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The Science points to Angiotensin II and 1,25-dihydroxyvitamin D
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Trevor G Marshall, Research Director SarcInfo, Thousand Oaks, California 91360, Frances E. Marshall
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trevor.m{at}yarcrip.com Trevor G Marshall, et al.
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Professor Sharma concluded his review "the search for a safe, reliable and easily available diagnostic test for cardiac sarcoidosis continues". While we agree that 'the science' is still 'imperfect', great strides have been made during the last few years. Here is a quick summary of the science, as we see it. The hormones 1,25-dihydroxyvitamin D (1,25-D) and Angiotensin II (A-II) have both been implicated in the pathogenesis of sarcoid inflammation [1] [2]. Measuring the former can give a clinician some valuable help in assessing the extent of systemic granulomatous inflammation, and blockade of the latter can reduce production of inflammatory cytokines, including TNF-α [3]. The secosteroid 1,25-dihydroxyvitamin D (1,25-D) is normally produced in the kidneys from its precursor, 25-hydroxyvitamin D. Keratinocytes also hydroxylate 25-D to 1,25-D upon exposure of the skin to sunlight [4].
Until recently, 1,25-D was studied only for its calcitropic activity. However, it is now recognized that this secosteroid also functions as a hormonal Cytokine and Hematopoetic factor [6]. Figure 1 shows the levels of serum 1,25-D measured in a heterogenous group of normolcalcemic sarcoidosis patients, plotted against their D-Ratio (calculated as 1,25-D pg/ml / 25-D ng/ml). The D-Ratio is a measure of the vigor with which 1,25-D is produced from 25-D. Its normal mean is 1.25 (σ=0.5). Merck gives 45 pg/ml as the upper limit of normal for 1,25-D [8], and it is clear that the mean 1,25-D of our normocalcemic cohort exceeds Merck's maximum level (P>0.95). The D-Ratio for most sarcoidosis patients is also elevated, beyond the 1.25 ratio we would expect if the kidneys were in control of 1,25-D homeostasis. The D-ratio can often be a useful indicator of systemic granulomatous inflammation [7a] even when serum ACE values are being depressed by Corticosteroids or ACE Inhibitor therapy. However, well perfused (eg cardiac) inflammation contributes disproportionately to the observed serum 1,25-D by comparison with, for example, poorly perfused skin lesions. Our "Angiotensin Hypothesis"[7b] is a working-description of the most probable molecular biochemistry fueling the inflammation of Sarcoidosis. It describes how the run-away inflammatory response is dependent on the paracrine interaction of 1,25-D, ACE and Angiotensin II. The blockade of A-II Type 1 receptors has been shown (in-vitro) to interdict this inflammatory process and reduce production of the Th1 cytokines [9], including TNF-α [3]. The FDA has approved several drugs for the blockade of A-II Type 1 receptors during treatment for mild hypertension, and these standard agonists can be made to work quite well [7c] (this protocol does not suffer from the problems of inadequate blockade which we reported in an earlier paper[10]). Angiotensin Blockade would seem to be ideally suited for use with with early-stage cardiac patients, many of whom would already be receiving anti-hypertensive treatment. 1,25-D has a profound effect on muscles [11]. Elevated 1,25-D can even cause paralysis of the facial muscles [12], leading to Palsy. Sarcoidosis patients often suffer from spasms and cramps in the voluntary muscle groups. Nevertheless, we do not yet have sufficient evidence to surmise what might happen if 1,25-D—induced spasms and cramps were able to manifest themselves as arrhythmia in the involuntary cardiac muscles... we leave that as an exercise for the reader... References: 2. Nagai S, Takeuchi M, Morita K, Mikuniya T, Satake N, Mio T, Izumi T: Angiotensin II receptor on BALF macrophages from Japanese patients with active sarcoidosis. Sarcoidosis Vasc Diffuse Lung Dis 1999 Mar; 16(1): 67-74 [PubMed Abstract] 3. Ruiz-Ortega M, Ruperez M, Lorenzo O, Esteban V, Blanco J, Mezzano S, Egido J: Angiotensin II regulates the synthesis of proinflammatory cytokines and chemokines in the kidney. Kidney Int Suppl 2002 Dec; (82): 12-22 [PubMed Abstract] 4. Lehmann B, Genehr T, Knuschke P, Pietzsch J, Meurer M: UVB-induced conversion of 7-dehydrocholesterol to 1alpha,25-dihydroxyvitamin D3 in an in vitro human skin equivalent model. J Invest Dermatol 2001, 117(5): 1179-85 [PubMed Abstract] 5. Adams JS: Vitamin D metabolite-mediated hypercalcemia. Endocrinol Metab Clin North Am 1989: 18(3):765-78 [PubMed Abstract] 6. Hewison M, Gacad MA, Lemire J, Adams JS: Vitamin D as a cytokine and hematopoetic factor. Rev Endocr Metab Disord 2001, 2(2):217-27 [PubMed Abstract] 7. Marshall TG, Marshall FE: New Treatments Emerge as Sarcoidosis Yields Up its Secrets. clinmed 2003 Jan 27; 2003010001 [Full Text] 8. The Merck Manual of Diagnosis and Therapy: Vitamin D Deficiency and Dependency. 17th Edition, Section 1, Chapter 3 [Full Text] 9. Ruiz-Ortega M, Lorenzo O, Ruperez M, Konig S, Wittig B, Egido J: Angiotensin II activates nuclear transcription factor kappaB through AT(1) and AT(2) in vascular smooth muscle cells - molecular mechanisms. Circ Res. 2000, 86(12):1266-72 [PubMed Abstract][Full Text] 10. Marshall TG, Marshall FE: Valsartan Dosing Regime Modulates Psychotic Events in Two Sarcoidosis Patients. clinmed Aug 29, 0(1999):1-2 [Full Text] 11. Bischoff HA, Borchers M, Gudat F, Duermueller U, Theiler R, Stahelin HB, Dick W: In situ detection of 1,25-dihydroxyvitamin D3 receptor in human skeletal muscle tissue. Histochem J 2001 Jan; 33(1): 19-24 [OubMed Abstract] 12. Muler H, Paquelin F, Cotin G, Luboinski B, Henin JM: Facial paralysis in children.
Ann Otolaryngol Chir Cervicofac 1975 May-Jun; 92(4-5): 229-34 [PubMed Abstract]
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