Risk factors for hypothyroidism

Are You at Risk for Thyroid Disease?

Thyroid disease is a common cause of hormonal imbalance in the body. The thyroid can make either too much thyroid hormone (hyperthyroidism) or too little thyroid hormone (hypothyroidism).

Thyroid disease generally isn’t preventable, but awareness of risk factors and symptoms, and regular screening by your doctor, can help prevent serious complications if you do have a thyroid disorder.

Understanding Hyperthyroidism

The most common cause of hyperthyroidism, or overactive thyroid, is an autoimmune disorder known as Graves’ disease.

Graves’ disease occurs when your body’s immune system, which usually protects you from viruses and bacteria, mistakenly attacks your thyroid gland. Damage to your thyroid causes it to produce too much thyroid hormone.

Pituitary gland problems and certain medications (e.g., iodine pills, amiodarone, and interferon) can also lead to hyperthyroidism.

Risk factors for hyperthyroidism include:

  • Being female
  • Being over age 60
  • Recent pregnancy
  • Having an autoimmune disease (such as type 1 diabetes)
  • Family history of thyroid disease or autoimmune disease
  • Personal history of thyroid problems, like goiter (an abnormally large thyroid gland) or having had thyroid surgery
  • Consuming significant amounts of iodine through food or medication

RELATED: Quitting Sugar Saved My Thyroid

Understanding Hypothyroidism

Hypothyroidism, or underactive thyroid, occurs when your thyroid gland doesn’t produce enough thyroid hormone, causing your body’s metabolism to slow down.

Hashimoto’s thyroiditis, another autoimmune disease, is the most common cause of hypothyroidism.

Pituitary gland dysfunction can slow down thyroid production, and some medications (such as lithium, amiodarone, and interferon) can result in hypothyroidism as well.

Risk factors for hypothyroidism include:

  • Being female
  • Being older than age 60
  • Exposure to radiation in the neck
  • Prior thyroid surgery
  • Having a family history of thyroid disease
  • Having a family history of autoimmune disease
  • Having an autoimmune disease
  • Being of Caucasian or Asian ethnicity
  • Experiencing hormonal changes due to pregnancy, childbirth, or menopause
  • Personal history of lithium use (often prescribed for bipolar disorder)
  • Having chromosomal abnormalities like Down syndrome or Turner’s syndrome

Getting Screened for Thyroid Disease

If you have symptoms related to thyroid disease — such as depression or anxiety, intolerance to hot or cold temperatures, or unexpected changes in your weight — in addition to risk factors for thyroid disease, particularly a family history of autoimmune disease, you should be screened for thyroid disease, advises Pamela Allweiss, MD, MSPH, an endocrinologist and an assistant professor in family practice at the University of Kentucky College of Medicine in Lexington.

While not much can be done to prevent thyroid disease, Dr. Allweiss says early detection is important. Oftentimes, thyroid disease symptoms can be vague, but people with a family history or other thyroid-disease risk factors should “think about thyroid disease” and talk to their doctor if they notice any unusual ailments, Dr. Allweiss notes.

If a person has ever been told that they have an enlarged thyroid or goiter in the past they should also be tested periodically for thyroid disease, Allweiss also suggests. Prompt diagnosis of thyroid disease is crucial since there’s not much you can do to prevent it and treatment is the only way to bring your hormone levels back into balance.

What You Need to Know About Nodules

Thyroid nodules — lumps and bumps that form on the thyroid gland — are very common. Though nodules can indicate cancer, they’re usually benign (non-cancerous). Approximately 5 percent of thyroid nodules turn out to be cancerous.

Women are much more likely than men to develop thyroid nodules, but men are at higher risk for cancerous nodules. Allweiss suggests that all men with thyroid nodules have a biopsy to determine whether they have thyroid cancer.

Risk factors for thyroid nodules include:

  • Insufficient dietary iodine
  • Personal history of thyroid disease
  • Family history of thyroid nodules
  • Hypothyroidism (especially Hashimoto’s thyroiditis)

Getting regular physical exams can help your doctor detect thyroid nodules early. Additional testing (such as a thyroid scan, ultrasound, and/or biopsy) may also be necessary if a nodule is found.

Being aware of your level of risk for thyroid disease, and telling your doctor about any symptoms, can allow for early diagnosis of thyroid problems. Early detection is key because it can prevent the development of additional health problems. If you have a family history of thyroid disease and notice possible thyroid disease symptoms, don’t hesitate to talk to your doctor.

Thyroid Cancer Risk Factors

A risk factor is anything that increases a person’s chance of getting a disease such as cancer. Different cancers have different risk factors. Some risk factors, like smoking, can be changed. Others, like a person’s age or family history, can’t be changed.

But risk factors don’t tell us everything. Having a risk factor, or even several risk factors, does not mean that you will get the disease. And many people who get the disease may have few or no known risk factors. Even if a person with thyroid cancer has a risk factor, it is very hard to know how much that risk factor may have contributed to the cancer.

Scientists have found a few risk factors that make a person more likely to develop thyroid cancer.

Risk factors that can’t be changed

Gender and age

For unclear reasons thyroid cancers (like almost all diseases of the thyroid) occur about 3 times more often in women than in men.

Thyroid cancer can occur at any age, but the risk peaks earlier for women (who are most often in their 40s or 50s when diagnosed) than for men (who are usually in their 60s or 70s).

Hereditary conditions

Several inherited conditions have been linked to different types of thyroid cancer, as has family history. Still, most people who develop thyroid cancer do not have an inherited condition or a family history of the disease.

Medullary thyroid cancer: About 2 out of 10 medullary thyroid carcinomas (MTCs) result from inheriting an abnormal gene. These cases are known as familial medullary thyroid carcinoma (FMTC). FMTC can occur alone, or it can be seen along with other tumors.

The combination of FMTC and tumors of other endocrine glands is called multiple endocrine neoplasia type 2 (MEN 2). There are 2 subtypes, MEN 2a and MEN 2b, both of which are caused by mutations (defects) in a gene called RET.

  • In MEN 2a, MTC occurs along with pheochromocytomas (tumors that make adrenaline) and with parathyroid gland tumors.
  • In MEN 2b, MTC is associated with pheochromocytomas and with benign growths of nerve tissue on the tongue and elsewhere called neuromas. This subtype is much less common than MEN 2a.

In these inherited forms of MTC, the cancers often develop during childhood or early adulthood and can spread early. MTC is most aggressive in the MEN 2b syndrome. If MEN 2a, MEN 2b, or isolated FMTC runs in your family, you may be at very high risk of developing MTC. Ask your doctor about having regular blood tests or ultrasound exams to look for problems and the possibility of genetic testing.

Other thyroid cancers: People with certain inherited medical conditions have a higher risk of more common forms of thyroid cancer. Higher rates of thyroid cancer occur among people with uncommon genetic conditions such as:

Familial adenomatous polyposis (FAP): People with this syndrome develop many colon polyps and have a very high risk of colon cancer. They also have an increased risk of some other cancers, including papillary thyroid cancer. Gardner syndrome is a subtype of FAP in which patients also get certain benign tumors. Both Gardner syndrome and FAP are caused by defects in the gene APC.

Cowden disease: People with this syndrome have an increased risk of thyroid problems and certain benign growths (including some called hamartomas). They also have an increased risk of cancers of the thyroid, uterus, breast, as well as some others. The thyroid cancers tend to be either the papillary or follicular type. This syndrome is most often caused by defects in the gene PTEN. It is also known as Multiple Hamartoma Syndrome and PTEN Hamartoma Tumor Syndrome

Carney complex, type I: People with this syndrome may develop a number of benign tumors and hormone problems. They also have an increased risk of papillary and follicular thyroid cancers. This syndrome is caused by defects in the gene PRKAR1A.

Familial nonmedullary thyroid carcinoma: Thyroid cancer occurs more often in some families, and is often seen at an earlier age. The papillary type of thyroid cancer most often runs in families. Genes on chromosome 19 and chromosome 1 are suspected of causing these familial cancers.

If you suspect you might have a familial condition, talk with your doctor, who might recommend genetic counseling if your medical history warrants it.

Family history

Having a first-degree relative (parent, brother, sister, or child) with thyroid cancer, even without a known inherited syndrome in the family, increases your risk of thyroid cancer. The genetic basis for these cancers is not totally clear.

Risk factors that may be changed

Radiation

Radiation exposure is a proven risk factor for thyroid cancer. Sources of such radiation include certain medical treatments and radiation fallout from power plant accidents or nuclear weapons.

Having had head or neck radiation treatments in childhood is a risk factor for thyroid cancer. Risk depends on how much radiation is given and the age of the child. In general, the risk increases with larger doses and with younger age at treatment.

Before the 1960s, children were sometimes treated with low doses of radiation for things we wouldn’t use radiation for now, like acne, fungus infections of the scalp (ringworm), or enlarged tonsils or adenoids. Years later, the people who had these treatments were found to have a higher risk of thyroid cancer. Radiation therapy in childhood for some cancers such as lymphoma, Wilms tumor, and neuroblastoma also increases risk. Thyroid cancers that develop after radiation therapy are not more serious than other thyroid cancers.

Imaging tests such as x-rays and CT scans also expose children to radiation, but at much lower doses, so it’s not clear how much those tests might raise the risk of thyroid cancer (or other cancers). If there is an increased risk it is likely to be small, but to be safe, children should not have these tests unless they are absolutely needed. When they are needed, they should be done using the lowest dose of radiation that still provides a clear picture.

Several studies have pointed to an increased risk of thyroid cancer in children because of radioactive fallout from nuclear weapons or power plant accidents. For instance, thyroid cancer was many times more common than normal in children who lived near Chernobyl, the site of a 1986 nuclear plant accident that exposed millions of people to radioactivity. Adults involved with the cleanup after the accident and those who lived near the plant have also had higher rates of thyroid cancer. Children who had more iodine in their diet appeared to have a lower risk.

Some radioactive fallout occurred over certain regions of the United States after nuclear weapons were tested in western states during the 1950s. This exposure was much, much lower than that around Chernobyl. A higher risk of thyroid cancer has not been proven at these low exposure levels. If you are concerned about possible exposure to radioactive fallout, discuss this with your doctor.

Being exposed to radiation when you are an adult carries much less risk of thyroid cancer.

Being overweight or obese

According to the International Agency for Research on Cancer (IARC), people who are overweight or obese have a higher risk of developing thyroid cancer than those who are not. The risk appears to go up as the body mass index (BMI) increases.

Iodine in the diet

Follicular thyroid cancers are more common in areas of the world where people’s diets are low in iodine. On the other hand, a diet high in iodine may increase the risk of papillary thyroid cancer. In the United States, most people get enough iodine in their diet because it is added to table salt and other foods.

Risk Factors for Thyroid Dysfunction among Type 2 Diabetic Patients in a Highly Diabetes Mellitus Prevalent Society

Abstract

Diabetes and thyroid dysfunction found to exist simultaneously. In this regard, the present study looked into the prevalence of different forms of thyroid dysfunction and their risk factors among Type 2 diabetic Saudi patients. Methodology. A cross-sectional retrospective randomized hospital-based study of 411 Type 2 diabetic Saudi patients of >25 years of age was conducted to test the prevalence of different types of thyroid dysfunction and their risk factors. Results. The prevalence of different types of thyroid dysfunction is 28.5%, of which 25.3% had hypothyroidism, where 15.3%, 9.5%, and 0.5% are clinical, subclinical, and overt hypothyroidism, respectively. The prevalence of hyperthyroidism is 3.2%, of which subclinical cases accounted for 2.7% and overt hyperthyroidism accounted for 0.5%. Risk factors for thyroid dysfunction among Saudi Type 2 diabetic patients are family history of thyroid disease, female gender, and duration of diabetes of >10 years, while the risk was not significant in patients with history of goiter and patients aged >60 years. Smoking and parity show a nonsignificant reduced risk. Conclusion. Thyroid dysfunction is highly prevalent among Saudi Type 2 diabetic patients, and the most significant risk factors are family history of thyroid disease, female gender, and >10 years duration of diabetes.

1. Introduction

Diabetes mellitus and thyroid dysfunction are the most common endocrine diseases seen in the adult population , while insulin or thyroid hormones metabolism can result in functional abnormalities of one another. The strong link between diabetes and thyroid diseases encouraged the American Diabetes Association (ADA) to propose that people with diabetes must be checked periodically for thyroid dysfunction . Thyroid disease should be screened annually in diabetic patients to detect asymptomatic thyroid dysfunction . At the same time, patients with thyroid dysfunction may need to be tested for the possibility of abnormal glucose metabolism, since excessive thyroid hormones cause increased glucose production in the liver, rapid absorption of glucose through the intestine, and increased insulin resistance . The thyroid gland is one of the endocrinal systems of the human body and can be affected by sustained hyperglycemia and the continuous endeavors by the body to correct for this carbohydrate imbalance. Studies have shown that diabetes and thyroid dysfunction can be found to exist together where thyroid disease can affect glucose metabolism and the untreated thyroid dysfunction can affect the management of diabetes . The association of the two endocrinal dysfunctions has been reported in different societies throughout the last two decades . Diabetic patients have susceptibility to different types of thyroid dysfunction, whether hypothyroidism or hyperthyroidism; at the same time, patients with thyroid dysfunction are susceptible to suffer from either Type 1 diabetes or Type 2 diabetes .

Thyroid disorder is divided into clinical and subclinical disease, according to the hormonal levels and clinical presentation that will affect the follow-up and management plan. Thyroid dysfunction has been found to be more prevalent among diabetic population when compared with the normal population .

In Scotland, the prevalence of thyroid dysfunction was 13.4% among diabetics, reaching 31.4% in Type 1 female diabetic patients and falling to 6.9% in Type 2 male diabetic patients , while among Type 2 diabetic patients in Jordan, the overall prevalence of thyroid dysfunction was found to be 12.5% . Subclinical hypothyroidism prevalence is variable among different ethnic groups or genders and was found to range from 4.8 to 6.3% . This was clearly shown in the United States, where prevalence was 5.8% in white women and 1.2% in black women but 3.4% in white men and 1.8% in black men .

Hyperthyroidism is a less common thyroid dysfunction in both general and diabetic patients. It has been reported to be 0.53% in Caucasian children with Type 1 diabetes mellitus and 4.4% in Type 2 diabetic adult patients , while subclinical hyperthyroidism is reported to be approximately 2% .

There are many risk factors known to be associated with thyroid dysfunction in the general population, including age, gender, BMI, family history of thyroid disease, smoking, and pregnancy. Incidence of hyperthyroidism and hypothyroidism increases with age, especially beyond 20 years, and it has been established that female gender is 10–20 times more likely to have this medical problem than males . Morbidly obese individuals show a high prevalence of overt and subclinical hypothyroidism, accounting for 19.5% . The United Kingdom DNA collection for Graves’ disease and Hashimoto’s thyroiditis study identified family history of thyroid disease to be risk for thyroid dysfunction .

Smoking has been reported to be a risk for thyroid dysfunction, where higher T4 levels and lower TSH levels were reported among smokers but not among nonsmokers or former smokers. This may be explained by the toxicological effect of smoking on increasing levels of thyroxin binding globulin among smokers .

Estrogen has been shown to be associated with low risk for thyroid dysfunction, while pregnancy has a higher risk for developing hyperthyroidism .

Risk factors for thyroid dysfunction among diabetic patients are similar to what have been reported in nondiabetics, although they will vary with the type of thyroid dysfunction. Autoimmune thyroid disease is seen to be more frequent in the younger age group and females , while hypothyroidism among diabetic patients is more prevalent among women and the older population . Diabetes duration has been found to be a risk for thyroid autoimmune disuses in children and adolescents with type 1 diabetes , but it was not a risk in patients suffering from Type 2 diabetes in different ethnic groups . Goiter has been recognized as a risk factor for thyroid dysfunction in diabetic patients , as observed in nondiabetics . Parity has been recognized to be a risk factor for thyroid dysfunction in diabetic women , which is also the case in nondiabetic mothers .

Saudi Arabia is the seventh of the top ten countries in terms of the prevalence of diabetes among the adult population aged 20–79, according to the IDF diabetes atlas 2012 . The prevalence of thyroid dysfunction among Saudi diabetic patients was reported to be 16%, as opposed to 7% in nondiabetics, as shown by Akbar et al. in 2006 . Since then, no study has been undertaken to investigate the relationship between diabetes and thyroid dysfunction, or to examine their risk factors in a community with high diabetes prevalence.

Since most studies investigating the prevalence of thyroid disease in diabetic patients have focused on Type 1 diabetes, the aim of this study is to assess the prevalence of different forms of thyroid dysfunction among Type 2 diabetic Saudi patients receiving care from April to October in 2012 at the University Diabetes Center (UDC) in King Abdul Aziz University Hospital (KAUH) in Riyadh. Determining the risk factors of thyroid dysfunction among Type 2 diabetic Saudi patients is part of this study’s objectives.

2. Methodology

This study is a cross-sectional retrospective randomized hospital-based study, in which 411 Type 2 diabetic Saudi patients were enrolled during the period April to October in 2012. The UDC is a tertiary diabetes center, which provides care for diabetic patients in Riyadh, the capital of Saudi Arabia.

Subjects recruited for this study were Saudi nationals with Type 2 diabetes of more than 25 years of age. The diagnosis of Type 2 diabetes was based on their initial presentation, using the American Diabetes Association (ADA) Criteria . Inclusion criteria included adult Saudi Type 2 diabetic patients older than 25 years visiting the UDC during the study period. Exclusion criteria included patients who had previous thyroid surgery, pregnant women, Type 1 diabetes mellitus, and patients on the following medications: cordarone “anti-arrhythmic medication” lithium, interferon, iodide, or high doses of glucocorticoids.

Chart review was conducted to collect data, including demographic parameters that is, age, gender, and duration of diabetes, in addition to anthropometric measurements including weight, height, and body mass index (BMI) in addition to blood pressure that was collected from their last visit. Family history of diabetes or thyroid disease with or without goiter was reported, in addition to smoking history and parity for females. The presence of any associated diseases like hypertension, dyslipidemia, and thyroid disease including goiter was also documented. Laboratory data were collected from the patients’ chart of the last visit, including HbA1c, fasting blood sugar (FBG), and 2 hour postprandial (2hpp) glucose, in addition to lipids profile including total cholesterol, triglyceride, high density lipoprotein (HDL), and low density lipoprotein (LDL). Thyroid function tests, namely, thyroid-stimulating hormone (TSH), free thyroxine (FT4) and free thyroxine (FT3), were collected during the same visit.

Each patient is evaluated for the presence of thyroid dysfunction, defined as biochemical abnormalities for clinical and subclinical hypothyroidism and hyperthyroidism, if they had been diagnosed and treated with either hypothyroidism or hyperthyroidism. Patients were classified as having clinical hypothyroidism if they have been diagnosed before and on thyroxin replacement therapy. Patients were labeled with sub-clinical hypothyroidism if they have TSH > 5 mIU/L but normal T4 (10.55–25.74 pmol/L), while overt hypothyroidism when TSH > 5.0 mIU/L with low T4 <10.55 pmol/L. Patients were labeled with hyperthyroidism if they have been treated surgically or given radioactive iodine therapy or on antithyroid medications. Diagnosis of subclinical hyperthyroidism is when TSH < 0.5 mIU/L with normal T4 (10.55–25.74 pmol/L), while overt hyperthyroidism is when TSH < 0.5 mIU/L with high T4 >25.74 pmol/L .

3. Statistical Analysis

Data were entered into SPSS software version 17.0. Continuous variables were expressed as mean ± standard deviation, and categorical variables were expressed, as percentages. -test was used for continuous variables and chi square test for categorical variables. Relative risk with 95% confidence interval (CI) was used to assess different risk factors of thyroid dysfunction among Type 2 diabetic patients. value of less than 0.05 was used as a level of significance, and GraphPad software was used to plot different relative risk factors.

4. Results

Thyroid dysfunctions were found in 117 patients (28.5%) of the total sample of 411 Type 2 DM Saudi patients. The patients’ baseline characteristics of the total sample showed a mean age of years but and for diabetic subjects with and without thyroid dysfunction, respectively, which is not significantly different ( ). Female gender percentage in the total sample was 52.3% but was significantly higher in patients with thyroid dysfunction of 68.6% when compared with normal thyroid subjects, where females accounted for 46.6% with value < 0.0001. The mean diabetes duration was also significantly higher in patients with thyroid dysfunction than in normal ones ( versus , resp.) with value = 0.032. The percentage of patients with a positive family history of thyroid disease was significantly higher in patients with thyroid dysfunction (14.7%) versus (1.03%) among the normal thyroid diabetic patients with value < 0.0001, while the percentage of family history of diabetes was not statistically different between the two groups. The percentage of smoking habits in the two groups did not show any significant difference.

The mean weight is and BMI of for the total sample, but without a significant difference between the patients with or without thyroid dysfunction. The height is significantly lower in patients with thyroid dysfunction, compared with the normal thyroid patients ( versus , resp.) with value < 0.0001. The mean systolic and diastolic blood pressures for the selected patients are and , respectively, but did not show significant difference in patients with or without thyroid dysfunction. Goiter was found in 2.8% of the studied samples and in 4.8% in patients with thyroid dysfunction but 2.1% in patients without thyroid dysfunction, although it was not significant. The mean HbA1c, FBS, triglyceride, total cholesterol, HDL, and LDL for total sample were , , , , , and , respectively, but there was no significant difference for patients with or without thyroid dysfunction.

Thyroid function tests showed a significantly higher mean TSH value for patients with thyroid dysfunction than normal ones ( versus , resp.; value < 0.0001) and FT4 ( versus with value 0.048), but no significant difference for FT3 ( versus , resp., with value 0.552) as shown in Table 1.

Table 1 Baseline characteristics of study sample for all subjects with or without thyroid dysfunction among Type 2 diabetic patients aged >25 years.

Figure 1 shows the prevalence of different types of thyroid dysfunction among the studied population, where the total prevalence of hypothyroidism was 25.3% and 3.2% for hyperthyroidism. The prevalence of different types of hypothyroidism includes clinical cases (15.3%), sub-clinical (9.5%), and overt hypothyroidism (0.5%). The prevalence of sub-clinical hyperthyroidism in the studied sample was 2.7% and 0.5% for overt hyperthyroidism.


Figure 1
Prevalence of different types of thyroid dysfunction among Type 2 diabetic Saudi patients. Clinical hypothyroidism for patients receiving thyroxin treatment, and Subclinical hypothyroidism when TSH > 5.0 mIU/L with normal T4 (10.55–25.74 pmol/L), while overt hypothyroidism when TSH > 5.0 mIU/L with low T4 <10.55 pmol/L. Subclinical hyperthyroidism when TSH < 0.5 mIU/L with normal T4 (10.55–25.74 pmol/L) and overt hyperthyroidism when TSH < 0.5 mIU/L with high T4 >25.74 pmol/L.

(a)
(b)
(a)
(b) Figure 2
Relative risks for thyroid dysfunction among Type 2 Saudi diabetic patients; (a) forest plot, (b) table of values.

5. Discussion

This study has demonstrated that thyroid dysfunction affects more than one quarter of Saudi Type 2 diabetic patients, which is more than that has been reported by Akbar et al. of 16% in 2006 although this study has a bigger sample and older cohort age. In this study, we report the highest prevalence of thyroid dysfunction in Type 2 diabetic patients when compared with other communities, shown by the Scotland study to be 13.4% among both Type 1 diatebes and Type 2 diabetes or by the Jordanian study, where it was 12.5% among Type 2 diabetes . This could be explained by the high prevalence of latent autoimmune diabetes of adult (LDA) in Saudi Type 2 diabetics reaching 26% and in the current study, those patients are not excluded. When comparing our findings of different types of thyroid dysfunction for similar Type 2 diabetic patients’ cohort from Spain published by Díez et al. in 2011 , we had identical findings for the prevalence of both total and subclinical hypothyroidism cases (25.3% versus 25.8% and 9.5% versus 10.7% resp.). The prevalence of clinical cases of hypothyroidism was 15.3% in our subjects, while overt hypothyroidism in Spain was 15.1%. We had a lower prevalence of total hyperthyroid cases when compared with Spain study (3.2% versus 6.6%) but not for subjects with subclinical hyperthyroidism. Overt hyperthyroid cases were higher in the Spain study when compared with our study (3.5% versus 0.5%).

Diabetic patients with a positive family history of thyroid disease had a higher chance of developing thyroid dysfunction, while the family history of diabetes did not increase the risk for thyroid dysfunction which is the same observation in the United Kingdom DNA collection for Graves’ disease and Hashimoto’s thyroiditis study . Among Saudi Type 2 diabetic patients of more than 25 years of age, positive family history of thyroid disease is the most prominent risk factor for thyroid dysfunction, as is also shown in Caucasians .

As shown in many ethnic groups , Saudi diabetic patients with thyroid dysfunction had a significant predominance of female gender. Diabetes duration of more than 10 years in our cohort has been shown to be an important risk factor, which is not the case in the studies of different ethnic groups like Spanish and Chinese population . This may explained by the fact that our cohort had a marked longer duration of 7.3 years versus 9.6 years in Spanish and 8.3 years in Chinese.

We did not find history of goiter to be a significant risk factor for thyroid dysfunction in this retrospective study which was similar to what has been reported by Díez et al. in a more representative prospective study , although history of goiter is recognized as a risk factor for thyroid dysfunction in general population . Our results have denied that age is a significant risk factor for thyroid dysfunction, as with what has been reported by different studies . While smoking has been identified as a risk factor for thyroid dysfunction in the general population, especially when smoking is highly prevalent , no studies have investigated the impact of smoking as a risk among the diabetic population. We report here that smoking has no effect on thyroid dysfunction among Type 2 diabetic patients. This finding in Type 2 diabetic patients is reported for the first time and has to be taken with special caution, since smoking has very low prevalence among Saudi females for cultural reasons .

Parity has been reported in many studies to be a risk factor for thyroid dysfunction in the general population , but we did not find this to be the case among Saudi Type 2 diabetic females, although diabetic pregnant women have an increased risk of developing postpartum thyroiditis .

Although thyroid autoimmunity is strong risk factors for thyroid dysfunction among diabetic patients, the current retrospective study lacks thyroid antibody data.

We conclude that more than one quarter of Saudi Type 2 diabetic patients of more than 25 years of age are affected by different types of thyroid dysfunction, whereby the majority are hypothyroid cases. Our findings regarding the prevalence of different thyroid dysfunction among Type 2 Saudi diabetic population are higher than those that have been reported by most of studies conducted in different ethnic groups. We have found that family history of thyroid disease, female gender, and duration of diabetes for more than 10 years are significant risk factors for different thyroid dysfunctions.

Based on a high prevalence of thyroid dysfunction among Saudi Type 2 diabetic patients, routine screening for thyroid dysfunction is highly recommended in Saudi diabetic population.

Acknowledgments

The study was approved by the Institutional Review Board (IRB) of the College of Medicine Research Center (CMRC). The authors would like to acknowledge the great support of research staff in research unit at the University Diabetes Center for their support in conducting that study.

New Genetic Insights from Autoimmune Thyroid Disease

The autoimmune thyroid diseases (AITDs) (Graves’ disease and Hashimoto’s thyroiditis) are complex genetic diseases which most likely have more than 20 genes contributing to the clinical phenotypes. To date, the genes known to be contributing fall into two categories: immune regulatory genes (including HLA, CTLA4, PTPN22, CD40, CD25, and FCRL3) and thyroid-specific genes (TG and TSHR). However, none of these genes contribute more than a 4-fold increase in risk of developing one of these diseases, and none of the polymorphisms discovered is essential for disease development. Hence, it appears that a variety of different gene interactions can combine to cause the same clinical disease pattern, but the contributing genes may differ from patient to patient and from population to population. Furthermore, this possible mechanism leaves open the powerful influence of the environment and epigenetic modifications of gene expression. For the clinician, this means that genetic profiling of such patients is unlikely to be fruitful in the near future.

Many diseases have a tendency to run in families, and we know that this may be due to either environmental influences, or family genetics, or both. The autoimmune thyroid diseases (AITDs), Graves’ disease and Hashimoto’s thyroiditis, are typical examples of such complex diseases and have been recognized for many years as having an important genetic component. In the last 10 years we have learned many new insights into the way genetic influences can enhance thyroid autoimmunity, but there remain large gaps in our knowledge which are unlikely to be filled without major theoretical and technical advances. This brief review examines the current state of knowledge and what new insights we have gained from exploring the genetics of the AITDs, and in particular Graves’ disease.

2. Thyroid Autoantibodies

Autoantibodies to thyroid peroxidase (TPO) and thyroglobulin (Tg) are reflections of thyroid disease rather than causative agents . Hence, such thyroid autoantibodies may develop before the onset of clinical AITD and have been long known to increase the risk of developing clinical AITD . The recognition of a familial association for the production of thyroid antibodies led to studies of first-degree relatives of probands with AITD and indicated a dominant pattern of inheritance. Indeed, up to 50% of the siblings of patients with AITD are thyroid antibody positive in contrast to ~15% in the general population . Several segregation analyses have also shown a Mendelian dominant pattern of inheritance for the expression of thyroid autoantibodies , and genetic transmission of TPO antibody subclass “fingerprints” has suggested that the pattern of autoantibody recognition of the TPO antigen was also genetically transmitted .

3. Genetic Susceptibility to AITD

The recognition of an association between AITD and certain human leukocyte antigens (HLA) first provided a mechanism for the genetic contribution to Graves’ disease and Hashimoto’s thyroiditis . This association has been especially well seen in identical twins . The HLA antigens provide a means for the immune system to recognize thyroid antigenic peptides, and recent data have demonstrated this enhanced association as secondary to the presence of particular residues in the HLA class II binding pocket such as Arg 74 . In addition, as the pathological and molecular mechanisms involved in AITD became known, many of which were not only common to all autoimmune diseases but also highly variable between individuals; this allowed the recognition of candidate genes responsible for disease susceptibility. Such genes could then be assessed by either linkage analysis or association studies (see Table 1).

(A) Linkage analysis
This is based on the principle that the chance for a recombination event between 2 loci (i.e., a marker, such as the candidate gene, and the true disease gene) is proportional to the chromosomal distance between them. Therefore, if a marker is close to a disease susceptibility gene, this marker will cosegregate with the disease in families.
The logarithm of odds (LOD) score is a measure of the evidence for or against linkage between a marker and a trait or disease . LOD score analysis has had important advantages for the study of AITD because it has allowed a way to test for the presence of heterogeneity within the data set and allowed deduction of the mode of inheritance and the degree of penetrance from the linkage data.
Linkage studies are highly specific but have been clearly shown not to be highly sensitive.
(B) Association studies
These studies simply compare the presence of a disease marker (such as the candidate gene) in the disease population with the presence of the marker in a control population without the disease.
Here, the difficulty may lie in the appropriate control population, which needs to be comparable and large.
If this difficulty is overcome, association studies can reveal a genetic influence, and with large patient groups, this type of study can be highly sensitive.

Table 1 Methods of genetic analysis.

4. Detecting Susceptibility Genes in AITD

The candidate HLA gene complex was first associated with AITD in association studies but then failed to show linkage with AITD . This showed that the genetic contribution of HLA to AITD was not strong enough to be seen in linkage analyses . This indicated that association studies were more likely to detect genes contributing small effects on disease susceptibility. As a consequence of the Human Genome Project, it became possible to identify genes for diseases that had a complex genetic basis without resorting to the candidate gene approach. This was achieved by “typing” individuals using a genome screen of genetic markers, at first with microsatellites (1 microsatellite per 10 cM DNA) and later single-nucleotide polymorphisms (SNPs) (~1 SNP per < 1 cM DNA), which covered the entire genome (Table 2) . Then investigators observed which markers segregated with the disease. However, the reduced sensitivity of linkage analyses, compared to association studies, made it more difficult to perform these analyses for the complex traits characteristic of a non-Mendelian pattern of inheritance and with variable clinical phenotypes. However, using large numbers of SNPs, developed as a result of the HapMap project , and which had a much greater degree of coverage of the whole genome, it was easier to decipher which markers segregated with the disease using association analyses. These SNP markers occur more frequently than microsatellite markers and are easy to detect, allowing for greater genetic sensitivity. The suspected gene region can then be further narrowed with more dense SNPs and the gene can be identified. Results are now available for a variety of autoimmune diseases including rheumatoid arthritis and type 1 diabetes mellitus and most recently for AITD .

(A) Microsatellites
These are regions in the genome that are composed of repetitive sequences. The most common microsatellites are the CA (dC-dA)n repeats. Microsatellite loci are highly polymorphic because of variation in the number of repeats (usually there are 5 to 15 alleles per locus), and they are uniformly distributed throughout the genome at distances of fewer than 1 million base pairs . Therefore, microsatellites served as useful markers in linkage studies designed to search for unknown disease susceptibility genes. Investigators then further narrowed the suspected gene region with more dense markers, and the gene could be identified.
(B) Single-nucleotide polymorphisms (SNPs)
Without having to enlist families, it is now possible to use genome-wide association studies involving up to 106 SNPs (on a microchip), each of which is in linkage disequilibrium with large segments of the genome, and then analyze their association with any disease.

Table 2 Methods for whole-genome screening.

It is obviously essential that whole-genome association study results must be reliably and repeatedly reproduced, but the complexity of this type of analysis and the high cost have raised problems . If common diseases are associated with common risks, then replication across populations can be expected. But common diseases may be related to population-specific risks, and, therefore, such data can only be reproduced in the same population as that which was studied in the original report. Reproducibility had been a problem for studies that used microsatellite screening, including the studies in patients with AITD, and this problem has persisted in the much larger studies using whole-genome association studies such as in those analyzing Parkinson’s disease and also obesity. Hence, all reports of genetic linkage and association require confirmation by independent studies before they can be accepted.

5. Genes for AITD

The HLA and CTLA4 genes were the first genes identified by the candidate approach (Table 3).

Gene symbol Gene name Chromosome location Odds ratio
HLA Major histocompatibility complex 6p21 2.0–4.0
CTLA4 Cytotoxic T-lymphocyte-associated protein 4 2q33 1.5–2.2
PTPN22 Protein tyrosine phosphatase, non-receptor type 22 (lymphoid) 1p13 1.4–1.9
CD40 CD40 molecule, TNF receptor superfamily member 5 20q11 1.3–1.8
IL2RA (CD25) Interleukin 2 receptor, alpha 10p15 1.1–1.4
FCRL3 Fc receptor-like 3 1q23 1.1–1.3
TG Thyroglobulin 8q24 1.3–1.6
TSHR Thyroid-stimulating hormone receptor 14q31 1.4–2.6

Table 3 Genes linked and/or associated with autoimmune thyroid disease.

As discussed earlier, the HLA genes make up the major histocompatibility complex (MHC) which contains many genes related to immune system function in humans. These include HLA class I (A, B, and C), HLA class II (DP, DM, DOA, DOB, DQ, and DR), and HLA class III (coding for other immune proteins). The major GD-associated HLA, HLA-DR3, locates at the HLA DR locus and plays a key role in the normal immune response by binding peptide antigens and presenting them to T-cell receptors.

The cytotoxic T-lymphocyte-associated protein 4 (CTLA4) gene is an immune regulatory molecule, which is expressed on the surface of Helper T cells and transmits an inhibitory signal to T cells. In addition to the HLA and CTLA4 gene loci, there are confirmed associations (2 or more reports) for a number of genes also common to many autoimmune diseases: PTPN22, CD40, IL2RA (CD25), and FCRL3 (Table 3).

The gene for protein tyrosine phosphatase, non-receptor type 22 (lymphoid), also known as just PTPN22, encodes a protein tyrosine phosphatase expressed primarily in lymphoid tissues. This enzyme associates with the molecular adapter protein CBL and may be involved in regulating CBL function in the T-cell receptor signaling pathway. A variant of the PTPN22 encodes Lyp phosphatase (Lyp620W) and confers risk for multiple autoimmune diseases. Most recently, Zhang et al. reported that levels of the Lyp620W variant were decreased in human T and B cells, and its calpain binding and cleavage were increased relative to wild-type Lyp620R. Therefore, calpain-mediated degradation with consequently reduced Lyp expression and lymphocyte and dendritic cell hyperresponsiveness represents a potential mechanism for unregulated autoimmunity. The LypR620W variant, with an arginine to tryptophan substitution, loses its function and influence on immune responses, which increases the risk for autoimmune disease.

The CD40 molecule, or TNF receptor superfamily member 5 gene, encodes a costimulatory receptor which is essential in mediating a broad variety of immune and inflammatory responses including T-cell-dependent immunoglobulin class switching, memory B-cell development, and germinal center formation . The interleukin 2 (IL2) receptor alpha gene (IL2RA or CD25) encodes one of the subunits of the IL-2 receptor that binds IL-2 and is vital in the regulation of T-cell function. The Fc receptor-like protein 3 (FCRL3) gene encodes a protein containing an immunoreceptor-tyrosine activation motif and immunoreceptor-tyrosine inhibitory motif in its cytoplasmic domain and may play a role in immune regulation.

To date, the only thyroid-related genes associated with AITD are TG (the gene encoding thyroglobulin) , in both Graves’ disease and Hashimoto’s thyroiditis, and TSHR (the gene encoding the thyrotropin receptor) restricted to Graves’ disease (Table 3).

The thyroglobulin (TG) gene encodes a large glycoprotein homodimer produced exclusively by the thyroid gland. It acts as a substrate for the synthesis of thyroid hormones thyroxine (T4) and triiodothyronine (T3) as well as the storage of the inactive forms of thyroid hormone and iodine. How this gene influences susceptibility is unclear but Stefan et al. have recently described a genetic/epigenetic mechanism by which a newly identified TG promoter SNP variant predisposes to AITD. Sequencing analyses followed by case control and family-based association studies identified a SNP (−1623A→G) that was associated with AITD in the Caucasian population, and the associated nucleotide substitution SNP (−1623A/G) modified a binding site for interferon regulatory factor-1 (IRF-1), a major interferon-induced transcription factor, indicating enhanced sensitivity to this inflammatory cytokine .

The thyroid stimulating hormone receptor (TSHR) gene encodes a membrane protein that signals through binding TSH ligand and is a major controller of thyroid cell growth and metabolism. SNPs in intron 1 (in Caucasians) and intron 7 (in Japanese) have been associated with Graves’ disease in a number of studies . Recent data suggest that TSHR-associated SNPs are related to defective thymic tolerance for the TSHR as shown by reduced expression within the thymus gland where it is needed to delete TSHR autoreactive T cells .

Because all the identified susceptibility genes found to date appear to have a low level of contribution to genetic susceptibility, a number of whole-genome screening studies have also been attempted in AITD to find more important genes . One whole-genome association study using only 104 nonsynonymous SNPs (those involving parts of a gene likely to affect the product character) showed a number of the previously recognized genes, as well as locating some new sites, but the new sites could not subsequently be confirmed . Most recently, the first full genome-wide study of Graves’ disease with 660 K SNPs has now been reported from China . This study again identified many of the known genes for AITD, but also described two new sites on chromosomes 6q and 4p. These await further confirmation. Again, however, no very highly associated new genes have emerged.

6. The Degree of Enhanced Susceptibility Remains Low

All the genes associated with AITD are individually able to confer only modest degrees of disease susceptibility (expressed as odds ratios, see Table 3). Hence, these data only allow us to conclude that the AITDs, both Graves’ disease (including Graves’ ophthalmopathy) and Hashimoto’s thyroiditis, are complex genetic disorders involving multiple genes that may interact to provide a susceptible background for disease development. Furthermore, there appear to be disease-specific genes, such as the gene encoding the TSHR in Graves’ disease and a larger group of susceptibility genes, such as CTLA4, which are common to many autoimmune diseases. This combination of gene polymorphisms likely allows epigenetic phenomena, subsequent to a variety of influences such as infection and the environment, to initiate disease.

7. The Controversy over Major Genes in AITD

After the clarification that multiple genes are at work in AITD, it is likely that more than 20 potential genes contribute to the AITD phenotypes. But major genes, those essential to disease development, have not been found . A major gene should be involved in the majority of patients with the disease, and the risk ratios, even for HLA, do not reveal such a gene (Table 3). This most likely means that different combinations of genes may produce similar clinical phenotypes or that epigenetic phenomena are dominant. So far, in the whole-genome screening of families, siblings, and populations with AITD, a number of sites have been established for Graves’ disease and Hashimoto’s thyroiditis susceptibility, but none of them have had very high statistical values (LOD scores) . This finding has been true not just for AITD, but also for other autoimmune diseases including type 1 diabetes mellitus. This is best understood by thinking of HLA once again. Not every patient with Graves’ disease has the associated HLA-DR3 subtype and not even the associated Arg74 in its binding pocket, irrespective of the HLA-DR subtype . Hence, the disease can occur in the absence of the expected HLA association.

8. A Note on Epigenetics

One mechanism by which environmental factors may combine with genetic risk to promote AITD is by altering the epigenetic control of gene expression as seen, for example, in the pancreas and as shown for a virus interacting with a susceptibility gene in Crohn’s disease . While little is known about such interactions with AITD, there has been wide confirmation of a role for X chromosome inactivation (XCI) . Patients with AITD more often than expected showed a biased expression of a maternal or paternal X chromosome leading to the hypothesis that the poorly expressed chromosome could become active in certain tissues such as the thyroid and express new antigenic sequences not previously recognized by the immune system. These potential mechanisms for enhanced susceptibility to AITD require further exploration.

9. Conclusions

How environmental factors combine with genetic risk at the molecular level to promote complex genetic diseases such as AITD is largely unknown. The genes that are linked to and/or associated with AITD are each small contributors to genetic risk. Multiple-gene polymorphisms (combinations of haplotypes) appear to be needed to develop AITD and may differ between geographic populations secondary to epigenetic influences. Much remains to be learned.

Abbreviations

AITD: Autoimmune thyroid disease
LOD: Logarithm of odds
SNP: Single-nucleotide polymorphism.

Disclosure

TFD is a Board Member of Kronus Inc., Star, Idaho (a distributor of thyroid antibody test kits). The other authors have no conflict of interests to disclose.

This work is supported in part by DK052464 and DK069713 from the National Institute of Diabetes and Digestive and Kidney Diseases, the VA Merit Award program, and the David Owen Segal Endowment.

What to know about common thyroid disorders

Hyperthyroidism is when a person has too much thyroid hormone in their body, which speeds up their metabolic processes.

Someone with hyperthyroidism may initially have more energy, but their body will break down more quickly, which can cause various issues, especially fatigue.

Causes

Share on PinterestSleep problems are a common symptom of hyperthyroidism.

Hyperthyroidism is most often due to an autoimmune problem called Graves’ disease that causes the whole thyroid gland to make too much thyroid hormone.

It is not clear why people develop Graves’ disease, although researchers believe that genetics plays a role.

Graves’ disease is an autoimmune condition because it occurs when a person’s immune system creates antibodies that signal the thyroid gland to grow and produce significantly more thyroid hormone than the body needs.

Another cause of hyperthyroidism is called multinodular goiter. This condition is the result of one or more hormone-producing nodules in the thyroid gland that enlarge and release excess thyroid hormone.

Two problems that cause a high thyroid hormone level without having an overactive thyroid gland are:

  • Thyroiditis, a temporary inflammation of the thyroid gland due to an autoimmune condition or a virus. The same illness can also cause hypothyroidism.
  • Taking thyroid hormone replacement for an underactive thyroid.

Symptoms

According to the American Thyroid Association, common symptoms of hyperthyroidism can include:

  • an initial increase in energy
  • fatigue over timesweating
  • rapid pulse
  • tremors in the hands
  • anxiety
  • problems sleeping
  • thin skin
  • nervousness
  • irritability
  • fine and brittle hair
  • muscle weakness
  • frequent bowel movements
  • unintended weight loss
  • a light menstrual flow or fewer periods

A person with Graves’ disease may also experience inflammation of the eyes. This pushes the eyes forward, and they appear to bulge out.

However, only 5 percent of people with Graves’ disease have their vision severely or permanently affected.

The overstimulation of the thyroid gland often makes it enlarge, which is called a goiter.

Diagnosis

When diagnosing hyperthyroidism, a doctor will look for key symptoms, including an enlarged thyroid, a rapid pulse, tremors in the fingers, and moist, smooth skin.

As with hypothyroidism, they will also use laboratory tests that measure the amount of thyroid hormone and TSH in a person’s blood.

When people have hyperthyroidism, the body senses the high level of thyroid hormone in the blood and stops releasing TSH. As a result, tests show a low level of TSH. Other tests can then be done to determine the cause of the condition.

Treatment

A doctor may recommend beta-blockers as a short-term treatment for hyperthyroidism. Beta-blockers stop some of the effects of the thyroid hormone and quickly reduce some of the symptoms, such as a rapid pulse and tremors.

According to the American Thyroid Association, a doctor may also suggest a more permanent treatment:

  • Antithyroid drugs: These stop the thyroid from making so much thyroid hormone.
  • Radioactive iodine tablets: Thyroid cells absorb the iodine. This treatment destroys them, and the gland’s hormone overproduction stops.
  • Surgery: This is done by a surgeon who removes part or all of the thyroid.

If a person takes radioactive iodine or undergoes surgery, their thyroid may no longer be able to produce enough hormones, and they may develop hypothyroidism. They would then require thyroid hormone replacement treatment.

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