Edited by: Tamara Tuuminen, University of Helsinki, Finland
Reviewed by: Mario M. D’Elios, University of Florence, Italy; Luke Theodore Curtis, Center for Occupational and Environmental Medicine, United States
Specialty section: This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology
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Long-term exposure to dampness microbiota induces multi-organ morbidity. One of the symptoms related to this disorder is non-thyroidal illness syndrome (NTIS). A retrospective study was carried out in nine patients with a history of mold exposure, experiencing chronic fatigue, cognitive disorder, and different kinds of hypothyroid symptoms despite provision of levothyroxine (3,5,3′,5′-tetraiodothyronine, LT4) monotherapy. Exposure to volatile organic compounds present in water-damaged buildings including metabolic products of toxigenic fungi and mold-derived inflammatory agents can lead to a deficiency or imbalance of many hormones, such as active T3 hormone. Since the 1970s, the synthetic prohormone, levothyroxine (LT4), has been the most commonly prescribed thyroid hormone in replacement monotherapy. It has been presumed that the peripheral conversion of T4 (3,5,3′,5′-tetraiodothyronine) into T3 (3,5,3′-triiodothyronine) is sufficient to satisfy the overall tissue requirements. However, evidence is presented that this not the case for all patients, especially those exposed to indoor air molds. This retrospective study describes the successful treatment of nine patients in whom NTIS was treated with T3-based thyroid hormone. The treatment was based on careful interview, clinical monitoring, and laboratory analysis of serum free T3 (FT3), reverse T3 (rT3) and thyroid-stimulating hormone, free T4, cortisol, and dehydroepiandrosterone (DHEA) values. The ratio of FT3/rT3 was calculated. In addition, some patients received adrenal support with hydrocortisone and DHEA. All patients received nutritional supplementation and dietary instructions. During the therapy, all nine patients reported improvements in all of the symptom groups. Those who had residual symptoms during T3-based therapy remained exposed to indoor air molds in their work places. Four patients were unable to work and had been on disability leave for a long time during LT4 monotherapy. However, during the T3-based and supportive therapy, all patients returned to work in so-called “healthy” buildings. The importance of avoiding mycotoxin exposure
Long-term exposure to molds in water-damaged buildings (WDB) has been associated with numerous health problems including allergic airway symptoms (
Exposure to volatile organic compounds including metabolites produced by toxigenic fungi, some of which are inflammatory agents, can lead to a deficiency or imbalance of many hormones, such as insufficient amounts of the active form of thyroid hormone, commonly abbreviated to T3 hormone (
Thyroid hormones play a very important role in development, growth, and glucose–fat–protein metabolic homeostasis in all tissues by affecting the expression of many genes. It has been shown that the most important factors in thyroid hormone regulation are the activities of the three deiodinase enzymes (DIO 1, 2, 3). In particular, DIO2 regulates the activities of thyroid hormone action by metabolizing the precursor molecule thyroxine (T4) that is secreted by the thyroid gland into the biologically active molecule, T3. Two of the deiodinases (DIO1, DIO2) contain selenium and are responsible for transforming T4 either into its active metabolite, i.e., T3 or to an inhibitory reversed T3 form, rT3 (DIO3) (
The toxins released by the microbes living in damp buildings can induce oxidative stress (OS). OS has been proposed to be one of the most important mechanisms behind the adverse health outcomes associated with living in a damp indoor environment. One of the putative consequences of mycotoxin-induced OS is a blockade of crucial mitochondrial functions (
Oxidative stress also impacts negatively on various hormonal influences, e.g., causing antioxidant imbalance and impairing the functions of the deiodinase enzymes. For example, OS reduces the capacity of DIO2 to convert thyroxine (T4) into its biologically active form of T3. Different defense mechanisms that protect against the free radical damage have been characterized in various cellular localizations, including the endoplasmic reticulum, mitochondria, plasma membrane, peroxisomes, and cytosol.
There are several enzymes such as superoxide dismutase, catalase and glutathione peroxidase, and transition-metal binding proteins, which rapidly inactivate free radicals (
Thus, OS can be defined as a failure of the antioxidant system to cope with the excess of free radicals. One putative hypothesis is that OS facilitates the development of hypothyroidism or rather a lack of availability of the T3 hormone at the tissue level, the so-called NTIS (
In insulin-resistant patients, the T3/rT3 ratio is significantly increased in comparison to the corresponding value in insulin-sensitive controls (
Patients who have been exposed for a prolonged time to indoor air molds have high serum levels of rT3 (unpublished observation). This indicates an imbalance between rT3 and FT3 and decreased tissue metabolism of T4 to be converted to T3, in other words NTIS. In these patients, DIO2 does not function properly (
Nine female patients, aged 31–49 years, with a history of mold exposure and a variety of symptoms compatible with NTIS were enrolled into this retrospective study. The patients received LT4 monotherapy without success. Data have been collected since 2012 in a private medical clinic. Informed written consent was obtained from all of the patients.
The patients’ symptoms were categorized as follows: allergic symptoms (AG), airway symptoms (AW), CD, CF, edema/swelling (E), gastrointestinal symptoms (GI), high body temperature/feeling cold and feverish (HBF), heart/vascular disorder (HV), infection sensitivity (Inf), low body temperature/feeling cold, freezing (LBF), multiple chemical sensitivity, muscle and joint symptoms (MJ), neurological symptoms (Neu), psychological symptoms (Psy), imbalance in sex hormones (Sex), stress intolerance (SI: physical, psychological, or social stress) (Figure
The number of all the individual symptom groups during levothyroxine monotherapy and during triiodothyronine monotherapy (T3) or combination therapy (T3 + T4) in all nine patients. All of the nine patients had fewer symptoms in all of the symptom groups during the T3-based therapy. In addition, all of the symptoms became either milder or were totally eliminated during T3-based therapy. Symptoms were categorized as follows: allergic symptoms (AG), airway symptoms (AW), cognitive dysfunction (CD), chronic fatigue (CF), edema/swelling (E), gastrointestinal symptoms (GI), high body temperature/feeling cold and feverish (HBF), heart/vascular disorder (HV), infection sensitivity (Inf), low body temperature/feeling cold, freezing (LBF), multiple chemical sensitivity (MCS), muscle and joint symptoms (MJ), neurological symptoms (Neu), psychological symptoms (Psy), imbalance in sex hormones (Sex), stress intolerance (SI: physical, psychological, or social stress).
Patients were instructed about aspects of nutritional therapy: adherence to a gluten-free diet, regular use of nutritional supplements, low-dose hydrocortisone, and/or dehydroepiandrosterone (DHEA) when required, and adrenal supportive therapy for a few months. If the above described treatment was not effective enough, T3-based therapy was initiated.
Serum TSH, FT4, FT3, TPOAb, TyglAb, cortisol, and DHEA were assayed by Genova Diagnostics (Asheville, NC, USA) and the United Medix Laboratories Ltd. (Helsinki, Finland). The level of reverse T3 was assayed by Mayo Clinic (Scottsdale, AZ, USA). DIO2 was measured in the ZRT Laboratory (Beaverton, OR, USA) and in the United Medix Laboratories Ltd. (Helsinki, Finland). Saliva concentrations of cortisol and DHEA were assayed by Genova Diagnostics (Asheville, NC, USA) and ZRT Laboratory (Beaverton, OR, USA). The FT3/rT3 ratio was calculated according to the formula (FT3 × 6.51/rT3), where FT3 is picomoles per litre and rT3 is nanograms per deciliter.
All patients reported an exposure to indoor air molds. The duration of exposure to molds ranged from 5 to 27 years (average 11.4 years). It is worth stressing that all of the patients reported that their disease started during a long exposure to a moldy environment and that their health condition deteriorated significantly during periods of re-exposure. In all cases, there was a correlation of symptoms with the growth of dampness microbiota in the buildings as well as visible evidence of water damage. Mold growth and indoor air investigations were done by accredited laboratories using accepted culture techniques with conventional isolation media and quantitation of colony forming units per, e.g., cubic meter (
Seven patients had been already diagnosed by hypothyreosis with clear or borderline levels of TSH and FT4; two patients had normal TSH and FT4 concentrations before initiating LT4 monotherapy. Four patients were not able to increase the prescribed dose of LT4 to the required level because of side effects (Table
Details during levothyroxine (LT4) monotherapy.
Patient | LT4 dose (μg) | LT4 therapy problems | Thyroid-stimulating hormone (TSH) (mU/l) | Free T4 (FT4) (pmol/l) | Free T3 (FT3) (pmol/l) | rT3 (ng/dl) | FT3/rT3 |
---|---|---|---|---|---|---|---|
1 | 62.5 | If dose elevated: side effects | 2.5 | 17 | 4.9 | 26 | 1.23 |
2 | 50 | 2 | 18 | 6 | 46 | 0.85 | |
3 | 200 | 0 | 28 | 6.8 | 59 | 0.75 | |
4 | 75 | If dose elevated: side effects | 2.5 | 17 | 5.2 | 29.5 | 1.15 |
5 | 200 | 0 | 16 | 4.2 | 21 | 1.3 | |
6 | 100 | If dose elevated: side effects | 0 | 12 | 3.5 | 22.3 | 1.02 |
7 | 50 | 2 | 14 | 4.6 | 12 | 2.5 | |
8 | 100 | 1.3 | 16 | 4.6 | 21 | 1.43 | |
9 | 100 | If dose elevated: side effects | 6.11 | 15 | 4.2 | 17 | 1.61 |
The symptoms of all nine patients were relieved in all of the symptom groups when they were administered T3-based therapy (Figures
The number of all 16 symptom groups [allergic symptoms (AG) to stress intolerance] in each of the nine patients during levothyroxine monotherapy and during triiodothyronine monotherapy (T3) or combination therapy (T3 + T4). Special remarks: patient 1–5, 8: all the symptoms were milder during T3-based therapy; patient 1: still a mild mold exposure at work, patient 2: strong symptoms if mold exposure, patient 3: need less asthma medication, no airway symptoms (AW) during T3 therapy, patient 4: strong mold exposure period just recently, gets AW and AG symptoms immediately if mold exposure, patient 9: if not mold exposure, all the symptoms stay away.
The transition from LT4 monotherapy to T3-based therapy was conducted over a 2-week period when the patient’s symptoms were monitored to adjust to an individually appropriate T3 dosage. T3 monotherapy was prescribed to four patients in a dosage range from 30 to 55 μg/day, with these doses subdivided to be taken three times in a day. Combination therapy with synthetic T3 and LT4 thyroid hormones (T3 12.5–35 µg and LT4 50–75 µg) was prescribed to four patients and one patient received biological thyroid hormone extract (LT4 + T3). Satisfactory results were achieved within 3–36 months (average 10.1), but a complete curative response was documented in six patients within a shorter time, between 3 and 6 months (Table
Details during T3 monotherapy or combination therapy.
Patient | T3 or T3 + T4 dose (μg) | Thyroid-stimulating hormone (TSH) (mU/l) | Free T4 (FT4) (pmol/l) | Free T3 (FT3) (pmol/l) | Duration of therapy/months |
---|---|---|---|---|---|
1 | T3 30 | 1.6 | 6.1 | 4 | 6 |
2 | T3 30 | 0 | 4.5 | 5.1 | 4 |
3 | T3 55 | 0 | <3 | 5.1 | 4 |
4 | T3 30 + T4 115 | 0 | 12 | 5.1 | 14 |
5 | T3 20 + T4 75 | 3.3 | 9.3 | 3.2 | 6 |
6 | T3 50 | 0 | <3 | 5.1 | 36 |
7 | T3 30 + T4 50 | 2.2 | 8.1 | 3.6 | 6 |
8 | T3 30 + T4 50 | 0.06 | 6.2 | 4.6 | 8 |
9 | T3 12.5 + T4 62 | 1.43 | 10.42 | 3.9 | 3 |
Details of the medical records before T3 or combination therapy.
Patient | Mold exp/years | Hashimoto | Goiter | Asthma | Low cortisol | Low dehydroepiandrosterone (DHEA) | DIO2 | Glucocort. (mg/day) | DHEA (mg/day) |
---|---|---|---|---|---|---|---|---|---|
1 | 10 | No | No | No | No | No | CT | No | No |
2 | 27 | No | No | No | Yes | No | nd | HC 25 | No |
3 | 7 | Yes | No | Yes | Yes | No | nd | HC 30 | No |
4 | 10 | No | Yes | No | Yes | Yes | nd | HC 30 | 25 |
5 | 5 | No | No | No | No | No | TT | No | No |
6 | 12 | Yes | No | No | Yes | Yes | nd | HC 25 + Pred 5 | 50 |
7 | 6 | No | Yes | No | Yes | No | TT | HC 25 | No |
8 | 5 | No | No | No | No | No | CC | No | No |
9 | 25 | No | No | Yes | No | No | nd | No | No |
At present, there is no unanimous consensus on diagnostic criteria or efficacious treatment modalities for mold-exposed individuals. It has been estimated that as many as 14.5% of residents in Finland suffer from sick building syndrome (
Hypothyroidism and NTIS appear to be common among patients with dampness and mold hypersensitivity syndrome (DMHS) (unpublished observation); this is often disregarded and neglected. It is well known that hypothyroidism is more common in females. In this study, all patients were females. The reasons may be that more women than men work in public institutions, which are often infested with indoor air molds. I have tackled this problem by treating patients with active T3 hormone, as well as supporting adrenal gland function and providing nutritional advice.
In an animal model of primary hypothyroidism, it has been demonstrated that the LT4 monotherapy could not achieve systemic euthyroidism (
Successful treatment of DMHS patients required stringent adherence to a gluten-free diet. They were allowed to eat only naturally gluten-free cereals, but not gluten-stripped cereals marketed as “gluten-free.” The rationale for this approach is that wheat, rye, spelt, and barley can contain various toxic compounds, such as trichothecene mycotoxins (
Another important mechanism in NTIS is DIO2 polymorphism. DIO2 is present in all cells of the human body. Patients who are heterozygotes (CT) or homozygotes (CC) have defective DIO2 activity, and they will benefit from T3-based therapy compared to LT4 monotherapy (
This article describes the successful treatment of patients with hypothyroidism and NTIS. The disease developed after prolonged and cumulative or massive exposure to indoor air dampness microbiota. The treatment was based on full laboratory assessment of thyroid and adrenal hormones as well as careful interviewing and clinical monitoring. DMHS with NTIS is a devastating condition caused by OS and toxicosis, which should be recognized and treated appropriately.
Ethical clearance was not needed because this study was a retrospective study using the medical records. Samples were taken during treatment and the patient provided written informed consent and provided permission to use their data for scientific purposes.
TS has interviewed, treated, and evaluated all the patients and wrote the study.
TS is one of the owners of a private clinic in Tampere, Finland.
I acknowledge the support and help from Jani Somppi, Merja Lindström, Marjo Sukeva-Hakanpää, Eeva Lundell, and Hilkka Mononen.