Stig Andersen

Environmental Iodine Intake Affects the Type of Nonmalignant Thyroid Disease

The relationship between the iodine intake level of a population and the occurrence of thyroid diseases is U-shaped with an increase in risk from both low and high iodine intakes. Developmental brain disorders and endemic goiter caused by severe iodine deficiency may seriously deteriorate overall health status and economic performance of a population. Severe iodine deficiency with a median 24-hour urinary iodine excretion of the population below 25 microg needs immediate attention and correction. Less severe iodine deficiency with median urinary iodine excretion below 120 microg per 24 hours is associated with multinodular autonomous growth and function of the thyroid gland leading to goiter and hyperthyroidism in middle aged and elderly subjects. The lower the iodine intake, the earlier and more prominent are the abnormalities. At the other end of the spectrum, severely excessive iodine intake starting at median urinary iodine excretion levels around 800 microg per 24 hours is associated with a higher prevalence of thyroid hypofunction and goiter in children. A number of studies indicate that moderate and mild iodine excess (median urinary iodine >220 microg per 24 hours) are associated with a more frequent occurrence of hypothyroidism, especially in elderly subjects. The exact mechanism leading to this has not been clarified, and more studies are needed to define the limits of excessive iodine intake precisely. Due to the frequent occurrence of thyroid disorders, proper monitoring and control of the population iodine intake level is a cost-effective alternative to diagnosing, therapy and control of the many individual cases of thyroid diseases that might have been prevented.

Iodine intake as a determinant of thyroid disorders in populations

UNLABELLED Depending on the availability of iodine, the thyroid gland is able to enhance or limit the use of iodine for thyroid hormone production. When compensation fails, as in severely iodine-deficient populations, hypothyroidism and developmental brain damage will be the dominating disorders. This is, out of all comparison, the most serious association between disease and the level of iodine intake in a population. In less severe iodine deficiency, the normal thyroid gland is able to adapt and keep thyroid hormone production within the normal range. However, the prolonged thyroid hyperactivity associated with such adaptation leads to thyroid growth, and during follicular cell proliferation there is a tendency to mutations leading to multifocal autonomous growth and function. In populations with mild and moderate iodine deficiency, such multifocal autonomous thyroid function is a common cause of hyperthyroidism in elderly people, and the prevalence of thyroid enlargement and nodularity is high. The average serum TSH tends to decrease with age in such populations caused by the high frequency of autonomous thyroid hormone production. On the other hand, epidemiological studies have shown that hypothyroidism is more prevalent in populations with a high iodine intake. Probably, this is also a complication to thyroid adaptation to iodine intake. Many thyroid processes are inhibited when iodine intake becomes high, and the frequency of apoptosis of follicular cells becomes higher. Abnormal inhibition of thyroid function by high levels of iodine is especially common in people affected by thyroid autoimmunity (Hashimotos thyroiditis). In populations with high iodine intake, the average serum thyroid-stimulating hormone (TSH) tends to increase with age. This phenomenon is especially pronounced in Caucasian populations with a genetically determined high tendency to thyroid autoimmunity. A small tendency to higher serum TSH may be observed already when iodine intake is brought from mildly deficient to adequate, but there is at present no evidence that slightly elevated serum TSH in elderly people leads to an increase in morbidity and mortality. CONCLUSION Even minor differences in iodine intake between populations are associated with differences in the occurrence of thyroid disorders. Both iodine intake levels below and above the recommended interval are associated with an increase in the risk of disease in the population. Optimally, iodine intake of a population should be kept within a relatively narrow interval where iodine deficiency disorders are prevented, but not higher. Monitoring and adjusting of iodine intake in a population is an important part of preventive medicine.

Hypothyroidism in the Elderly: Pathophysiology, Diagnosis and Treatment

Some degree of hypothyroidism is common in the elderly. It affects 5–20% of women and 3–8% of men. The occurrence varies with genetics with a high prevalence in Caucasians, and the disease is more common in populations with a high iodine intake.The common causes of hypothyroidism are autoimmune destruction of the thyroid gland and previous thyroid surgery or radioiodine therapy. Various types of medication, including amiodarone, cytokines and lithium, often induce hypothyroidism.Symptoms may be atypical and measurement of serum thyroid-stimulating hormone (TSH) levels should be part of biochemical testing for undiagnosed medical conditions in elderly subjects. The finding of an elevated serum TSH level should be confirmed by repeated testing and supplemented with measurements of serum levels of thyroxine (T4) and thyroid peroxidase antibodies to verify, quantify and subclassify the abnormality.The recommended and appropriate replacement therapy for hypothyroidism is levothyroxine sodium. The initial replacement dose should be low if heart disease is suspected. Because of the long half-life of levothyroxine sodium small dosage adjustments may be performed by adding or withdrawing a tablet once or twice weekly. Levothyroxine sodium is only partly absorbed after oral ingestion, and food, minerals, drugs and tablet composition influence absorption.Studies performed a few years ago suggested that a combination of levothyroxine sodium and liothyronine may improve clinical results, but recent more comprehensive studies have not supported this hypothesis. Accordingly, liothyronine replacement is not documented to be of benefit. If liothyronine is added to replacement, the liothyronine dose should be kept low, within the physiological range and, preferably be administered twice daily.Thyroid hormone therapy has no beneficial effect above placebo in elderly individuals with normal serum TSH levels and T4 levels. The major risk of levothyroxine sodium therapy is over-replacement, with anxiety, muscle wasting, osteoporosis and atrial fibrillation as adverse effects.Subclinical hypothyroidism with elevated serum TSH levels but T4 levels within the laboratory reference range is a mild variant of overt hypothyroidism. Patients with subclinical hypothyroidism should be informed about the disease and offered the possibility of replacement. Only some patients treated for subclinical hypothyroidism will feel better after therapy.In elderly patients on replacement therapy, care should include estimation of serum TSH level once or twice a year, with small dosage adjustments of levothyroxine sodium to keep serum TSH level within the normal range.

The TSH upper reference limit: where are we at?

The diagnosis of subclinical hypothyroidism—serum TSH levels above and T4 levels within the laboratory reference ranges—depends critically on the upper limit of the TSH reference interval. Calls have been made to lower the current upper TSH reference limit of 4.0 mU/l to 2.5 mU/l to exclude patients with occult hypothyroidism. However, data from population studies do not indicate that the distribution of TSH is altered owing to inclusion of such individuals. The opposite suggestion has also been put forward; the TSH upper reference limit is often too low, especially in the elderly, in women and in white individuals, which may lead to unnecessary or even harmful therapy. Studies in elderly individuals have shown that although aging may be associated with increased TSH levels, paradoxically, overt hypothyroidism in this population may be associated with a less robust TSH response than in young individuals. This Review highlights the interindividual and intraindividual variability of TSH levels and discusses the current controversy that surrounds the appropriateness of reference ranges defined on the basis of age, race, sex and amount of iodine intake. Moreover, the current evidence on lowering or increasing the upper limit of the TSH reference interval is reviewed and the need to individualize levothyroxine treatment in patients with elevated TSH levels is discussed.

Variation in Thyroid Function Tests in Patients with Stable Untreated Subclinical Hypothyroidism

OBJECTIVE Knowledge of variation in thyroid function is important for interpretation of thyroid function tests. We aimed to describe intra-individual variation in thyroid function in patients with stable, untreated subclinical hypothyroidism (SCH) compared to euthyroid individuals to assess the importance of monitoring SCH patients. DESIGN We measured thyrotropin (TSH), free thyroxine (fT4), and free triiodothyronine (fT3) monthly for 1 year in a longitudinal study of 15 untreated SCH patients with initial TSH 5-12 mU/L, without trends in TSH, and compared findings with results from 15 euthyroid individuals. MAIN OUTCOME CV% was 17.0, 6.1, and 6.2 for TSH, fT4, and fT3, respectively. Overall CV% for TSH was lower in SCH patients than controls. Contrary to euthyroid individuals, CV% in SCH patients increased with rising mean TSH (r2 = 0.29, p = 0.04). Individual disease set points were established with 45, 6, and 6 tests for TSH, fT4, and fT3, with 95% confidence. Differences required between two test results were 40%, 15%, and 15%, respectively, with 90% confidence. CONCLUSION Percent variation in TSH was lower in SCH than in euthyroid controls, but increased with higher mean TSH. The number of tests needed to establish disease set points was high. The difference required between two tests to be truly different was 40% for TSH and 15% for fT4 and fT3.

Evaluating iodine deficiency in pregnant women and young infants—complex physiology with a risk of misinterpretation

OBJECTIVE To review methods for evaluating iodine deficiency in pregnant women and young infants and to discuss factors to be considered in the interpretation of their results. DESIGN Review of the literature regarding the various methods available for assessing iodine status. SETTING Population surveys and research studies. SUBJECTS Pregnant women and young infants. RESULTS Several factors to consider when assessing iodine status in pregnant women and young infants include: 1) the urinary iodine (UI) concentration (microg l-1) is not interchangeable with 24 h UI excretion (microg per 24 h); 2) the concentration of iodine in a spot or casual urine sample cannot be used to diagnose iodine deficiency in an individual; 3) a moderate fall in the concentration of serum free T4 during pregnancy is not a sign of maternal iodine deficiency; 4) an increase in the concentration of serum thyroglobulin (Tg) during pregnancy is not a sign of maternal iodine deficiency; 5) a higher concentration of TSH and Tg in cord blood than in maternal blood is not a sign of iodine deficiency in the mother or neonate; and 6) thyroid function in a full-term foetus, a neonate or a small child is not more sensitive to a mild iodine deficiency than in the mother. CONCLUSIONS If the iodine status of pregnant women and small children is not to be misjudged, the above six factors need to be taken into account.

Variation in thyroid function in subclinical hypothyroidism: importance of clinical follow-up and therapy

Subclinical hypothyroidism (SCH) is a common condition that is often observed without therapy. However, no evidence-based recommendation exists with regards to how patients with untreated SCH should be monitored. Monitoring involves regular assessment of symptoms and signs of hypothyroidism (HYPO) and biochemical tests of thyroid function. An important question when repeated tests of thyroid function are performed is how large a difference in test results is needed to be confident that the change is real and not just due to chance variation. Recent data show that the least significant difference between two tests in SCH is 40% for TSH and 15% for free thyroxine and free triiodothyronine, with 90% confidence. Furthermore, monitoring has to be based on biochemical function testing because serial evaluation of symptoms and signs related to HYPO is rather insensitive in detecting worsening of thyroid insufficiency. When the presence of thyroid peroxidase auto-antibodies (TPO-Ab) in serum has been demonstrated, repeated measurements do not add much useful information in the monitoring of individual subclinical hypothyroid patients, as levels of TPO-Ab vary in parallel with TSH in these patients. Lastly, we discuss how differences in the monitoring procedure influence the diagnostic outcome, and we suggest a follow-up approach for untreated subclinical hypothyroid patients.

Thyroid Function and Obesity

Important interaction exists between thyroid function, weight control, and obesity. Several mechanisms seem to be involved, and in studies of groups of people the pattern of thyroid function tests depends on the balance of obesity and underlying thyroid disease in the cohort studied. Obese people with a normal thyroid gland tend to have activation of the hypothalamic-pituitary-thyroid axis with higher serum TSH and thyroid hormones in serum. On the other hand, small differences in thyroid function are associated with up to 5 kg difference in body weight. The weight loss after therapy of overt hypothyroidism is caused by excretion of water bound in tissues (myxoedema). Many patients treated for hyperthyroidism experience a gain of more weight than they lost during the active phase of the disease. The mechanism for this excessive weight gain has not been fully elucidated. New studies on the relation between L-T3 therapy and weight control are discussed. The interaction between weight control and therapy of thyroid disease is important to many patients and it should be studied in more detail.

Decreasing overweight and central fat patterning with Westernization among the Inuit in Greenland and Inuit migrants.

OBJECTIVE: To analyse overweight, obesity and central fat patterning among the Inuit of Greenland and Inuit migrants in Denmark and their relation to Westernization.DESIGN: Cross-sectional, population-based epidemiological study.SUBJECTS: A total of 2046 adult Greenlanders (Inuit), 61% of those invited to participate, living in three areas of Greenland and in Denmark.MEASUREMENTS: Height, weight, waist and hip circumferences were measured and body mass index (BMI in kg/m2) and waist–hip ratio calculated. Sociocultural information was obtained by questionnaire and interview. Westernization was estimated by language and place of residence.RESULTS: The prevalence of obesity (≥30 kg/m2) was 16 and 22% among men and women in Greenland (P=0.004), and 12 and 11%, respectively, in Denmark (NS). Westernization was accompanied by a decrease in the proportion of obese people, in particular among women. Adjusted for BMI, age and Inuit heritage waist circumference decreased with Westernization (among women), while hip circumference did not change. The differences were particularly pronounced for migrants compared with residents of Greenland.CONCLUSION: BMI and central fat patterning decrease with Westernization among Greenland Inuit women contrary to most studies of migrants. The changes were less prominent among men. This suggests a reduced cardiovascular risk profile with Westernization among Greenland Inuit.

Benign course of long-standing hepatitis B virus infection among Greenland Inuit?

Objective. Chronic hepatitis B virus (HBV) infection can present in different ways, from inactive carrier to liver failure or cancer. The role of the virus subtype is controversial. The purpose of this study was to characterize HBV infection in detail and its impact on general health, body-build and liver biochemistry. Material and methods. The study comprised a population-based cohort of Inuit exposed to HBV 3–7 decades ago in the capital in West Greenland, a coastal town and four settlements in rural East Greenland. Participants included 95% of the invited Inuit: 229 men, 205 women, aged 50–69 years. Results. Only 25% of the participants had never had HBV infection. HBsAg was positive in 86 participants (20.0%), more being found positive in rural East Greenland than in the city in West Greenland (28.9% versus 2.7%; p < 0.001). HBV-DNA was positive in 61 of those with median HBV-DNA 40,000 copies/ml. HBV genotype could be determined in 52: 47 participants had genotype B, 4 genotype D, and 1 had both B and D. At sequencing, genotype B resembled subtype Bj, but with more than 5% diversity in the C-gene it could be a new subtype B. Pre-core mutation was found in 55 of 56 participants investigated. None of the participants had signs of liver disease, and HBV infection did not influence body-build or liver biochemistry. Conclusions. More than 75% of participants had a marker of present or previous HBV infection but the infection seemed dormant. The majority harbored a special variant of genotype B that might be a new subtype giving a relatively benign disease. The role of detailed subtyping of HBV for prognostic evaluation should be investigated in more detail.