Mood disorders and thyroid autoimmunity

Mood disorders and thyroid autoimmunity are linked by aberrant levels of hematopoietic/neuronal growth factors in an excellent study just published in PLOS One (Public Library of Science). Their fascinating data show how, even before hypothyroidism has developed, and also in relatives of thyroid autoimmunity subjects, growth factors necessary for healthy brain function are at levels associated with a range of mood disorders including bipolar, depression and psychosis. They also include an important reminder that antibodies can predict clinical disease years in advance.

Hypothyroidism predicted years in advance

The authors state:

"Autoimmune hypothyroidism is characterized by a combination of clinical features, elevated serum TSH with reduced free T4 (FT4) levels, the presence of serum antibodies against thyroid antigens, and reduced echogenicity of the thyroid sonogram. It is the most common organ-specific autoimmune disorder with an estimated prevalence of 2%, with a higher prevalence in women and depending on iodine intake. Thyroid peroxidase (TPO) is the major autoantigen and TPO antibodies (TPO-Abs) are present in almost all patients with autoimmune hypothyroidism and precede the clinical phase of autoimmune hypothyroidism by many years. Subclinical autoimmune hypothyroidism (the presence of TPO-Abs with raised TSH and normal FT4 levels) is even more prevalent and affects about 9% of the population. In the Whickham follow-up study, women with TPO-Abs had an eight-fold higher risk of developing clinically overt hypothyroidism over 20 years than did antibody-negative women."

And family members have a pronounced risk of thyroid autoimmunity showing up down the road:

"In our own studies on the Amsterdam AITD [autoimmune thyroid disease] cohort (euthyroid females with at least one first or second degree relative with a documented autoimmune hyper- or hypothyroidism) TPO-Ab positivity at the start of the study also represented a higher risk to develop overt hypothyroidism in a follow-up of 5 years. In addition, there was a higher conversion rate from TPO-Abs negativity to positivity, showing a familial proneness for thyroid autoimmune reactivity."

And in another earlier study normal thyroid relatives showed a slew of abnormalities including a 'background' higher inflammatory state:

"We concluded that euthyroid females within AITD families show a characteristic pattern of abnormalities in serum levels of growth factors, chemokines, adhesion molecules and cytokines, suggesting an already compromised thyroid-immune system interaction in the euthyroid family members. Also, pre-seroconversion stages might be predicted using serum analytes pointing to a higher inflammatory state."

Mood disorders and AITD

The emerging evidence shows that depression in association with autoimmune thyroid disease is caused by more than lower thyroid hormone in the brain. Just the presence of anti-thyroid antibodies while thyroid hormone levels are still normal is associated with increased risk of anxiety and mood disorders.

"Autoimmune hypothyroidism is commonly accompanied by depressive symptoms. A large epidemiological Danish nationwide, prospective cohort study showed that various autoimmune diseases including AITD, are associated with subsequent lifetime mood disorder diagnosis (e.g. bipolar affective disorder, unipolar depression, psychotic depression and other remaining mood disorders). In hypothyroid patients the lack of thyroid hormone in the brain is likely an important determinant for these mood disturbances. However, a deficit of thyroid hormone may not be the only cause, as even subjects with TPO-Abs with normal thyroid function have a higher risk to develop anxiety disorders and mood disorders."

And further evidence supports the assertion of a shared pathogenesis for autoimmune thyroid disease and mood disorders:

"Also offspring of patients with a bipolar affective disorder have a higher prevalence of TPO-Abs, even if they are not affected by the psychiatric disorder. In addition, a higher prevalence of TPO Abs and autoimmune hypothyroidism has been reported in patients with bipolar affective disorder, irrespective of the usage of lithium. Taken together, these associations might imply a shared immune pathogenesis for both AITD and mood disorders."

Brain growth factors and AITD

To explore this relationship the authors examined data for 64 TPO-Ab-negative females with relatives with AITD. 32 of these subjects did and 32 did not seroconvert to TPO-Ab positivity in their 5-year follow-up. These were compared with 32 healthy controls (HCs). Importantly, they measured serum levels of brain-derived neurotrophic factor (BDNF), Stem Cell Factor (SCF), Insulin-like Growth Factor-Binding Protein 2 (IGFBP-2), Epidermal Growth Factor (EGF) and IL-7.

"We therefore additionally determined, in the sera used in the previous study, 5 growth and differentiation factors that have repeatedly* been shown to be abnormally expressed in the circulation of mood disorder patients and that are capable of influencing both immune and/or neuronal cell growth, i.e. SCF, IGFBP-2, EGF, BDNF and IL-7. In addition we studied the inter relationship of these factors with the previously determined factors using a cluster analysis to study patterns of TPO-Ab seroconversion."

* Authors' emphasis.

Even relatives of AITD patients are at higher risk of mood disorders

Their data showed an eye-opening correlation:

"BDNF was significantly lower (8.2 vs 18.9 ng/ml, P<0.001), while EGF (506.9 vs 307.6 pg/ml, P = 0.003) and IGFBP-2 (388.3 vs 188.5 ng/ml, P = 0.028) were significantly higher in relatives than in HCs. Relatives who seroconverted in the next 5 years had significantly higher levels of SCF than non-seroconverters (26.5 vs 16.7 pg/ml, P = 0.017). In a cluster analysis with the previously published growth factors/cytokines SCF clustered together with IL-1β, IL-6 and CCL-3, of which high levels also preceded seroconversion."

In other words, abnormal levels of growth factors necessary for brain health and higher levels of biomarkers for inflammation were both observed. Bear in mind that BDNF (brain derived neurotrophic factor) in particular has been identified as important for neurogenesis, plasticity and synaptic transmission. BDNF deficiency is associated with disorders of mood, cognition and memory. And an increase in BDNF is though to be a mechanism by which exercise (and certain medications) exert a beneficial effect on brain-based conditions.

"It is of note that the 5 studied factors have been highlighted as serum biomarkers for major mood disorders in several studies and are involved in neurogenesis, neuroprotection and hematopoietic differentiation. This is in particular known for BDNF. Neurotrophic factors, like BDNF, play an important role in neuronal plasticity, modulating not only axonal and dendritic growth and remodeling, but also neurotransmitter release and synapse formation."

This makes striking the finding that even euthyroid (normal thyroid) relatives of autoimmune thyroid subjects are at higher risk of mood disorders with markedly lower levels of BDNF.

"The present study shows that euthyroid females, who are relatives of AITD patients and at risk of developing AITD, have an aberrant serum level of 4 of the 5 tested hematopoietic/neuronal growth and differentiation factors, i.e. of BDNF, IGFBP-2, EGF and SCF. BDNF levels were significantly lower and IGFBP-2 and EGF higher expressed in sera of the relatives of the AITD patients (in both SCs and NSCs) than in healthy controls. IL-7 levels were normal. We also found in the healthy relatives, who converted in the following 5 years to TPO-Ab positivity, significantly higher serum levels of SCF than in relatives who did not."

Earlier diagnosis

This certainly underscores the clinical significance of predictive (low levels of) anti-thyroid antibodies. It also invites the possibility of even earlier diagnoses and interventions as stated by the authors:

"This study and the previous one therefore underscore the widespread changes in immune-neuro-endocrine molecular networks that apparently precede the appearance of TPO-Abs, which opens avenues for developing assays for the detection of individuals at risk for thyroid autoimmunity."

Moreover...

"We assume that the generally low expression in NSCs in cluster A reflects an immune suppressive state preventing autoimmunity, while a rise of these pro-inflammatory compounds precedes a conversion to TPO-Ab positivity and thus may reflect a very early stage of thyroid auto reactivity."

Clinical Note

This presents the tantalizing possibility of very early diagnosis and the opportunity to intervene in thyroid and mood disorders at the earliest possible stage when easiest to treat. Meanwhile, clinicians should be attentive to even low levels of anti-thyroid antibodies.The authors summarize:

"We conclude that subjects at risk for AITD show changes in growth and differentiation factors in serum, which are both active as neuronal and hematopoietic growth and differentiation factors and are abnormally expressed in patients with mood disorders. This suggests that shared growth and differentiation defects in both the hematopoietic and neuronal system may underlie both thyroid autoimmunity and mood disorders."

Colleagues interested in our practice model incorporating predictive antibodies and bioidentical (human recombinant) low dose BDNF are welcome to contact.