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Research Articles and Papers on:

Subclinical Hypothyroidism


The occurrence of permanent thyroid failure in patients with subclinical postpartum thyroiditis

F. Azizi European Journal of Endocrinology, Vol 153, Issue 3, 367-371

Objective: The long-term effect of the subclinical form of postpartum thyroid dysfunction (PPTD) has not been well established. This study was conducted to evaluate the outcome of permanent hypothyroidism in a large cohort of women with PPTD.

Design and methods: Of 213 women with PPTD, 172 (81%) returned for follow-up. There were 27 (16%) with subclinical (group 1) and 145 (84%) with overt hypothyroidism (group 2). They were  all treated with levothyroxine for 23 ± 16 months and followed-up for thyroid function after thyroxine (T4) withdrawal.

Results: In group 1, the time of occurrence of PPTD was longer, serum T4 was higher and TSH was lower than in group 2. After T4 withdrawal, 59% and 64% of patients became hypothyroid in groups 1 and 2 respectively; however, serum TSH was increased in group 2 as compared with group 1.  The duration of euthyroidism, serum free T4 and T3 indices and thyroperoxidase antibodies were not significantly different between the two groups.

Conclusion: It was concluded that a high percentage of patients with the subclinical form of PPTD proceed to permanent thyroid  failure. The timely recognition of mild to severe cases of PPTD  is important for the improvement of life for mothers and infants.


Cardiac function in borderline hypothyroidism: a study by pulsed wave tissue Doppler imaging

European Journal of Endocrinology, Vol 152, Issue 4, 527-533
Sandra Zoncu, Francesca Pigliaru1, Claudia Putzu1, Lorella Pisano, Sara Vargiu, Martino Deidda, Stefano Mariotti1 and Giuseppe Mercuro

(April 2005)

Some of you will already know about the workings of the heart due to having heart problems but I thought I would explain briefly what diastolic dysfunction and systolic dysfunction means:

“The heart contracts and relaxes with each heartbeat. The contraction part of this cycle is called systole (SIS'to-le). The relaxation portion is called diastole (di-AS'to-le).

“In some people with heart failure, the contraction function is normal but there's impaired relaxation of the heart. This affects the heart's lower, pumping chambers (the ventricles) specifically. If the relaxation part of the cycle is abnormal, it's called diastolic (di"as-TOL'ik) dysfunction. Because the ventricle doesn't relax normally, the pressure in it increases and exceeds what's normal as blood for the next heartbeat. (It's harder for all of the blood to go into the ventricle.)

“This can cause increased pressure and fluid in the blood vessels of the lungs. (This is called pulmonary congestion.) It can also cause increased pressure and fluid in the blood vessels coming back to the heart. (This is called systemic congestion.) People with certain types of cardiomyopathy (kar"de-o-mi-OP'ah-the) may also have diastolic dysfunction.”1

It is well known that impaired diastolic function has been documented both at rest and on effort in sub-clinical hypothyroidism but systolic dysfunction has only been assessed on effort. The researchers’ aim of this study was to further assess systolic function at rest in sub-clinical hypothyroidism and to ascertain whether cardiac dysfunction could precede TSH increase in euthyroid patients with a high risk of developing sub-clinical hypothyroidism.

The researchers studied 32 patients with Hashimoto’s disease using Doppler Imagining – a special type of 3D radar - (22 with TSH of over 3.0 mU/ml; 10 “normal” patients who had TSH levels of less than 3.0 mU/ml and a group of 13 healthy controls (people without Hashimoto’s Disease).

In both groups with Hashimoto’s Disease, it was found they had a significant impairment of systyolic ejection, a delay in diastolic relaxation and a decrease in the compliance to the ventricular filling. Several significant correlations were found between these patients and free T3 and T4 and TSH concentrations.

The researchers concluded that the significant correlations of several pulsed wave tissue Doppler imaging indices with serum FT3 and TSH concentrations strongly support the concept of a continuum spectrum of a slight thyroid failure in auto-immune thyroiditis extending to subjects with serum TSH still within the normal range. In other words, people with Hashimoto’s Disease have heart problems, even if they have normal TSH levels. Very worrying. If you have Hashimoto’s Disease with normal TSH levels and your doctor won’t give you a trial of thyroxine, perhaps you should show him this research paper

1) http://www.americanheart.org/presenter.jhtml?identifier=4558 Effects of Prophylactic Thyroid Hormone Replacement in Euthyroid Hashimoto’s Thyroiditis


Subchemical Hypothyroidism

Sir-James Haddow and co-workers (Dec 21/28, p 2081 )1 report that the presence of thyroid (peroxidase) autoantibodies is a strong predictor of hypothyroidism in patients with concentrations of thyroid-stimulating hormone (TSH) conventionally regarded as normal. We agree that, in patients with symptoms compatible with hypothyroidism, such as chronic fatigue, the issue of autoimmunity should be addressed in depth.

We have previously reported2 (see next page) findings of examination by fine needle aspiration cytology of the thyroid in chronic fatigue. 40% of patients with chronic fatigue had unequivocal evidence of chronic lymphocytic (autoimmune) thyroiditis. Thyroid autoantibodies (peroxidase, thyroglobulin, or both) were present in only half of those with definite lymphocytic thyroiditis.

Baseline TSH concentrations were scattered in our patients with chronic fatigue and documented evidence of lymphocytic thyroiditis (median 3-8 mU/L [upper limit of reference range 5]). After treatment with thyroxine, clinical response was favourable, irrespective of baseline TSH concentration. Our interpretation of these findings is that fine-needle aspiration cytology of the thyroid has a higher diagnostic sensitivity than antibody assay in showing thyroid autoimmune activity; and that, compared with biochemical assessment alone, a higher proportion of patients with clinical hypothyroidism is identified.

To describe the group of patients with clinical hypothyroidism not meeting conventional biochemical criteria, but showing definite evidence of thyroid autoimmunity, we propose the term "subchemical hypothyroidism".

*Bo Wikland, P 0 Sandberg, Hans Wallinder

*Hotorget Medical Centre, PO Box 1417, SE-111 84 Stockholm, Sweden (BW); and Departments of Cytology (POS) and Clinical Chemistry (HW), Medilab, Taby, Sweden
1 Haddow JE, Palomaki GE, Williams J. Thyroid-stimulating-hormone concentrations and risk of hypothyroidism. Lancet 2002; 360: 2081-82.
2 Wikland B, Lowhagen T, Sandberg PO. Fine-needle aspiration cytology of the thyroid in chronic fatigue. Lancet 2001; 357: 956- 57.

The Lancet
Volume 357, Number 9260     24 March 2001



Fine-needle aspiration cytology of the thyroid in chronic fatigue

Sir--Armando Bartolazzi and Alessandra Gasbarri (Dec 9, p 2010)1 and D N Poller and colleagues (Dec 9, p 2010)2 discuss the use of fine-needle aspiration (FNA) cytology of the thyroid. In this context, the technique is used for the classification of lesions according to degree of suspicion of malignancy.
FNA cytology of the thyroid has other applications. Inflammatory dis-orders, especially chronic lymphocytic (autoimmune) thyroiditis, can be clearly ascertained by this technique. In non-iodine-deficient areas, lymphocytic thyroiditis is the most common cause of hypothyroidism.3

In the investigation of patients complaining of chronic (>1 year) fatigue, FNA cytologic assessment of the thyroid has been tested in addition to conventional first-line biochemical thyroid function tests. Of 219 patients (90% women), 87 (40%) were diagnosed with definite cytological lymphocytic thyroiditis.
The distribution of thyrotropin ([thyroid stimulating hormone] reference range 0·1-5 mU/L) among the 87 with lymphocytic thyroiditis is shown in the figure. In patients with chronic fatigue and lymphocytic thyroiditis, thyrotropin values were scattered (median 3·8 mU/L). Clinical response to thyroxine was equally favourable among patients with lymphocytic thyroiditis, irrespective of initial thyrotropin concentration.
We strongly advocate FNA cytologic assessment of the thyroid in the investigation of chronic fatigue. TL died before this letter was published.

*Bo Wikland, Torsten Löwhagen, P 0 Sandberg

*Hötorget Medical Centre, PO 1417, SE-11184 Stockholm, Sweden; and Department of Clinical Cytology, Medilab, PO Box 1550, Täby, Sweden (e-mail:bo.wikland@telia.com)

1 Bartolazzi A, Gasbarri A. Thyroid disease classification. Lancet 2000; 356: 2010.
2 Poller DN, Yiangou C, Cummings ME, Boote D. Thyroid disease classification. Lancet 2000; 356: 2010-11.
3 Braverman LE, Utiger RD, eds. Werner and Ingbar's the thyroid, 7th edn. Philadelphia: Lippincott-Raven, 1996.

NB: Dr Peatfield feels that diagnosis should be perfectly clear clinically without the necessity of sticking needles into peoples necks; and that the diagnosis can then be confirmed by a trial of treatment.This article just goes to show that  if we did use fine-needle aspiration cytology, many more people would be diagnosed!


Even Mild Thyroid Problems Double Risk Of Heart Condition

According to a new study presented on Thursday, Oct. 4, at the 78th Annual Meeting of the American Thyroid Association (ATA) in New York, individuals with subclinical hypothyroidism—a mildly underactive thyroid only detectable by a blood test—are twice as likely to develop heart failure, compared to those with normal thyroid levels.  Heart failure is when the heart can't pump enough blood to the body's other organs, which can cause fatigue, ankle swelling and shortness of breath.

Although previous studies have shown that hyperthyroidism—an overactive thyroid—and hypothyroidism can cause heart problems, this is the first time that a large study found a negative effect on heart function when the thyroid was only mildly under-active.

Doug Bauer, M.D., an author of the study and a Professor of Medicine, Epidemiology and Biostatistics at the University of California at San Francisco School of Medicine in San Francisco stated, “If other studies confirm these findings, then physicians might want to consider treating mild thyroid problems to prevent potential cardiac problems or to avoid increasing the severity of an existing heart condition.”

Subclinical hypothyroidism is defined by TSH levels greater than 4.5 mU/L and normal free thyroxine levels. Individuals with subclinical hypothyroidism can evolve into overt hypothyroidism, where the free thyroxine levels fall below normal, which always requires thyroid hormone therapy.

The Cardiovascular Health Study involved over 3,000 adults 65 years and older, who were evaluated to determine if those individuals who had subclinical hypothyroidism had an increased risk of developing heart failure over a twelve-year period. The study shows that individuals who had a TSH level equal or greater than 10 mU/L had a two-fold risk of developing heart failure, compared to those who had normal thyroid levels.



The association between TSH within the reference range and serum lipid concentrations in a population-based study. The HUNT Study

Bjørn O Åsvold1,2, Lars J Vatten1, Tom I L Nilsen1 and Trine Bjøro3
1 Department of Public Health, Faculty of Medicine, Norwegian University of Science and Technology, N-7489 Trondheim, Norway, 2 St Olavs Hospital, Trondheim University Hospital, Trondheim, Norway and 3 Department of Medical Biochemistry, Rikshospitalet-Radiumhospitalet Medical Center, Oslo, Norway
(June 2007)


Because recent studies have suggested that relatively low thyroid function within the clinical reference range showed a positive association with risk factors for coronary heart disease (CHD), these researchers examined the association of TSH levels within the reference range with CHD death rates in Norway.

There were more than 25,000 participants without known thyroid disease, heart disease or diabetes. Follow up was approximately 8.3 years and during this time 228 women and 182 men died of CHD.  Of these people 192 women and 164 men had TSH levels within the clinical reference range of 0.50 to 3.5 mIU/L.

The researchers found that, overall, TSH levels within the reference range were positively associated with death from CHD and that there was a statistical significance (this means that a relationship exists) in women but not in men.

The researchers concluded that “We found that total serum cholesterol, LDL cholesterol, non-HDL cholesterol and triglycerides increased consistently with increasing TSH and that HDL decreased consistently.” and “TSH levels indicating clinically normal thyroid function may have long-term harmful effects on cardiovascular health through the association with serum lipids. However, the strengths of the associations were modest, and their clinical significance remains to be determined in prospective studies of variations in normal thyroid function related to risk of cardiovascular disease.”

In other words, there is a clear connection between low but clinically normal thyroid function in women and fatal coronary heart disease.


Prevalence of Thyroid Dysfunction and Its Effect on Serum Lipid
Profiles in a Murzok, Libya Population

Ali M. Nouh, Ibrahim A. M. Eshnaf, and Mohamed A. Basher
Sebha University Faculty of Engineering and Technology Department of Medical Laboratory Sciences


For this study the researchers wanted to see the prevalence (frequency) of thyroid dysfunction and its relationship with fat levels among the adult population of Murzok City, Libya. Blood samples were collected randomly from 356 subjects (179 male and 177 female) in the age range of 20 to 65 years. The blood was tested for the levels of TT3 , TT4 , FT4, and TSH, Cholesterol, triacylglycerol (TAG) (a naturally occurring ester of three fatty acids and glycerol that is the chief constituent of fats and oils), low-density lipoprotein (LDL) (bad fats) and high-density lipoprotein (HDL) (good fats) were measured.

The prevalence of thyroid dysfunction types was as follows:

 overt (full) hyperthyroidism (0.84%)
 subclinical hyperthyroidism (0.84%)
 overt (full) hypothyroidism (1.12%)
 subclinical hypothyroidism (6.18%)

Also, thyroid dysfunction was more common in females than in males.

The researchers found a higher prevalence of subclinical hypothyroidism (27%) among the subjects with high levels of cholesterol.

The researchers state, “We found a higher prevalence of subclinical hypothyroidism (27%) among the subjects with hypercholesterolemia. We also found a significant negative correlation between subjects with normal T3 and hypercholesterolemia and a significant positive correlation between subjects with high T4 and HDL.



The effect of L-thyroxine replacement therapy on lipid based cardiovascular risk in subclinical hypothyroidism.

Serter R, Demirbas B, Korukluoglu B, Culha C, Cakal E, Aral Y  Endocrinology and Metabolism, Ankara Education and Research Hospital, Ankara, Turkey.
Journal of Endocrinology Invest. 2004 Nov: 27(10):897-903

The aim of this study was to assess the changes in serum lipid profiles after replacement therapy with thyroxine in patients with subclinical hypothyroidism (SCH) and to see whether there is an improvement in dyslipidemia based cardiovascular risk.  30 non-smoker pre-menopausal women with newly diagnosed (SCH)  (TSH between 4 and 10) were involved in the study and 26 euthyroid healthy subjects were used as the control group. All patients were tested for TSH, FT3, FT4, total cholesterol (TC), triglyceride,(TG) HDL cholesterol (HDL) and LDL cholesterol (HDL-C). These tests were taken before thyroxine was given and again 6 months after thyroxine was given. The patients with SCH had significantly higher levels of TC and LDL-C.  After six months the TC, LDL-C levels and the TC/HDL-C ratio were reduced significantly.  In conclusion, even mild elevations of TSH are associated with changes in lipid profile significant enough to raise the cardiovascular risk ratio, and these changes are corrected once the patients have been rendered euthyroid.



Spontaneous Normalization of Thyrotropin Concentrations in Patients with Subclinical Hypothyroidism

 Juan J. Díez, Pedro Iglesias and Kenneth D. Burman -  The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 7 4124-4127
(July 2005)

These doctors wanted to look at whether patients with subclinical hypothyroidism may revert to normal TSH values and if so, how long it took. This was a prospective, observational study with no intervention and the patients were followed-up between 12–72 months.

There were 40 patients who participated in the study - 32 of which were women with an average age of 62 with spontaneous subclinical hypothyroidism (TSH more than 5 and normal free T4). Each patient normalized their TSH values without T4 therapy throughout the follow-up.  TSH and free T4 levels were evaluated every 6 months.

Normalization occurred at a median time of 18 months (range  6–60 months). Fifteen patients normalized their TSH levels during the first year of follow-up and 27 during the first 2 yrs. Ten patients normalized their TSH values at the fourth or fifth year. Only four patients reverted to TSH values less than 2 mU/liter.

There was no clear pattern of TSH normalization, although most patients normalize their TSH values early in the follow-up.



Clinical Case Report: Ultrastructural Evidence of Skeletal Muscle Mitochondrial Dysfunction in Patients With Subclinical Hypothyroidism

Michael E. Dunn,1 James V. Hennessey,2 Arthur C. Cosmas,1
Linda S. Lamont,1 and Thomas G. Manfredi1
1Department of Kinesiology, University of Rhode Island, Kingston, Rhode Island 02881;
2Division of Endocrinology, Rhode Island Hospital, Brown University School of Medicine,
Providence, Rhode Island 02912

(May 2009)

These researchers felt that some patients with subclinical hypothyroidism did not have many signs and symptoms and that the controversies around the thyroid stimulating hormone(TSH) reference range variability make the management of subclinical hypothyroidism a challenge.

Because muscle cramps and weakness have been noted in sHT, they felt that  the examination of skeletal muscle may be of diagnostic significance as the presence of abnormalities would confirm a significant consequence of the mild thyroid failure possibly present in patients with sHT.

The objective of this study was to investigate changes of skeletal muscle associated with sHT.

Design: Skeletal muscle biopsies from leg muscles were obtained from four subjects with sHT.

Main Outcome: Analyses revealed alterations and quantitative (a number of them) mitochondrial variations between subjects, indicating skeletal muscle mitochondrial dysfunction in sHT patients.     

Conclusions: These alterations show previously undocumented skeletal muscle alterations associated with sHT and possibly show a trend of progression of sHT into full hypothyroidism as a result of mitochondrial dysfunction and associated metabolic changes.

The identification of these skeletal muscle alterations as a consequence of sHT may show convincing objective evidence of significant abnormal changes in patients with sHT.

The researchers state, “If so, this should diminish the substantial resistance to treatment of these patients at an early stage of disease and attenuate the progression to overt hypothyroidism.”



Myxedema Coma in a Patient with Subclinical Hypothyroidism

Akhila Mallipedhi, Hamza Vali, and Onyebuchi Okosieme
THYROID  Volume 21, Number 1, 2011

Myxedema coma is typically seen in patients with severe biochemical hypothyroidism. Its occurrence in association with subclinical hypothyroidism is extremely unusual. This paper describes a patient with subclinical hypothyroidism who developed clinical manifestations of myxedema coma.

A 47-year-old woman presented to the endocrine clinic with fatigue and blood tests found she had subclinical hypothyroidism.    

She was started on treatment with thyroxine but remained unwell and was later admitted to hospital with persisting subclinical hypothyroidism - her TSH was 6.09mU/L (reference range 0.4–4.0); her FT4 was 10.7 pmol/L (reference range 10.3–24.5), and her FT3 was 2.7 pmol/L (reference range 2.67–7.03.)

She developed hypothermia (temperature 33.28C), circulatory collapse, and coma.  

Tests showed she had hyponatremia, (low sodium levels), elevated creatinine phosphokinase (an enzyme found mainly in the heart, brain, and skeletal muscle), metabolic acidosis (too much acid) and renal failure. An echocardiogram showed fluid around the heart. We diagnosed myxedema coma and started treatment with intravenous (by vein) T3. She responded dramatically. No explanation was found other than hypothyroidism to account for the coma.

Adrenocorticotrophic hormone (ACTH) stimulation tests for adrenal insufficiency were negative and other pituitary hormone tests were within the normal reference range.  Other tests were also negative.

The doctors concluded, “To the best of our knowledge this is the first report of myxedema coma in a patient with subclinical hypothyroidism. The reason for normal thyroid hormone levels is unclear but may reflect deviation from a higher pre-morbid set-point. The case highlights the importance of careful clinical evaluation in patients with disparate clinical and laboratory findings.”