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Prevention in endocrinology 

Prevention in endocrinology
Chapter:
Prevention in endocrinology
Author(s):

Peter Laurberg

and Stig Andersen

DOI:
10.1093/med/9780199235292.003.1006
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Introduction

The basis of health care is that it is much better for the individual member of society to be healthy and well than to be ill or deceased (1). To assist the individual in staying alive and well the health care system provides a broad range of services aimed at cure or control of disease. These services are available when someone becomes ill.

A different approach to preservation of good health and longevity is the prevention of disease. Prevention may take many forms. This may vary from legislation on food declaration via public campaigns on the importance of physical exercise to neonatal screening programmes. The intervention may be directed at decreasing the risk for disease in healthy subjects (primary prevention). A common variation is prevention of the severe consequences of disease by early detection of subclinical disease by screening or case-finding (secondary prevention). Other variants are prevention of complications of disease (tertiary prevention) or prevention of recurrence of disease by secondary intervention.

Often the costs of classic clinical care and prevention are compared in a way suggesting that the primary advantage of prevention is that it saves money. This conclusion may be correct in some areas of prevention such as in iodine deficiency disorders. It is, however, far too simple when it comes to many other areas such as prevention of complications in elderly patients with diabetes mellitus (1). The major appeal of prevention is that it is a most effective and often also a cost-effective way of reducing the burden of disease.

Identification of risk factors

A major obstacle to prevention may be uncertainty of risk factors. For many years it was debated whether tight blood glucose control in patients with type 1 diabetes would prevent development of diabetic retinopathy and nephropathy and other late complications of diabetes. Tight blood glucose control involves a high degree of focus on the balance between insulin, meals, and physical activity, and it increases the risk of hypoglycaemia. Thus, tight control is not that attractive to patients. Results of large intervention studies were necessary to document the overall beneficial effects of keeping blood glucose near normal in diabetes. Now tight control of blood glucose is essential in diabetes care (2). The importance of carefully controlled studies to document the beneficial effects (and possible adverse effects) of preventive measures cannot be stressed too much. Often large-scale studies involving much public funding are necessary.

The relations of risk to exposure

Another problem may be lack of knowledge on dose–effect relationship. The relation between exposure to a risk factor (e.g. high blood glucose) and the risk for disease (e.g. retinopathy) may vary. In the case of diabetes it is assumed that absolute normalization of blood glucose (if possible) would reduce the diabetes related risk to zero. Hence there is a certain threshold level of safety above which the risk increases more or less linearly. Several other types of relation between exposure and risk may exist (Fig. 1.2.1). The risk may increase gradually over the whole range of exposure. Probably such a relation exists between external radiation to the thyroid gland during childhood and later development of thyroid cancer. It means that no absolute safety limit can be delineated (Fig. 1.2.1(b)). The relation may be more exponential with acceleration in risk with increasing exposure. Such a relation exists between low bone mineral density and risk of fracture (Fig. 1.2.1(c)).


Fig. 1.2.1a–d Various types of relation between a risk factor (e.g. high blood glucose in diabetes) and the risk for disease (e.g. retinopathy). Examples are given for each type.

Fig. 1.2.1a–d
Various types of relation between a risk factor (e.g. high blood glucose in diabetes) and the risk for disease (e.g. retinopathy). Examples are given for each type.

A special case is where both low and high exposure is associated with an increase in risk of disease. This type of relation is well known from several studies of alcohol consumption and disease. Optimal health is found in those with a moderate consumption while both heavy users and abstainers have a lower life expectancy. In endocrinology a similar relation is found between thyroid disease and iodine intake (Fig. 1.2.1(d)). The serious consequences of extremes are found in severe iodine deficiency with cretinism, but a high iodine intake also correlates to an increase in disease frequency. Such a relation reinforces the need for monitoring to see that prevention of the consequences of one extreme should not lead to disease caused by the other extreme.

Preventive strategies

Population strategy of prevention

Several strategies of preventive medicine exist. In general, mass disease and mass exposure require a population strategy of prevention. A typical example of this is the widely applied iodine supplementation programmes where the iodine intake levels of populations are increased by the addition of iodine to salt. The risk of type 2 diabetes as part of the metabolic syndrome with overweight and sedate lifestyle is another mass problem clearly needing a population strategy of prevention, as well as more individual guidance. Some reasons for adoption of a population strategy of prevention are given in Box 1.2.1.

Effective population-based prevention depends on some kind of monitoring of disease frequency. This is necessary to evaluate whether a prevention programme should be initiated and to see if a running programme is effective.

The high-risk strategy of prevention

The high-risk strategy implies that individuals with a particularly high risk for disease are identified and prevention attempted. The power of this type of prevention is that the intervention is matched to the needs of the individual. This improves motivation and accommodates naturally into the organization of medical care. Resources can be directed at those in need, and if a small risk for side effects is part of the prevention this is much better balanced in high-risk/high-benefit subjects.

A weakness of the high-risk prevention strategy is that it tends to tackle the situations mentioned in Box 1.2.1 insufficiently. It means that an isolated high-risk strategy in some situations will fail if not combined with a population strategy of prevention. Type 2 diabetes is an example. Even considerable efforts to modify lifestyle by individual education of patients with type 2 diabetes might be insufficient or only temporarily effective if not combined with a population-directed programme to reinforce exercise and nonsmoking, and to modify diet and reduce overweight. The practical consequence of a lack of population prevention will be that modifications of lifestyle in patients with type 2 diabetes will be more or less hopeless and totally replaced by prescription of a series of medications to lower the blood glucose, treat hypertension, and regulate blood lipids. Both population and high-risk strategies are needed to obtain a proper balance between prevention by lifestyle modifications and prevention of diabetic complications by medication.

In some areas of endocrinology the high-risk strategy is optimal. In families where multiple endocrine neoplasia type 2 has been found, investigation of genomic DNA for mutation of the RET proto-oncogene may identify family members who should be offered thyroidectomy to prevent medullary thyroid carcinoma.

Screening

The high-risk strategy of prevention often involves screening to identify high-risk subjects. Screening implies an early detection of an asymptomatic condition which might develop to a symptomatic disease if not detected and treated. In the pure form of screening the full initiative for the investigation comes from the health system to which the subjects are urged to respond. The clinical policy guidelines for screening were set up by Wilson and Jungner (3) in a WHO report (Box 1.2.2). Rose (1) has given the following additional principles relating to examinations aimed at risk assessment.

  • There should be no screening without adequate resources for advice and long term care. Risk identification should be linked to professional care and follow-up, which may need to be maintained for years. Hence screening of selected groups for osteoporosis implies that a follow-up system of adequate capacity should be ready to care for subjects with low bone mineral density.

  • Selective screening and care are more cost-effective than mass screening. Screening of pregnant women for diabetes is more relevant than whole population screening. Gestational diabetes mellitus is more prevalent than undiagnosed diabetes in otherwise similar nonpregnant women, and not diagnosing the condition may have consequences for the outcome of pregnancy.

  • The purpose is to assess reversible risk—not risk factors. A single risk factor should be evaluated in concert with other risk factors to assess the overall reversible risk and the need for intervention. Blood pressure should be measured regularly in type 1 diabetics. Risk assessment and need for intervention should include measurements of urinary albumin excretion and be influenced by the higher risk of increased blood pressure in people with diabetes.

Other important aspects to take into consideration before a screening programme is initiated are the consequences of false-positive and false-negative results. The increase in techniques allowing early detection of disease or risk of disease has made both theoretical and practical aspects of screening an area of development (4). A form of screening is case-finding, where a patient seen for another reason is investigated. This overlaps with normal patient care.

Prevention integrates itself in many parts of endocrinology. Two areas will be mentioned where public programmes of classic prevention have been implemented worldwide: one is iodine deficiency disorders and the other is learning difficulties due to congenital hypothyroidism.

Type 1 and type 2 diabetes and osteoporosis have special relations with preventive medicine because they are large and expanding disorders where the major part of normal clinical care aims at prevention at one or another level. Finally it is interesting to evaluate with an endocrinologist eye the targets for public preventive campaigns in many countries, such as smoking, diet, and exercise.

Iodine deficiency disorders

Prevention of iodine deficiency disorders using a population strategy was introduced in the mid-western states of the USA and in Switzerland early in the twentieth century. At the beginning of the present century it had become the classic and most widespread preventive measure in endocrinology. Around two billion people in more than 100 countries live in areas where the natural supply of iodine through locally produced food and beverage is low enough to cause an increase in the incidence and prevalence of thyroid disorders (5).

Iodine is a component of thyroid hormones and severe iodine deficiency as found in areas with an average daily iodine intake below 25 µg may cause impaired thyroid hormone synthesis and secretion. Risk of such impairments also exists in moderate iodine deficiency, with an average daily iodine intake of 25–50 µg. Thyroid hormones are essential for normal brain development in the fetus and during the first years of life, and the most severe consequence of iodine deficiency is the complex of developmental brain disorders known as cretinism (6). In severely iodine deficient isolated areas this may affect up to 5–10% of the population and subtle brain damage with reduction in performance may be even more common. Abortion and stillbirths may be prevalent in areas with severe iodine deficiency.

The second main type of complication caused by iodine deficiency is related to thyroid growth. The thyroid gland possesses a number of mechanisms to compensate for variations in iodine supply. A low iodine supply is, among other things, accompanied by thyroid cell proliferation. When the iodine intake is permanently low this process tends to ‘get out of control’ with irreversible multiple foci of autonomous growth and function. In severe iodine deficiency nearly the entire population may be affected by goitre, but increases in the prevalence rate of goitre and of the incidence of hyperthyroidism due to autonomous thyroid nodules may be seen when the average iodine intake of adults is below approximately 100 µg per day. This inflicts considerable burden on affected patients and on the health economy.

Screening for iodine deficiency disorders

Screening for iodine deficiency is not individual oriented case-finding. Goitre may occur sporadically even in high iodine intake areas, and day-to-day variations in individual iodine intake and thereby iodine excretion in urine are large. Iodine deficiency in an area is usually evaluated by examination of the distribution of urinary iodine excretion, which reflects intake (up to 90%) and of the prevalence rate of goitre in a subpopulation.

The recommended daily iodine intake in adults is 150 µg/day with extra iodine intake during pregnancy and lactation (7). From individual variation in iodine excretion it has been calculated that examination of urinary iodine excretion should be performed in at least 100 people to give a reliable estimate of iodine intake in the group of population under study (8).

Prevention of iodine deficiency disorders

Iodine supplementation is the most effective way of eradicating iodine deficiency disorders. This is of urgent importance in areas with severe iodine deficiency to prevent iodine deficiency-induced brain damage in the fetus and infant. Worldwide programmes involving regional health authorities and governed by international organizations have made major progress in the field. Also the consequences of a more moderate iodine deficiency—high prevalence and incidence of non-toxic and multinodular toxic goitre in the elderly (9, 10)—should be prevented by an iodine supplementation programme.

The most widespread type of population iodine supplementation is by iodization of salt. Preferably all salt—both table salt and salt used by various food industries, bakeries etc.—should be fortified to obtain a universal increase in iodine intake irrespective of dietary habits. Where iodization of salt is not feasible, other principles have been used such as iodized bread or water, iodized vegetable oil or iodine tablets given as a bolus.

Precautions in the prevention of iodine deficiency

Iodine is a major substrate for thyroid hormone production. Individuals with autonomous thyroid nodules may develop hyperthyroidism when the iodine intake is increased. Since longstanding low iodine intake may lead to the development of such nodules an increase in the iodine intake level of the population may provoke a surge of hyperthyroidism. Figure 1.2.2 demonstrates the increase in cases of hyperthyroidism after iodine supplementation in Tasmania (11). The surge was self-limiting as should be expected, since the increase in iodine intake would prevent future development of autonomous thyroid nodules. Severe cases of hyperthyroidism with mortality have been seen where iodine supplementation has been too active.


Fig. 1.2.2 New cases of hyperthyroidism reported from Tasmania before and after iodine supplementation of the population (initiated early 1966). Separate lines for patients younger and older than 40 years. Peaks in 1964, 1971, 1972, 1978, and 1980 coincided with rises in ambient iodine levels (11) Number of cases is not corrected for variations in size of population. (With permission from Stanbury JB, Ermans AE, Bourdoux P, Todd C, Oken E, Tonglet R, et al. Iodine-induced hyperthyroidism: occurrence and epidemiology. Thyroid, 1998; 8: 83–100 (11).)

Fig. 1.2.2
New cases of hyperthyroidism reported from Tasmania before and after iodine supplementation of the population (initiated early 1966). Separate lines for patients younger and older than 40 years. Peaks in 1964, 1971, 1972, 1978, and 1980 coincided with rises in ambient iodine levels (11) Number of cases is not corrected for variations in size of population. (With permission from Stanbury JB, Ermans AE, Bourdoux P, Todd C, Oken E, Tonglet R, et al. Iodine-induced hyperthyroidism: occurrence and epidemiology. Thyroid, 1998; 8: 83–100 (11).)

Another concern is the long time effects of a high iodine intake. Figure 1.2.3 shows the difference in the prevalence rates of subclinical hyperthyroidism with low serum thyroid-stimulating hormone (TSH) and subclinical hypothyroidism with high serum TSH in elderly people from areas with longstanding mild to moderate iodine deficiency (Jutland, Denmark) and longstanding high iodine intake (Iceland). The autonomous nodules leading to hyperthyroidism with low TSH which was common in Denmark was prevented by the high iodine intake in Iceland. On the other hand subclinical hypothyroidism with elevated TSH was much more common when the iodine intake was high.


Fig. 1.2.3 Prevalence rates of subclinical hyper- and hypothyroidism in random population samples of 68-year-old subjects in Jutland, Denmark, with longstanding mild iodine deficiency, and in Iceland with longstanding high iodine intake. Subjects receiving thyroid medication were excluded. F: females; M: males. Young healthy subjects had serum thyroid-stimulating hormone (s-TSH) 0.4–4.0 mU/l. Note the high prevalence of various degree of hyperthyroidism with low TSH in the low iodine intake area versus the high prevalence of impaired thyroid function with high TSH in the high iodine intake area. (With permission from Laurberg P, Pedersen KM, Hreidarsson A, Sigfusson N, Iversen E, Knudsen PR. Iodine intake and the pattern of thyroid disorders: a comparative epidemiological study of thyroid abnormalities in the elderly in Iceland and in Jutland, Denmark. J Clin Endocrinol Metab, 1998; 83: 765–9 (10).)

Fig. 1.2.3
Prevalence rates of subclinical hyper- and hypothyroidism in random population samples of 68-year-old subjects in Jutland, Denmark, with longstanding mild iodine deficiency, and in Iceland with longstanding high iodine intake. Subjects receiving thyroid medication were excluded. F: females; M: males. Young healthy subjects had serum thyroid-stimulating hormone (s-TSH) 0.4–4.0 mU/l. Note the high prevalence of various degree of hyperthyroidism with low TSH in the low iodine intake area versus the high prevalence of impaired thyroid function with high TSH in the high iodine intake area. (With permission from Laurberg P, Pedersen KM, Hreidarsson A, Sigfusson N, Iversen E, Knudsen PR. Iodine intake and the pattern of thyroid disorders: a comparative epidemiological study of thyroid abnormalities in the elderly in Iceland and in Jutland, Denmark. J Clin Endocrinol Metab, 1998; 83: 765–9 (10).)

Excess iodine inhibits many processes in the thyroid gland, and it may worsen autoimmune thyroiditis, but the exact mechanism behind the increase in hypothyroidism with high iodine intake remains to be elucidated. The level of iodine intake that gives the lowest risk for thyroid disorders in a population is within a rather narrow interval around the recommended intake level of 150 µg/day in adults (7).

In many countries iodine intake of the population has varied unpredictably and unplanned due to variation in farming practices and the use of iodine-containing chemicals in the food industry. Ample supportive evidence exists that this has major consequences for the occurrence of thyroid disorders and that iodine intake of populations should be monitored. Also programmes of monitoring the effects and quality should be obligatory parts of iodine supplementation programmes. Detailed guidelines on the identification and eradication of iodine deficiency have been published by the World Health Organization (WHO)/UNICEF/International Council for the Control of Iodine Deficiency Disorders (ICCIDD) (7), and information is available via the ICCIDD website (www.iccidd.org).

Congenital hypothyroidism

Another programme of prevention in endocrinology, which is well organized in many areas of the world, is screening for and early treatment of congenital hypothyroidism (12). Approximately 1 in 4000 newborns has permanent hypothyroidism. The major cause is dysgenesis of the thyroid gland but various selective defects in thyroid gland function are also found. Even if the placental crossing of thyroid hormones is limited, the fetus develops nearly normal due to thyroid hormones received from the mother. After birth, permanent brain malfunction with learning difficulties may develop if thyroid hormone substitution therapy is delayed until the condition is diagnosed from clinical findings. Before screening was introduced, the majority of cases were diagnosed too late and the average IQ in children with congenital hypothyroidism was reduced to 70–80%. If, on the other hand, the diagnosis is made and therapy started within the first month after birth the child develops normally.

Neonatal screening for congenital hypothyroidism was introduced in the 1970s when cheap and sensitive diagnostic methods had been developed. They were modified to enable measurements on eluates of blood spots collected for the screening of phenylketonuria. The organization of screening and subsequent follow-up varies, being adapted to local puerperal and neonatal care. TSH or TSH + thyroxine (T4) in serum or blood is measured during the first week of life. Abnormal values are followed by retesting and clinical evaluation to allow rapid confirmation of the diagnosis and start of therapy.

Neonatal screening for congenital hypothyroidism clearly follows the guidelines for screening given in Box 1.2.2. Since the costs of lifelong caring for an individual with brain damage are very high in developed countries, it is an area of screening and prevention which is highly cost-effective.

Type 1 diabetes mellitus

Type 1 diabetes results from autoimmune destruction of the insulin-producing β‎ cells in the pancreatic islets of Langerhans. Like other autoimmune disorders the pathogenic mechanisms are only partially known. Both genetic and environmental aetiological factors seem to be involved.

The idea to be able to prevent autoimmunity is very appealing and various ideas and principles have been tested in subjects with a high risk of developing type 1 diabetes. Unfortunately this has achieved limited success, and prevention of type 1 diabetes plays at present no practical role.

This is in sharp contrast to the clinical situation once the disease has developed. The goal of diabetic care is dual: one is to enable normal daily living and wellbeing. This may be problematic in some patients but is often not so difficult. Many patients feel quite comfortable if ketosis and hypoglycaemia are absent and with blood glucose giving a HbA1c level of 9–10% (74.9–85.8 mmol/mol). This can often be achieved with one or two daily insulin injections, and moderate restrictions in the diet. The problems develop after years: nephropathy, retinopathy, neuropathy, accelerated atherosclerosis, etc. Hence the other goal of diabetes care is to prevent (tertiary prevention) diabetic complications. After years of uncertainty the results of the Diabetes Control and Complications Trial (DCCT) (13) finalized discussions on the importance of near normalization of blood glucose levels for the prevention of complications in type 1 diabetes.

Screening of diabetic patients for subclinical complications with measurements of urinary albumin, blood pressure, ophthalmoscopy, and foot examination is a well-established part of diabetes care. The aim is to prevent or delay disease progression by early intervention. Hence the majority of efforts in care of patients with type 1 diabetes as described elsewhere in this book aim at tertiary prevention.

Type 2 diabetes

Type 2 diabetes develops epidemically in many countries because of changes in lifestyle with a high fat intake, low levels of physical exercise and a high frequency of overweight. This is a prime target for both a population-based and a high-risk individual prevention. A type 2 diabetes risk assessment form has been developed for public use with guidance on lifestyle modifications, and recommendations on who should have blood glucose measured (14, 15).

Subclinical type 2 diabetes is common and screening of selected groups such as pregnant women is performed in many countries. Case-finding in overweight patients is the normal practice with the aim of preventing complications by intervention (16). Currently various studies are evaluating the effect of medications to prevent development of type 2 diabetes.

It is in general easy to treat patients to the level of having no diabetic symptoms. These patients have a high morbidity and mortality due to complications. The UK Prospective Diabetes Study (UKPDS) (17, 18) demonstrated the importance (and difficulty) of blood glucose normalization, with treatment of hypertension and regulation of blood lipids being particularly important as dealt with in detail in Part 13.

Osteoporosis

Although most health care efforts in type 2 diabetes are in essence prevention, this is even more so in osteoporosis. Osteoporosis has few if any clinical symptoms and signs, but it increases the risk for fractures (19). Hence it can be discussed whether osteoporosis is a disease or a risk factor.

The whole spectrum of preventive medicine as described previously in this chapter is applied in osteoporosis. Primary prevention is attempted using both a population and a high-risk strategy, and guidelines include both screening of selected groups and case-finding (19).

Osteoporosis is dealt with in detail in Part 4. The approach to identifying and treating osteoporosis covers both secondary prevention (of fractures) in patients diagnosed as having osteoporosis with low bone mineral density, and tertiary prevention (of more fractures) in patients who already have fractures due to osteoporosis. A tool to estimate absolute risk for fracture in a patient based on the presence of various risk factors is available (20). This allows discussing with the patient the change in risk induced by a certain change in lifestyle. A special area of current concern in this field is the role of widespread vitamin D deficiency for development of osteoporosis, and how this may be prevented (21).

Endocrinology and lifestyle modifications

Campaigns to reinforce physical exercise and nonsmoking and to modify diet and reduce overweight are common in many countries. Such lifestyle modifications are important for prevention of endocrine diseases.

Smoking is a risk factor for development of goitre, probably due to generation of thiocyanates, which inhibit thyroid iodine transport and hormone formation. Smoking increases the risk of development of Graves’ disease and especially the development of orbitopathy, where a 10-fold increase in risk has been observed (22). Accordingly many patients with severe orbitopathy are heavy smokers. Even if controlled studies directly demonstrating a beneficial effect of stopping smoking are few, this should be encouraged because the consequences of Graves’ orbitopathy are often severe and treatment is difficult. Cessation of smoking and avoidance of radioiodine therapy are the most important tertiary preventive measures in orbitopathy (22).

In diabetic people treated with insulin smoking alters subcutaneous blood flow and insulin absorption and thereby tends to induce more brittle diabetes. More importantly smoking increases the risk for diabetic micro- and macrovascular disease considerably. Smoking is an independent risk factor for osteoporosis.

Regular aerobic exercise improves glycaemic control in diabetes and prevents osteoporotic fractures, and weight reduction is probably the single most important factor in prevention of type 2 diabetes. Even if there are side effects such as the tendency to increase in weight after cessation of smoking and an increase in osteoporotic fractures with low body weight, the overall picture is that many endocrine disorders can be prevented by lifestyle modifications and that population-directed campaigns are important in this field of medicine.

References

1. Rose G. The Strategy of Preventive Medicine. Oxford: Oxford Medical Publications, 1992.Find this resource:

    2. Bangstad HJ, Danne T, Deeb LC, Jarosz-Chobot P, Urakami T, Hanas R. International Society for Pediatric and Adolescent Diabetes (ISPAD). Insulin treatment. ISPAD clinical practice consensus guidelines 2006–2007. Pediatr Diabetes, 2007; 8: 88–102.Find this resource:

      3. Wilson JMG, Jungner G. Principles and Practice of Screening for Disease. Geneva: WHO, 1968.Find this resource:

        4. Peckham C, Dezateux C, eds. Screening. Br Med Bull, 1998; 54: 4.Find this resource:

        5. Zimmermann MB, Jooste PL, Pandav CS. Iodine-deficiency disorders. Lancet, 2008; 372: 1251–62.Find this resource:

        6. Williams GR. Neurodevelopmental and neurophysiological actions of thyroid hormone. J Neuroendocrinol, 2008; 20: 784–94.Find this resource:

        7. WHO, UNICEF, ICCIDD. Elimination of Iodine Deficiency Disorders. A Manual for Health Workers. EMRO Technical Publications Series, No. 35, 2008.Find this resource:

          8. Andersen S, Karmisholt J, Pedersen KM, Laurberg P. Reliability of studies of iodine intake and recommendations for number of samples in groups and in individuals. Br J Nutr, 2008; 99: 813–18.Find this resource:

          9. Laurberg P, Pedersen KM, Vestergaard H, Sigurdsson G. High incidence of multinodular toxic goitre in the elderly population in a low iodine intake area vs. high incidence of Graves’ disease in the young in a high iodine intake area: comparative surveys of thyrotoxicosis epidemiology in East-Jutland, Denmark and Iceland. J Intern Med1991; 229: 415–20.Find this resource:

            10. Laurberg P, Pedersen KM, Hreidarsson A, Sigfusson N, Iversen E, Knudsen PR. Iodine intake and the pattern of thyroid disorders: a comparative epidemiological study of thyroid abnormalities in the elderly in Iceland and in Jutland, Denmark. J Clin Endocrinol Metab, 1998; 83: 765–69.Find this resource:

            11. Stanbury JB, Ermans AE, Bourdoux P, Todd C, Oken E, Tonglet R, et al. Iodine-induced hyperthyroidism: occurrence and epidemiology. Thyroid, 1998; 8: 83–100.Find this resource:

            12. Grüters A, Krude H. Update on the management of congenital hypothyroidism. Horm Res, 2007; 5: 107–111.Find this resource:

              13. The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med, 1993; 329: 977–86.Find this resource:

                14. Lindstrom J, Tuomilehto J. The Diabetes Risk Score: A practical tool to predict type 2 diabetes risk. Diabetes Care, 2003; 26: 725–31.Find this resource:

                15. Alberti KG, Zimmet P, Shaw J. International Diabetes Federation: a consensus on Type 2 diabetes prevention. Diabet Med, 2007; 24: 451–63.Find this resource:

                16. IDF Clinical Guidelines Task Force. Global Guideline for Type 2 Diabetes: recommendations for standard, comprehensive, and minimal care. Diabet Med, 2006; 23: 579–93.Find this resource:

                17. UK Prospective Diabetes Study (UKPDS) Group. Intensive blood glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet, 1998; 352: 837–53.Find this resource:

                18. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ, 1998; 317: 703–13.Find this resource:

                  19. Kanis JA, Burlet N, Cooper C, Delmas PD, Reginster JY, Borgstrom F, et al. European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int, 2008; 19: 399–428.Find this resource:

                  20. Kanis JA, McCloskey EV, Johansson H, Strom O, Borgstrom F, Oden A, National Osteoporosis Guideline Group. Case finding for the management of osteoporosis with FRAX—assessment and intervention thresholds for the UK. Osteoporos Int, 2008; 10: 1395–408.Find this resource:

                    21. Holick MF, Chen TC. Vitamin D deficiency: a worldwide problem with health consequences. Am J Clin Nutr, 2008; 87: 1080S–6S.Find this resource:

                    22. Wiersinga WM. Preventing Graves’ ophthalmopathy. N Engl J Med 1998; 338: 121–2.Find this resource: