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Primary Thyroid cancer

Sunday, September 1, 2013 6:53

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Home of Kyle J. Norton for The Better of Living & Living Health Thyroid is one of the largest endocrine glands found in the neck, below the Adam’s Apple with the function of regulating the body use of energy, make of proteins by producing its hormones as a result of the stimulation of thyroid-stimulating hormone (TSH) produced by the anterior pituitary.
Thyroid disease is defined as a condition of malfunction of thyroid. Hyperthyroidism is a condition in which the thyroid gland is over active and produces too much thyroid hormones. Hypothyroidism is a condition in which the thyroid gland is under active and produces very little thyroid hormones. Thyroid cancer is defined as condition in which the cells in the thyroid gland have become cancerous.
Thyroid cancer is defined as condition in which the cells in the thyroid gland have become cancerous.

Types of thyroid cancer
The most common types of thyroid cancer include
1. Papillary thyroid cancer
Papillary thyroid cancer, the most common type of thyroid cancer, makes up about 80 percent of all thyroid cancers. The cancer tends to develop in the women age group between 30-40 years of age and grow slowly. Papillary thyroid cancer can be cure if diagnosed early.
2. Follicular thyroid cancer
Follicular thyroid cancer, the second most common thyroid cancer, makes up about 15 percent of all case. It is a low grow cancer with peak onset ages 40 through 60. Follicular thyroid cancer can be treat successful, if diagnosed early.
3. Medullary thyroid cancer
Medullary thyroid cancer, third most common thyroid cance makes up about 3 percent of all cases, arise from thyroid hormone producing cells with abnormally high levels of calcitonin. Medullary thyroid cancer tends to grow slowly but it can spread to distant parts of the body, if not treated early.
4. Anaplastic thyroid cancer
Anaplastic thyroid cancer the rare case of thyroid cancer, makes up less than 2 percent of all cases. The cancer cells tend to grow and spread very quickly. Anaplastic thyroid cancer is deadly, with only 10% of alive rate, 3 years after it is diagnosed.

Symptoms
1. Lump in the neck
Due to uncontrollable cells growth and only 5% of this lumps are found to be cancerous.
2. Enlarged lymph node
Cancer has invaded the lymph nodes and its surrounding
3. Change of voice
Hoarseness or difficulty speaking in a normal voice as the tumor has affected the voice-box region.
4. Pain or discomfort in the throat or neck.
5. problem of swallowing
As a result of tumor has affected the esophagus or of enlarged lymph node
6. Difficult breathing
Cancer may have invaded the lung or may affect either the upper or lower of respiratory track or due to enlarged lymph node
7. Etc.

Causes and risk factors
1. Age
Risk of thyroid cancer increase with age after 30
2. Gender
Women are twice at risk to develop thyroid cancer than men.
3. Race
In US, according to statistic, Caucasians are at greater risk than African Americans to develop thyroid cancer.
5. Exposure to radiation
People who exposed to the radiation therapy at a young age to treat certain cancer are at higher risk to develop thyroid cancer at later age.
6. Family history
Increased risk of thyroid cancer if one of your direct family has a history of thyroid cancer
7. chronic goiter
Risk of thyroid cancer increased if you have a history of enlargement of the thyroid gland.
8. Exposure to certain chemical agents
In a study by Copenhagen researchers, the effect of chemicals such as polychlorinated biphenyls and dioxins on the thyroid. Ron and co-authors noted the correlation between chemicals and increased TSH and the resulting potential “in an increased opportunity for mutations and the development of cancer.”
9. Low level of iodine
People with life-long iodine deficiency are more likely to develop thyroid cancer.
10. Heredity
People born with mutation in the RET proto-oncogene are at risk in developing medullary thyroid cancer (MTC).
11. Etc.

Diagnosis and tests
After family history and careful physical examination, If you have a family history of medullary thyroid cancer, blood test for calcitoninis is necessary
1. Blood test
The blood is to determine the levels of calcitoninis, elevation of calcitoninis may be signed of thyroid cancer.

2. Thyroid scan
With the inject of asotope, your doctor can view the images capture which will be classified according the amount asotope of absorption by the thyroid gland. If the gland is actively taking up the isotope, ultrasound will show whether the abnormality is a cyst or not. Thyroid biopsy may be required to further assessment.

3. Thyroid biopsy
In thyroid biopsy, a sample ofthe effected area is taken by a thin needle instrument (thin needle aspirate, under local anesthesia and examined by a pathologist under microscopy to view the type and stage of the cancer.

4. CT Scan (computerized tomography)
A CT scan generates a large series of two-dimensional X-ray images taken around a single axis of rotation, to create a three-dimensional picture of the inside of the body in details.The pictures are viewed by your doctor to see the extent of the tumors abnormalities, such as spreading of cancer to the nearby structure and lymph nodes.

5. Etc.

Grades
The Grades of Thyroid cancer are depending to the tendency of spreading. Low grade cancers usually grow more slowly and are less likely to spread while high grade cancer indicates otherwise.

Stages
Thyroid cancer is classified as 5 stages
1. Stage 0
If the cancerous cell have not penetrated in deeper tissue but in the surface of the thyroid lining.

2. Stage I
In stage I, The cancerous cells are no longer in the surface but have invaded into deep thyroid lining, but still completely inside the thyroid gland.
Stage IA1

The cancer is not ≤ 3 mm (1/8 inch) deep and ≤ 7 mm (1/4 inch) wide.
a.1. Stage IA1:
The spreading is not less than 3mm(1/8 inch) deep and & less than 7mm (1/4 inch) wide.
a.2. Stage IA2: The invasion area is ≥ 3 mm but ≤ 5 mm (about 1/5 inch) deep and & less than 7 mm (about 1/4 inch) wide.

b. Stage IB:The cancer in this stage have invaded the connective tissue, & less than 5mm (1/5 inch).
b.1. Stage IB1:
Cancer is 4 cm large (1 3/4 inches).
b.2. Stage IB2:
Cancer is ≥ 4 cm (1 3/4 inches) but & less than 5cm (1/5 inch)

3. Stage II
In stage II, the cancerous cells have spread to distant tissues, but is still within the thyroid gland.

4. Stage III
In this stage, cancerous cells has spread to the tissues immediately surrounding thethyroid gland

5. Stage IV
In this stage, cancerous cells has spread to the tissues immediately outside of the thyroid gland, other distant parts of the body.

Preventions
A. What to avoid
1. Potassium Iodide
Potassium Iodide (KI) is one of the drug which can absorb radioactive iodine cause of thyroid disease and cancer. Today it has been used worldwide to prevent thyroid cancer in people who are exposed to radioactive iodides.

2. Avoid exposure to radiation
People who exposed to the radiation therapy at a young age to treat certain cancer are at higher risk to develop thyroid cancer at later age. Extra precaution to prevent exposure the thyroid gland when X ray is taken.

3. Avoid Iodine deficiency
Increase Iodine intake from diet to prevent iodine deficiency cause of thyroid cancer.

4. Avoid certain chemical agents
Chemicals such as polychlorinated biphenyls and dioxins can increase the risk of thyroid cancer

5. Lose weight
In an article Published in the journal Cancer Epidemiology, Biomarkers and Prevention the meta-study indicated that the risk of thyroid cancer increases for obese men at roughly the same rate as it does for women.

5. Avoid chlorine and fluoride
Chlorine and fluoride are chemically related to iodine and they can block iodine receptors

6. Etc.

B. Diet
1. Cruciferous vegetables
Cruciferous vegetables such as cauliflower, broccoli, cabbage, etc. beside contain high amount of antioxidants, but also phytonutrients that have been shown to help prevent the onset and halt the progression of certain cancers.

2. Green tea
In some clinical studies researchers suggested that the polyphenols in green tea, may play an important role in the prevention of cancer by killing cancerous cells and stopping their progression.

3. Garlic
An analysis of several case-controlled studies in Europe suggests an inverse association between garlic consumption and risk of common cancers.

4. Tomato
Many studies showed that antioxidant lycopene in tomato inhibits cancer cell growth and exhibit apoptosis, causing cell death.

5. Soy
In laboratory studies, saponins have shown the ability to inhibit the reproduction of cancer cells and slow the growth of tumors in several different tissues.

6. Etc.

C. Nutritional supplements
1. Free radicals scavengers
Vitamin A, C, E are free radical scavengers enhanced the immune system against the forming of free radicals and prevent the alternation of cell DNA cause of abnormal cell growth. For more information of how antioxidants help to treat cancer, click here

2. Modified citrus pectin
In a study of researcher found modified citrus pectin may help block the growth and metastasis of solid tumors.

3. Selenium
Research showed that selenium has a protective effect on various stages of cancer, including both the early and later stages of the disease. In a study in large groups of people, researchers found that in areas of the world where selenium levels in the soil are high, death rates from cancer are significantly lower than in areas where selenium levels are low.

4. Lycopene
Many studies showed that antioxidant lycopene in tomato inhibits cancer cell growth and exhibit apoptosis, causing cell death.

5. Beta -carotene
In some laboratory, animal, and human studies, researchers found that vitamin A, certain retinoids may also inhibit cancer development.

6. Etc.

Treatments
A. In conventional medicine
Treatment of thyroid cancer not only depends on the stage, grade but also age of the patient. Thyroid cancer occurs in older people tends to be aggressive, while in young adulthood and adolescence are curative

1. Surgery
The objective of the surgery is to cure, especial in the younger age group. If the cancer is low-grow and in the early stage, in most case after the thyroid gland was removed, patient will need to take thyroxine tablets for the rest of his/her life. If the cancer has spread to the nearby lymph nodes, the lymph nodes are also removed in the same surgery.
If your blood indicates that you have an elevation of calcitoninis, an inherited medullary thyroid cancer, then surgery may be only treatment.

2. Radioactive Iodine
Radioactive iodine usually is also used to treat hyperthyroidism. In case of thyroid cancer, radioactive iodine helps to destroy any remaining thyroid cancer cells after surgery.
Since it is highly radioactive, avoid exposing radioactivity to your family members or other people, there are some instructions that you must follow for the first 5 days after your treatment
a. Drink plenty of fluids.
b. Avoid contact with children and pregnant women.
c. Sleep in your own room.
d. Use separate towels, face cloths, and sheets.
e. Wash above and your personal clothing separately for 5 days
f. Etc.

3. Radiotherapy
a. Radiation may be used for stages II, III, and IV to kill any cancer cells remaining in the body. By using high-energy x-rays or other types of radiation, radiation therapy kills the cancer cells and keep them from growing or regrowing.
b. Side effects
b.1. Fatigue
b.2. Chest pain
b.3. Heart problem
b.4. Short of breath
b.5. Skin discoloration or pinkness, irritation.
b.6. Etc.
In the elder, and if the cancer has spread, chemotherapy may be recommended

4. Chemotherapy
Chemotherapy is most use to treat with advance stage of cancer combined with radio therapy, as it has spread to a distant parts of the body by using drugs taken by mouth or injected into a vein or muscle of the patient to stop the growth of or to kill cancer cells.
b. Side effects
b.1. Nausea
b.2. Vomiting
b.3. Hair loss
b.4. Fatigue
b.5. Anemia
b.6. Mouth sores taste and smell changes
b.7. Infection
b.8. Etc.

B. Herbal medicine
1. Aloe
in some studies, researchers suggest that some chemical compounds of aloe, such as acemannan, aloeride, and di(2-ethylhexyl)phthalate (DEHP) may have immunomodulating and anticancer effects.

2. Absinthe
Absinthe is also known as Wormwood, a distilled, highly alcoholic beverage flowers extracted from leaves of the herb Artemisia absinthium. In a study, researcher at the University of Washington found that wormwood can be used as a promising potential treatment for cancer.

3. Fenugreek
Fenugreek is used both as a herb (the leaves) and as a spice (the seed), genus Trigonella, belonging to family Fabaceae. Vitro studies have shown that fenugreek exhibits chemopreventive properties against certain cancers.

4. Devil’s Claw
The extract of Harpagophytum procumbens, commonly known as devil’s claw,
In vitro studies, researchers found that cat’s claw demonstrated anticancer effects against several cancer cell lines and has been reported to be effective in the treatment of lymphoma cancer, according to a study conducted by K. S. Wilson, M.D., which was published in the journal “Current Oncology” in August 2009.

5. Celandine
Celandine is a herbaceous perennial plant, genus Chelidonium, belonging to the family Papaveraceae, native to Europe and western Asia and introduced widely in North America.
In a study of Ukrain (Ukrain is an anticancer drug based on the extract of the plant)– a new cancer cure? A systematic review of randomised clinical trials, researcher suggested, according to the data from randomised clinical trials that Ukrain to have potential as an anticancer drug. However, numerous caveats prevent a positive conclusion, and independent rigorous studies are urgently needed.

6. Etc

C. Traditional Chinese medicine
1. Pu Kong Yin (Dandelion Root)
In a study of the efficacy of dandelion root extract in inducing apoptosis in drug-resistant human melanoma cells, researchers found that treatment with this common, yet potent extract of natural compounds has proven novel in specifically inducing apoptosis in chemoresistant melanoma, without toxicity to healthy cells.

2. Xia Ku Cao (Selfheal Fruit-Spike)
Researchers found that cyasterone in Xia Ku Cao showed anti tumor activity.

3. Qing hao
Qing hao is also known as wormwood. In a study, researcher at the University of Washington researcher found that wormwood can be used as a promising potential treatment for cancer among the ancient arts of Chinese folk medicine.

4. Jie Geng
The Researchers found that aponins in Jie Geng have been shown to very significantly augment the cytotoxicity of immunotoxins and other targeted toxins directed against human cancer cells.

5. Gan Cao
Gan Cao is also known as Licorice root. In-vitro, researchers found that saponins in Gan Cao stimulate the immune system and inhibit Epstein-Barr virus expression and possess anti-cancer activities.

Sources
(a) http://www.ncbi.nlm.nih.gov/pubmed/9510123
(1) http://link.springer.com/article/10.1007%2FBF02307032#page-1

II. Functional disorders
II.1. Hypothyroidism
Hypothyroidism is a condition in which the thyroid gland is under active and produces very little thyroid hormones.
A. Symptoms
Symptoms of the Hypothyroidism is depended to the severe stage of the disease. as it progresses slowly over years. Most common symptoms include
1. Fatigue, weight gain, depression, myalgia, edema
In the study by the Universitatsspital Zürich, the main symptoms of Hypothyroidism are
fatigue, weight gain, depression, myalgia, edema
1. Weight gainand fatigue
In a prospective observational research design where 198 consecutive breast cancer patients receiving adjuvant chemotherapy were monitored from start to end and 6 months post-therapy on changes in anthropometics, fatigue, nutritional intake, physical activity, thyroid and steroid hormones, found that a weight gain over >5 lb in 22.2% of this patient population with a significant and progressive gain of 6.7 lb (P < 0.0001) at 6 months. Ninety four percent of all patients reported fatigue and 56% of patients reported lowered physical activity. A significant reduction in serum free and total estradiol (P < 0.0001) was observed indicative of reduction in ovarian function with 86% amenorrehic at the end of treatment. A significant reduction in mean serum triiodothyronine uptake levels (P < 0.05), in addition to a significant increase in TBG (P < 0.0001) from baseline to end of chemotherapy, was observed. In addition 20-25% of this patient group was already diagnosed with clinical hypothyroidism at diagnosis and treated. Changes in fatigue frequency and serum sex-hormone-binding globulin (SHBG) were variables significantly predictive of weight gain (P < 0.0001)(1).

2. Vitiligo and alopecia areata
There is a report of the parents of an 18-year-old woman had noticed white hair while combing their daughter’s hair 12 years ago. They found tiny white spots on her scalp, but she was asymptomatic. The spots have since progressed. Examination of the affected skin on the scalp was marked by the presence of a chalky/ivory white macule, 8 to 10 cm in diameter, conforming to that of segmental (zosteriformis) vitiligo (Figure 1). The lesions were located on the temporoparietal region of the scalp. The hair over the macules was white (leukotrichia) and dry, coarse, and brittle. The patient’s nails were thin and dull. Her thyroid profile revealed the following: triiodothyronine, 1.12 nmol/L (0.95-2.5 nmol/L); thyroxine, 69.21 nmol/L (60.0-120.0 nmol/L); and thyroid-stimulating hormone, 6.26 microIU/mL (0.25-5.00 microIU/mL), indicative of primary hypothyroidism(2).

3. Chronic constipation
Geriatric patient educational material and a general practice review suggest insufficient dietary fiber intake, inadequate fluid intake, decrease physical activity, side effects of drugs, hypothyroidism, sex hormones and colorectal cancer obstruction may play a role in the pathogenesis of constipation, according to the study by the University of California at Los Angele(3).

4. Urticaria and puffiness of hands and feet, yellow ivory skin, coarse rough dry skin, alopecia periorbital edema, amenorrhe, dysparunia, PCO, PMS and Breast tenderness, menstrual irregularities and infertility
In the study to study is to highlight the presenting dermatologic and gynecologic manifestations of firstly-diagnosed hypothyroid females, showed that Compared to euthyroid cases, hypothyroid ones were presenting mostly with amenorrhea (OR=7.76). Other gynecologic manifestations that were prominent in hypothyroid cases were dysparunia, PCO, PMS and Breast tenderness. On the other hand, rate of menstrual irregularities and infertility were non-significantly different in both groups.hypothyroid women showed also significantly higher frequency of urticaria and puffiness of hands and feet (both were present in 16.7% in hypothyroid vs. 3.3% of euthyroid cases, p =0.007, OR=5.8). Hypothyroid cases showed also significantly higher frequency of yellow ivory skin (OR=5.4) and coarse rough dry skin (OR=3.8). On the other hand, alopecia and periorbital edema were observed only among cases of hypothyroidsm and none of euthyroid cases(4).

5. Depression
In the study to investigate the depression-like behavior performances of subclinical hypothyroidism (SCH) rat. SCH rat model induced by hemi-thyroid electrocauterization, and the behavior performances were measured by sucrose preference test, force swimming test (FST), and tail suspension test (TST). SCH rat model was established successfully by hemi-thyroid electrocauterization, found that SCH could result in depression-like behavior, accompanied with subtle hyperactivity of HPA axis. The reduced hippocampal T3 prior to the reduction of thyroid hormone in serum might be taken as an early sign of hippocampus impairment in the progression from SCH to CH(5).

6. Mood, declarative memory, motor learning and working memory
In a double-blinded, randomized, cross-over study of usual dose l-T(4) (euthyroid arm) vs. higher dose l-T(4) (subclinical thyrotoxicosis arm) in hypothyroid subjects, showed that The Profile of Mood States (POMS) confusion, depression, and tension subscales were improved during the subclinical thyrotoxicosis arm. Motor learning was better during the subclinical thyrotoxicosis arm, whereas declarative and working memory measures did not change. This improvement was related to changes in the SF-36 physical component summary and POMS tension subscales and free T(3) levels(6).

7.

B. Causes and Risk factors
B1. Causes
1. Autoimmune disease
Primary overt autoimmune hypothyroidism is often divided into primary idiopathic hypothyroidism with thyroid atrophy (Ord’s disease) and hypothyroidism with goitre (Hashimoto’s disease). According to the study by the Aarhus University Hospita, in primary autoimmune hypothyroidism, thyroid volume follows a normal distribution. Cases with thyroid atrophy and goiter are only extremes within this distribution and do not represent separate disorders. However, patients with low vs. high thyroid volume differ with respects to several characteristics(7).

2. Congenital Hypothyroidism
The incidence of CH and other thyroid dysfunctions were greater in our population for 2007 to 2010, after which there was an unexplained decline. The study underlines the importance of continued newborn screening for thyroid dysfunction, according to the study by the Columbia University Medical Center(8).

3. Pituitary disorder
It is important to recognise that a normal TSH does not exclude central hypothyroidism. By raising awareness with general practitioners of pituitary disease, with potential for deficiency of other anterior pituitary hormones, would focus more specific questioning on related symptoms(9).

4. Pregnancy
According to the University of Texas Southwestern Medical Center, in the data of all women who presented to Parkland Hospital for prenatal care between November 1, 2000, and April 14, 2003, had thyroid screening using a chemiluminescent TSH assay. Women with TSH values at or above the 97.5th percentile for gestational age at screening and with free thyroxine more than 0.680 ng/dL were retrospectively identified with subclinical hypothyroidism(10).

2. Iodine deficiency
Iodine is a key element in the synthesis of thyroid hormones and as a consequence, severe iodine deficiency results in hypothyroidism, goiter, and cretinism with the well known biochemical alterations, according to the study by Verheesen RH and Schweitzer CM(11)

B.2 Risk factors
1. Genetic and environmental factors and family history
Genetic and environmental factors are involved in the pathogenesis of autoimmune thyroid disease (AITD). Family members of patients with AITD are at increased risk for AITD, but not all will develop overt hypothyroidism or hyperthyroidism, according to the study by the Academic Medical Center, Netherlands(11)

2. Smoking
smoking is a powerful risk factor for thyroid disease, especially in populations with a high smoking frequency, according to the study by the Aarhus University Hospital(12). Other study indicated that smoking reduced the risk of hypothyroidism and increased the risk of hyperthyroidism(13).

3. Age
Hypothyroidism is associated to increased age. In the study to evaluate the ability of the aged rat pituitary to increase TSH secretion in response to major decreases in serum thyroid hormones, hypothyroidism was induced by methimazole in young and old, male and female, Dutch-Miranda and Wistar rats, showed that the ability of the pituitary thyrotrophs to increase hormonal secretion in response to decreased levels of thyroid hormones is impaired in the old rat, even when the thyroid hormone levels are dramatically reduced(14).

4. Autoimmune disorders, thyroid injury, post partum state, non-thyroidal illness, or medications
According to the study by the Universitätsspital Basel, in the study of Hypothyroidism suggested that s
earch for hypothyroidism should therefore focus on patients with symptoms and signs and/or those presenting risk factors for development of hypothyroidism (e.g., autoimmune disorders, thyroid injury, post partum state). Because of the lack of specificity of sings and symptoms of this frequent disorder the diagnosis is based on measurement of TSH or TSH and fT4 in case of conditions that may affect TSH values such as non-thyroidal illness, or medications(15).

5. Radiation
In the study to investigate the possible histopathological effects of pulse modulated Radiofrequency (RF) fields on the thyroid gland using light microscopy, electron microscopy and immunohistochemical methods, indicated that whole body exposure to pulse-modulated RF radiation that is similar to that emitted by global system for mobile communications (GSM) mobile phones can cause pathological changes in the thyroid gland by altering the gland structure and enhancing caspase-dependent pathways of apoptosis(16).

6. Post preganacy
In the study of the spontaneous occurrence of, and recovery from primary hypothyroidism were observed after delivery in 6 women with autoimmune thyroiditis, showed that diffuse goiter was noticed 1-3 months after delivery. The blood thyroid hormone level was found to be lowest at 3-6 months post-partum, with a thyroxine iodine value of 1.0 +/- 0.6 mug/dl (mean +/- SD) (normal 3.0-7.2), triiodithyronine value of 77 +/- 11 ng/dl (normal 90-190) and T3 resin sponge uptake of 21 +/- 2.8% (normal 24-37)(17).

7. Partial thyroidectomy
is associated to increased risk of hypothyroidism, but according to study of one hundred and twenty-two patients reviewed 1-7 years after partial thyroidectomy for thyrotoxicosis by two surgeons who had left thyroid remnants of different size, there was no significant difference in the prevalence of hypothyroidism or in the serum levels of thyroxine, tri-iodothyronine or thyroid-stimulating hormone between the two groups of patients. The overall prevalence of hypothyroidism was 16 per cent(18).

C. Complications and diseases associated to hypothyroidism
C.1. Complications
1. Coronary heart disease and mortality
In the study to assess the risks of coronary heart disease (CHD) and total mortality for adults with subclinical hypothyroidism of Individual data on 55,287 participants with 542,494 person-years of follow-up between 1972 and 2007 were supplied from 11 prospective cohorts in the United States, Europe, Australia, Brazil, and Japan. The risk of CHD events was examined in 25,977 participants from 7 cohorts with available data. showed that subclinical hypothyroidism is associated with an increased risk of CHD events and CHD mortality in those with higher TSH levels, particularly in those with a TSH concentration of 10 mIU/L or greater(19).

2. Recurrent pregnancy loss
Thyroid disturbances are common in women during their reproductive years. Thyroid dysfunction interferes with human reproductive physiology, reduces the likelihood of pregnancy and adversely affects pregnancy outcome, thus becoming relevant in the algorithm of reproductive dysfunction. According to the study by the MGM Medical College, pregnant women with subclinical hypothyroidism or thyroid antibodies have an increased risk of complications, especially pre-eclampsia, perinatal mortality, and miscarriage. Universal screening for thyroid hormone abnormalities is not routinely recommended at present, but thyroid function must be examined in female with fetal loss or menstrual disturbances. Practitioners providing health care for women should be alert to thyroid disorders as an underlying etiology for recurrent pregnancy loss(21).

3. Ovulatory dysfunction, adverse pregnancy, miscarriage rate, sperm motility, decrease fertility and increased genetic malformation rate
Subclinical hypothyroidism may be associated with ovulatory dysfunction and adverse pregnancy outcome. Thyroid autoimmunity increases the miscarriage rate, and thyroxine treatment does not seem to protect. Menstrual disturbances, frequent in thyrotoxicosis are restored following treatment. In males, thyrotoxicosis has a significant but reversible effect on sperm motility. Although radioactive Iodine (I) in ablation doses may transiently affect the gonads, it does not decrease fertility or increase genetic malformation rate in the offspring, according to the study by the Pedieos IVF Center, Cyprus(21).
Other study indicated that pregnant women with subclinical hypothyroidism or thyroid antibodies have an increased risk of complications, especially pre-eclampsia, perinatal mortality, and miscarriage(22)

4. Increased susceptibility to inflammatory diseases in the CNS of offspring
A deficiency in maternal thyroid hormones during gestation can influence the outcome of a CNS inflammatory disease, such as EAE, in their offspring. These data strongly support evaluating thyroid hormones in pregnant women and treating hypothyroidism during pregnancy to prevent increased susceptibility to inflammatory diseases in the CNS of offspring, according to the study by the Universidad Andres Bello, Ciencias Biologicas(23).

5. Auditory function
Although only a limited number of studies have directly investigated the relationship between iodine deficiency and auditory function, most studies point toward an association. However, evidence from good randomised controlled trials is lacking. Inclusion of auditory outcomes in iodine supplementation studies is therefore to be recommended, especially for trials in pregnancy. Hearing deficit is an invisible abnormality, but has major consequences for educational and social skills if not detected, according to the study by the Wageningen University, Wageningen(24).

6. Hearing loss
In the study to assess hearing and its determinants in a population-based registry of young adult patients with CH, showed that despite major improvements in prognosis, hearing loss remains a significant problem, particularly in patients with severe CH. Parents and primary care providers should be aware of this risk, as early diagnosis and intervention could improve the long-term prognosis of these patients(25).

7. Goiter
There is a report of IgG4 thyroiditis in a Graves’ disease patient with large goiter developing hypothyroidism, according to the study by the Kuma Hospital(25a)

C.2. Diseases associated to hypothyroidism
1. Systemic Sclerosis
Context:Systemic sclerosis (SSc) is a connective tissue disease of unknown etiology, and several studies reported its association with thyroid autoimmune disorders, according to the study by the University of Pisa and University of Modena and Reggio Emilia, there is a high incidence of new cases of hypothyroidism and thyroid dysfunction in female sclerodermic patients. Female sclerodermic patients, who are at high risk (a borderline high [even if in the normal range] TSH value, anti-thyroperoxidase antibody positivity, and a hypoechoic and small thyroid) should have periodic thyroid function follow-up(26).

2. Osteoarthritis and fibromyalgia
In the study of 91 women with RA evaluated, 29 (30%) had evidence of thyroid dysfunction compared with 10 (11%) of 93 controlsto determine whether thyroid dysfunction is found with increased frequency in patients with rheumatoid arthritis (RA), showed that thyroid dysfunction is seen at least three times more often in women with RA than in women with similar demographic features with non-inflammatory rheumatic diseases such as osteoarthritis and fibromyalgia(27).

3. Type 1 diabetes mellitus (T1DM)
In the study of the data of consecutive patients of T1DM presenting to department of Endocrinology from May 1997 to December 2011 were retrospectively analyzed in context of associated clinical profile, found that among 260 patients diagnosed as T1DM, 21 (8%) had hypothyroidism, 4 (1.5%) had hyperthyroidism and 2 (0.7%) had primary adrenal insufficiency. Eighteen patients (7%) had celiac disease, 9 (3.5%) had Turner’s syndrome, 5 patients (1.9%) had Klinefelter’s syndrome, whereas Down’s syndrome and Noonan’s syndrome was present in 2 and 1 patients (0.7%) respectively(28).

4. Increased pituitary corticotroph responsiveness to CRH and abnormalities in all three components of the HPA axis
According to the study by the, long-term hypothyroidism is associated with adrenal insufficiency with abnormalities in all three components of the HPA axis. Short-term hypothyroidism, on the other hand, is associated with increased pituitary corticotroph responsiveness to CRH(29).

5. Hyponatremia
According to the study by the Leiden University Medical Center, hyponatremia in hypothyroidism is due to a pure renal mechanism, and cannot be ascribed to inappropriate secretion of antidiuretic hormone(30).

6. Hashimoto’s Thyroiditis
Hashimoto’s thyroiditis is the most common cause of hypothyroidismas a result of an autoimmune disease.

7. Solitary toxic thyroid nodules
According to the study lead by Ross DS of the Forty-five patients with solitary toxic thyroid adenomas received 131I (mean dose, 10.3 mCi) for treatment of hyperthyroidism and were followed for 4.9 +/- 3.2 years (range, 0.5 to 13.5). Seventy-seven percent were euthyroid by 2 months, 91% by 6 months, and 93% by 1 year. Only 3 patients did not respond to a single dose of 131I, but all responded to multiple doses. Late recurrent hyperthyroidism occurred in 3 patients at 4.5, 6, and 10 years after treatment with a single dose of 131I(31).

8. Rhabdomyolysis
There is a report of a case of rhabdomyolysis associating hypothyroidism. Hypothyroidism frequently leads to myalgias, muscle stiffness, cramps and sometimes elevated levels of muscle enzymes, but rhabdomyolysis is quite rare, according to the study by the Selcuk University(32).

9. Thyroid cancer
Acute hypothyroidism induced by thyroid hormone withdrawal in patients with differentiated thyroid cancer during monitoring for remnant or metastatic disease, seriously affects multiple organs and systems, and especially in severe cases can impair quality of life, according to the study by the University of Athens(33).

10. Restless leg syndrome
There is a study indicated that Restless leg syndrome as a result of moderate hypothyroidism(34).

11. Myxedema coma
Myxedema coma is the extreme manifestation of hypothyroidism, typically seen in patients with severe biochemical hypothyroidism. Its occurrence in association with subclinical hypothyroidism is extremely unusual, according to the study by the Prince Charles Hospital(35).

12. Tarsal Tunnel Syndrome
Tarsal tunnel syndromeis associated to hypothyroidism, according to the study by the
Atkinson Morley’s Hospital, Wimbledon(36).

13. Carpal Tunnel Syndrome
There is a report of a patient who developed symptoms of bilateral carpal tunnel syndrome following radioactive iodine induced hypothyroidism(37).

14. Fatty liver
According to the study by the research team lead by Xu L, there is an Impact of subclinical hypothyroidism on the development of non-alcoholic fatty liver disease(38).

15. Sleep apnea and sleep disorders
Hypothyroidism is associated with abnormal ventilatory drive, abnormal sleep architecture, and sleep apnea. Central, obstructive, and mixed patterns of sleep apnea are commonly observed in hypothyroidism, according to the study by the Medical College of Georgia(39).

D. Misdiagnosis and Diagnosis
D.1. Misdiagnosis
1. Normal aging process and to the patient’s other health conditions
A diagnosis of hypothyroidism in the elderly can easily be overlooked if we rely exclusively on its clinical presentation because this may be highly non-specific, since the signs and symptoms of the disease are common to other diseases typical of old age, and even to the normal aging process. There is a report of a case of primary hypothyroidism that was diagnosed late because the correlated signs and symptoms (asthenia, bradycardia, pleural effusions, hyponatremia, worsening renal and respiratory insufficiency, hoarseness) had previously been attributed to the normal aging process and to the patient’s other health conditions (Parkinson’s disease, PD; chronic obstructive pulmonary disease, COPD)(40).

2. Reversal deterioration of renal function
There are a report of two patients with elevated serum creatinine levels due to primary autoimmune hypothyroidism, with complete recovery of creatinine clearance after thyroid hormone substitution therapy are presented. The first patient was a young male whose laboratory tests suggested acute renal failure, and the delicate clinical presentation of reduced thyroid function. The second patient was an elderly woman with a history of a long-term signs and symptoms attributed to ageing, including the deterioration of renal function, with consequently delayed diagnosis of hypothyroidism, according to the study by the Military Medical Academy, Clinic of Endocrinology(41).

3. Respiratory failure
There is a report of a 36 years male, admitted to the hospital for progressive respiratory failure. Chest X ray and CT scan were normal. On admission, a severe bradycardia and slow intellectual activity were noted. Serum thyroid function tests showed a TSH over 150 microU/ml and T3 of 75 ng/ml. Thyroid substitution therapy was associated with a progressive improvement of respiratory function, according to the study by the Servicio de Medicina del Hospital(42).

4. Brain stem infarct
Myxedema coma is the extreme form of untreated hypothyroidism. There is report of a patient with myxedema coma which was initially misdiagnosed as a brain stem infarct. The diagnosis of myxedema coma was often missed or delayed due to various clinical findings and concomitant medical condition and precipitating factors. It is more difficult to diagnose when a patient has no medical history of hypothyroidism, according to the study by the Hallym University(43).

5. Statin intolerance
There is a report of a case of Hypothyroidism misdiagnosed initially as statin intolerance, according to the study by Krieger EV, and Knopp RH(44).

6. Hypercholesterolaemia and simvastatin-induced myositis
There is a report of report of a 50-year-old woman who presented with hypertension. She was given simvastatin for hypercholesterolaemia. The creatine kinase level was 3180 U/L at the 3-month follow-up visit, which was thought to be due to simvastatin treatment. Although treatment was discontinued, the creatine kinase level 4 months later remained higher than 3000 U/L. Echocardiography revealed mild pericardial effusion and normal left ventricular function; the electromyogram was also normal. The patient subsequently showed signs and symptoms suggestive of hypothyroidism, which was confirmed by measurements of the concentration of thyroid-stimulating hormone (>100 mU/L) and free thyroxine (<2 pmol/L)(45)..

D.2. Diagnosis
If you are experience certain symptoms of above and/or have had previous thyroid problems or goiter. , your doctor may suspect that you have underactive thyroid. Your doctor may order blood test to measure the level of TSH and the level of the thyroid hormone thyroxine and triiodothyronine, depending to the stage of the diseases. According to the study by the College of Medicine, Mayo Clinic, hypothyroidism is the result of inadequate production of thyroid hormone or inadequate action of thyroid hormone in target tissues. Primary hypothyroidism is the principal manifestation of hypothyroidism, but other causes include central deficiency of thyrotropin-releasing hormone or thyroid-stimulating hormone (TSH), or consumptive hypothyroidism from excessive inactivation of thyroid hormone. Subclinical hypothyroidism is present when there is elevated TSH but a normal free thyroxine level(46).

E. Prevention
E.1. Diet to prevent Hypothyroidism
1. Seaweed, kelp or laver, seafood and seawater fish
According to the study by the University of Hong Kong, in the study carried out to analyse the urine iodine excretion in Hong Kong, a coastal city in the southern part of China because of a high incidence of transient neonatal hypothyroidism and a relatively high mean cord blood thyrotropin (TSH) concentration, found that 5.3% of the children, 51.7% of the adults and 55.3% of the elderly had urine iodine concentration below the criteria for iodine sufficiency (< 0.79 mumol/l). Iodine content in the drinking water and salt was low. A dietary survey revealed that seafood was not commonly consumed. 50-80% of the subjects never consumed high-iodine containing food such as seaweed, kelp or laver, and only 50% consumed seawater fish daily(47).

2. Iodized salt
In the study of Eearly morning urine collected from healthy volunteers including children (n = 104), adults (n = 112) and elderly subjects (n = 349) with a semi-quantitative questionnaire survey on the pattern of food intake was conducted in the adults and elderly, found that 45.3% of the children, 51.7% of the adults and 55.3% of the elderly had urine iodine concentration below the criteria for iodine sufficiency (< 0.79 mumol/l). Iodine content in the drinking water and salt was low(48).

3. Soy and seaweed
In the study to evaluate the relevant literature and provide the clinician guidance for advising their patients about the effects of soy on thyroid function, showed that soy foods, by inhibiting absorption, may increase the dose of thyroid hormone required by hypothyroid patients. However, hypothyroid adults need not avoid soy foods. In addition, there remains a theoretical concern based on in vitro and animal data that in individuals with compromised thyroid function and/or whose iodine intake is marginal soy foods may increase risk of developing clinical hypothyroidism(49a). Others suggested that Seaweed ingestion increased I/C concentrations (P < .0001) and serum TSH (P < .0001) (1.69 +/- 0.22 vs. 2.19 +/- 0.22 microU/mL, mean +/- SE). Soy supplementation did not affect thyroid end points. Seven weeks of 5 g/day seaweed supplementation was associated with a small but statistically significant increase in TSH. Soy protein isolate supplementation was not associated with changes in serum thyroid hormone concentrations(49).

E.2. Antioxidants and phytochemical to prevent Hypothyroidism
1. Iodine
There is a report of the Japanese experience may indicate a protective effect against breast cancer for an iodine rich seaweed containing diet. Similarly thyroid autoimmunity may also be associated with improved prognosis. Whether this phenomenon is breast specific and its possible relationship to iodine or selenium status awaits resolution(50).

1. Resveratrol
In the study of resveratrol, the main ingredient found in skin and seed of grape and its impact on aging and thyroid function, showed that resveratrol is believed to regulate several biological processes, mainly metabolism and aging, by modulating the mammalian silent information regulator 1 (SIRT1) of the sirtuin family. Resveratrol may arrest, among various tumors, cell growth in both papillary and follicular thyroid cancer by activation of the mitogen-activated protein kinase (MAPK) signal transduction pathway as well as increase of p53 and its phosphorylation. Finally, resveratrol also influences thyroid function by enhancing iodide trapping and, by increasing TSH secretion via activation of sirtuins and the phosphatidylinositol- 4-phosphate 5 kinase γ (PIP5Kγ) pathway, positively affects metabolism(51)

2. Polyphenolic flavonoids
In the comparison of the efficacy of polyphenolic flavonoids found in black and green tea in thyroid function, showed that green tea extract at 2.5 g% and 5.0 g% doses and black tea extract only at 5.0 g% dose have the potential to alter the thyroid gland physiology and architecture, that is, enlargement of thyroid gland as well as hypertrophy and/or hyperplasia of the thyroid follicles and inhibition of the activity of thyroid peroxidase and 5(‘)-deiodinase I with elevated thyroidal Na+, K+-ATPase activity along with significant decrease in serum T3 and T4, and a parallel increase in serum thyroid stimulating hormone (TSH)(52)

F. Treatments
F.1. In conventional medicine perspective
Most patients with hypothyroidism are treated by Thyroid hormone therapy with doses depending to the stage and types of the diseases

In patients with overt hypothyroidism defined as low FT4 and elevated TSH or TSH > 10 mU/L a replacement with levothyroxine is clearly indicated. In patients with subclinical hypothyroidism defined as a TSH between 4 and 10 mU/L and normal FT4, the treatment with Levothyroxine depends on the underlying disease and symptoms. Levothyroxine is a prohormone with is activated by deiodination in the organs to triiodothyronine, according to the study by Medizinische Klinik IV der Universität München(52a).
Standard therapy for patients with primary hypothyroidism is replacement with synthetic thyroxine, which undergoes peripheral conversion to triiodothyronine, the active form of thyroid hormone. According to the study by the University College Dublin, in a randomized, double-blind, placebo-controlled trial conducted from May 2000 to February 2002 at a military treatment facility that serves active duty and retired military personnel and their family members, indicated that compared with levothyroxine alone, treatment of primary hypothyroidism with combination levothyroxine plus liothyronine demonstrated no beneficial changes in body weight, serum lipid levels, hypothyroid symptoms as measured by a HRQL questionnaire, and standard measures of cognitive performance(53). Other in the study to examine the efficacy of combination therapy with levothyroxine and liothyronine in improvement of general health, psychological problems, and metabolic status in primary hypothyroidism, showed that Psychosocial scores, body weight, heart rate, blood pressure, and lipid profile in the two groups remained constant(54).

F.2. In Herbal medicine perspective
1. Echinacea
a. Immune modulator
In the observation of ethanolic extract of fresh Echinacea purpurea and the changes in cytokine production in blood samples from 30 volunteers before and during 8-day oral administration found that Echinaforce regulates the production of chemokines and cytokines according to current immune status, such as responsiveness to exogenous stimuli, susceptibility to viral infection and exposure to stress, according to the study of “Effects of Echinaforce® treatment on ex vivo-stimulated blood cells” by Ritchie MR, Gertsch J, Klein P, Schoop R.(55)

b. Anxiety
In the evaluation of five different extract from Echinacea preparationsand it effects on anxiety found that three of these decreased anxiety but two of them had a very narrow effective dose range. Only one extract decreased anxiety within a wide dose-range (3-8 mg/kg). Anxiolytic effects were consistently seen in three different tests of anxiety, the elevated plus-maze, social interaction and shock-induced social avoidance tests. No locomotor suppressant effects were seen at any dose, according to “The effect of Echinacea preparations in three laboratory tests of anxiety: comparison with chlordiazepoxide” by Haller J, Hohmann J, Freund TF(56).

2. Ashwagandha
Ashwagandha also known as Withania somnifera is a nightshape plant in the genus of Withania, belonging to the family Solanaceae, native to the dry parts of India, North Africa, Middle East, and the Mediterranean. It has been considered as Indian ginseng and used in Ayurvedic medicine over 3000 years to treat tumors and tubercular glands, carbuncles, memory loss and ulcers and considered as anti-stress, cognition-facilitating, anti-inflammatory and anti-aging herbal medicine.
Ashwagandha can enhances immune function by increasing immunoglobulin production and regulating antibody production by augmenting both Th1 and Th2 cytokine production, according to the study of “A comparison of the immunostimulatory effects of the medicinal herbs Echinacea, Ashwagandha and Brahmi” by Yamada K, Hung P, Park TK, Park PJ, Lim BO., posted in PubMed(57).

3. Fucus vesiculosus
Fucus vesiculosus is also known as Bladderwrack is a source of iodine, discovered in 1811, and was used extensively to treat goitre, a swelling of the thyroid gland related to iodine deficiency.used for thyroid disorders including underactive thyroid (myxedema), over-sized thyroid gland. According to the study by Unidad de Salud Mental Hospital de Laredo, Fucus vesiculosus is a marine alga rich in iodine, which is being used in alternative medicine as a laxative, diuretic, and as a complement for weight loss diets. Fucus vesiculosus may cause hyperthyroidism given its high iodine content. Herbal preparations should be taken in account when treating a patient due to the possibility of adverse effects and interactions with other drugs(57a)

4. Kelp
In the study of the prevalence of thyroid dysfunction in relation to iodine intake in adults (n = 1061) in five coastal areas of Japan that produce iodine-rich seaweed (kelp), found that
indicate that 1) the prevalence of hypothyroidism in iodine sufficient areas may be associated with the amount of iodine ingested; 2) hypothyroidism is more prevalent and marked in subjects consuming further excessive amounts of iodine; and 3) excessive intake of iodine should be considered an etiology of hypothyroidism in addition to chronic thyroiditis in these areas(58).

F.3. In traditional Chinese medicine perspective
1. Herbs tonify kidney-yang
According to the study by the Guangzhou University of TCM, in the study of The rectal temperature (Tr) and heart rate (HR) of three groups of New Zealand white rabbits, indicated that the Tr and HR in G1 were decreased, and the circadian rhythms of the Tr and HR disordered significantly, while these changes in G2 were corrected obviously(59).

2. Yang tonifying herbs
According to the study by the Department of Medicine, University of Western Australia, In a randomly divided into three groups study, each contained six rabbits, i.e. thyroidectomized and untreated rabbits (group 1), thyroidectomized rabbits treated by the Yang tonifying herbs (group 2) and sham thyroidectomized rabbits as controls (group 3), indiaced that the Bmax, T4, T3 and HR in group 1 were lower significantly than that in group 3 (P < 0.01-0.001), but the change of Kd in group 1 was not significant; the deviation of the indices from the normal value in group 2 was less remarkably than in group 1 other than T4(60).

3. Baji Zibugao
In the study of the effect of Baji Zibugao (BJZBG, a medicinal plaster mainly consisting of Radix Morindae Officinalis) on the endocrine functions of hypothyroid rabbits in three groups of rabbits: total thyroidectomized and untreated (group I), total thyroidectomized and treated with BJZBG (group II) and controls (group III). to determine the serum levels of thyroxine (T4), triiodothyronine (T3), cAMP, cGMP and corticosteron, showed that (1) The serum level of T4 in group I and II after operation was significantly lower than that before operation (P < 0.005), and the serum level of T3 in group I was also lower than that before operation (P 0.05); (2) The serum cAMP level in group I after operation decreased and the cGMP level increased (P 0.05), (3) The change of serum corticosterone level in group I or II after operation was not remarkable (P > 0.05)(61).

4. Cnidium monnieri (She Chuang Zi)
In the study the effects of total coumarins, essential oil and water extracts of Cnidium monnieri on plasma prostaglandin (PGE2 and PGF2 alpha) and cyclic nucleotide levels in rats of Kidney-Yang insufficiency with 55 rats divided randomly into 5 groups (Group I was administered orally with saline (normal group), group II was injected with intraperitonally hydrocortison acetate to induce Kidney-Yang insufficiency (control group), group III, group IV and group V (experimental groups) were injected with hydrocortison acetate, the same as group II, and administered orally with the total coumarins, essential oil and water extracts of Fructus Cnidii respectively) showed that the levels of plasma PGE2, PG2 alpha and plasma cAMP, cGMP were measured. In group II, in comparing with those of group I, the levels of plasma PGE2, and PGF2 alpha decreased significantly (P < 0.01), and the value of cAMP/cGMP also lowered obviously (P < 0.01) due to the significant reduction of cAMP and insignificant change of cGMP. In group III and group V, the above-mentioned indices changed significantly (P < 0.01 or 0.05) compared with those of group II, and after treatment it normalized basically in comparing with those of group I. In group IV, those indices didn’t change regularly and apparently as group III and group V did, compared with group II, and could not normalize satisfactorily. It is suggested that the coumarins in the fruit of Cnidium monnieri are probably the effective ingredients to invigorate Kidney and strengthen Yang, while the efficacy of essential oil remained unconfirmed(62).

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