known hypothalamic or pituitary disease, a mass lesion is present in the pituitary, and/or when symptoms and signs of hypothyroidism are associated with other hormonal deficiencies.
Because the problem here is either TRH or TSH production (hypothalamic or pituitary problem) then the body is unable to increase TSH levels to compensate for the falling T4 levels.
Other presentations: the free T4 may be low normal with a low normal TSH. The TSH may even occasionally be slightly elevated because of biologically inactive secretion of TSH.
More than 90% of patients with Hashimotos will be positive for thyroid peroxidase antibodies – keep in mind that routine measurement is not needed. Keep in mind that these antibodies can also be present in Graves disease.
Now, you’re not always going to have patients who come in with symptoms (or symptoms that they wish to discuss) since the process happens slowly. So, some of the cases will be diagnosed on routine screening. Who should get screened?
Those who are at increased risk: goiter, history of autoimmune disease, previous radioactive iodine therapy, head and neck irradiation, family history of thyroid disease, and use of medications that may impair thyroid function. There is currently no data supporting routine screening. Universal screening during the first trimester of pregnancy is also controversial and there isn’t an agreed upon consensus.
We don’t routinely screen in our clinic during first trimester pregnancy. But, we do order a TSH in those who are at high risk and/or those who present with symptoms.
Medications that may impair TSH measurement include: dopamine, glucocorticoids, octreotide, metoclopramide, and amiodarone.
Do we need an ultrasound for the hypothyroid patient?
Patients who have an abnormal TSH should NOT routinely get an ultrasound of the neck. It adds nothing to the diagnosis. It is only useful when your physical exam uncovers a possible nodule.
The reason why we want to to evaluate nodules is because of the possibility for malignancy. If you have abnormal TSH levels – then it’s rare to have malignancy. Signs of malignancy on ultrasound include: hypoechoic solid nodules with infiltrative borders and microcalcifications.
It can also be used to help during biopsy. Ultrasound-guided FNA biopsy of thyroid lesions lowers the rate of inadequate sampling and decreases sample error, thereby reducing the false- negative rate of FNA cytology.
It’s estimated that up to 50% of patients diagnosed with subclinical hypothyroidism will progress to overt hypothyroidism. Those who have TSH values over 15 and those who present with antibodies have the most risk.
The big question here is if your patient needs treatment. As we said those who have higher levels of TSH are at increased risk of developing hypothyroidism – this is why it’s advisable to treat patients who have a TSH over 10.
It’s not clear what to do with those patients who have a TSH under 10. The consensus is to treat if the patient presents with any hypothyroid like symptom. There are many studies that show conflicting evidence – some show improvement in symptoms while others show no difference after levothyroxine administration.
There are some experts who argue that the asymptomatic patient who has a TSH under 10 should also be treated because unrecognized symptoms may improve, correction of abnormal serum lipid concentrations may be cardioprotective, and there is little risk associated with monitored T4 replacement. But, this is not universally accepted.
Those who have goiter (has been shown to reduce size) and those with very high antibody levels are also candidates when the TSH is under 10. Women who have a TSH over the trimester specific value should also be treated. Women who also wish to become pregnant or those having difficulty conceiving should also be treated.
Treatment for Hypothyroid
We’ll be discussing the treatment on Friday 🙂 Make sure to subscribe on youtube and/or the podcast to get Fridays lecture!