Introduction – Hypothyroidism
Primary hypothyroidism affects 2-3% of all women, who get diagnosed with the condition 5-10 times more often than men. It is especially common during and after menopause. Postpartum women are also at high risk of (sometimes transient) hypothyroidism, post-partum thyroiditis. The symptoms are initially nonspecific, and the diagnosis is then difficult to make clinically. The pathogenesis of primary hypothyroidism in countries with adequate iodine intake is, in practice, always autoimmune in adults. In severe cases, laboratory diagnosis is easy. Patients are often diagnosed in primary care and can generally be managed at this level.
Hypothyroidism may be primary (most common, thyroid malfunction) or secondary/central (unusual, pituitary insufficiency).
The disease is easy to miss – be observant!
Laboratory tests – Hypothyroidism
- Thyreotropin (TSH)
- (free) thyroxine: T4
- (free) triiodothyronine: T3
- Thyroid Antibodies: Antithyreoperoxidase Antibodies (TPOAb) – NOTE: found in 10-15% of normal healthy female population, is a marker of autoimmunity and supports the hypothyroidism diagnosis but is not pathogenic. Available in approximately 90% of hypothyroidism patients.
Since hypothyroidism is very rarely caused by blocking TSH receptor antibodies (TRAK), there is no reason to routinely analyze these in hypothyroidism. TRAK should be checked for inexplicably oscillating values of thyroxine-substituted patients when compliance problems are excluded.
The basis of the analysis strategy is TSH, which is elevated in primary hypothyroidism. In case of less pronounced elevations (<10 mIE / L) complementary analysis of TPOAb should be done. In central (pituitary) hypothyroidism – unusually – TSH may be low, normal or slightly elevated.
Disease Stages – Hypothyroidism
- “Subclinical” hypothyroidism:
TPOAb usually detectable. TSH elevated. (Free) T4, T3 is normal.
About 25% in this group may have mild nonspecific symptoms.
- Mild hypothyroidism:
TPOAb is usually detectable. TSH elevated. (Free) T4 lowered. (Free) T3 normal.
- Severe hypothyroidism:
TPOAb is usually detectable. TSH elevated. (Free) T4 and T3 are low.
Symptoms – Hypothyroidism
The patient may have any of the following symptoms:
- A general feeling that something is wrong
Later, more specific symptoms
These can affect most organ systems, including:
- Pronounced fatigue
- Feeling cold
- Dry skin
- Mental inertia
- Facial swelling
- Hair Loss
Diagnostics – Hypothyroidism
- In severe cases with typical symptoms, the diagnosis is easily verified with analysis of TSH and (free) T4:
– Elevated TSH results (> 10 mU / L) confirm the diagnosis.
– A very low value of (free) T4 (below about 6-7 pmol / L, method dependent) confirms that the disease is severe, see below.
– In severe cases, no TPOAb testing is needed.
- Mild cases with unclear symptoms :
– TSH> 10 mU / L: The patient should receive thyroxine as there is a high risk of hypothyroidism. The indication is strengthened if TPOAb is clearly elevated.
– TSH 4- 10 mIE / L and no symptoms: new lab follow-up in ½ to 1 year
– TSH 4-10 mU / L and nonspecific symptoms: This slight increase can be seen in mild hypothyroidism, but also in convalescence after other non-thyroid diseases ( e.g.flu, pneumonia, infarction). Repeat the test after 6-12 weeks, with complement the testing with TPOAb. If TSH is still elevated, and especially if TPOAb can be detected, it may be justified to initialize thyroxine treatment for 6 months (in slight TSH elevation: suggested 25 µg daily for the first 4-6 weeks, then lab follow-up tests and possibly increase to 50 µg daily for a total of 6 months, the dose is adjusted based on lab results) if the patient has symptoms (even non-specific, such as fatigue). Elevated serum cholesterol and/or goiter strengthen the treatment indication.
Treatment – Hypothyroidism
Treatment with thyroxine (Euthyrox, Levaxin)
Prior to therapy, the patient should be informed of the condition, that it may take up to 6 months before she is fully recovered, and that treatment is likely to be life-long. Women of childbearing age should be informed that they must protect themselves from pregnancy until the correct dose of thyroxine is reached. Then, no precautions against pregnancy or breastfeeding are issued. Note that concomitant adrenal insufficiency may be present (patient with low blood pressure, which is usually normal, patient who has been severely affected, for example in connection with influenza disease, pigmentation), adrenal insufficiency may cause a slight increase in TSH. In suspected cases, the condition must be excluded (S-cortisol) and treated before initiating thyroxine therapy.
Thyroxine dose escalation is performed slowly in small increments. In severe hypothyroidism that has been diagnosed for a long time, for the elderly and for cardiovascular patients, a low dose of 25 µg every two days should be started with dose increases every 6 weeks. Cardiovascular disease can be aggravated if the escalation occurs too quickly. For mild hypothyroidism that has lasted less than 1 year, a slightly higher dose of 25-50 µg / day can be started and evaluated after 4 weeks. In pregnancy, faster escalation is made, see below.
- Start with 25-50 µg every other day every day po, with 25 µg increase every 4-6 weeks (see above).
- Laboratory testing: TSH the week before the planned dose increase.
- Treatment target for TSH: 0.4-2.5 mU / L (method dependent, applies method with a reference interval of about 0.4-4.0 mU / L).
- Well treated patient: follow-up once a year.
- Some patients report feeling better with a thyroxine dose that produces a slightly suppressed TSH and do not want to take a lower dose of thyroxine. Inform about risks (slightly increased risk of osteoporosis, atrial fibrillation especially). Pulse, ECG, bone density imaging is tailored to the individual case.
- Do not forget that the patient may have or later suffer from other autoimmune diseases: mainly diabetes, B12 deficiency (atrophic gastritis or gluten intolerance) or Addison’s disease. Special care should be taken in patients with cardiovascular disease. Consultation with a cardiologist may be warranted.
The following preparations may affect the resorption of thyroxine
- Fe preparations
- Calcium supplements
- Ion exchangers (lipid lowering agents, against bile acid-associated diarrhea – for example in Crohn’s disease)
Thyroxine should be taken at least 4 hours after intake of the above agents, eg at bedtime.
The resorption of thyroxine is also likely to be affected by a fiber rich diet. Thyroxine should not be kept warm.
Alternative treatments (combination therapy T3 / T4)
Some patients who are still experiencing symptoms from hypothyroidism despite being well-adjusted for thyroxine for a long time sometimes require alternative treatment with a combination of T3 / T4 or desiccated thyroid extract. In these cases, other possible explanations for the patient’s symptoms such as depression must be considered.
- Combination therapy T3 / T4
The idea of combination treatment with T3 and T4 is to try to better imitate the body’s own physiology. Synthetic T3 (Liothyronine) is available for prescription. T3 has a much shorter half-life than T4 (24 hours, compared to 1 week for thyroxine) and T3 treatment may have the disadvantage of fluctuating serum concentrations of the thyroid hormone throughout the day.
In the late 1990s, a study showed positive effects of T3 in addition to T4. Since then, a number of randomized double-blind studies have been conducted in which a few have shown good effects from T3 supplementation, but most studies have shown no significant additive effect. Theoretically, it has been shown that the effects of T3 may be dependent on gene polymorphisms. This means that perhaps a small proportion of patients benefit from T3. In systematic reviews of a total of twelve randomized studies in which T3 / T4 treatment was compared with T4 treatment, no significant difference was seen in the groups regarding hypothyroidism symptoms, quality of life and hormone levels. The European Thyroid Association (ETA) concludes in its guidelines that there is insufficient evidence that T3 / T4 is better than T4 alone and that T4 monotherapy should continue to be the first-line treatment. In cases where T3 supplements are still used, the T3 dose should be kept low, and combination preparations such as desiccated thyroid extracts are not recommended due to the high T3 / T4 ratio.
In practice, combination therapy is sometimes used in patients with a strong desire for such treatment. Then, the following regimen is recommended: 0.25-0.5 tablets (5-10 µg) of Liothyronine one to two times a day and the thyroxine dose is reduced by 25-50 µg. The treatment is considered experimental and must be evaluated after 6 months. Liothyronine treatment is not suitable during pregnancy.
Some patients feel better when they are slightly over-treated with depressed TSH values. Over-treatment, in the long run, involves an increased risk of osteoporosis, atrial fibrillation, and heart disease, and in these cases, one should investigate whether there may be other causes of the patient’s symptoms at normal TSH levels.
Difficulties in lab result interpretation in thyroxine treated patient
- High TSH with normal free T4:
Probably poor compliance. TSH responds more slowly, usually in 1-2 months, unlike free T4, which normalizes fluctuations after a few days. Thus, a patient who has neglected the medication but has started taking the medication regularly again before the doctor’s visit gets such a result.
- Depressed TSH with normally free T4:
Mild over-treatment. It can also be a patient who over-medicates from time to time but adhered to the prescription prior to the doctor’s visit.
Minor functional impairments should also be treated in fertility problems. In cases of established infertility and where IVF treatment is planned, a TSH ≤ 2.5 is desired. Early screening of all pregnant women with regard to hypothyroidism has been discussed, as adequate thyroxine delivery to the fetus is very important throughout pregnancy from early in the first trimester when the central nervous system begins to be established. Women with another autoimmune disease (don’t forget type 1 diabetes), or thyroid disease or other autoimmune diseases in the family should preferably be screened (Free-T4, TSH) already when pregnancy is planned.
In women with already known hypothyroidism and ongoing thyroxine treatment, of course, once pregnancy is established, this treatment should be continued. Assessing TSH as soon as possible, and then every 4-6 weeks (50 µg dose increase is often required) + postpartum (then dose reduction to the previous dose can generally be done). If hypothyroidism is found in an already pregnant patient – contact endocrinologist/thyroid expert.
In the case of severe hypothyroidism – start directly with thyroxine 100 µg/day. Contact OBGYN specialist.
Uncommon diagnosis, but suspicion can be raised relatively often; low free T4, TSH can be low, normal or slightly elevated (confusing clinical picture, since the biochemical analysis determines both active and inactive TSH).
Free T4 may be slightly depressed during pregnancy, estrogen therapy, some neuroleptics/antidepressants / antiepileptic therapy, and systemic non-thyroid disease.
In central hypothyroidism, the patient may exhibit symptoms similar to the signs of the presence of a pituitary tumor (headache, visual field loss) and symptoms of other hormone deficiencies. In case of suspicion, failure of the adrenal cortex should be excluded.
In depressed free T4 and normal/low TSH:
- Repeat the analysis
- If T4 is still low: Check if the patient has hypothyroidism, is on psychoactive drugs / antiepileptic drugs/estrogen? Symptoms of pituitary tumors (visual field loss, headache)? Check other pituitary axes (especially S-cortisol, prolactin, menstrual disorders) and consider referral to an endocrinologist.
Patients with typical hypothyroidism symptoms and normal (free) T4, TSH, TPOAb
This patient category does not have hypothyroidism and should not be treated with thyroxine. Other underlying disease? Exclude depression.
- Hypothyroidism is a common condition that is easy to treat and can generally be managed at the primary care level.
- The diagnosis can be difficult to make in milder manifestations of the disease. Significant suspicion should be raised if:
– the patient has relatives with thyroid disease
– the patient himself or another relative has another autoimmune disease
– the patient has a goiter
– the patient is female
- Important group: Women who are planning a pregnancy or are pregnant! The fetus must (via the mother) have sufficient access to thyroxine for the CNS to develop normally.
- Important groups:
– woman 2-4 months after childbirth
– woman over 45 years.
Every patient who seeks a doctor when he/she is not feeling well should be assessed with regard to thyroid function if this has not been done in the last 2 years!
- Wiersinga WM, Duntas L, Fadeyev V, Nygaard B, Vanderpump MP. 2012 ETA Guidelines: The Use of L-T4 + L-T3 in the Treatment of Hypothyroidism. Eur Thyroid J. 2012 Jul; 1 (2): 55-7.
- Grozinsky-Glasberg S, Fraser A, Nahshoni E, Weizman A, Leibovici L. Thyroxine triiodothyronine combination therapy versus thyroxine monotherapy for clinical hypothyroidism: meta-analysis of randomized controlled trials. J Clin Endocrin Metab 91 (2006) 2592-9.
- Association of Thyroid Hormone Therapy With Quality of Life and Thyroid-Related Symptoms in Patients With Subclinical Hypothyroidism: A Systematic Review and Meta-analysis.