Autoimmune hypothyroidism is the end result of an immune attack on the thyroid gland, as the autoimmune note explained. Lymphocytes destroy the gland gradually, which is why the failure takes years, as the causes note explained.
The picture is this. The gland’s follicles make and store hormone. In Hashimoto’s thyroiditis, lymphocytes gather in the gland, cytotoxic T cells mainly kill follicular cells directly, and cytokines add to the killing to a minor extent. Lymphoid tissue grows in the spaces between the follicles, and scar forms there too. The atrophic gland is the same process at a later stage. What follows looks at each part of that picture.
What does the attack look like inside the gland?
The lead named the attack; here is what it does to the tissue. The gland is infiltrated by lymphocytes, and they are the cells that later do the killing. The infiltrate is organized: germinal centers form inside the gland, as in a lymph node. That is why the gland takes on the look of immune tissue. And the immune tissue replaces the working gland.
What is left of the follicles?
The infiltrate replaces working tissue. Most follicular cells are destroyed, but not all. When follicles are destroyed, colloid is reduced, so less hormone is stored. In Hashimoto’s thyroiditis, fibrosis is mild to moderate, so part of the gland still works.
Does the gland end up as a different disease?
The scar and the loss continue until the gland is largely fibrous. That stage is atrophic thyroiditis, and it is the same process as Hashimoto’s thyroiditis at a later stage. The difference between the two lies in how far destruction has gone, a difference of degree and not of kind. So atrophic thyroiditis is the end stage of Hashimoto’s thyroiditis, not a separate clinical entity.
What does the end stage look like?
The end stage is the same process with more fibrosis. The infiltration of lymphocytes is less pronounced, the fibrosis is extensive, and the thyroid follicles are almost completely absent. With the follicles gone, little working tissue is left.
Is there a variant with IgG4 plasma cells?
The same tissue can show a different cell type. In some cases atrophic thyroiditis has a peculiar fibrosis with a high number of IgG-4 positive plasma cells inside the gland. This variant marks the tissue as part of the same autoimmune spectrum.
Which cells do the killing?
Among the immune cells in the gland, some do the killing. Follicular cell death is caused mainly by cytotoxic T cells, which kill other cells directly. Inflammatory cytokines such as IL-1 and TNF contribute to follicular cell death to a minor extent. They do so through activation of death receptors such as Fas: IL-1, for example, induces Fas on the thyroid cells, and when Fas is cross-linked the cell goes into apoptosis.
What do the antibodies add?
Killing is by cells, and antibodies add to it. Antibodies against TPO and Tg amplify this destruction, and a proposed route is antibody-dependent cell killing and complement-mediated lysis. They do not initiate it. Maternal TPO and Tg antibodies cross the placenta, yet fetal thyroid destruction does not occur, because destruction always has to be started by cell-mediated killing. So antibodies are markers and accelerators of the process rather than its trigger.
Why does it happen to some people?
The cells act on a background set by genes. The risk of autoimmune hypothyroidism depends on both genetic and environmental factors. The main genetic predisposing features are polymorphisms in two genes, HLA-DR and CTLA-4. HLA-DR is involved in presenting antigens to T cells. CTLA-4 is a receptor that restrains T-cell activation. Variants of both are among the strongest and most widely shared genetic risk factors across autoimmune diseases. That sharing explains why patients with another autoimmune disease, such as type 1 diabetes mellitus, Addison’s disease, pernicious anemia or vitiligo, are more susceptible to autoimmune thyroid disease. Environmental factors act on this genetic background.
Which outside factors add to the risk?
Outside factors act on that same background. Studies show that high exposure to iodine increases the chance of autoimmune hypothyroidism. Proposed explanations are that excess iodine makes thyroglobulin more antigenic and draws immune cells into the gland, though the mechanisms are not settled. Studies show that low exposure to selenium also increases the chance. A proposed explanation is that selenium is needed for the enzyme that breaks down hydrogen peroxide, so with low selenium that protection falls. Studies show that low exposure to microorganisms during childhood also increases the chance.
Two further findings are associations. Smoking cessation increases the incidence of autoimmune thyroiditis, and people who drink more alcohol have a lower incidence. These are not recommendations, since the harms of continuing to smoke or drink outweigh any protective signal.
Can drugs trigger it?
Drugs can disturb the same regulatory cells. Regulatory T cells normally restrain autoimmunity, so some drugs that disturb them raise risk. Drugs that raise risk include tyrosine kinase inhibitors, immune checkpoint inhibitors and alemtuzumab. For tyrosine kinase inhibitors, the proposed mechanisms involve immune dysregulation. Alemtuzumab depletes regulatory T cells and may trigger autoimmune complications.
How fast does the hormone fall?
The damage can be far along or early, and the hormone falls with it. Because the gland fails slowly, the hormone level falls gradually, and overt hypothyroidism begins when the gland’s reserve is used up, as the subclinical note explained. How the disease looks in a patient therefore depends on how far the destruction has gone, which is the histology of the early and late stages described above. What does a low thyroid hormone level do to the body?