• Cytomegalovirus – Cytomegalovirus affects hundreds of genes including downregulating the VDR 2.2 fold.[link widoczny dla zalogowanych Użytkowników]
  • Hepatitis C virus – Gal-Tanamy et al. showed that HCV infections interfere with the VDR by inhibiting the creation of CYP24A1, the enzyme responsible for breaking down excess 1,25-D.[link widoczny dla zalogowanych Użytkowników]

Evidence for high 1,25-D in patients with chronic disease
Under most normal conditions, serum levels of 1,25-dihydroxyvitamin D are constant throughout the year (no variability due to sun exposure), but there is no such tight biochemical regulation in at least some chronic inflammatory diseases such as [link widoczny dla zalogowanych Użytkowników].[link widoczny dla zalogowanych Użytkowników]
At the site of infection
It is sometimes thought that the liver and kidney are the only sites for conversion of 25-D into 1,25-D, but there is evidence that this process happens outside those organs – not coincidentally, at the very sites where patients report symptoms of chronic disease. High levels of 1,25-D and the enzyme which leads to the production of 1,25-D, 1 α-hydroxylase, have been found at various locations where the human body needs a strong host defense.[link widoczny dla zalogowanych Użytkowników]

  • skin cells of [link widoczny dla zalogowanych Użytkowników] patients – Sarcoidosis patients have a variety of skin symptoms including bumps, ulcers, or discolored skin. Zehnder et al found increased expression of the enzyme 1 α-hydroxylase – the enzyme which converts 25-D into 1,25-D – in the skin cells of sarcoidosis patients.[link widoczny dla zalogowanych Użytkowników] They write:

In particular, the expression of 1α-OHase [1 α-hydroxylase] by activated macrophages and epidermal keratinocytes [skin cells] suggests a role for 1,25(OH)2D3 [1,25-D] as an immunomodulatory and/or antiproliferative hormone.

  • synovial fluid surrounding the joints of patients with [link widoczny dla zalogowanych Użytkowników] – Mawer et al found that 1,25-D levels were particulary elevated in the synovial fluid surrounding the joints of patients with rheumatoid arthritis (RA).[link widoczny dla zalogowanych Użytkowników] In this study, median serum levels of 1,25-D at baseline was not elevated in the RA patients — only 24 pg/ml. Thus, the extrarenal synthesis of 1,25-D was not obvious from the routine blood test for 1,25-D. There is no reason to think that the metabolism of other diseases is any different.
  • immune cells including macrophages – Research has also shown that 1,25-D is synthesized in cells of the immune system, including the T cells and antigen-presenting cells[link widoczny dla zalogowanych Użytkowników] as well as the macrophages.[link widoczny dla zalogowanych Użytkowników][link widoczny dla zalogowanych Użytkowników] The fact that the immune cells are a site for 1,25-D synthesis is notable, because it is these cell types, especially macrophages, which are often infected by the [link widoczny dla zalogowanych Użytkowników].

There is strong evidence that the extrarenal enzyme located in macrophages plays a major role in certain granulomatous conditions (e.g., sarcoidosis), causing uncontrolled elevations of blood 1,25-(OH)2D3 levels….
Glenville et al.[link widoczny dla zalogowanych Użytkowników]

  • respiratory epithelial cells – The primary lung epithelial cells, which play an important role in the defense against airborne pathogens, have been shown to express high baseline levels of activating 1 α-hydroxylase and low levels of inactivating 24-hydroxylase. This activity leads to increased expression of genes by the Vitamin D Receptor.[link widoczny dla zalogowanych Użytkowników]

These disease site-specific peaks in 1,25-D somewhat undercuts the validity of the 1,25-D serum blood test as the gold standard for measuring the presence of chronic disease. There is currently no clinically available whole body test for elevated 1,25-D. For this reason, the ultimate measure of diseases treatable by the [link widoczny dla zalogowanych Użytkowników] is the [link widoczny dla zalogowanych Użytkowników].
[link widoczny dla zalogowanych Użytkowników]
A cohort of 100 patients was shown to have significantly (p<0.0001) higher serum levels of 1,25-D compared to the standard range. This data was described in [link widoczny dla zalogowanych Użytkowników] at the International Congress on Autoimmunity in Portugal
In the blood serum
As 1,25-D increases, it sometimes leaks into the bloodstream where it can be detected by measures of the metabolite in blood serum, but certainly not always.
A number of studies have demonstrated that the level of the hormone 1,25-D rises in patients with certain chronic diseases.

  • autoimmune disease – Greg Blaney MD, a physician who practices in Vancouver, British Columbia (a setting with relatively infrequent sunlight), found that of a group of 100 patients with a variety of chronic inflammatory diseases, 85 had elevated measures of 1,25-D, which was defined as greater than or equal to 110 pmol/L.[link widoczny dla zalogowanych Użytkowników]
  • Crohn's disease – One study found that in a cohort of 88 Crohn's disease patients, 35 patients or 40% had elevated levels of 1,25-D, which the authors defined as above 60 pg/mL.[link widoczny dla zalogowanych Użytkowników]
  • obesity – Moan et al. showed that, in contrast to healthy people, patients with a high body mass index (BMI) had a significant seasonal variation in, not only 25(OH) vitamin D, but also of 1,25-D.[link widoczny dla zalogowanych Użytkowników]
  • sarcoidosis – Kavathia et al found that in patients with sarcoidosis, those with high serum levels of 1,25-D have more pronounced chronic treatment needs.[link widoczny dla zalogowanych Użytkowników]
  • [link widoczny dla zalogowanych Użytkowników] – Liu et al. showed that levels of vitamin D metabolites, particularly 1,25-D, were low within the airways and increased after allergen challenge. The increases correlated with the magnitude of inflammation and increases in cathelicidin.[link widoczny dla zalogowanych Użytkowników]

Bell listed the following diseases and conditions, which manifest with high levels of 1,25-D: tuberculosis, AIDS with Pneumocystis carinii pneumonia, AIDS with cytomegalovirus infection, disseminated candidiasis, leprosy, rheumatoid arthritis, silicone-induced granulomas, Wegerner’s granulomatosis, Hodgkin’s disease, lymphoma, histocytic lymphoma, T-cell leukemia, plasma cell granuloma, leiomyoblastoma, seminoma, and subcutaneous fat necrosis.[link widoczny dla zalogowanych Użytkowników]
Effect of high 1,25-D on nuclear receptors
In our study, the response to 1,25(OH)2D3 appears to be biphasic with a stimulatory effect at lower concentrations, and becoming inhibitory or ineffective at the higher levels.
Saveria Aquila et al.[link widoczny dla zalogowanych Użytkowników]
At normal levels, the active vitamin D metabolite, 1,25-D, serves an important role in host defense,[link widoczny dla zalogowanych Użytkowników] but high levels of the hormone are immunosuppressive[link widoczny dla zalogowanych Użytkowników] – if for no other reason than the fact that it is calcitriol (1,25-D) and its analogues are used widely to treat autoimmune disease. One of the mechanisms by which 1,25-D may be immunosuppressive (and contribute to symptoms of disease) is by interacting with the body's other nuclear receptors. Selvaraj et al. have suggested that the high levels of 1,25-D seen in patients with pulmonary tuberculosis “might lead to downregulation of VDR expression” and that “decreased VDR levels could result in defective VDR signaling.”[link widoczny dla zalogowanych Użytkowników] More recently, Johan Lundqvist's 2011 study showed that, consistent with the 2009 study by Proal et al. that “1α,25-dihydroxyvitamin D3 exerts tissue-specific effects on estrogen and androgen production and metabolism.”[link widoczny dla zalogowanych Użytkowników]
Molecular modeling data show that at high levels, 1,25-D not only binds the VDR but also has a strong affinity for other key receptors that control the body's major hormonal systems including those that regulate the body's sex, thyroid, and adrenal hormones. As 1,25-D rises, it pushes out the molecules that are meant to control these receptors. Compromising these receptors can disrupt the body's ability to regulate temperature, libido, and any number of other functions.[table of affinities needed] Indeed, in the human brain, the VDR tends to be most common in the hypothalamus, which is responsible for these functions.[link widoczny dla zalogowanych Użytkowników]
Molecular research also shows that, like the VDR, several of these nuclear receptors (including the alpha/beta thyroid receptors, glucocorticoid receptor, and androgen receptor) also express many families of antimicrobial peptides. A recent analysis of AmP expression by Brahmachary showed that the glucocorticoid receptor, the androgen receptor, and the Vitamin