Post by Sarcoidawareness on May 28, 2006 9:14:59 GMT -5
New Treatments Emerge as Sarcoidosis Yields Up its Secrets
Authors:
Trevor G. Marshall, Ph.D.,
SarcInfo, Thousand Oaks, California, trevor.m@yarcrip.com
Frances E.(Liz) Marshall, Grad. Dipl. Pharm,
Los Robles Regional Medical Center, Thousand Oaks, California, liz.m@yarcrip.com
Address for Correspondence:
Trevor G Marshall, 3423 Hill Canyon Ave, Thousand Oaks, CA 91360, phone (805)492-3693 FAX:(707)897-8687
22 June 2002 (Revision 2.2: 18 Jan 2003)
Abstract
Background:
Sarcoidosis is a hyper-inflammatory disorder of uncertain etiology. The objective of this study was to identify patients who were reporting hypersensitivities to sunlight, and investigate whether this trait might help to identify the etiology of sarcoid inflammation.
Results:
After studying patients who were able to control their Sarcoidosis symptoms simply by limiting their exposure to sunlight, and others who were benefiting from Angiotensin Receptor Blockade, we identified, and confirmed, a working hypothesis detailing each step of the molecular chemistry leading to the inflammation seen in Sarcoidosis. The study also identified, and validated, a number of novel treatments.
Discussion:
We found that the secosteroid hormone 1,25-dihydroxyvitamin D (1,25-D) clearly plays an important part in the etiology and symptomology of Sarcoidosis, regardless of the calcemic state of the patient. We described an inflammatory biochemistry which identified 1,25-D and Angiotensin II as the key hormonal mediators.
Many patients’ symptoms were eased when the concentration of the metabolite 25-hydroxyvitamin D (25-D) was reduced by isolation from sunlight, and the removal of all sources of Vitamin D from the diet. 25-D provides fuel for the unregulated extra-renal production of the secosteroid. This novel therapy also improved markers of disease activity, such as Angiotensin Converting Enzyme, and Alkaline Phosphatase, at the same time that the 1,25-D levels were being normalized.
The D-Ratio, serum 1,25-D (pg/ml) divided by 25-D (ng/ml), gives an indication of the amount of nonrenal 1,25-D being produced within the granulomatous inflammation. It can be used to monitor a patient’s response to therapy.
Angiotensin II plays a vital role in the inflammatory cycle, and a novel form of Angiotensin Receptor Blockade was confirmed as a probable therapeutic alternative to the use of systemic corticosteroids.
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1. Introduction
The etiology of Sarcoidosis has remained a mystery since its discovery over a century ago. It is a hyper-inflammatory disease primarily treated with systemic corticosteroids. Many patients achieve remission during steroid treatment. Those who do not remit, face the prospect of a lifetime of steroid usage, with the possibility of concomitant severe side effects, including Osteoporosis, Avascular Necrosis, and Diabetes.
Recent studies [1,2,3] have identified that Sarcoidosis most probably has a bacterial pathogenesis. We build on that knowledge by bringing together a number of previously uncoordinated in-vitro studies [4,5,6,7,8,9,10,11,12,13,14] to form a coherent, verifiable, working description of the inflammatory proliferation in sarcoidosis.
Paracrine vs. Endocrine biochemistries
Many centers are studying sarcoid inflammation at the paracrine level, examining the cytokine and chemokine biochemistry. Our interest, however, is primarily in the endocrine system, particularly in the roles of the hormones that have an anomalous presentation in sarcoid patients.
1,25-dihydroxyvitamin D and Sunlight
The secosteroid hormone 1,25-dihydroxyvitamin D (1,25-D) is the active vitamin D metabolite, which can be directly produced by the action of sunlight on the skin [23]. Sunlight also causes the skin to produce Vitamin D and 25-hydroxyvitamin D (25-D), which are both stored in the body’s fat reserves. This storage ensures that an adequate concentration of the active hormone (1,25-D) will be available, even in the absence of sunlight. The stored Vitamin D is hydroxylated to 25-D in the liver, and this 25-D is then converted into the active hormone within the kidneys, which maintain 1,25-D homeostasis.
Adams [15] noted that the sarcoid "disease-activated macrophage" also hydroxylates 25-D to 1,25-D, and that the hormone produced in the sarcoid inflammation was in excess of the body’s requirements. He suggested that this excess hormone might be reduced by "controlling vitamin D intake and sunlight exposure in susceptible hosts".
However, we suspected that the atypical regulation of this hormone in sarcoid patients [4,15,16,17] might not only be a result of the "disease-activated macrophage", but that the excess 1,25-D might actually be a cause of the run-away inflammatory process leading to the production of sarcoid granuloma.
Cadranel [9] had come to a similar conclusion in 1995, proposing that 1,25-D was responsible for the "formulation and maturation of granulomas", but was unable to identify the remaining element(s) of the inflammatory cycle.
We set out to identify patients who were convinced that exposure to sunlight exacerbated their sarcoid symptoms. We hoped that they might be able to provide the clue which would allow us to define the precise role of 1,25-D in sarcoid inflammation.
1,25-dihydroxyvitamin D in Sarcoidosis
Before the advent of oral corticosteroids, large ‘therapeutic doses’ of Vitamin D were often administered to Sarcoidosis patients. Anderson, et al [16], found that although normal adults could tolerate 150,000 IU of exogenous Vitamin D, some sarcoid patients exhibited toxicity after only 9,000 IU. Scadding [17] reported that some of his patients could not tolerate any exogenous Vitamin D at all, and that those patients who were most sensitive to Vitamin D were less likely to achieve remission.
This enhanced sensitivity of Sarcoidosis patients to Vitamin D makes Adams’ suggestion of lowering 1,25-D concentrations by "controlling .. sunlight exposure" very difficult to implement. Almost total isolation from sunlight is required before many sarcoid patients begin to significantly depress the circulating levels of 1,25-D, and very few patients have found this to be socially acceptable.
2. Results
Figure 1 is a scatter plot of all serum 1,25-D and serum 25-D values measured in our study cohort of sarcoidosis patients (21 patients, 24 data sets)