Organic solvents and other chemical agents have been linked with scleroderma.One of the suspected mechanisms behind the autoimmune phenomenon is the existence of microchimerism, i.e. fetal cells circulating in maternal blood, triggering an immune reaction to what is perceived as foreign material.A distinct form of scleroderma and systemic sclerosis may develop in patients with chronic kidney failure. This form, nephrogenic fibrosing dermopathy or nephrogenic systemic fibrosis, has been linked to exposure to gadolinium-containing radiocontrast.Bleomycin (a chemotherapeutic agent) and possibly taxane chemotherapy may cause scleroderma, and occupational exposure to solvents has been linked to an increased risk of systemic sclerosis. Pathophysiology
Overproduction of collagen is thought to result from an autoimmune dysfunction, in which the immune system starts to attack the kinetochore of the chromosomes. This would lead to genetic malfunction of nearby genes. T cells accumulate in the skin; these are thought to secrete cytokines and other proteins that stimulate collagen deposition. Stimulation of the fibroblast, in particular, seems to be crucial to the disease process, and studies have converged on the potential factors that produce this effect. A significant player in the process is transforming growth factor (TGFβ). This protein appears to be overproduced, and the fibroblast (possibly in response to other stimuli) also overexpresses the receptor for this mediator. An intracellular pathway (consisting of SMAD2/SMAD3, SMAD4, and the inhibitor SMAD7) is responsible for the secondary messenger system that induces transcription of the proteins and enzymes responsible for collagen deposition. Sp1 is a transcription factor most closely studied in this context.
Type 1 (D1) deiodinates T4 to the biologically active T3, as well as the hormonally inactive and possibly inhibitory rT3. Type 2 (D2) converts T4 into T3, and breaks down rT3. D3 produces rT3 from T4, and breaks down T3. The balance of D2 and D3 is important for overall T3/rT3 balance.In NTIS, the concentrations of these deiodinases are altered, although  whether NTIS is the cause or effect of this in peripheral tissues is unclear; in some studies, the alterations in thyroid hormone concentrations occurred before the changes in deiodinase activity. Typically, peripheral D1 and D2 are downregulated, while peripheral D3 is upregulated; this is associated with lower T4 and increased rT3. Hypothalamic-pituitary-thyroid axis downregulation
Thyrotropin releasing hormone (TRH) neurons in the hypothalamus integrate global signals about the bodys energy state. They may be stimulated by signals such as leptin, alpha-MSH, and catecholamines; and inhibited by glucocorticoids, neuropeptide Y, and agouti-related peptide. In critical illness, inflammation increases tanycyte D2 in the paraventricular nucleus (PVN) of the hypothalamus, leading to local tissue hyperthyroidism. There may also be decreased central D3. This causes negative feedback on the HPT axis, and therefore reduced TRH gene expression in the PVN. This is exemplified by the common NTIS phenotype of low TSH even in the face of peripheral hypothyroidism. Cytokines
Illness can cause inflammation, which often involves an increase in cytokines such as TNFa, IL-1, and IL-6. Cytokines are implicated in NTIS. IL-1β has been shown to decrease liver D1, as well as thyroid hormone receptor (THR) levels.