Compensated hypothyroidism

Compensated hypothyroidism DEFAULT

Management of the unexpected result: compensated hypothyroidism.

Abstract

The combination of elevated serum thyrotropin and normal serum thyroxine is called compensated or subclinical hypothyroidism. This most commonly represents clinically silent autoimmune thyroiditis. Whether this condition warrants treatment or simply observation is still debated. The risk of developing overt hypothyroidism is high in females with elevated thyrotropin above 10 mU/l and/or positive thyroid microsomal antibodies. Males are also at high risk of progression towards overt hypothyroidism, regardless of antibody status or degree of thyrotropin elevation. We advise routine treatment of only those at high risk of developing overt hypothyroidism.

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Selected References

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Sours: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2431636/

What Is Subclinical Hypothyroidism?

Subclinical hypothyroidism is an early, mild form of hypothyroidism, a condition in which the body doesn’t produce enough thyroid hormones.

It’s called subclinical because only the serum level of thyroid-stimulating hormone from the front of the pituitary gland is a little bit above normal. The thyroid hormones produced by the thyroid gland are still within the laboratory’s normal range.

These hormones help support heart, brain, and metabolic functions. When thyroid hormones aren’t working properly, this affects the body.

According to published research, of people have subclinical hypothyroidism. This condition can progress to full-blown hypothyroidism.

In one study, of those with subclinical hypothyroidism developed full-blown hypothyroidism within 6 years of their initial diagnosis.

What causes this?

The pituitary gland, located at the base of the brain, secretes multiple hormones, including a substance called thyroid-stimulating hormone (TSH).

TSH triggers the thyroid, a butterfly-shaped gland at the front of the neck, to make the hormones T3 and T4. Subclinical hypothyroidism occurs when TSH levels are slightly elevated but T3 and T4 are normal.

Subclinical hypothyroidism and full-blown hypothyroidism share the same causes. These include:

  • a family history of autoimmune thyroid disease, such as Hashimoto’s thyroiditis (an autoimmune condition that harms thyroid cells)
  • injury to the thyroid (for example, having some abnormal thyroid tissue removed during head and neck surgery)
  • the use of radioactive iodine therapy, a treatment for hyperthyroidism (a condition when too much thyroid hormone is produced)
  • taking medications that contain lithium or iodine

Who’s at risk?

A variety of things, most of which are outside of your control, increase the chances of developing subclinical hypothyroidism. These include:

  • Gender. A study published in the journal showed that women are more likely to develop subclinical hypothyroidism than men. The reasons aren’t entirely clear, but researchers suspect the female hormone estrogen may play a role.
  • Age. TSH tends to rise as you age, making subclinical hypothyroidism more prevalent in older adults.
  • Iodine intake. Subclinical hypothyroidism tends to be more prevalent in populations that consume sufficient or excess iodine, a trace mineral essential for proper thyroid function. It can help to be familiar with the signs and symptoms of an iodine deficiency.

Common symptoms

Subclinical hypothyroidism most of the times has no symptoms. This is especially true when TSH levels are only mildly elevated. When symptoms do arise, however, they tend to be vague and general and include:

It’s important to note that these symptoms are nonspecific, meaning they can be present in individuals with normal thyroid function and not related to subclinical hypothyroidism.

How it’s diagnosed

Subclinical hypothyroidism is diagnosed with a blood test.

A person with a normal functioning thyroid should have a blood TSH reading within the normal reference range, which commonly goes up to 4.5 milli-international units per liter (mIU/L) or .

However, there’s debate underway in the medical community about lowering the highest normal threshold.

People with a TSH level above the normal range, who have normal thyroid gland hormone levels, are considered to have subclinical hypothyroidism.

Because amounts of TSH in the blood can fluctuate, the test may need to be repeated after a few months to see if the TSH level has normalized.

How it’s treated

There’s a lot of debate about how — and even if — to treat those with subclinical hypothyroidism. This is especially true if TSH levels are lower than 10 mIU/L.

Because a higher TSH level can start to produce adverse effects on the body, people with a TSH level over 10 mIU/L are generally treated.

According to , evidence is mostly inconclusive that those with TSH levels between 5.1 and 10 mIU/L will benefit from treatment.

In deciding whether or not to treat you, your doctor will take into consideration things like:

  • your TSH level
  • whether or not you have antithyroid antibodies in your blood and a goiter (both are indications the condition may progress to hypothyroidism)
  • your symptoms and how much they’re affecting your life
  • your age
  • your medical history

When treatment is used, levothyroxine (Levoxyl, Synthroid), a synthetic thyroid hormone taken orally, is often recommended and is generally well tolerated.

Are there complications?

Heart disease

The connection between subclinical hypothyroidism and cardiovascular disease is still being debated. Some studies do suggest that elevated TSH levels, when left untreated, may contribute to developing the following:

  • high blood pressure
  • high cholesterol

In a looking at older men and women, those with a blood TSH level of 7 mIU/L and above were at twice the risk or more for having congestive heart failure compared to those with a normal TSH level. But some other studies didn’t confirm this finding.

Pregnancy loss

During pregnancy, a blood TSH level is considered elevated when it exceeds 2.5 mIU/L in the first trimester and 3.0 mIU/L in the second and third. Proper thyroid hormone levels are necessary for fetal brain and nervous system development.

Research published in found that pregnant women with a TSH level between 4.1 and 10 mIU/L who were subsequently treated were less likely to have a miscarriage than their counterparts who weren’t treated.

Interestingly, though, women with a TSH level between 2.5 and 4 mIU/L didn’t see any reduced risk of pregnancy loss between those treated and those untreated if they had negative thyroid antibodies.

Assessing the status of antithyroid antibodies is important.

According to a 2014 study, women with subclinical hypothyroidism and positive antithyroid peroxidase (TPO) antibodies tend to have the highest risk of adverse pregnancy outcomes, and adverse outcomes happen at a lower TSH level than in women without TPO antibodies.

A 2017 systematic review found that the risk of pregnancy complications was apparent in TPO-positive women with a TSH level greater than 2.5 mU/L. This risk wasn’t consistently apparent in TPO-negative women until their TSH level exceeded 5 to 10 mU/L.

Best diet to follow

There’s no good scientific evidence that eating or not eating certain foods will definitely help to stave off subclinical hypothyroidism or treat it if you’ve already been diagnosed. It’s important, however, to get an optimal amount of iodine in your diet.

Too little iodine can lead to hypothyroidism. On the other hand, too much may lead to either hypothyroidism or hyperthyroidism. Good sources of iodine include iodized table salt, saltwater fish, dairy products, and eggs.

The National Institutes of Health recommends for most adults and teenagers. One-quarter teaspoon of iodized salt or 1 cup of low-fat plain yogurt provides about 50 percent of your daily iodine needs.

All in all, the best thing you can do for your thyroid function is to eat a well-balanced, nutritious diet.

What’s the outlook?

Because of conflicting studies, there’s still a lot of debate about how and if subclinical hypothyroidism should be treated. The best approach is an individual one.

Talk to your doctor about any symptoms, your medical history, and what your blood tests show. This handy discussion guide can help you get started. Study your options and decide on the best course of action together.

Sours: https://www.healthline.com/health/subclinical-hypothyroidism
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Subclinical hypothyroidism is defined as an elevated serum TSH level associated with normal total or free T4 and T3 values. The overall prevalence has been reported to range from 4–10% in large general population screening surveys (1–5) and from 7–26% in studies of the elderly (1–3, 6–11). Because of the frequency with which this condition is encountered, important questions have been raised regarding its clinical relevance and appropriate management. One of the myths that surrounds subclinical hypothyroidism is that the laboratory profile of an elevated serum TSH and normal free thyroid hormone levels really represents “compensated hypothyroidism.” The reasoning behind this idea is that, since the circulating levels of thyroid hormones are within the normal range with only the serum TSH being elevated, the affected subject is really euthyroid because the increased TSH is stimulating and driving the thyroid gland to produce normal thyroid hormone levels. Certainly, elevated serum TSH levels do stimulate even a diseased thyroid gland to produce and release more thyroid hormone. However, as long as the serum TSH level remains elevated, the thyroid hormone levels are not truly normal for that individual. The clearance kinetics of thyroid hormones and TSH from the circulation actually make such a conclusion inescapable. Because the half-life of T4 is 7 d and that of T3 is 1 d, the serum TSH, which has a half-life of less than 1 h, would certainly be expected to return to normal if thyroid hormone levels were, indeed, normal for that individual. An elevated TSH in an individual patient, thus, means that the circulating thyroid hormone concentrations are insufficient, with a few rare exceptions (TSH-secreting tumors, thyroid hormone resistance syndromes). We, indeed, believe that subclinical hypothyroidism represents mild thyroid failure and is a clinically important disorder that has adverse clinical consequences and that should be treated in most, if not all, cases. We will support this position by reviewing the reported objective data regarding its natural history, its clinical manifestations, and the benefits of treatment.

Natural history

Mild thyroid failure represents an early stage of thyroid disease that will commonly progress to overt hypothyroidism. Progression has, in fact, been reported to occur in approximately 3–18% of affected patients per year (10–17). One study evaluated the natural history of mild thyroid failure in 154 female patients over a 10-yr period; 57% of patients continued to have mild thyroid failure, 34% of patients progressed to overt hypothyroidism, and 9% of patients reverted to a normal TSH level. How many of the 9% had a transient form of thyroiditis such as silent, subacute, or postpartum thyroiditis is unclear (17). The strongest predictors of progression are the presence of antithyroid antibodies, serum TSH values greater than 20 μU/ml, a history of radioiodine ablation for Graves’ disease, a history of external radiation therapy for nonthyroid malignancies, and chronic lithium treatment (10–16).

Clinical manifestations

Symptoms. Mild thyroid failure is often asymptomatic; however, nearly 30% of patients with this condition may have symptoms that are suggestive of thyroid hormone deficiency (2, 18). The Colorado Thyroid Disease Prevalence Study (2) measured serum TSH levels and conducted symptom surveys in over 25,000 state residents. Elevated serum TSH values were found in 9.5% of all subjects and in 8.9% of those who were not already on thyroid hormone therapy (Fig. 1); 75% of these individuals had serum TSH levels in the 5–10 μU/ml range. In response to a validated survey regarding symptoms of thyroid hormone deficiency, the 2,336 subjects who were identified as having mild thyroid failure significantly more often reported having dry skin (28%; P < 0.001), poor memory (24%; P < 0.001), slow thinking (22%; P < 0.001), muscle weakness (22%; P < 0.001), fatigue (18%; P < 0.01), muscle cramps (17%; P < 0.001), cold intolerance (15%; P< 0.001), puffy eyes (12%; P < 0.05), constipation (8%; P < 0.05), and hoarseness (7%; P < 0.05) than did euthyroid subjects. It is important to note that, whereas euthyroid subjects experienced a mean of 12.1% of all listed symptoms, overtly hypothyroid subjects had 16.6% of these symptoms (P < 0.05 vs. euthyroid group), and subjects with mild thyroid failure reported an intermediate 13.7% of the symptoms (P < 0.05 vs. euthyroid group) (Fig. 2). This suggests a “dosage effect” between levels of thyroid hormones and symptoms. Consistent with these findings, a Swiss study involving 332 women with hypothyroidism reported that 24% of the 93 subjects with mild thyroid failure exhibited typical symptoms of hypothyroidism (18). These studies also emphasize the difficulty in making the diagnosis of primary hypothyroidism using clinical symptoms alone; euthyroid subjects and patients with mild or overt hypothyroidism all had similar constellations of symptoms. Despite statistical significance in large groups, it can be difficult in an individual patient to distinguish a euthyroid subject from one with either mild or overt thyroid disease.

Figure 1.

The Colorado Thyroid Disease Prevalence Study (2 ). Shown are the age- and gender-specific prevalences of high serum TSH levels found during the screening of 25,862 Colorado state residents in 1995.

Figure 1.

The Colorado Thyroid Disease Prevalence Study (2 ). Shown are the age- and gender-specific prevalences of high serum TSH levels found during the screening of 25,862 Colorado state residents in 1995.

Figure 2.

The Colorado Thyroid Disease Prevalence Study (2 ). Participants were given a validated survey containing questions regarding symptoms of thyroid hormone deficiency. Of all the symptoms listed, euthyroid subjects (n = 22,842) reported having 12.1%, mild thyroid failure patients (n = 2,336) had 13.7%, and overtly hypothyroid patients (114) had 16.6%. Compared with the euthyroid subjects, total symptoms reported were significantly higher for both the mild thyroid failure patients (P < 0.05) and those with overt hypothyroidism (P < 0.05).

Figure 2.

The Colorado Thyroid Disease Prevalence Study (2 ). Participants were given a validated survey containing questions regarding symptoms of thyroid hormone deficiency. Of all the symptoms listed, euthyroid subjects (n = 22,842) reported having 12.1%, mild thyroid failure patients (n = 2,336) had 13.7%, and overtly hypothyroid patients (114) had 16.6%. Compared with the euthyroid subjects, total symptoms reported were significantly higher for both the mild thyroid failure patients (P < 0.05) and those with overt hypothyroidism (P < 0.05).

Neurobehavioral abnormalities and neuromuscular function. Other cross-sectional studies have demonstrated evidence of specific neurobehavioral and neuromuscular dysfunction in mild thyroid failure patients (19–31). Depression (19–23), memory loss (2, 19, 24), cognitive impairment (25) and a variety of neuromuscular complaints (26, 27) have all been reported to occur more frequently in patients with this condition. Objective peripheral nerve dysfunction, manifested by decreased conduction amplitude in peripheral nerves (28), and an abnormal stapedial reflex (29) have been demonstrated in these patients. Skeletal muscle abnormalities, including elevated serum creatine phosphokinase levels (30), increased circulating lactate levels during exercise (26), and repetitive discharges on surface electromyography (27), have also been reported. Finally, there is intriguing evidence that mild thyroid failure in pregnant women may result in reduced intellectual development of their euthyroid offspring (31).

Cardiac-pulmonary function. Myocardial function has been reported in multiple studies to be subtly impaired in patients with mild thyroid failure (32–41). Identified functional abnormalities include impaired myocardial contractility (32–40) and diastolic dysfunction (39–41), at rest (32, 34, 37, 39–41) or with exercise (35–39). Myocardial texture has also been shown to be abnormal by videodensitometric analysis (40). In one comprehensive study of exercise capacity (38), patients with mild thyroid failure were shown to have significant impairment of exercise-related stroke volume, cardiac index, and maximal aortic flow velocity. Pulmonary testing in these same patients revealed decreased vital capacity, reduced anaerobic thresholds, and decreased oxygen uptake at the anaerobic threshold (38). These data clearly demonstrate that cardiovascular function in mild thyroid failure is slightly impaired and not identical to that in the euthyroid state. The important question is whether these differences result in clinically significant impairment of performance in affected patients.

Cardiovascular risk factor. Mild thyroid failure has been extensively evaluated as a cardiovascular risk factor. The condition has been shown to be associated with increased serum levels of total cholesterol (Fig. 3) and low-density lipoprotein (LDL) cholesterol in most but not all studies (2, 38, 42, 43) and with reduced high-density lipoprotein cholesterol in some studies (38). Some reports have suggested that even high normal serum TSH values may adversely affect serum lipid and lipoprotein levels (44–46). It has been estimated that an increase in the serum TSH level of 1 μU/ml is associated with a rise in the serum total cholesterol concentration of 0.09 mmol/liter (3.5 mg/dl) in women and 0.16 mmol/liter (6.2 mg/dl) in men (45). The relationship between TSH and LDL cholesterol seems to be most significant in individuals who have underlying insulin resistance (46). One recent study reported that patients with mild thyroid failure, and even subjects with high normal serum TSH values, have evidence of endothelial dysfunction, manifested by impaired flow-mediated, endothelial-dependent vasodilatation (47). An association between mild thyroid failure and peripheral vascular disease was suggested by an older case-control study involving elderly women (48). A 20-yr follow-up study of the original Whickham Survey found no association between initial hypothyroidism, raised serum TSH levels, or antithyroid antibodies and the development of coronary artery disease (49). In contrast, a more recent report from the Rotterdam Study (9) concluded that patients with mild thyroid failure have a significantly increased prevalence of aortic atherosclerosis and myocardial infarctions. After adjustment for multiple known coronary artery disease risk factors, the authors found mild thyroid failure to be an independent and equivalently important risk factor for myocardial infarctions (Fig. 4).

Figure 3.

The Colorado Thyroid Disease Prevalence Study (2 ). Shown are the mean serum total cholesterol levels in the 22,842 euthyroid subjects (216 mg/dl), the 2,336 mild thyroid failure subjects (224 mg/dl), and the 114 subjects with overt hypothyroidism (251 mg/dl); both thyroid disease groups had statistically higher total cholesterol levels and LDL cholesterol levels (data not shown) than did the euthyroid controls (P < 0.001).

Figure 3.

The Colorado Thyroid Disease Prevalence Study (2 ). Shown are the mean serum total cholesterol levels in the 22,842 euthyroid subjects (216 mg/dl), the 2,336 mild thyroid failure subjects (224 mg/dl), and the 114 subjects with overt hypothyroidism (251 mg/dl); both thyroid disease groups had statistically higher total cholesterol levels and LDL cholesterol levels (data not shown) than did the euthyroid controls (P < 0.001).

Figure 4.

The Rotterdam Study (9 ). Analysis of the relationship between subclinical hypothyroidism (SCH) and myocardial infarctions in this study revealed an attributable risk of 60% (SCH contributed to 60% of the myocardial infarctions in the 124 women who had SCH) and a population attributable risk of 14% (SCH was involved in 14% of all myocardial infarctions in the entire group of 1149 women). These risks were similar to those associated with the major recognized cardiovascular risk factors—hypercholesterolemia, hypertension (BP), smoking, and diabetes mellitus.

Figure 4.

The Rotterdam Study (9 ). Analysis of the relationship between subclinical hypothyroidism (SCH) and myocardial infarctions in this study revealed an attributable risk of 60% (SCH contributed to 60% of the myocardial infarctions in the 124 women who had SCH) and a population attributable risk of 14% (SCH was involved in 14% of all myocardial infarctions in the entire group of 1149 women). These risks were similar to those associated with the major recognized cardiovascular risk factors—hypercholesterolemia, hypertension (BP), smoking, and diabetes mellitus.

Benefits of treatment

Having defined the scope, natural history, clinical features, and potential morbidity of mild thyroid failure, one must next ask whether treatment of the condition has demonstrable benefits. A number of studies have addressed this issue.

Symptoms. There have been three randomized controlled trials (RCT) examining the effects of l-thyroxine treatment on general symptoms in subjects with mild thyroid failure (Table 1). Two of these RCTs (33, 34) reported that mild thyroid failure subjects who were treated with l-thyroxine had significantly greater improvement in general hypothyroid symptom scores than did subjects who were treated with placebo (Fig. 5). A third RCT (50) showed no symptomatic treatment benefit; in this study, however, the mean serum TSH level on l-thyroxine treatment was 4.6 μU/ml, which was at the high end of the normal range. One uncontrolled study also reported a reduction of general somatic complaints after l-thyroxine treatment was instituted (19).

Figure 5.

A RCT of l-thyroxine (L-T4) therapy in subjects with mild thyroid failure (33 ). Subjects (n= 33) were randomly assigned to received l-thyroxine therapy or placebo for a period of 1 yr. l-thyroxine-treated subjects had a significant improvement in their mean symptom score compared with the placebo-treated group (P < 0.05).

Figure 5.

A RCT of l-thyroxine (L-T4) therapy in subjects with mild thyroid failure (33 ). Subjects (n= 33) were randomly assigned to received l-thyroxine therapy or placebo for a period of 1 yr. l-thyroxine-treated subjects had a significant improvement in their mean symptom score compared with the placebo-treated group (P < 0.05).

Table 1.

Randomized controlled trials investigating the effects of l-thyroxine treatment on general symptoms in patients with mild thyroid failure

Author (Ref.) . nDesign . TSH (uU/ml) . Results . 
Pre-l-thyroxine . On l-thyroxine . 
Cooper (33 ) 33 Randomized, double-blind, placebo-controlled (1 yr) 10.8 2.6 Symptom score improvement in l-thyroxine group (P < 0.05) 
Nystrom (34 ) 17 Randomized, double-blind, placebo-controlled crossover (6 months) 7.7 1.9 Symptom score improvement in l-thyroxine group (P < 0.01) 
Jaeschke (50 ) 32 Randomized, double-blind, placebo-controlled (11 months) 12.3 4.6 Symptom score not improved in l-thyroxine group (P = ns); memory improved (P < 0.01) 
Author (Ref.) . nDesign . TSH (uU/ml) . Results . 
Pre-l-thyroxine . On l-thyroxine . 
Cooper (33 ) 33 Randomized, double-blind, placebo-controlled (1 yr) 10.8 2.6 Symptom score improvement in l-thyroxine group (P < 0.05) 
Nystrom (34 ) 17 Randomized, double-blind, placebo-controlled crossover (6 months) 7.7 1.9 Symptom score improvement in l-thyroxine group (P < 0.01) 
Jaeschke (50 ) 32 Randomized, double-blind, placebo-controlled (11 months) 12.3 4.6 Symptom score not improved in l-thyroxine group (P = ns); memory improved (P < 0.01) 

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Table 1.

Randomized controlled trials investigating the effects of l-thyroxine treatment on general symptoms in patients with mild thyroid failure

Author (Ref.) . nDesign . TSH (uU/ml) . Results . 
Pre-l-thyroxine . On l-thyroxine . 
Cooper (33 ) 33 Randomized, double-blind, placebo-controlled (1 yr) 10.8 2.6 Symptom score improvement in l-thyroxine group (P < 0.05) 
Nystrom (34 ) 17 Randomized, double-blind, placebo-controlled crossover (6 months) 7.7 1.9 Symptom score improvement in l-thyroxine group (P < 0.01) 
Jaeschke (50 ) 32 Randomized, double-blind, placebo-controlled (11 months) 12.3 4.6 Symptom score not improved in l-thyroxine group (P = ns); memory improved (P < 0.01) 
Author (Ref.) . nDesign . TSH (uU/ml) . Results . 
Pre-l-thyroxine . On l-thyroxine . 
Cooper (33 ) 33 Randomized, double-blind, placebo-controlled (1 yr) 10.8 2.6 Symptom score improvement in l-thyroxine group (P < 0.05) 
Nystrom (34 ) 17 Randomized, double-blind, placebo-controlled crossover (6 months) 7.7 1.9 Symptom score improvement in l-thyroxine group (P < 0.01) 
Jaeschke (50 ) 32 Randomized, double-blind, placebo-controlled (11 months) 12.3 4.6 Symptom score not improved in l-thyroxine group (P = ns); memory improved (P < 0.01) 

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Neurobehavioral abnormalities and neuromuscular function. Memory has been shown to improve significantly in one RCT (50) and in two uncontrolled studies in which mild thyroid failure patients were given l-thyroxine therapy (19, 24). Other reported benefits from uncontrolled interventional studies include reduction in neuromuscular complaints (19, 27) and normalization of initially abnormal electromyograms (27).

Cardiac-pulmonary function. Studies that have examined the effects of l-thyroxine treatment on cardiac function, including one RCT (40), have reported modest but relatively consistent beneficial results (Table 2). Observed responses to treatment have included enhanced cardiac contractility (32–41), improvement of diastolic function (40, 41), and normalization of videodensitometric myocardial texture (40). Increases in pulmonary vital capacity, the anaerobic threshold and oxygen uptake at the anaerobic threshold have also been demonstrated (38).

Table 2.

Studies that have investigated the effects of l-thyroxine on cardiac function in patients with mild thyroid failure

Author (Ref.) . nTSH (uU/ml) . Untreated . l-thyroxine Therapy . Methodsa
Pre-l-thyroxine . On l-thyroxine . Rest . Exercise . Rest . Exercise . 
Ridgway (32 ) 20 28 1.9 ↓MC ↑MC 
Cooper (33 ) 33 10.8 2.6 Normal ↑MCb
Nystrom (34 ) 17 7.7 1.9 ↓MC ↑MC 
Bell (35 ) 18 17.9 3.2 Normal ↓MC ↑MC 
Forfar (36 ) 10 18.2 3.5 Normal ↓MC ↑MC 
Foldes (37 ) 17 10.3 ↓MC ↓MC ↑MC 1,2 
Kahaly (38 ) 20 11.2 Normal ↓MC ↑MC 1,3 
Arem (39 ) 14.8 3.0 ↓DF ↓MC ↑MC 1,3 
Monzani (40 ) 20 5.4 1.2 ↓MC, DF ↑MC, DF 1,3,4 
Biondi (41 ) 10 8.6 1.7 ↓DF ↑MC, DF 
Author (Ref.) . nTSH (uU/ml) . Untreated . l-thyroxine Therapy . Methodsa
Pre-l-thyroxine . On l-thyroxine . Rest . Exercise . Rest . Exercise . 
Ridgway (32 ) 20 28 1.9 ↓MC ↑MC 
Cooper (33 ) 33 10.8 2.6 Normal ↑MCb
Nystrom (34 ) 17 7.7 1.9 ↓MC ↑MC 
Bell (35 ) 18 17.9 3.2 Normal ↓MC ↑MC 
Forfar (36 ) 10 18.2 3.5 Normal ↓MC ↑MC 
Foldes (37 ) 17 10.3 ↓MC ↓MC ↑MC 1,2 
Kahaly (38 ) 20 11.2 Normal ↓MC ↑MC 1,3 
Arem (39 ) 14.8 3.0 ↓DF ↓MC ↑MC 1,3 
Monzani (40 ) 20 5.4 1.2 ↓MC, DF ↑MC, DF 1,3,4 
Biondi (41 ) 10 8.6 1.7 ↓DF ↑MC, DF 

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Table 2.

Studies that have investigated the effects of l-thyroxine on cardiac function in patients with mild thyroid failure

Author (Ref.) . nTSH (uU/ml) . Untreated . l-thyroxine Therapy . Methodsa
Pre-l-thyroxine . On l-thyroxine . Rest . Exercise . Rest . Exercise . 
Ridgway (32 ) 20 28 1.9 ↓MC ↑MC 
Cooper (33 ) 33 10.8 2.6 Normal ↑MCb
Nystrom (34 ) 17 7.7 1.9 ↓MC ↑MC 
Bell (35 ) 18 17.9 3.2 Normal ↓MC ↑MC 
Forfar (36 ) 10 18.2 3.5 Normal ↓MC ↑MC 
Foldes (37 ) 17 10.3 ↓MC ↓MC ↑MC 1,2 
Kahaly (38 ) 20 11.2 Normal ↓MC ↑MC 1,3 
Arem (39 ) 14.8 3.0 ↓DF ↓MC ↑MC 1,3 
Monzani (40 ) 20 5.4 1.2 ↓MC, DF ↑MC, DF 1,3,4 
Biondi (41 ) 10 8.6 1.7 ↓DF ↑MC, DF 
Author (Ref.) . nTSH (uU/ml) . Untreated . l-thyroxine Therapy . Methodsa
Pre-l-thyroxine . On l-thyroxine . Rest . Exercise . Rest . Exercise . 
Ridgway (32 ) 20 28 1.9 ↓MC ↑MC 
Cooper (33 ) 33 10.8 2.6 Normal ↑MCb
Nystrom (34 ) 17 7.7 1.9 ↓MC ↑MC 
Bell (35 ) 18 17.9 3.2 Normal ↓MC ↑MC 
Forfar (36 ) 10 18.2 3.5 Normal ↓MC ↑MC 
Foldes (37 ) 17 10.3 ↓MC ↓MC ↑MC 1,2 
Kahaly (38 ) 20 11.2 Normal ↓MC ↑MC 1,3 
Arem (39 ) 14.8 3.0 ↓DF ↓MC ↑MC 1,3 
Monzani (40 ) 20 5.4 1.2 ↓MC, DF ↑MC, DF 1,3,4 
Biondi (41 ) 10 8.6 1.7 ↓DF ↑MC, DF 

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Cardiovascular risk factor. The reported lipid and lipoprotein responses to treatment of mild thyroid failure with thyroid hormone have been somewhat inconsistent (38). A retrospective evaluation suggested that thyroid hormone replacement had very little lipid-lowering effect in patients whose initial TSH values were less than 10 μU/ml (51). However, two quantitative literature reviews (42, 43) of the prospective studies examining this issue have concluded that l-thyroxine treatment of patients with mild thyroid failure lowers serum total cholesterol by approximately 0.2–0.4 mmol/liter (7.9–15.8 mg/dl) and LDL cholesterol by about 0.26 mmol/liter (10 mg/dl). The observed cholesterol reductions were greater in patients with inadequately treated overt hypothyroidism (0.44 mmol/liter; 17.4 mg/dl) than in those with untreated spontaneous mild thyroid failure (0.14 mmol/liter; 5.5 mg/dl) and were also greater in patients with higher initial cholesterol levels (43). There have been no reported beneficial effects on high-density lipoprotein cholesterol or triglycerides (42, 43). One intriguing, but uncontrolled, retrospective analysis (52) showed progression of coronary atherosclerosis in subjects on l-thyroxine therapy with elevated serum TSH levels compared with those with normal TSH levels (P < 0.02).

Treatment goals. Firm data-based guidelines for treatment goals have not yet been established. The distribution of serum TSH values in the normal population is skewed, with the majority of individuals having TSH values at the lower end of the normal range (53). Recent studies have reported that “high normal” TSH values may be associated with modest increases in serum cholesterol levels (44–46) and that serum cholesterol levels improve when TSH values are reduced from the high end to the low end of the normal range with l-thyroxine supplementation (44). Furthermore, individuals with high normal serum TSH levels may have endothelial dysfunction (47). Thus, although not based on prospective outcomes data, these findings would suggest to us that the optimal goal TSH range for l-thyroxine-treated patients is 0.5–2.0 μU/ml.

Cost-effectiveness and consensus opinion. Additional support for a decision to treat comes from a recent analysis, which concluded that screening for and treating mild thyroid failure in all adults greater than 35 yr old is as cost-effective as many other screening procedures used in the United States today (54). Finally, we have recently conducted a survey seeking opinions from both primary care providers (PCPs) and members of the American Thyroid Association (ATA) regarding the management of hypothyroidism (55). When presented the case of a 26-yr-old woman with minimally symptomatic mild thyroid failure, the majority of respondents (70% of PCPs and 65% of ATA members) indicated that they would treat the patient if antithyroid antibodies were negative, whereas 95% of ATA members recommended treatment if antibodies were positive. Responses were similar when the case was a 71-yr-old woman with minimally symptomatic mild thyroid failure; the majority (64% of PCPs and 61% of ATA members) chose to treat if antithyroid antibodies were negative, and 92% of ATA members recommended treatment if antibodies were positive.

Summary

We believe that mild thyroid failure is a common disorder that frequently progresses to overt hypothyroidism. The condition may clearly be associated with somatic symptoms, depression, memory and cognitive impairment, subtle neuromuscular abnormalities, subtle systolic and diastolic cardiac dysfunction, raised serum levels of total and LDL cholesterol, and an increased risk for the development of atherosclerosis. There is documented evidence that many, if not most, of these adverse effects are improved or corrected when l-thyroxine replacement is instituted. Furthermore, treatment of mild thyroid failure has been reported to be cost-effective. Early treatment may even be justified in asymptomatic individuals to prevent the symptoms of more severe thyroid hormone deficiency that eventually develop as the thyroid gland progressively fails; this is particularly true of antithyroid antibody-positive patients, who have the highest risk of disease progression. For these reasons, we recommend l-thyroxine treatment for the majority of patients with mild thyroid failure, particularly those who have symptoms, other cardiovascular risk factors, goiters, or positive antithyroid antibodies, and in those who are pregnant. However, despite these positive indications that treatment with thyroid hormone carries a benefit, there are many unanswered questions. There are few prospective, randomized placebo-controlled studies that have been performed, a shame when compared with other common disorders such as hypercholesterolemia and osteoporosis. The potential consequences of untreated mild thyroid failure on atherosclerosis in adults and on intellectual potential in infants born to mothers with mild thyroid failure begs for definitive answers about the therapeutic benefits of thyroid hormone replacement. It is no longer scientifically or morally justifiable to argue whether mild thyroid failure is “something” or“ nothing.” What is clearly needed now are clean, randomized, prospective, and adequately powered trials to provide unequivocal answers to the lingering but critical questions regarding the effects of mild thyroid failure and its treatment on important end points such as intellectual function, ischemic heart disease, and quality of life.

Abbreviations:

  • ATA,

    American Thyroid Association;

  • PCP,

  • RCT,

    randomized controlled trial.

3

Hollowell J, Braverman LE, Spencer CA, Staehling N, Flanders D, Hannon H Serum TSH, T4, and thyroid antibodies in the United States population: NHANES III. 72nd Annual Meeting of the American Thyroid Association, Palm Beach, FL, 1999; Abstract 213

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Sours: https://academic.oup.com/jcem/article/86/10/4585/2848862
Subclinical Hypothyroidism - Overt hypothyroidism - Subclinical Hypothyroidism Treatment

Subclinical Hypothyroidism

US Pharm. 2010;35(6):20-22.

Thyroid disorders are common in the elderly. These conditions are diagnostically challenging and are often overlooked in seniors since signs and symptoms are frequently nonspecific and are attributed to comorbidities or the normal aging process.1 Pharmacists who interact with patients and/or monitor patients’ response to pharmacotherapy have an opportunity to recognize the signs and symptoms of hypothyroidism (TABLE 1) and identify medications that may affect thyroid function (TABLE 2). This column will focus on the relatively common condition known as subclinical hypothyroidism, also referred to as mild thyroid failure.

Role of the Thyroid Gland

With regard to metabolism, the thyroid gland and thyroid hormones influence practically all cellular function.2 The largest endocrine organ in the body, the two-lobed thyroid gland, is located in the anterior neck and produces the two main thyroid hormones: triiodothyronine (T3), the most active form, and tetraiodothyronine (thyroxine, T4), which has minimal hormonal activity.1,3,4 Approximately 80% of the production of T3 is derived from T4-to-T3 conversion in extrathyroidal tissues (liver, muscles, kidneys); the thyroid gland secretes the remaining 20% of T3.1  

The hypothalamus, the anterior pituitary, and the thyroid gland regulate thyroid hormones through a negative feedback loop.1 Thyrotropin-releasing hormone (TRH) within the hypothalamus stimulates the release of thyroid-stimulating hormone (TSH) from the anterior pituitary gland; TSH is responsible for increasing thyroid hormone synthesis and secretion.1 From the serum, T3 and T4 feed back to inhibit TSH and TRH production and secretion.1

Of note, the thyroid gland also secretes the hormone calcitonin, which is classified as a serum calcium–lowering hormone.4 Preparations of calcitonin (e.g., calcitonin-salmon) help regulate calcium via bone, renal, and gastrointestinal effects, and are used in the treatment of osteitis deformans, postmenopausal osteoporosis, and hypercalcemia.5,6

While the thyroid gland is not essential for life, in a newborn, thyroid hormone is required for normal brain function and somatic tissue development; in individuals of all ages, thyroid hormone regulates protein, carbohydrate, and fat metabolism.3,4 By maintaining a level of metabolism in the tissues that is optimal for normal function, the thyroid gland facilitates normal growth and maturation.4

Age-Related Changes in Thyroid Function

The notion that biological aging is a multifactorial process, is commonly accepted.7 In general, changes associated with aging occur morphologically (e.g., sclerosis of heart valves, decreased elasticity of lung) and/or functionally (e.g., decreased T-cell activity, increased motor response time, slowed intestinal motility).7 With regard to the thyroid, age-related changes manifest as alterations in anatomy (e.g., increase in fibrosis) and function (e.g., decrease in T3 concentration); the vast majority of seniors, however, maintain normal thyroid function.1

Thyroid Failure

The insidious process of thyroid failure and a state of decreased thyroid hormone available to peripheral tissues constitutes the clinical situation known as hypothyroidism.1 In the general population, in patients over the age of 60 years the incidence of overt hypothyroidism is approximately 2% to 10%.1 Medications such as amiodarone and lithium often induce hypothyroidism.8 Other risk factors for failure of the thyroid gland can be found in TABLE 3

Inadequate secretion of thyroid hormone (hypothyroidism) results in a variety of signs and symptoms (TABLE 1), including bradycardia, cold intolerance, and mental and physical slowing. There may be a delay in clinical suspicion of hypothyroidism in elderly patients because early manifestations, such as fatigue and constipation, may be attributed to aging itself.9 In fact, elderly patients have fewer symptoms of hypothyroidism than their younger counterparts and present with more subtle and vague complaints.10

Pharmacists should note that this is in contrast to excess secretion of thyroid hormones (hyperthyroidism) resulting in signs and symptoms including tachycardia, cardiac arrhythmias, body wasting, nervousness, tremor, and excess heat production.4

Serum TSH (adult reference range approximately 0.3-4 mIU/L) is generally considered the best screening test for thyroid disease due to its sensitivity and specificity; elevated values usually are indicative of hypothyroidism, and decreased values usually are indicative of hyperthyroidism.6,9 Laurberg et al recommend that TSH levels be part of biochemical testing for undiagnosed medical conditions in elderly patients.8

The sensitivity of serum TSH measurement may reveal patients with elevated serum TSH levels, however, implying hypothyroidism but with an accompanying normal free T4 levels (adult reference range approximately 0.8-1.8 ng/dL); see Subclinical Hypothyroidism, below.6,9

Subclinical Hypothyroidism

During a routine screening for thyroid disease, a patient may be found to have subclinical hypothyroidism—an elevated TSH level in conjunction with a free T4 level that is not below normal and is also referred to as mild thyroid failure.1,9 The patient may be asymptomatic or present with minimal symptoms of hypothyroidism.7 Subclinical hypothyroidism is frequently an early stage of hypothyroidism.9 When a patient presents with a serum TSH > 10.0 mIU/L, there is a high likelihood of progression to overt hypothyroidism presenting with low serum free T4 in the upcoming 10 years.3

The prevalence of subclinical hypothyroidism is approximately 3% to 8.5% of the general population; it is more common in women than in men, and its prevalence increases with age—rising to as high as 20% in women over the age of 60 years.11,12 Subclinical hypothyroidism progresses to overt hypothyroidism at a rate of 5% to 20% per year in patients who have both mildly elevated TSH levels and antithyroid (peroxidase) antibodies.1,9 Patients with this condition are more likely to have hypercholesterolemia.3 According to Hak et al, the Rotterdam study indicated that subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women.13 Furthermore, Biondi et al have noted subclinical hypothyroidism to be associated with left ventricular diastolic dysfunction that is improved with T4 therapy.14

Subclinical hypothyroidism is far more common than subclinical hyperthyroidism.3 It occurs especially in geriatric women with an underlying autoimmune thyroiditis (Hashimoto’s thyroiditis).3 While Surks et al indicate that there is insufficient evidence to support population-based screening, they indicate that aggressive case finding is appropriate in pregnant women, women older than 60 years, and others at high risk for thyroid dysfunction.15

Treatment

Although it has been controversial as to whether or not to treat patients with subclinical hypothyroidism, patients with this condition sometimes have subtle hypothyroid symptoms and may have mild abnormalities of serum lipoproteins and cardiac function.12 Furthermore, there is the risk of progression to overt hypothyroidism in these individuals; therefore, patients with definite and persistent TSH elevation should be considered for thyroid treatment.9,16

While various preparations of thyroid hormone are available, levothyroxine is preferred; therapy is initiated at low doses (12.5-25 mcg) in the elderly.3 Fatourechi notes that large-scale randomized studies are required for evidence-based recommendations regarding screening for subclinical hypothyroidism and levothyroxine therapy for this condition.12 However, these researchers note that currently the practical approach is routine levothyroxine therapy, which normalizes serum TSH levels for persons with a persistent serum TSH of greater than 10.0 mIU/L, and individually tailored therapy for those with a TSH of less than 10.0 mIU/L.12 Other experts specify that for those patients with TSH levels between 4.5 and 10 mIU/L, it is reasonable to introduce a trial of levothyroxine if early hypothyroid symptoms (e.g., fatigue, depression) are present.3 Treatment is also recommended in patients with subclinical hypothyroidism if there are clinical features of hyperlipidemia or goiter.1

Pharmacists may also refer to an algorithm for the management of subclinical hypothyroidism that has been proposed by Cooper (see Reference 17).   

Of note, pregnant women and women who plan to become pregnant are treated with levothyroxine to avoid harmful effects secondary to hypothyroidism with regard not only to the pregnancy but to fetal development as well.3 

Monitoring for Efficacy and Toxicity

Patients under treatment for subclinical hypothyroidism should be evaluated for efficacy of thyroid hormone therapy; assessment of serum lipid concentrations, cognitive function, and psychiatric status is recommended.1 Since therapy with levothyroxine decreases LDL-C and apolipoprotein B level and decreases the ratio of cholesterol to HDL-C in patients with subclinical hypothyroidism, there may be a reduction in the risk for the development of coronary artery disease.1

Patients with subclinical hypothyroidism who are asymptomatic and do not receive levothyroxine therapy should be monitored to assess the progress of their condition; this is achieved by measurement of serum TSH and free T4 every 6 months to annually.1,3 Symptoms of hyperthyroidism (e.g., weight loss, increased sweating, palpitations) will occur with excessive thyroid hormone replacement.2 Patients should be made aware of this possibility and instructed to report such occurrences to a health care professional. Due to the long half-life of levothyroxine, laboratory assessment is generally not carried out at less than 6-week intervals.2 

Conclusion

The prevalence of hypothyroidism increases dramatically in geriatric individuals. Subclinical hypothyroidism is more common in women than in men, and its prevalence increases with age. According to researchers, the most important implication of this disorder is the high likelihood of progression to overt hypothyroidism. Furthermore, patients with subclinical hypothyroidism are more likely to have hypercholesterolemia and atherosclerosis. Pharmacists can assist in the identification of subclinical hypothyroidism and provide recommendations regarding appropriate pharmacotherapy, thyroid function testing and outcome management including monitoring for efficacy and toxicity.

REFERENCES

1. Hak AE, Pols HAP, Visser TJ, et al. Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women: the Rotterdam study. Ann Intern Med. 2000;132:270-278.
2. Biondi B, Fazio S, Palmieri EA, et al. Left ventricular diastolic function in patients with subclinical hypothyroidism. J Clin Endocrinol Metab. 1999;84:2064-2067.
3. Cooper DS. Subclinical hypothyroidism. N Eng J Med. 2001;345:260.
4. Huber G, Staub J-J, Meier C, et al. Prospective study of the spontaneous course of subclinical hypothyroidism: prognostic value of thyrotropin, thyroid reserve, and thyroid antibodies. J Clin Endocrinol Metabl. 2002;87:3221-3226.
5. Laurberg P, Andersen S, Bülow Pedersen I, et al. Hypothyroidism in the elderly: pathophysiology, diagnosis and treatment. Drugs Aging. 2005;22:23-38.
6. Rosario PW. Natural history of subclinical hyperthyroidism in elderly patients with TSH between 0.1 and 0.4 mIU/l: a prospective study.
Clin Endocrinol (Oxf). 2010;72:685-688.
7.
Surks MI, Ortiz E, Daniels GH, et al. Subclinical thyroid disease: scientific review and guidelines for diagnosis and management. JAMA. 2004;291:228-238.
8. Wilson GR,
Curry RW Jr. Subclinical thyroid disease. Am Fam Physician. 2005 Oct 15;72(8):1517-24.
9.
Fatourechi V. Subclinical hypothyroidism: an update for primary care physicians. Mayo Clin Proc. 2009;84:65-71.
10. Adlin V. Subclinical hypothyroidism: Deciding when to treat. American Academy of Family Physicians.org. 1998. American Family Physician. www.aafp.org/afp/980215ap/adlin.html. Accessed May 17, 2010.
11. Hassani S, Hershman JM. Thyroid Diseases. In: Hazzard WR, Blass JP, Halter JB, et al, eds. Principles of Geriatric Medicine and Gerontology. 5th ed. New York, NY: McGraw-Hill, Inc; 2003:837-853.
12. Kane RL, Ouslander JG, Abrass IB. Essentials of Clinical Geriatrics. 5th ed. New York, NY: McGraw-Hill, Inc; 2004:3-15,305-334.
13. Beers MH, Porter RS, Jones TV, et al. The Merck Manual of Diagnosis and Therapy. 18th ed. Whitehouse Station, NJ: Merck Research Laboratories; 2006:937,1192,1202-1203.
14. Dorland’s Pocket Medical Dictionary. 28th ed. Philadelphia, PA: Elsevier Saunders: 2009.
15. Monaghan MS, Kissinger JF, Archer Jeanne. Endocrine disorders: thyroid and adrenal conditions. In: Youngkin EQ, Sawin KJ, Kissinger JF, et al, eds. Pharmacotherapeutics: A Primary Care Guide. Upper Saddle River, New Jersey: Pearson Prentice Hall; 2005:649-667.
16. Howland RD, Mycek MJ. Pharmacology, 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2006:271-280.
17. My Epocrates, Version 9.0. San Mateo, CA: Epocrates, Inc. www.epocrates.com. Accessed May 15, 2010.
18. Beers MH, Jones TV, Berkwits M, et al, eds. The Merck Manual of Geriatrics. 3rd ed. Whitehouse Station, NJ: Merck Research Laboratories; 2000:642-647.

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Read More On: ENDOCRINOLOGY/METABOLISM

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Hypothyroidism compensated

Are you sure the patient has subclinical hypothyroidism?

Subclinical hypothyroidism is usually detected in patients who have had thyroid function testing performed due to symptoms of hypothyroidism. Despite a name that suggests a requirement for an absence of symptoms, subclinical hypothyroidism is purely a biochemical diagnosis. It is defined by finding an elevated thyroid stimulating hormone (TSH) level with normal free thyroxine (free T4) levels.

Patients may have any of the myriad of signs and symptoms of hypothyroidism or none at all.

The causes of subclinical hypothyroidism are the same as those of (overt) hypothyroidism and include chronic lymphocytic (Hashimoto’s) thyroiditis, partial thyroidectomy, radioactive iodine therapy, and damage to the thyroid from radiation treatment. Overtreatment with anti-thyroid medications, undertreatment with thyroid hormone replacement, and iodine-containing medications such as amiodarone may also lead to subclinical hypothyroidism.

What else could the patient have?

It is important to consider the clinical context in which the thyroid testing was performed. Thyroid function testing suggesting subclinical hypothyroidism may be transient in two types of clinical conditions:

Acute inflammation of the thyroid can cause the release of preformed thyroid hormones from the gland in one of several types of thyroiditis (subacute, silent, or postpartum). After these thyroid hormones are cleared from the body, there is a recovery period during which new thyroid hormone is synthesized. Patients may have testing consistent with subclinical hypothyroidism during this recovery period. Not all patients present for clinical attention during the initial hyperthyroid phase, and their first presentation may only be during this recovery period.

Patients with recent severe illness, particularly those in the intensive care unit, may have low thyroid hormone levels due to nonthyroidal illness. During recovery from the primary illness, thyroid function tests also recover. TSH may appropriately be elevated to stimulate the normalization of thyroid hormone levels, and subclinical hypothyroidism may be detected during this window of time.

Key laboratory and imaging tests

Because subclinical hypothyroidism due to thyroiditis or nonthyroidal illness usually spontaneously resolves, repeat thyroid function testing 1-3 months after initial testing, consistent with subclinical hypothyroidism, will confirm this. This testing should include serum TSH and free T4 levels. Serum total or free triiodothyronine (T3) levels are not indicated, nor are thyroid ultrasound or thyroid nuclear uptake and scan.

Other tests that may prove helpful diagnostically

Testing for serum anti-thyroid peroxidase (anti-TPO) antibodies may be helpful in suggesting the underlying etiology of subclinical hypothyroidism and the likelihood of progression to overt hypothyroidism. Positive anti-TPO antibodies are more likely to be found in chronic lymphocytic, silent, and postpartum thyroiditis. Observational studies of the natural history of subclinical hypothyroidism show a higher rate progression to overt hypothyroidism in those with positive anti-TPO antibodies than in those with negative anti-TPO antibodies.

Management and treatment of the disease

All women with subclinical hypothyroidism who are pregnant or who are trying to conceive should be treated with levothyroxine therapy without the 1-3 month delay indicated for other patient populations, regardless of their degree of TSH elevation. Untreated subclinical hypothyroidism may be associated with adverse obstetric and/or neonatal outcomes, including fetal and neonatal death.

Patients who are taking anti-thyroid drugs or thyroid hormone should have their medications adjusted to normalize TSH levels.

In all other patient populations, if repeat testing confirms subclinical hypothyroidism, either treatment or ongoing monitoring can be considered.

The degree of TSH elevation is helpful in determining which patients should be treated. Those with higher TSH levels more closely resemble patients with overt hypothyroidism and those with lower TSH levels more closely resemble euthyroid individuals. All patients with TSH levels of 10 mU/L or higher should be treated, regardless of symptoms, because of a higher risk of progression to overt hypothyroidism and development of cardiovascular disease if left untreated, and an improvement in symptoms with treatment.

There is some evidence to suggest that these risks and benefits are present to a milder degree in those whose TSH levels range from 7.0 to 9.9 mU/L, and, unless the patient strongly prefers continued monitoring, treatment should be initiated in this TSH range as well.

Most patients with subclinical hypothyroidism have TSH levels that are below 7.0 mU/L, a range in which treatment is controversial. In addition, TSH levels of 5 and 6 mU/L are very common in patients aged 70 years and older; these patients were not included in therapeutic clinical trials and they may also be more susceptible to risks from over-replacement.

There are no data from large randomized trials with clinical endpoints. Evidence from smaller trials and observational data do not suggest clinical benefit to initiating thyroid replacement therapy in those with TSH levels below 7.0 mU/L. However, a therapeutic trial may be considered in symptomatic patients, with a target TSH in the lower half of the reference range. If symptoms do not resolve within several months of TSH levels in the euthyroid range, levothyroxine therapy should be discontinued and other etiologies of individual symptoms should be explored.

For patients in whom treatment is indicated, levothyroxine (LT4) is the treatment of choice. The usual starting dose is 25 to 50 mcg daily, with upward dose titration at 6-8 week intervals, until TSH levels are in the lower half of the reference range. The average levothyroxine dose requirement in subclinical hypothyroidism is 0.5 mcg/kg/day. There is no role for T3-containing preparations in the management of subclinical hypothyroidism.

For patients who are being monitored with sequential testing, TSH levels should be obtained at 6-12 month intervals (sooner if new symptoms develop).

What’s the Evidence?/References

Biondi, B, Cooper, DS. “The clinical significance of subclinical thyroid dysfunction”. Endocr Rev. vol. 29. 2008. pp. 76-131. (This comprehensive review presents all of the studies of subclinical hypothyroidism through the time of publication.)

Surks, MI, Ortiz, E, Daniels, GH, Sawin, CT, Col, NF. “Subclinical thyroid disease: scientific review and guidelines for diagnosis and management”. JAMA. vol. 291. 2004. pp. 228-38. (These are the most recent management guidelines from an expert panel.)

Gharib, H, Tuttle, RM, Baskin, HJ, Fish, LH, Singer, PA. “Subclinical thyroid dysfunction: a joint statement on management from the American Association of Clinical Endocrinologists, the American Thyroid Association, and the Endocrine Society”. J Clin Endocrinol Metab. vol. 90. 2005. pp. 581-5. (This is a response to the guidelines from the expert panel.)

Diez, JJ, Iglesias, P. “Spontaneous subclinical hypothyroidism in patients older than 55 years: an analysis of natural course and risk factors for the development of overt thyroid failure”. J Clin Endocrinol Metab. vol. 89. 2004. pp. 4890-7. (Observational study of patients with subclinical hypothyroidism showing increased risk of progression to overt hypothyroidism at higher levels of TSH and increased risk of reversion to euthyroidism at lower levels of TSH.)

Vanderpump, MP, Tunbridge, WM, French, JM, Appleton, D, Bates, D. “The incidence of thyroid disorders in the community: a twenty-year follow-up of the Whickham Survey”. Clin Endocrinol (Oxf). vol. 43. 1995. pp. 55-68. (Observational study of the natural history of subclinical hypothyroidism, with 20 years of follow-up. Annual incidence of overt hypothyroidism was 2.6% in those with elevated TSH and 4.3% in those with both elevated TSH and positive anti-TPO antibodies.)

Rodondi, N, den Elzen, WP, Bauer, DC, Cappola, AR, Razvi, S. “Subclinical hypothyroidism and the risk of coronary heart disease and mortality”. JAMA. vol. 304. 2010. pp. 1365-74. (Meta-analysis of eleven observational studies demonstrating increased risk of coronary heart disease and cardiovascular death in those with subclinical hypothyroidism with TSH levels greater than 10 mU/L, increased risk of cardiovascular death in those with TSH levels of 7.0-9.9 mU/L, and no cardiovascular risk in the 4.5-6.9 mU/L range.)

Surks, MI, Hollowell, JG. “Age-specific distribution of serum thyrotropin and antithyroid antibodies in the US population: implications for the prevalence of subclinical hypothyroidism”. J Clin Endocrinol Metab. vol. 92. 2007. pp. 4575-82. (Data from the National Health and Nutrition Examination Survey (NHANES) in people without underlying thyroid disease showing a shift in the TSH distribution to higher levels with increasing age.)

Gussekloo, J, van, EE, de Craen, AJ, Meinders, AE, Frolich, M. “Thyroid status, disability and cognitive function, and survival in old age”. JAMA. vol. 292. 2004. pp. 2591-9. (Study of men and women aged 85 years showing no difference in disability or cognitive function between those with subclinical hypothyroidism and euthyroid individuals, and decreased mortality in those with higher TSH levels.)

Abalovich, M, Amino, N, Barbour, LA, Cobin, RH, De Groot, LJ. “Management of thyroid dysfunction during pregnancy and postpartum: an Endocrine Society Clinical Practice Guideline”. J Clin Endocrinol Metab. vol. 92. 2007. pp. S1-47. (These guidelines include management of subclinical hypothyroidism during pregnancy.)

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Subclinical Hypothyroidism - Thyroid Series - Dr.Ravi Sankar -Endocrinologist - Hi9

Subclinical Hypothyroidism

Subclinical hypothyroidism (SCH) is diagnosed when peripheral thyroid hormone levels are within the normal range, but thyroid-stimulating hormone (TSH) is mildly elevated.

About 62% of TSH levels between 4 and 10 mIU/L normalise without intervention within five years[1].

Biochemical measurement

There is biological variation in TSH levels which may rise in response to stress and transient disease. TSH secretion also has a diurnal variation with a peak late at night/early hours of morning.This biological variation in TSH values means that one abnormal TSH level should be followed by a repeat blood test to confirm the diagnosis.

Measurement of serum TSH is generally considered the best screening test for thyroid disease. Increased values indicate hypothyroidism. The test is both sensitive and specific. Serum TSH concentrations have a logarithmic relationship with serum thyroxine, so that a doubling in thyroxine produces a hundredfold change in TSH.

TSH is thus a much more sensitive test. The population reference laboratory normal ranges for thyroxine are set wide compared to the normal individual range, so that a fall in thyroxine levels at the lower end of the range may elevate the TSH above normal. However, its sensitivity causes a dilemma, as some patients are found to have elevated TSH levels, but have normal free thyroxine hormone levels, and may also be asymptomatic. Most of the circulating T3 is generated by peripheral conversion from T4, mainly by the liver, through enzymatic removal of an iodine atom from T4. Very little T3 is produced by the thyroid gland itself.

Reference ranges are usually defined as those into which 95% of the population will fall. They are altered slightly by ethnicity, age and iodine intake, and more substantially by pregnancy. There is, however, some debate regarding the upper limits of the TSH reference range. The high background prevalence of autoimmune thyroid disease as well as the age, iodine status, smoking prevalence and ethnicity of the 'normal' population may have raised the 'normal' upper limit. In people without these factors the normal upper limit may be lower.

Epidemiology

Subclinical hypothyroidism is a common condition. Prevalence increases with age and is more common in women. Approximately 8% of women (10% of women over 55 years of age) and 3% of men have subclinical hypothyroidism[2].

In studies restricted to older persons, the reported prevalence of subclinical hypothyroidism is between 1.5-12.5%[3]. Treatment with thyroid hormones is increasing and more than 10-15% of people aged over 80 years are prescribed levothyroxine replacement therapy.

Aetiology

Causes are the same as those of overt thyroid disease:

  • Chronic autoimmune thyroiditis - Hashimoto's disease. This is by far the most common cause, accounting for over 90% of cases.
  • Treatment of hyperthyroidism - most commonly after radioactive iodine treatment.
  • Hypothyroidism can occur in 5-25% of patients treated with surgery or antithyroid drugs.
  • Less common causes are medications - eg, lithium or amiodarone.
  • Other causes include head and neck surgery or radiotherapy.

Clinical features

The term subclinical is at times inaccurate, as some patients have symptoms. In the elderly a diagnosis of hypothyroidism may be delayed by wrongly attributing the symptoms of, for example, fatigue and constipation to ageing.

Clinical manifestations can be explained by assuming that a T4 level of 6-7 mcg/dL, although inside the normal range, may represent a significant decrease from a previous normal of 10 mcg/dL, and is low for this particular patient.

Some studies have suggested that if symptoms are present then treatment with thyroxine will resolve them.

Common clinical features of hypothyroidism include:

Investigations

In The UK, screening is not felt to be warranted although case-finding in women at the menopause or if visiting a doctor with nonspecific symptoms may be justified.

The practical approach may be to measure thyroid function in those patients who have persistent, nonspecific complaints - women in particular, and the elderly[4].

Borderline results and asymptomatic patients need to be repeated at a consistent time of day, with consistent fasting status.

Differential diagnosis

There are a few other causes of a raised TSH in the presence of normal thyroxine levels:

  • Recovery from acute (non-thyroidal) illness.
  • Assay variability.
  • Heterophile antibodies interfering with the TSH assay (heterophile antibodies are weak antibodies with multispecific activities, which can cause significant interference immunoassays).
  • Central hypothyroidism: in these patients there is hypothalamic or pituitary failure, usually leading to normal or only mildly raised TSH in the presence of low serum T4 and T3, with overt hypothyroidism (but no goitre). It is rare - around 1 in 100,000, and usually associated with other pituitary axis abnormalities. Causes include pituitary microadenoma and pituitary infarction.

Associated diseases

TSH elevation is important as a risk factor for cardiovascular disease.

Patients with full hypothyroidism have serum levels of triglycerides, total cholesterol and low-density lipoprotein (LDL) cholesterol that are elevated. The same changes exist in subclinical hypothyroidism, but are less marked and less consistent.

Management

A 2019 review and meta-analysis concluded that almost all adults with subclinical hypothyroidism would not benefit from treatment with thyroid hormones[1]. However the National Institute for Health and Care Excellence (NICE) committee found that most of the evidence related to older adults. The committee agreed that as most studies used 65 years as a cut-off it was appropriate to define older adults as over 65 and make separate recommendations for this group.

The NICE committee also noted that a TSH level above 10 mlU/L is more often associated with symptoms. They therefore agreed that levothyroxine should be considered for all adults with a TSH level of 10 mlU/L or more because this may improve symptoms and may have long-term benefits including on cardiovascular outcomes. For people with a TSH level lower than 10 mIU/L, the committee agreed based on their experience that treatment was less likely to have a benefit but that the balance of risks to benefits was most favourable for adults under the age of 65. The committee noted that for people over 65 there was less likely to be an improvement in symptoms and the potential for harms from suppressing TSH (such as atrial fibrillation) is greater.

Therefore the 2019 NICE Guidelines suggest that levothyroxine treatment should be considered for adults with subclinical hypothyroidism who have a TSH of 10 mlU/litre or higher on two separate occasions three months apart[5]. A six-month trial of levothyroxine should also be considered for adults under 65 with SCH who have a TSH above the reference range but lower than 10 mlU/L on two separate occasions three months apart, and symptoms of hypothyroidism.

If symptoms do not improve after starting levothyroxine, re-measure TSH and if the level remains raised, adjust the dose. If symptoms persist when serum TSH is within the reference range, consider stopping levothyroxine and follow the recommendations on monitoring untreated SCH and monitoring after stopping treatment.

Patients with a history of radio-iodine treatment or positive thyroid antibody test should be treated, as this subgroup will nearly always progress to overt hypothyroidism.

For people with untreated SCH consider measuring TSH and FT4 once a year if they have features suggesting underlying thyroid disease, or once every two to three years if they have no features suggesting underlying thyroid disease.

Medication

If the decision is made to treat:

  • Levothyroxine is the drug of choice as it has a long half-life (seven days) and is partially converted to T3 in the body, resulting in a constant physiological level of both T3 and T4 with a single daily dose.
  • Dosing: <65 years old start at 50 micrograms od.
  • Elderly: >65 years old at 12.5 to 25 micrograms od.
  • Monitor at 6- to 8-week intervals initially. Once the correct dose has been established, monitoring can be 6- to 12-monthly.
  • Aim to lower TSH to mid-normal: 1-3 mlU/L.
  • Contra-indications to treatment are osteoporosis and fracture risk.
  • Goals for treatment are symptomatic improvement, or TSH normalising.

Prognosis[2]

About 62% of TSH levels between 4 and 10 mIU/L normalise without intervention within five years. About 2-5% of people with SCH develop overt hypothyroidism (OH) - progression to OH is particularly more likely with higher serum TSH levels (especially greater than 10 mU/L), with positive thyroid autoantibodies (to thyroid peroxidase), and in women[6].

Observational data suggest that SCH is associated with an increased risk of coronary heart disease, heart failure, and cardiovascular mortality, particularly in those with TSH levels >10 mIU/L[1]. Such associations were not found for most adults with TSH levels of 5-10 mIU/L.

The annual rate of progression from subclinical to overt hypothyroidism has been estimated as about 4% in women with raised TSH and positive anti-thyroid antibodies, 2-4% in those with raised TSH alone, and 1-3% in those with anti-thyroid antibodies alone.

Pregnancy

During the first trimester thyroxine is supplied exclusively by the mother. Fetal production begins at 10-12 weeks of gestation. Thyroxine is important for fetal neural development throughout pregnancy, but particularly so in the first trimester. Maternal hypothyroidism has been associated with learning difficulties in euthyroid children, and with increased fetal loss.

Maternal hypothyroidism in the third trimester may increase the chances of caesarean section and of low birth weight. Thyroxine requirement increases during pregnancy so close monitoring is needed to maintain a normal serum TSH.

Pregnant women with goitre, high anti-thyroid antibody titre, family history of thyroid disease or symptoms suggestive of hypothyroidism, should be screened early in pregnancy, or preferably prior to conception, and treated[7].

All women with SCH who are planning a pregnancy should be referred to an endocrinology specialist[2].

  • Check TFTs before conception if possible.
  • If TFTs are not within the euthyroid range, advise delaying conception, until stabilised on levothyroxine treatment - discuss with an endocrinologist if there is any uncertainty about initiation of treatment or what dose to prescribe while waiting for review.
  • Check that the woman understands that her dose of levothyroxine must be adjusted as early as possible in pregnancy to reduce the chance of obstetric and neonatal complications.
  • Advise the woman to seek medical advice immediately if pregnancy is suspected or a menstrual period is missed.

If the woman is pregnant:

  • Check TFTs immediately once pregnancy is confirmed.
  • Discuss urgently with an endocrinologist regarding initiation of, or changes to, dosage of levothyroxine and TFT monitoring while waiting for review - trimester-specific TFT reference ranges may vary locally.
  1. Bekkering GE, Agoritsas T, Lytvyn L, et al; Thyroid hormones treatment for subclinical hypothyroidism: a clinical practice guideline. BMJ. 2019 May 14365:l2006. doi: 10.1136/bmj.l2006.

  2. Hypothyroidism; NICE CKS, June 2018 (UK access only)

  3. Leng O, Razvi S; Hypothyroidism in the older population. Thyroid Res. 2019 Feb 812:2. doi: 10.1186/s13044-019-0063-3. eCollection 2019.

  4. Thyroid Function Tests; British Thyroid Foundation, 2018

  5. Thyroid disease: assessment and management; NICE (November 2019)

  6. Gosi SKY, Garla VV; Subclinical Hypothyroidism

  7. Alexander EK, Pearce EN, Brent GA, et al; 2017 Guidelines of the American Thyroid Association for the Diagnosis and Management of Thyroid Disease During Pregnancy and the Postpartum. Thyroid. 2017 Mar27(3):315-389. doi: 10.1089/thy.2016.0457.

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