Is subclinical hypothyroidism always to be treated in HASHIMOTO's autoimmune thyroiditis?

Autoimmune thyroiditis (AIT) is not only one of the most prevalent human autoimmune diseases, but also the most frequent cause of primary hypothyroidism. It is characterized by lymphocytic infiltration of the thyroid gland with subsequent gradual destruction and fibrous replacement of thyroid tissue. Genetic predisposition, epigenetic modifications and environmental factors are suspected as disease triggers. Signs and symptoms of hypothyroidism include fatigue, bradycardia, constipation and cold intolerance. In subclinical hypothyroidism, symptoms may be absent. The diagnosis of AIT is based on the presence of antibodies against thyroid specific antigens, primarily anti-thyroid peroxidase antibodies and on a sonographically proven reduced echogenicity of the thyroid parenchyma. The diagnosis of concomitant hypothyroidism is primarily based on clinical signs and symptoms as well as measurement of thyroid-stimulating hormone (TSH)-concentration. Subclinical hypothyroidism is characterized by elevated TSH with normal serum free thyroxine (fT4) and triiodothyronine (fT3) levels, while in manifest hypothyroidism serum fT4 and fT3 levels are reduced. Levothyroxine (LT4) treatment in subclinical hypothyroidism is a controversy in the scientific literature and should be discussed individually. It not only depends on the level of TSH-elevation, but also on other factors, such as patient age, presence of comorbidities and clinical symptoms of hypothyroidism. In contrast, overt hypothyroidism and subclinical hypothyroidism with a TSH-level > 10 mIU/L is a strong indication for LT4 administration, aiming at rapid achievement of euthyroidism. In patients with dissatisfaction due to persistence of symptoms despite optimal LT4-treatment LT4/T3-combination therapy should be considered, based on expert opinion.



Dtsch Med Wochenschr 2021 10; 146(20):1329-1336.

Autoimmune thyroiditis, otherwise known as HASHIMOTO and intestinal MICROBIOTA.

considerations on chronic autoimmune thyroiditis, otherwise known as: HASHIMOTO's thyroiditis. a significant number of patients observed by me over the years have always presented high values ​​of auto antibodies both towards thyroglobulin and towards thyroid peroxidase, but have never had values ​​of low thyroid hormones. Autoimmune diseases and the microbiota

In the case of dysbiosis, the microbiota acts as a trigger (i.e. trigger) of numerous pathologies.

In physiological conditions the microbiota and the individual are in a symbiotic relationship: on the one hand, the microbiota helps the host digest carbohydrates, synthesize vitamins, prevent the colonization of pathogenic bacteria and develop gastrointestinal lymphoid tissue (GALT), involved in the immune system; on the other hand, the individual offers the nutrients necessary for the survival of the microbiota.
If this relationship is compromised by alteration of the bacteria, the microbiota contributes to the development of autoimmune diseases, by altering the intestinal barrier, inflammation and the interaction between intestinal bacteria and immune cells.

This has been associated with several autoimmune diseases, including chronic inflammatory bowel diseases such as Crohn's disease and ulcerative colitis, but also with non-bowel related diseases such as rheumatoid arthritis, diabetes 1 or lupus. systemic erythematosus. In light of current studies, the microbiota seems to be strongly involved in the onset of:

multiple sclerosis
rheumatoid arthritis
Ulcerative colitis
Hashimoto's autoimmune thyroiditis
Graves' disease
Crohn's disease
type 1 diabetes
celiac disease




Front. Endocrinol., 17 November 2021 |

Association Between Gut Microbiota and Autoimmune Thyroid Disease: A Systematic Review and Meta-Analysis

Boshen GongChuyuan Wang, Fanrui Meng, Haoyu Wang, Bo SongYang Yangand Zhongyan Shan*
  • Department of Endocrinology and Metabolism, Institute of Endocrinology, National Health Commission (NHC) Key Laboratory of Diagnosis and Treatment of Thyroid Diseases, The First Affiliated Hospital of China Medical University, China Medical University, Shenyang, China

Background: Autoimmune thyroid disease (AITD) is characterized by thyroid dysfunction and deficits in the autoimmune system. Growing attention has been paid toward the field of gut microbiota over the last few decades. Several recent studies have found that gut microbiota composition in patients with AITD has altered, but no studies have conducted systematic reviews on the association between gut microbiota and ATID.

Methods: We searched PubMed, Web of Science, Embase, and Cochrane databases without language restrictions and conducted a systematic review and meta-analysis of eight studies, including 196 patients with AITD.

Results: The meta-analysis showed that the alpha diversity and abundance of certain gut microbiota were changed in patients with AITD compared to the controls. Chao1,the index of the microflora richness, was increased in the Hashimoto’s thyroiditis group compared to controls (SMD, 0.68, 95%CI: 0.16 to 1.20), while it was decreased in the Graves’ disease group (SMD, -0.87, 95%CI: -1.46 to -0.28). In addition, we found that some beneficial bacteria like Bifidobacterium and Lactobacillus were decreased in the AITD group, and harmful microbiota like Bacteroides fragilis was significantly increased compared with the controls. Furthermore, the percentage of relevant abundance of other commensal bacteria such as BacteroidetesBacteroides, and Lachnospiraceae was increased compared with the controls.

Conclusions: This meta-analysis indicates an association between AITD and alteration of microbiota composition at the family, genus, and species levels.

Systematic Review Registration: PROSPERO, identifier CRD42021251557.



Hashimoto’s thyroiditis (HT) and Graves’ disease (GD) are the main types of autoimmune thyroid disease (AITD). AITDs are the most common organ-specific autoimmune disorders. Although the clinical manifestations of GD and HT are different, such as hyperthyroidism and hypothyroidism, respectively, GD and HT share similar immune-mediated mechanisms of disease, even alternating from one to the other (12). Many studies have revealed the possible causes of AITD, such as genetic susceptibility factors, dysregulation of the immune system, inflammation, stress, and other environmental factors; however, its etiology remains unclear (34).

Emerging evidence suggests that the alterations of the gut microbiota play a key role in the development and progress of AITD in individuals. From the embryology aspect, the thyroid and gut share a common embryological origin, explaining some morphological and functional similarities between the gut and thyroid follicular cells (5). The association between autoimmune thyroid disorders and gut autoimmune disease atrophic gastritis was first described in the early 1960s (6). More recently, owing to the development of the 16S ribosomal RNA (16SrRNA) gene sequencing technique, the gut microbiota, which comprises trillions of microorganisms, has been proposed to be involved in the pathogenesis of many autoimmune diseases, such as type 1 diabetes, lupus nephritis, Rheumatoid arthritis, Celiac Disease, and AITD (710). Although there is no direct evidence that AITD and gut microbiota have a cause-effect relationship, several studies have suggested that the thyroid-gut axis has beneficial or detrimental effects on thyroid function (11). The gut microbiota shapes the thyroid mainly through the following possible microbial-related mechanisms. First, dysbiosis leads to the damaged intestinal barrier and increased intestinal permeability, allowing the antigens to pass into the circulation and activate the immune system (12). Second, the antibodies in the circulation may react with the bacterial antigen and enhance the activation of the inflammasome in the thyroid gland (13). Guo et al. (14) has found that the expression of the inflammasome, including the NOD-like receptor (NLR) family pyrin domain containing 3 (NLRP3), AIM2, caspase-1, and IL-1β mRNA and protein from patients with HT, was significantly increased, which can be regulated by the gut microbiota and its metabolism (1517). Third, the short-chain fatty acids (SCFAs),metabolites of commensal bacteria fermentation of dietary fiber, are speculated to play a crucial role in the development, functioning, and modulation of the immune system (1819). For example, butyrate, a SCFAs, is associated with reduced levels of TNF-α, IL-6 and suppressed activation of the NLRP3 inflammasome via GPR109A (20).

Recently, many researchers have found that AITD patients have reduced α diversity and abundances of certain microbiota compared with healthy controls (2123). The α diversity mainly contains community diversity (Simpson and Shannon) and community richness indices (ACE and Chao1) (24). Among the AITD patients, those with HT tend to have a higher Chao1 value than healthy volunteers; however, patients with GD have a lower Chao1 value than the controls (2526). In addition, the current results revealed the correlation between the clinical parameters of AITD, such as TRAb or TPOAb and the certain microbiota (222728). For example, Chen et al. (29) found that the proportion of Synergistetes was negatively correlated with TRAb, and Jiang et al. (30) found that Lactobacillus was positively correlated with TRAb. At the phylum level, Yang et al. (31) found a higher Firmicutes/Bacteroidetes ratio in GD patients than in the control group, which may be relevant to inflammation disease, whereas Hanaa et al. (32) found that the ratio was significantly decreased in patients with AITD. Due to different conflicting data, a further study of the association between the gut microbiota and AITD is needed. To better understand the potential role of gut microbiota in the pathogenesis of AITD,we carried out a meta-analysis to assess the alteration in the microbial population between patients with AITD and healthy controls at different levels.

Materials and Methods

Search Strategy

We conducted a systematic literature search in PubMed, Web of Science, Embase, and Cochrane databases up to August 2021 using the following search string: (thyroiditis OR Hashimoto Disease OR Thyroiditis, Autoimmune OR Hashimoto Thyroiditis OR Thyroiditis, and Chronic Lymphocytic OR Chronic Lymphocytic Thyroiditis OR Thyroid Diseases OR Graves’ Disease OR Disease, Graves OR Goiter, Exophthalmic OR Basedow’s Disease OR Hyperthyroidism, Autoimmune) AND (microbiota OR Gut Microbiome OR Microbial Community OR Microbial Community OR Gastrointestinal Microbiome OR Microbiome OR Gut Flora OR Gastrointestinal Microbiota OR Microflora, Gastrointestinal OR Gastric Microbiome OR Intestinal Microbiota OR Intestinal Flora).

Inclusion and Exclusion Criteria

Studies were considered eligible if they met the following criteria: 1) investigating the gut microbiota and patients diagnosed with AITD. 2) providing sufficient data on the relationship between AITD and intestinal microbiota and could be extracted to analyze the 95% confidence interval (CI). 3) written in English. 4) full-text availability. However, comments, animal model subjects, conference abstract, and reviews were excluded. We also excluded studies with incomplete outcome data on the percentages or relative abundance of gut microbiota and studies with fewer than 20 participants.

Data Extraction

Three reviewers independently extracted the following data from each study: authors, publication year, country of population, population age, clinical parameters of thyroid function, diagnosis of AITD, and microbiology assessment methods.

Quality Assessment

Two reviewers completed the quality assessment using the Newcastle-Ottawa scale (NOS) to evaluate all the included studies, comprising the trial group selection, comparability, and exposure. The total score ranged from 5−9, where a higher score represents a higher quality of assessment. All the discrepancies or poor agreement were resolved through a consensus discussion with a third author.

Statistical Analysis

Standardized mean differences (SMD) were calculated between the HT and GD groups to assess the bacterial alpha diversity indices (Chao1). SMD >0 indicates that participants with HT have a higher level of richness in the intestinal microflora. A fixed- and random-effects were used to assess the percentages or relative abundances of certain gut microbiota with AITD compared with the healthy controls. We examined the statistical heterogeneity using the I2 statistic. I2 values of 25%, 50%, and 75% were related to low, moderate, and high heterogeneity, respectively. A Random-effects model was used to pool the results when high heterogeneity (I2>50%) existed. Additionally, the fixed-effects model was used if the heterogeneity was low. Furthermore, we performed a sensitivity analysis as well as Begg’s test to assess the potential influences of bias. All statistical analyses were performed using Stata software (version 12.0).


Characteristics of Included Studies

The initial literature searches retrieved 282 records from the online database. Among them,92 studies were excluded for duplication, and after the review of titles and abstracts,175 articles were eliminated because they did not fulfill the inclusion criteria. Then, we evaluated the remaining 15 articles individually; seven were excluded because the studies did not provide quantitative or appropriate data on the gut microbiota relative abundance. Finally, eight studies were included in our meta-analysis (Figure 1). This meta-analysis included 196 patients with AITD and 160 age-matched healthy controls (Table 1). The clinical parameters of AITD and microbiology assessment methods used in the included studies are shown in Table 2. Fecal samples were collected, and microbiota was analyzed by pyrosequencing or high-throughput sequencing of the 16SrRNA gene, real-time PCR, and PCR-DGGE of the 16SrRNA gene (33). The percentage of gut microbiota composition at a different level and relevant abundance were analyzed based on the assessment methods, preventing the potential deviation caused by the detection methods

Be careful in treating subxlinical hypothyroidism too early and in elderly subjects


Be careful in treating subxlinical hypothyroidism too early and in elderly subjects


Subclinical hypothyroidism is usually a laboratory diagnosis without significant symptoms and is defined by an elevated thyroid-stimulating hormone (thyrotropin, TSH) with normal thyroid hormone levels. On laboratory checks after two to three months, spontaneous normalization is found in 50 % of all cases in the sense of a transient elevation.With persistently elevated TSH levels, subclinical hypothyroidism is associated with evidence of thyroid-specific antibodies in the sense of autoimmune thyroiditis. Physiologically higher TSH levels are found in old age. It can therefore be assumed that the diagnosis of subclinical hypothyroidism is made and treated too frequently in older people over 70 years of age.Studies have so far failed to show a positive effect of substitution therapy of subclinical hypothyroidism, especially in elderly patients. On the other hand, there is a not inconsiderable risk of overtreatment with the development of subclinical hyperthyroidism. Its negative consequences in the form of atrial fibrillation and osteoporosis impair the quality and duration of life. Therefore, the indication for substitution therapy of subclinical hypothyroidism should be made with caution.One group in which diagnosis and therapy require special sensitivity is pregnant women. Here, two individuals, mother and child, must be treated. Varying target values and dosages in relation to the gestational age must be taken into account.



Dtsch Med Wochenschr 2022 Mar; 147(6):289-294.



Dosage CALCITONIN in the clinical practice.



Thyroid Hormone Therapy for Older Adults with Subclinical Hypothyroidism

David J. Stott, M.B., Ch.B., M.D., Nicolas Rodondi, M.D., Patricia M. Kearney, M.D., P…
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June 29, 2017
N Engl J Med 2017; 376:2534-2544

Abstract / Article Extract


The use of levothyroxine to treat subclinical hypothyroidism is controversial. We aimed to determine whether levothyroxine provided clinical benefits in older persons with this condition.


We conducted a double-blind, randomized, placebo-controlled, parallel-group trial involving 737 adults who were at least 65 years of age and who had persisting subclinical hypothyroidism (thyrotropin level, 4.60 to 19.99 mIU per liter; free thyroxine level within the reference range). A total of 368 patients were assigned to receive levothyroxine (at a starting dose of 50 μg daily, or 25 μg if the body weight was <50 kg or the patient had coronary heart disease), with dose adjustment according to the thyrotropin level; 369 patients were assigned to receive placebo with mock dose adjustment. The two primary outcomes were the change in the Hypothyroid Symptoms score and Tiredness score on a thyroid-related quality-of-life questionnaire at 1 year (range of each scale is 0 to 100, with higher scores indicating more symptoms or tiredness, respectively; minimum clinically important difference, 9 points).


The mean age of the patients was 74.4 years, and 396 patients (53.7%) were women. The mean (±SD) thyrotropin level was 6.40±2.01 mIU per liter at baseline; at 1 year, this level had decreased to 5.48 mIU per liter in the placebo group, as compared with 3.63 mIU per liter in the levothyroxine group (P<0.001), at a median dose of 50 μg. We found no differences in the mean change at 1 year in the Hypothyroid Symptoms score (0.2±15.3 in the placebo group and 0.2±14.4 in the levothyroxine group; between-group difference, 0.0; 95% confidence interval [CI], −2.0 to 2.1) or the Tiredness score (3.2±17.7 and 3.8±18.4, respectively; between-group difference, 0.4; 95% CI, −2.1 to 2.9). No beneficial effects of levothyroxine were seen on secondary-outcome measures. There was no significant excess of serious adverse events prespecified as being of special interest.


Levothyroxine provided no apparent benefits in older persons with subclinical hypothyroidism. (Funded by European Union FP7 and others; TRUST number, NCT01660126.)