Q: Thryoid

[Guest guest]

Hello great minds-I have a very strange case of thyroid labs that don't make any sense.  My patient has lupus and we are currently working with treating multiple infections and she's been doing better.  She has a history of being hypothyroid (since 19 yo) and been on thyroid hormone.    In 4/2011, she had a TSH of 0.08 and then 0.97 with a free T4 of 0.87 in 12/11 (another doctor was managing her thyroid at that time).  She had at various times stopped or reduced her thyroid and then restarted.  In December she had just restarted 125 mcg QD and said she was feeling strange in general.  She decided to stop it completely and I retested her in 4/12.  Her TSH was 249.7 (yes, 249) with a total T4 of 1.2 (alert level).  We restarted her thyroid immediately and she took 1 pill BID for 3-4 days, then dropped to 1.5 pills QD for 3-4 days and then stayed at 1 pill QD since (she made the drops herself).  I just retested her and as of yesterday, her TSH is now 0.219 and her total T4 is 10.5.  Over the last 2 months she's felt better overall, but with some specific symptoms being better and worse.  She was tired and a little dizzy in April, but nothing really remarkable, and that hasn't changed dramatically with the addition of the thyroid.

Her TPO antibodies were tested 2008 and were negative.  I am wondering what to do with this kind of dramatic change in only 2 months at a not excessive thyroid dose, ie., her total T4 is still within lab normal range.  I've decreased her dose for now but am curious about her type of response given her history and dosing- from a physiologic perspective, it doesn't make sense to me that at that thyroid dose, her TSH would change 1000x in two months with the type of T4 rise she shows.

Thanks- Hindman, ND, LAcPortland, OR

[Guest guest]

Hi ,I've copied and pasted an article from Up to Date on treatment of hypothyroidism and highlighted relevant sections below (in case you are interested).

My experience is limited, but here are a few thoughts:1.  The general recommendation is to recheck thyroid hormone levels six weeks after starting therapy because this is how long it takes (although it can take longer) for TSH concentrations to reach a steady state.  So the pt's lab values at eight weeks post initiating therapy do not seem odd to me.  I would not necessarily expect it to take longer than that for her hormone levels to normalize.  I have seen one patient who also had a TSH that was somewhere in the 100 to 200 range (don't remember exactly) who responded similarly in that her values normalized when labs were rechecked.  I also know of a doctor who had a patient with similar TSH values and no hypothyroid symptoms.  So I'm not so sure that a through-the-roof TSH is necessarily as shocking or difficult to correct as it might first seem.

2.  I would have been worried about having a pt on doses of thyroid replacement that were as high and frequent as her initial doses especially if she had not decided to taper down (see article below for standard dosing recommendations), and have been told more than once that it is much safer to start low and increase as needed.  The current recommendation on Up to Date for a patient in Myxedema coma (which your pt was at risk for given her lab values, but she had not deteriorated to this state) is a IV loading dose of 200 to 400 mcg T4 (possibly with concomitant T3) followed by the standard dosing recommendation of 1.6 mcg/kg T4.  Again, my experience here is limited, so if others have different thoughts/experience/knowledge on dosing, please correct me.

3.  I came across some very interesting research on PubMed recently from which I learned that WBCs can make TSH (who knew?!). I didn't delve into this in detail, but from what I read it seems that the role of WBC TSH isn't entirely clear.  It may act as a cytokine and it may actually have inhibitory action on the thyroid rather than stimulatory action.  In any case, the fact that your patient has ongoing infections will effect the function of her endocrine system (according to drainage theory, inability to clear infections, which is often associated with the tubercular miasm, will result in recruitment of the thyroid gland), and maybe even TSH lab values.

4.  Considering that the pt has another autoimmune condition, I would be very surprised if she did not have Hashimoto's.  According to Datis Kharrhazian, thyroid antibodies can wax and wane and he does not believe that a negative TPO rules out Hashimoto's.  If your patient has waxing and waning of antibodies and thyroid gland destruction, it could explain a varying need for hormone replacement as well as variable lab values.  It may be worth retesting TG/TPO Abs and it may be particularly telling to do this when she is having a flare of SLE symptoms.  It might also be beneficial to just assume Hashimoto's and treat it as such (supplements/lifestyle to push Th3, gluten-free diet, etc).

almost ND, graduating next weekPortland, OR

Treatment of hypothyroidism

Author

S Ross, MD

Section Editor

S , MD

Deputy Editor

E Mulder, MD

Disclosures

All topics are updated as new evidence becomes available and our peer review process is complete.

Literature review current through: May 2012. | This topic last updated: Feb 3, 2012.

INTRODUCTION — In most patients, hypothyroidism is a permanent condition requiring lifelong treatment. Therapy consists of thyroid hormone replacement unless the hypothyroidism is transient (as after painless thyroiditis or subacute thyroiditis) or reversible (due to a drug that can be discontinued). (See " Disorders that cause hypothyroidism " .)

The goal of therapy is restoration of the euthyroid state, which can be readily accomplished in almost all patients by oral administration of synthetic thyroxine (T4). Appropriate treatment reverses all the clinical manifestations of hypothyroidism.

This review will discuss the major issues that must be addressed in the treatment of patients with overt primary hypothyroidism. The approach to therapy of patients with subclinical, congenital, and central hypothyroidism is discussed separately. (See  " Subclinical hypothyroidism "  and  " Treatment and prognosis of congenital hypothyroidism "  and  " Central hypothyroidism " .)

STANDARD REPLACEMENT THERAPY — The treatment of choice for correction of hypothyroidism is synthetic thyroxine (T4). Approximately 80 percent of a dose of T4 is absorbed and, because the plasma half-life of T4 is long (seven days), once-daily treatment results in nearly constant serum T4 and triiodothyronine (T3) concentrations when a steady state is reached [1].

T4 is a prohormone with very little intrinsic activity. It is deiodinated in peripheral tissues to form T3, the active thyroid hormone. This deiodination process accounts for about 80 percent of the total daily production of T3 in normal subjects; as a result, serum T3 concentrations are within the normal range in hypothyroid patients receiving adequate T4 therapy. This was illustrated in a prospective study of recently athyreotic patients receiving T4 therapy to normalize serum TSH concentrations; serum T3 on treatment were, in most cases, comparable to the patients' pre-operative T3 values [2]. The prohormone nature of T4 is an advantage over other thyroid hormone preparations, because the patient's own physiologic mechanisms control the production of active hormone.

T4 formulations — Several formulations of T4 are available, but there has been considerable controversy about their bioequivalence. In the past, variation in the T4 content of brand-name and generic formulations led many experts to prefer a specific preparation [3]. In 1997, a study of two brand name and two generic formulations of T4, using FDA-recommended methodology for determining bioequivalence, reported that all four preparations were equivalent [4]. However, the methodology used to determine bioequivalence in the study is considered by some to be flawed since endogenous T4 concentrations were not taken into account [5].

In 2004, the FDA approved generic substitution for branded levothyroxine products. The American Thyroid Association, Endocrine Society, and American Association of Clinical Endocrinologists opposed this decision, and recommend that patients remain on the same brand that was initially prescribed [6].

Because there may be subtle differences in bioavailability between T4 formulations, we feel that it is preferable to stay with one formulation when possible. We generally avoid generics because of the potential for frequent interchange of preparations by the pharmacy. Often, however, the generic manufacturer can be identified from the prescription label, and the patient may request refills from the same generic pharmaceutical company. If the preparation must be changed, follow-up biochemical monitoring should be done to determine if retitration of the dose is necessary. We typically measure a serum TSH six weeks after changing preparations.

The brand-name and most generic formulations are available in color-coded tablets at small increments in hormone content to allow precise titration of the dose according to the serum concentration of thyrotropin (TSH).

Adverse effects of T4 replacement are rare as long as the correct dose is given. Rare patients have an allergy to the dye or filler in the tablets. For dye sensitivities, multiples of the white 50 mcg tablets can be given.

Dose and monitoring — The average replacement dose of T4 in adults is approximately 1.6 mcg/kg body weight per day (112 mcg/day in a 70-kg adult), but the range of required doses is wide, varying from 50 to 200 mcg/day. T4 requirements correlate better with lean body mass than total body weight [7]. The necessary dose per kg body weight is higher in infants and children. (See  " Treatment and prognosis of congenital hypothyroidism " .)

The dose may vary according to the cause of hypothyroidism. In a study of patients receiving chronic T4 therapy who were clinically euthyroid and had serum free T4 index values within the upper half of the normal range and normal serum TSH concentration, 73 patients with hypothyroidism caused by chronic autoimmune thyroiditis or radioiodine therapy were receiving less T4 (118 mcg/day, 1.6 mcg/kg/day) than 36 patients with thyroid cancer after near-total thyroidectomy (152 mcg/day, 2.1 mcg/kg/day) [8]. In 36 patients with central hypothyroidism and similar serum free T4 index values, the T4 dose was higher (155 mcg/day, 1.9 mcg/kg/day). These results suggest that both normal amounts of TSH and the presence of residual thyroid tissue are determinants of T4 dose in patients with hypothyroidism.

Timing of dose — T4 should be taken on an empty stomach, ideally an hour before breakfast, but few patients are able to wait a full hour. One study showed higher serum T4 and lower TSH concentrations in 90 patients receiving T4 at bedtime, but patients had nothing to eat for several hours before bedtime and were compared to patients who took it in the morning and waited only 30 minutes before breakfast [9], suggesting the proximity to food ingestion rather than time of day is the more critical parameter. In a study of 65 patients, serum TSH concentrations were lower and less variable with standard fasting administration of T4 when compared with nonfasting administration (mean serum TSH 1.06 ± 1.23, 2.93 ± 3.29, and 2.19 ± 2.66 mU/L if taken one hour before breakfast, with breakfast, or at bedtime two hours after the last meal, respectively) [10], and in one small study, coffee appeared to interfere with T4 absorption [11].

T4 should not be taken with other medications that interfere with its absorption, such as bile acid resins, proton pump inhibitors, calcium carbonate, andferrous sulfate. (See  " Drug interactions with thyroid hormones " , section on 'Drugs that affect gastrointestinal absorption of thyroid hormone'.)

Starting dose — The initial dose can be the full anticipated dose (1.6 mcg/kg/day) in young, healthy patients, but older patients should be started on a lower dose (25 to 50 mcg daily). (See 'Older patients or those with coronary heart disease' below.)

In one prospective study of different starting doses of T4, 50 hypothyroid patients (mean age 47 years) were randomly assigned to receive a full starting dose of T4 (1.6 mcg/kg/day) or T4 25 mcg/day with dose adjustments every four weeks. Euthyroidism was achieved more rapidly in the full dose group, but signs and symptoms of hypothyroidism and quality of life improved at a similar rate in the two groups. No adverse cardiac effects were seen in either group, but the subjects in the study, including elderly patients, had been carefully screened to rule out cardiovascular disease prior to enrollment [12].

Initial monitoring and dose adjustments — Patients who are treated with T4 usually begin to improve within two weeks, but complete recovery can take several months in those with severe hypothyroidism. Although symptoms may begin to resolve after two to three weeks, steady-state TSH concentrations are not achieved for at least six weeks. Serum thyroid hormone concentrations increase first, and then TSH secretion begins to fall because of the negative feedback action of T4 on the pituitary and hypothalamus. Thus, after initiation of T4 therapy, the patient should be reevaluated and serum TSH measured in six weeks. If the TSH remains above the normal reference range, the dose of T4 can be increased by 12 to 25 mcg/day. The patient will require a repeat TSH measurement in six weeks.

For patients who continue to have symptoms after two to three weeks, a serum free T4 and TSH can be measured in three weeks. If the serum free T4 is below normal, the dose can be increased in three weeks without additional testing, but it should be recognized that serum T4 (and TSH) concentrations at this time are not steady-state values, and serum TSH levels may still be falling despite normal (or even high) serum T4 concentrations. Given the one-week plasma half life of T4, it takes about six weeks (six half-lives) before a steady state is attained after therapy is initiated or the dose is changed.

This process of increasing the dose of T4 every three to six weeks (depending upon the patient's symptoms) should continue, based upon periodic measurements of serum TSH (and free T4 if steady state conditions have not yet been achieved), until the high values of TSH in patients with primary hypothyroidism return to the reference range. Once this is achieved, periodic monitoring is warranted. (See 'Adjustment of maintenance dose' below.)

Goals of therapy — The goals of therapy are amelioration of symptoms and normalization of TSH secretion. An additional goal in patients with goitrous autoimmune thyroiditis (Hashimoto's disease) is a reduction in the size of the goiter. Approximately 50 percent of patients have some decrease, which lags behind the fall in TSH secretion [13,14].

There is considerable controversy as to the appropriate upper limit of normal for serum TSH [15]. Most laboratories have used values of about 4.5 to 5.0 mU/L. However, others have argued that the upper limit of normal of the euthyroid reference range should be reduced to 2.5 mU/L because 95 percent of rigorously screened euthyroid volunteers have serum values between 0.4 and 2.5 mU/L [16]. This topic is reviewed in detail separately. (See  " Laboratory assessment of thyroid function " , section on 'Serum TSH concentration'.)

Until there are data demonstrating an adverse biologic significance for serum TSH values between 2.5 and 5.0 mU/L, the wisdom of labeling such patients as hypothyroid is questionable [17]. We aim to keep TSH within the normal reference range (approximately 0.5 to 5.0 mU/L). However, if a patient has possible hypothyroid symptoms, and the TSH is confirmed by repeat measurement to be at the upper limits or above the normal reference range, it is reasonable to increase the dose and to aim for a serum TSH value in the lower half of the normal range. (See 'Persistent symptoms' below.)

Adjustment of maintenance dose — After identification of the proper maintenance dose, the patient should be examined and serum TSH measured once yearly, or more often if there is an abnormal result or a change in the patient's status. Further dose adjustment is usually not required, but there are situations in which a different dose may be needed (table 1):

Increases in dose may be required during pregnancy (see  " Hypothyroidism during pregnancy: Clinical manifestations, diagnosis, and treatment " , section on 'Preexisting hypothyroidism').

Small increases also may be required in patients in whom thyroid hormone absorption is diminished (patients with impaired acid secretion or other gastrointestinal disorders), excretion is increased (nephrotic syndrome), or the rate of metabolism is increased (therapy with rifampin, carbamazepine,phenytoin, or phenobarbital) (table 1). (See 'Other factors affecting thyroid hormone metabolism' below and  " Endocrine dysfunction in the nephrotic syndrome "  and  " Drug interactions with thyroid hormones " , section on 'Drugs that affect gastrointestinal absorption of thyroid hormone'.)

Small decreases in dose may be needed as patients age, after parturition, if the patient loses weight, or during androgen therapy [18,19].

Longterm outcomes — Successful treatment reverses all the symptoms and signs of hypothyroidism, although some neuromuscular and psychiatric symptoms may not disappear for several months. Long-term treatment of hypothyroidism is not associated with impaired cognitive function or depressed mood [20]. Limited evidence also suggests no increase in all-cause mortality among patients with treated hypothyroidism [21,22].

In contrast, infants with congenital hypothyroidism in whom treatment is inadequate or delayed for several months may have permanent brain damage, even if they are adequately treated several months later. (See  " Treatment and prognosis of congenital hypothyroidism " .)

Persistent symptoms — Because many symptoms of hypothyroidism are nonspecific, patients often think that their T4 dose is inadequate when they feel tired or gain weight. The possibility of an inadequate current T4 dose should be verified by measuring serum TSH before the dose is increased. The dose need not be altered in patients who are clinically euthyroid if their serum TSH concentration is only slightly above (or below) the normal range. TSH values may be slightly high (or low) because of laboratory error or normal circadian fluctuations in TSH secretion, so a slightly high (or low) value should be confirmed with repeat measurement before the dose is changed.

On the other hand, if a patient has possible hypothyroid symptoms, and the serum TSH is confirmed by repeat measurement to be at the upper limits or above the normal reference range, it is reasonable to increase the dose and to aim for a serum TSH value in the lower half of the normal range.

Whether or not the dose adjustment will improve symptoms is uncertain. In one study of 697 patients on thyroid hormone replacement, psychological well-being assessed by the General Health Questionnaire-12 correlated positively with serum free T4 and negatively with serum TSH for TSH values between 0.3 to 4.0 mU/L [23]. More specifically, psychological well-being was better in patients with lower serum TSH concentrations. However, in a blinded, placebo-controlled, cross-over trial, patients could not distinguish between their usual T4 dose and doses that were 25 to 50 mcg/day higher, ie, they could not distinguish between TSH values that averaged 2.8 mU/L from those that averaged 0.3 mU/L [24].

Overreplacement — Overreplacement with T4 should be discouraged. Overreplacement causes subclinical hyperthyroidism (normal serum T4 and T3 and low serum TSH concentrations), or even overt hyperthyroidism. The main risk of subclinical hyperthyroidism is atrial fibrillation, which occurs three times more often in older patients with serum TSH concentrations <0.1mU/L than in normal subjects (figure 1) [25]. Patients with subclinical hyperthyroidism, particularly postmenopausal women, may also have accelerated bone loss. It is therefore important to educate patients about the potential adverse effects of overtreatment with T4. (See  " Subclinical hyperthyroidism " , section on 'Clinical findings' and  " Bone disease with hyperthyroidism and thyroid hormone therapy " .)

The risks associated with overreplacement of thyroid hormone are greatest in those with the most suppressed TSH concentrations. This was illustrated by the findings from a cohort study of 17,684 patients taking T4 replacement therapy. Patients with TSH concentrations between 0.04 and 0.4 mU/L were not at risk for arrhythmias or fractures compared to those with a TSH in the normal reference range. However, patients with more severe iatrogenic hyperthyroidism (TSH <0.03 mU/L) had a significantly increased risk of arrhythmia (HR 1.6) and fractures (HR 2.0) [26].

Combination T4 and T3 therapy — Some hypothyroid patients remain symptomatic in spite of T4 replacement and normal serum TSH concentrations [27]. As an example, in a large community-based questionnaire study of patients taking T4 who had normal serum TSH concentrations, 9 to 13 percent more patients had impaired psychological well being as compared with normal subjects [28]. This observation raises the question of whether hypothyroid patients might benefit from substitution of some T3 for T4, an idea that has now been evaluated in multiple randomized trials, almost all of which have been negative [29-40].

In a systematic review of nine randomized trials, only one trial reported beneficial effects of combination T4-T3 therapy on mood, quality of life, and psychometric performance when compared with T4 therapy alone [41]. A subsequent meta-analysis of 11 published randomized trials including 1216 patients showed that there was no benefit (fatigue, bodily pain, anxiety, depression, quality of life) of combined therapy [42].

In one of the largest trials, 697 hypothyroid patients, who were treated with a stable dose of T4 and who had TSH levels in the normal laboratory reference range, were randomly assigned to partial substitution of 50 mcg T4 by 10 mcg T3 versus the original dose of T4 [37]. After three months, both groups had significant improvement compared with baseline in the General Health Questionnaire (GHQ) score. Throughout the 12 month trial, there were no significant differences in GHQ scores between the two groups. However, the substitution of a fixed dose of 10 mcg T3 for 50 mcg T4 resulted in a fall in free T4 and a rise in TSH, indicating possible under-replacement with T4 in the intervention group.

Another double-blind randomized controlled trial comparing T4 alone to T4 and T3 in a molar ratio of 10:1 or 5:1, also failed to demonstrate improvement in mood, fatigue, psychological symptoms or neurocognitive testing [38]. However, patients preferred combined therapy to T4 alone. Forty-four percent of the patients who preferred combined therapy had TSH values less than 0.11. In addition, those patients taking T4:T3 in a molar ratio of 5:1 had a 1.8 kg weight loss, which correlated with a preference for the combined treatment, and 54 percent of these patients had subnormal serum TSH concentrations.

A re-analysis of the largest trial [37] examined the relationship of polymorphisms in the type 2 deiodinase, which converts T4 to T3, with baseline psychological well-being and the response to combined T4-T3 therapy [43]. Sixteen percent of the population studied had the CC genotype of the rs225014 polymorphism in the deiodinase 2 gene (DIO2); these patients had worse baseline General Health Questionnaire (GHQ) scores and showed greater improvement after T4-T3 therapy compared with T4 alone. If confirmed, it appears likely that T4-T3 therapy may improve symptoms in the subgroup of patients with a polymorphism in the type 2 deiodinase.

T3 containing preparations — Thyroid hormone preparations containing T3 alone or in combination with T4 include the following (table 2): Cytomel (T3 alone), T4-T3 combination preparations (eg, Thyrolar), and desiccated thyroid (a mixture of T3 and T4 made from porcine thyroid glands, eg, Armour® thyroid).

For most patients with hypothyroidism, we do not suggest treatment with T3 containing preparations. Patients treated with currently available T3-containing preparations have wide fluctuations in serum T3 concentrations throughout the day due to its rapid gastrointestinal absorption and its relatively short half-life in the circulation (about one day).

In addition, serum T4 concentrations remain low in patients treated with T3, and relatively low in those treated with preparations containing both T3 and T4; while serum TSH in steady state conditions will reflect the adequacy of therapy, measurement of serum T4 may be confusing and lead to inappropriate changes in dose.

Temporary treatment with T3 is appropriate in patients with thyroid cancer who are to undergo radioiodine imaging and possible treatment. To shorten the period of hypothyroidism, the patient's T4 therapy is discontinued and T3 is substituted for three to four weeks until the T4 is cleared. (See  " Radioiodine treatment of differentiated thyroid cancer " .)

Converting from desiccated thyroid extract to T4 — For patients who are taking desiccated thyroid or T4-T3 combination preparations, we prefer to switch them to T4.

In general, 1 grain of desiccated thyroid extract (60 mg) contains about 38 mcg T4 and 9 mcg T3; 9 mcg T3 is equivalent to about 36 mcg T4, so 1 grain is equivalent to a total of about 74 mcg T4. However, to switch patients from thyroid extract to T4, many clinicians use a simple conversion factor of 1 grain = 100 mcg T4. As an example, for a patient who is taking 1½ grains (90 mg) of desiccated thyroid, an equivalent T4 dose ranges from 112 to 150 mcg. Some clinicians prefer to begin with the higher dose (150 mcg) and slowly taper the dose if the TSH measured six weeks after switching remains below the reference range.

For patients taking T4-T3 combination preparations, the equivalent dose of T4 can be calculated based upon the amount of T4 and T3 in the preparation. As an example, for a patient who is taking a preparation of 12.5 mcg T3 combined with 50 mcg T4, the equivalent dose of T4 is approximately 100 mcg (50 mcg T4 plus four times the dose of T3).

Often, patients who are doing well symptomatically on a combination preparation (eg, Armour thyroid) refuse to be switched to T4. As long as their thyroid function tests are normal and are monitored periodically, it is probably safe for them to continue to take the thyroid preparation they prefer. Also, Armour thyroid is cheaper than most branded T4 products.

Summary — In most trials, combination T4 -T3 therapy does not appear to be superior to T4 monotherapy for the management of hypothyroid symptoms. In three trials, patients preferred combined therapy to T4 monotherapy; however, in one of those studies, patients were given overzealous doses of thyroid hormone resulting in mild hyperthyroidism. In general, clinical trials of combination T4-T3 therapy have not successfully replicated physiologic T4-T3 production [44].

A small group of patients with a polymorphism in DIO2 may benefit from T4-T3 therapy. In addition, the available data, including the study demonstrating comparable pre- and post-T3 levels in thyroidectomized patients taking T4 [2], do not rule out the possibility that some thyroidectomized patients who have no residual endogenous T3 production might derive benefit from the addition of T3, while patients with autoimmune thyroiditis do not [35].

Well-designed blinded studies are still needed to address this ongoing controversy. In addition, slow-release T3 preparations, which may avoid supraphysiologic peaks in serum T3 concentrations, have not yet been combined with T4 and compared to T4 monotherapy [45]. A combination T4-slow release T3 preparation may better replicate physiological T4-T3 production. Until more data are available, for the majority of hypothyroid patients, we do not suggest combination T4-T3 therapy.

SPECIAL TREATMENT SITUATIONS — There are several situations in which therapy should be more conservative or the dosage may need modification:

Older patients or those with coronary heart disease — Elderly patients and those with coronary disease or multiple coronary risk factors should be treated conservatively. Thyroid hormone increases myocardial oxygen demand, which is associated with a small risk of inducing cardiac arrhythmias, angina pectoris, or myocardial infarction in older patients. In one study of 55 hypothyroid patients with angina, for example, the angina worsened in nine after the initiation of thyroid hormone therapy and did not change or improved in the others [46].

Older patients (older than 50 or 60 years depending upon coexisting medical problems) should initially be treated with 50 mcg T4/day. Those who have a history of coronary heart disease should initially be treated with 25 mcg/day. In either group the dose can be increased by 25 mcg/day every three to six weeks until replacement is complete, as determined by a normal serum TSH concentration, or an increase in dose results in cardiac symptoms, in which case something less than full replacement may have to be accepted.

Many older patients receiving thyroid hormone replacement are over- or undertreated, as illustrated by a community survey that identified 339 individuals over age 65 years taking thyroid hormone [47]. Forty-one percent of patients had a subnormal TSH; 16 percent had a high TSH; and only 43 percent were euthyroid [47]. Patients with low body weight were more likely to have a subnormal TSH, while those with diabetes were at risk for having low and high serum TSH.

The clinical manifestations and consequences of hypothyroidism (subclinical and overt) in the elderly are discussed in detail elsewhere. (See  " Clinical manifestations of hypothyroidism " .)

Hypothyroidism during pregnancy — Women need more thyroid hormone during pregnancy and, unlike normal women, those with hypothyroidism are unable to increase thyroidal T4 and T3 secretion. Approximately 75 to 85 percent of women with preexisting hypothyroidism need a higher dose of T4 during pregnancy to maintain normal TSH secretion. The increase in T4 requirements occurs as early as the fifth week of gestation and plateaus by week 16 to 20. The treatment of hypothyroidism during pregnancy is reviewed separately. (See  " Hypothyroidism during pregnancy: Clinical manifestations, diagnosis, and treatment " , section on 'Preexisting hypothyroidism'.)

Euthyroid women with thyroid peroxidase antibodies who become pregnant are also discussed separately. (See  " Overview of thyroid disease in pregnancy " , section on 'Thyroid peroxidase antibodies'.)

Estrogen therapy — In women receiving T4 therapy, estrogens increase serum TBG concentrations, as they do in normal women, and may increase the need for T4. In a study of postmenopausal women (25 women with hypothyroidism and 11 normal women) treated with 0.625 mg conjugated estrogens daily for 48 weeks, serum T4 and TBG concentrations increased in both the hypothyroid and normal women. Serum free T4 and TSH concentrations did not change in the normal women, but decreased and increased, respectively, in the hypothyroid women [48]. Among the latter, seven women had serum TSH concentrations >7 mU/L and were given more T4. These data suggest that serum TSH should be measured approximately 12 weeks after starting estrogen therapy in women receiving T4 therapy to determine if an increase in T4 dose is needed.

Other factors affecting thyroid hormone metabolism — When drugs that affect the catabolism or absorption of T4 are begun for coexisting medical conditions (table 3), serum TSH should be measured four to six weeks later to confirm that the T4 dose is still adequate. The dose should be increased if the serum TSH value is high. Medications that interfere with T4 absorption should be taken several hours after the T4 dose. (See  " Drug interactions with thyroid hormones " .)

A high-fiber diet is another factor that can interfere with the absorption of T4 [49]. It is not known whether natural fiber-containing medications (eg, psyllium) affect T4 absorption, but the synthetic fiber substitute FiberCon© does not.

Coffee, in comparison to water, reduces the absorption of levothyroxine by 27 to 36 percent (assessed by the area under the curve increase in serum T4 administered simultaneously) [11].

Patients with autoimmune gastritis have higher T4 requirements. In one study, the T4 dose was 17 percent higher in patients with parietal cell antibodies [50].

A polymorphism in the type 2 deiodinase has been described which shows reduced activity. Athyreotic patients with this polymorphism required 10 percent higher doses of T4 to obtain normal TSH concentrations [51].

Several patients who appeared to be resistant to levothyroxine administration did not absorb levothyroxine tablets well but absorbed levothyroxine tablets after they were pulverized [52].

Surgical patients — Several studies have investigated the safety of general anesthesia and surgery in patients with untreated or inadequately treated hypothyroidism [53-55]. Surprisingly few adverse effects were reported, although the hypothyroid patients had a higher frequency of perioperative and postoperative ileus, hypotension, hyponatremia, and central nervous system dysfunction than did the euthyroid patients. They also had less fever during serious infections and increased sensitivity to anesthesia and opiate pain medications.

Thus, urgent surgery should not be postponed in hypothyroid patients, but the patient should be managed expectantly for the complications described above. On the other hand, it is prudent to postpone surgery until the euthyroid state is restored when hypothyroidism is discovered in a patient being evaluated for elective surgery.

Patients receiving chronic T4 therapy who undergo surgery and are unable to eat for several days need not be given T4 parenterally. If oral intake cannot be resumed in five to seven days, then T4 should be given intravenously. The dose should be approximately 70 to 80 percent of the patient's usual oral dose, because that is about the fraction of oral T4 that is absorbed [1,56]. We typically give 80 percent.

Subclinical hypothyroidism — If the serum TSH concentration is higher than 10 mU/L or the serum antithyroid peroxidase (microsomal) antibody concentration is high, patients with subclinical hypothyroidism should be treated with T4 to prevent progression to overt hypothyroidism. Treatment may also be indicated in patients with TSH levels between 5 and 10 mU/L who have a goiter or nonspecific symptoms of hypothyroidism such as fatigue, constipation, or depression. (See  " Subclinical hypothyroidism " .)

Poorly compliant patients — Some patients do not take their T4 regularly and do not respond to efforts to improve compliance. These patients may be given their total weekly dose of T4 once per week. The efficacy of this approach was evaluated in a crossover trial of 12 patients [57]. The mean serum TSH concentration one week after a single weekly dose was slightly higher than when the usual dose was given daily (6.6 versus 3.9 mU/L), but the raised value returned to normal one day after the next weekly dose. There was no difference in symptoms between daily or weekly dosing. Weekly dosing should probably not be used in patients with coronary heart disease.

Secondary or central hypothyroidism — Most patients with hypothyroidism caused by hypothalamic or pituitary disease have low serum T4 concentrations and low or normal serum TSH concentrations (a normal value is inappropriately low in the presence of hypothyroidism). A few, however, have slightly high serum TSH concentrations, because the TSH that is secreted is poorly glycosylated and has low bioactivity (but normal immunoactivity). (See " Central hypothyroidism " , section on 'Laboratory findings'.)

The efficacy of T4 therapy in patients with central hypothyroidism must be monitored clinically and by measurements of serum T4; measurements of serum TSH are of no value. Thus, the dose should be adjusted according to the patient's symptoms and serum T4 values, aiming to maintain the serum T4 concentration in the upper part of the normal range. Patients with central hypothyroidism may need more T4 to achieve serum T4 values in the upper half of the normal range than patients with primary hypothyroidism caused by chronic autoimmune thyroiditis or radioiodine therapy. (See  " Central hypothyroidism " , section on 'Treatment'.)

The possible presence of other hormonal deficiencies should be kept in mind because administration of T4 to patients with unsuspected and untreated secondary adrenal insufficiency can precipitate an acute adrenal crisis. Thus, pituitary-adrenal function should be assessed, usually by an ACTH stimulation test, before T4 therapy is begun in patients with central hypothyroidism, and glucocorticoid therapy should be given with T4 if adrenal insufficiency is present. (See  " Diagnosis of hypopituitarism " .)

Thyroid cancer — Patients who have had a thyroidectomy for thyroid cancer, with or without additional treatment with I-131, need to take T4 not only for treatment of hypothyroidism, but also to prevent recurrence of their thyroid cancer. T4 therapy should be life-long in these patients, and should not be discontinued even if sufficient residual normal thyroid tissue remains to provide adequate hormone secretion. (See  " Overview of the management of differentiated thyroid cancer " , section on 'Thyroid hormone suppression'.)

Myxedema coma — Myxedema coma is defined as severe hypothyroidism leading to decreased mental status, hypothermia, and other symptoms. It is a medical emergency with a high mortality rate. Fortunately, it is now a rare presentation of hypothyroidism, probably because of earlier diagnosis. The clinical presentation, diagnosis, and treatment of myxedema coma are reviewed separately. (See  " Myxedema coma " .)

When the diagnosis of hypothyroidism is uncertain — Some patients take thyroid hormone for questionable indications (eg, obesity or hypercholesterolemia), or the diagnosis of hypothyroidism is uncertain. In such a patient, a high serum TSH concentration suggests that the patient is hypothyroid, and the T4 dose should be increased accordingly. If, however, the serum TSH values are normal or low, the dose of thyroid hormone can be reduced by one-half and serum TSH measured again in four to six weeks. If the value is normal, the dose can be reduced further or stopped. Most patients with hypothyroidism have symptoms and a high serum TSH concentration within one month after discontinuing therapy.

Many of these patients are reluctant to discontinue their thyroid hormone, especially if they have taken it for many years. In this case, the goal should be to provide an appropriate dose of T4 (adjusted to maintain a normal serum TSH concentration) to avoid the potential adverse cardiac and skeletal effects of overtreatment.

Pharmacologic use of thyroid hormone in euthyroid patients — Thyroid hormone has been administered to euthyroid patients with several clinical problems in whom it was hoped that outcome would be improved. These include patients undergoing coronary artery bypass graft surgery [58] and those with refractory depression in an attempt to enhance the response to antidepressant drug therapy. (See  " Early noncardiac complications of coronary artery bypass graft surgery " .)

A meta-analysis on the efficacy of thyroid hormone therapy in depressed patients was equivocal [59]. Although there was evidence for overall benefit, the analysis limited to randomized, double-blind trials revealed no benefit of T3. In addition, T3 did not help in an open-label study of patients with severe depression [60]. Finally, T4 therapy in euthyroid patients with " hypothyroid symptoms " was no more effective than placebo in ameliorating symptoms [61].

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Basics topics (see  " Patient information: Hypothyroidism (underactive thyroid) (The Basics) " )

Beyond the Basics topics (see  " Patient information: Hypothyroidism (underactive thyroid) (Beyond the Basics) " )

SUMMARY AND RECOMMENDATIONS

The treatment of choice for correction of hypothyroidism is synthetic thyroxine (T4). For the vast majority of patients with hypothyroidism, we suggest NOT using combination T4-T3 therapy (Grade 2B). T4-T3 therapy may improve symptoms in the rare subgroup of patients with a polymorphism in the type 2 deiodinase, which converts T4 to T3. (See 'Combination T4 and T3 therapy' above.)

We suggest that patients remain on the same formulation of T4 (Grade 2C). We generally avoid generics because of the potential for frequent interchange of preparations by the pharmacy. If the preparation must be changed, follow-up biochemical monitoring (TSH) should be performed six weeks later to determine if retitration of the dose is necessary. (See 'T4 formulations' above.)

The initial dose can be the full anticipated dose (1.6 mcg/kg/day) in young, healthy patients, but older patients should be started on a lower dose (25 to 50 mcg daily). T4 should be taken on an empty stomach, ideally an hour before breakfast. (See 'Starting dose' above and 'Timing of dose' above.)

After initiation of T4 therapy, the patient should be reevaluated and serum TSH should be measured in six weeks, and the dose adjusted accordingly. Symptoms may begin to resolve after two to three weeks, but steady-state TSH concentrations are not achieved for at least six weeks. (See 'Initial monitoring and dose adjustments' above.)

The goals of therapy are amelioration of symptoms and normalization of TSH secretion. We aim to keep TSH within the normal reference range (approximately 0.5 to 5.0 mU/L). (See 'Goals of therapy' above.)

For patients who have possible hypothyroid symptoms, and a serum TSH that is confirmed by repeat measurement to be at the upper limits or above the normal reference range, we suggest increasing the dose of T4 with the aim of lowering the serum TSH value into the lower half of the normal range (Grade 2C). (See 'Persistent symptoms' above.)

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Topic 7855 Version 8.0

 

Hello great minds-I have a very strange case of thyroid labs that don't make any sense.  My patient has lupus and we are currently working with treating multiple infections and she's been doing better.  She has a history of being hypothyroid (since 19 yo) and been on thyroid hormone.    In 4/2011, she had a TSH of 0.08 and then 0.97 with a free T4 of 0.87 in 12/11 (another doctor was managing her thyroid at that time).  She had at various times stopped or reduced her thyroid and then restarted.  In December she had just restarted 125 mcg QD and said she was feeling strange in general.  She decided to stop it completely and I retested her in 4/12.  Her TSH was 249.7 (yes, 249) with a total T4 of 1.2 (alert level).  We restarted her thyroid immediately and she took 1 pill BID for 3-4 days, then dropped to 1.5 pills QD for 3-4 days and then stayed at 1 pill QD since (she made the drops herself).  I just retested her and as of yesterday, her TSH is now 0.219 and her total T4 is 10.5.  Over the last 2 months she's felt better overall, but with some specific symptoms being better and worse.  She was tired and a little dizzy in April, but nothing really remarkable, and that hasn't changed dramatically with the addition of the thyroid.

Her TPO antibodies were tested 2008 and were negative.  I am wondering what to do with this kind of dramatic change in only 2 months at a not excessive thyroid dose, ie., her total T4 is still within lab normal range.  I've decreased her dose for now but am curious about her type of response given her history and dosing- from a physiologic perspective, it doesn't make sense to me that at that thyroid dose, her TSH would change 1000x in two months with the type of T4 rise she shows.

Thanks- Hindman, ND, LAcPortland, OR