Levothyroxine and dizziness

In the form of questions and answers the topic of vertigo in hypothyroid subjects is discussed, with particular reference to the possibility that it is an adverse drug reaction. Or maybe not?

Can the appearance of vertigo in a patient undergoing therapy with levothyroxine be an adverse event due to the drug?

The primary symptoms of hypothyroidism include fatigue, tiredness, dizziness, lightheadedness, weight changes, hypertension, electrolyte imbalances, and labyrinthitis.^1,2 Since hypothyroidism is associated with dizziness and malaise and the Summary of Product Characteristics for levothyroxine does not report such side effects as known, these could therefore be the result of reduced pharmacologic efficacy in restoring adequate hormone levels, rather than an adverse drug reaction.
Examples of the association of dizziness and malaise with hypothyroidism are numerous. Patients with congenital hypothyroidism have a high incidence of vestibular dysfunction.³ In a Japanese study, it was reported that the essential factors in distinguishing peripheral or central vestibular abnormalities are the initial serum thyroxine level and the time of initiation of replacement therapy. Vestibulo-cerebellar impairment was associated with severe and prolonged thyroid hormone deficiency, whereas peripheral vestibular damage was associated with mild hypothyroidism.³
Bhatia and associates demonstrated that the incidence of symptoms such as vertigo and hearing problems correlated linearly with the severity of hypothyroidism. Substantial improvement in patient-reported symptoms has also been described once euthyroid status is achieved.⁴
In another study, emergency department admissions for dizziness and malaise due to hypothyroidism were reported in patients awaiting treatment with radioactive iodine (post-thyroidectomy therapy); these subjects had to follow a low iodine diet in the weeks before therapy.^5,6 In another study 100 patients who came to the emergency department complaining of dizziness, thyroid alterations were found, 2 of them with hypothyroidism not yet diagnosed.⁷
Finally, a case report described the case of a patient who presented to the hospital with dizziness and malaise who had no chronic pathology; the diagnosis was “myxedematous coma”, a severe form of hypothyroidism (the patient had TSH values >100 mUI/l).⁸
Some endocrine diseases, such as hypothyroidism, can lead to balance disturbances and thus cause dizziness by affecting the labyrinthic functions of the vestibular system.⁷ Inflammatory or metabolic changes in patients with thyroid disease may impact inner ear inflammation and endolymphatic flow homeostasis. One hypothesis is that hypothyroidism alters the composition of endolymphatic fluid through the diffusion of thyroid autoantibody complexes into the endolymph. Another hypothesis is related to alterations in the SLC26A4 transporter protein called “pendrin”; as seen in the case of Pendred syndrome (a genetic disorder involving bilateral deafness associated with reduced thyroid gland function), this protein could be defective in patients with goiter and/or hypothyroidism, thus altering endolymphatic composition and endocochlear potential.^9,10
Ménière syndrome itself, a condition associated with attacks of vertigo and tinnitus, appears to be related to thyroid hormone levels. Women under 65 years of age enrolled in a recent study showed an association of Ménière’s disease with hypothyroidism. The study results were adjusted for levothyroxine medication and other thyroid diseases, thus analyzing the relationship of each thyroid condition to Ménière’s disease separately.¹¹
In a case-control study, thyroid hormone drug use was higher in patients with Ménière’s disease compared with the control group of the same age and sex (32% versus 4%, p<0.001).¹²

How can reports of levothyroxine-related vertigo be interpreted in the FAERS database?

A survey of FAERS, the U.S. Food and Drug Administration’s spontaneous adverse event reporting system, was conducted and showed that generally these symptoms, when recognized, are reported as an adverse drug reaction.
As of April 12, 2019, after excluding all cases with any other suspected or concomitant medication, 23,310 cases of suspected levothyroxine-related adverse events were reported in FAERS: 1,200 report cards reported “dizziness”, 941 “vertigo”, and 3,534 “fatigue”. An increase in TSH levels was reported in 2,144 subjects, along with symptoms correlated with poorly controlled hypothyroidism: dizziness (n=289, 13.4%), vertigo (n=333, 15.5%), and fatigue (n=969,45.2%). True drug ineffectiveness, however, was recorded by the reporter in only 18 cases.¹³

If dizziness is not an adverse drug event, but instead a sign of levothyroxine inefficacy, should the dosage be increased? What to do in such cases?

After the diagnosis of hypothyroidism, chronic therapy with levothyroxine is imposed, except in cases where hypothyroidism is caused by transient forms of thyroiditis or medication. The initial dose depends on the age of the patient, the presence of cardiac comorbidities, and the etiology and severity of the hypothyroidism. However, levothyroxine is titrated until TSH levels normalize between 0.4 and 4.0 mIU/l.²
According to the guidelines, TSH and FT4 concentrations should be monitored 4 to 6 weeks after initiation of therapy and thereafter only in case of dose changes or for any other event that could lead to alterations in thyroid function or the efficacy of therapy.^14,15 Patients with stable TSH levels should still be monitored every 12 months.^2,15 However, no specific suggestion for monitoring TSH levels in case of dizziness or symptomatology associated with potential inefficacy is reported. The most recent Italian guideline for the treatment of hypothyroidism does not report any information regarding how to manage cases of inefficacy, but it does acknowledge the possible fluctuation of TSH levels with consequent possible repercussions on the patient’s quality of life.¹⁶
In contrast, the American Academy of Family Physicians states that myxedematous coma may have milder symptoms or even no symptoms at all in patients with compensated hypothyroidism.¹⁷
On the basis of the data available to date, annual checks of TSH and FT4 levels for possible therapeutic adjustments and additional monitoring in case of symptoms related to dizziness and vertigo should be performed. Possible comorbidities of the patient, especially if hypertensive, and concomitant therapies should also be taken into account. Also in this case, given the influence of these aspects on thyroid hormone levels, it is desirable to adequately control the dose of levothyroxine. This would avoid confusing a potential symptom of hypothyroidism with a further diagnosis, which would inevitably lead to a prescriptive cascade.