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clinmed/2002080004v1 (August 22, 2002)
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Remission in Sarcoidosis

Authors:

Trevor G. Marshall, Ph.D., Yarc Inc., Thousand Oaks, California, trevor.m{at}yarcrip.com
Frances E.(Liz) Marshall, Grad. Dipl. Pharm, Los Robles Regional Medical Center, Thousand Oaks, California, liz.m{at}yarcrip.com

Address for Correspondence:
Frances E Marshall, 3423 Hill Canyon Ave, Thousand Oaks, CA 91360, phone (805)492-3693 FAX:(707)897-8687

18 August 2002 (revision 1.31)

Abstract

The granulomatous inflammation of Sarcoidosis is triggered by one or more microbes behaving in a non-infectious fashion in a genetically predisposed individual. Once started, the inflammation is fed and nurtured by the secosteroid hormone 1,25-dihydroxyvitamin D. Lipopolysaccharide from gram-negative bacteria living in the inflamed tissues causes macrophages to extra-renally convert 25-hydroxyvitamin D into 1,25-dihydroxyvitamin D. Once this hormone builds to a concentration sufficient to catalyze the formation of granuloma, its production is also fueled by the Gamma Interferon produced within those granuloma. The inflammatory cycle can be interdicted by removing 25-hydroxyvitamin D, thus removing the fuel for the extra-renal production of the secosteroid. This can be achieved by isolating the patient from sunlight and removing all sources of Vitamin D from the diet. Minocin can reduce the bacterial activity. Remission is observed as a gradual decrease in the amount of extra-renal 1,25-dihydroxyvitamin D being produced within the granulomatous biochemistry. A clinician can follow this process by tracking the D-Ratio, serum 1,25-dihydroxyvitamin D to serum 25-hydroxyvitamin D. Although the D-Ratio will often reach 4.5 in active sarcoidosis, 1.25 is the normal mean. When this D-Ratio has fallen to within the normal range we have an indication that the secosteroid is again being regulated within the kidneys and that remission has been achieved.

Introduction

Sarcoidosis is a hyper-inflammatory disorder characterized by the formation of ‘Granuloma’ in the body’s soft tissue, most commonly in the interstitial tissue of the lungs. Granuloma are an aggregation of lymphocytes, monocytes, macrophages and epithelioid giant cells (multi-nucleated cells).

In a recent review6, McGrath, et al, concluded that "one or more microbes behaving in a non-infectious fashion in a genetically predisposed individual, trigger the sarcoidosis granulomatous response".

Lipopolysaccharide (LPS) is the major constituent of the cell walls of gram-negative bacteria. Reichel2, et al, observed that LPS can induce macrophages to convert circulating 25-hydroxyvitamin D directly to the secosteroid hormone 1,25-dihydroxyvitamin D, a process which is normally regulated within the kidneys. Since monocytes and macrophages will differentiate to epithelioid giant cells under the influence of this extra-renal 1,25-dihydroxyvitamin D, LPS stimulation of macrophages can provide the trigger for sarcoid granulomatous inflammation

Our previous paper1, "The Angiotensin hypothesis – how sunlight feeds the run-away inflammation of sarcoidosis" described how improper regulation of the secosteroid hormone 1,25-dihydroxyvitamin D feeds the proliferation of the granuloma in the following manner:

As the concentration of 1,25-dihydroxyvitamin D increases within the inflamed tissue, a much larger quantity of hematopoetic stem cells differentiate to produce monocytes, macrophages and giant cells. These release Angiotensin Converting Enzyme, which then catalyzes the formation of Angiotensin II. A cascade of Th1 cytokines is produced when Angiotensin II binds at its Type 1 receptors in the macrophages. At least one of these Th1 cytokines, Gamma Interferon, then causes those macrophages to directly convert circulating 25-hydroxyvitamin D into 1,25-dihydroxyvitamin D. This additional 1,25-dihydroxyvitamin D catalyzes the formation of more monocytes, macrophages and giant cells, and the inflammation begins to proliferate, without proper regulation of the total amount of 1,25-dihydroxyvitamin D being produced1. As this hormone circulates throughout the body it is responsible for causing fatigue, paresthesia, muscle dysfunction and even facial palsy. These are the symptoms of Hypervitaminosis D.

Sunlight and dietary Vitamin D provide the 25-hydroxyvitamin D which fuels the extra-renal synthesis of 1,25-dihydroxyvitamin D, and, in the absence of 25-hydroxyvitamin D storage in body fat, the presence of either Sunlight or Vitamin D is necessary to maintain the inflammatory cycle.

Symptomatic Relief

We discussed three patients1 who had achieved symptomatic relief from the fatigue and paresthesia of sarcoidosis by staying away from sunlight, shielding their eyes from bright lights, and eliminating dietary sources of Vitamin D.

Two of these patients used high-dose Angiotensin Receptor Blocker therapy to decrease their sensitivity to Sunlight, and to help them to return to a near-normal lifestyle (ARBs interdict the inflammatory cycle by stopping Angiotensin II from binding to its receptors in the granuloma). The third used cranio-sacral and lymphatic-pump therapies to relieve the pain resulting from occasional sun exposures.

Once symptomatic relief is achieved, then the question logically arises: "As the granulomatous inflammation in the patient becomes less widespread, what are the treatment options and biochemical pathways leading to ‘remission’ of the Sarcoid event?"

Guy Scadding’s observations

In 1949, prior to the widespread availability of corticosteroids, John Guyette (Guy) Scadding described fifteen sarcoidosis patients, at varying stages of remission, in his Bradshaw Lecture to the Royal College of Physicians3.

Scadding’s observations are extremely valuable, as they were made before it became customary to prescribe corticosteroids in sarcoidosis, and before we began to (incorrectly) view the hormone 1,25-dihydroxyvitamin D as being primarily associated with clinical hypercalcemia and hypercalcuria.

The cases he described, and their varying outcomes, serve as a baseline for the progress of this disease in an ‘untreated’ patient population.

Scadding administered Calciferol (Vitamin D2) to 9 of his 15 patients. Calciferol supplementation had worked quite well for Lupus Vulgaris patients, and the expectation was that it would also speed remission from Sarcoidosis.

We now know that the 25-hydroxyvitamin D produced by Calciferol is actively converted to the hormone 1,25-dihydroxyvitamin D within the granulomatous inflammation of sarcoidosis, and that high levels of this hormone will lead to Hypervitaminosis D. Scadding’s data is consistent with this. Of the 9 patients with which he attempted supplementation, 3 were able to tolerate large doses of Calciferol, 3 were able to tolerate lower doses, and 3 were not able to tolerate any Calciferol at all.

The prognoses of the 6 patients able to tolerate Calciferol were good, 3 radiographs cleared, three improved. But the prognosis for the third group, those intolerant to Calciferol, was grim. Two were unchanged and one worsened.

Scadding’s data confirms that not all patients exhibit the same sensitivity to Vitamin D and sunlight, and those which are less affected are closer to remission.

Tracking Treatment Effectiveness

In refractory cases of Sarcoidosis, the production of 1,25-dihydroxyvitamin D is essentially unregulated, and there is an extremely active hydroxylase biochemistry within the granuloma. Any 25-hydroxyvitamin D resulting from sunlight exposure or dietary supplement is vigorously converted into the active hormone within the inflammatory granuloma. This results in sarcoid patients typically having lower values of serum 25-hydroxyvitamin D than normals.

We have developed the D-Ratio:

Serum 1,25-dihydroxyvitamin D (pg/ml)
---------------------------------------------
Serum 25-hydroxyvitamin D (ng/ml)

to reflect the activity of the 25-OH-D-1-hydroxylase4 in the inflamed tissue. We use a D-Ratio of 1.25 as the normal mean, with a 0.5 standard deviation. Sarcoid patients, typically have D-Ratios above 4.0 and are thus sensitive to dietary Vitamin D and extremely sensitive to sunlight. D-Ratios less than 2.5 indicate that inflammatory production of 1,25-dihydroxyvitamin D is approaching ‘normal’, and that renal control is returning. The patient is approaching remission from the run-away inflammation of sarcoidosis.

Interpreting the Patient’s D-Ratio data

In the table below are shown the assays for serum1,25-dihydroxyvitamin D, serum 25-hydroxyvitamin D, and Angiotensin Converting Enzyme, from 5 sarcoidosis patients.

Patient

1,25-D pg/ml

25-D ng/ml

D-Ratio

ACE

Prednisone?

A

58

15

3.9

<5

5mg q.d.

B

54

42

1.3

22

no

C

61.1

14.3

4.3

99

no

D

83.1

15.2

5.5

unknown

no

E

33.8

7.9

4.28

unknown

no

All these patients present with fatigue and paresthesia, together with a sampling of other symptoms of Hypervitaminosis D. Based on data from the Danish population study5, we use a value of 25 pg/ml for the 1,25-dihydroxyvitamin D population mean, and a 9.5 Standard Deviation. Four of the patients had 1,25-dihydroxyvitamin D values in the top percentile of the population (99% of the population would have lower values).

Patient A had been on 5mg of prednisone daily for two years. Although the corticosteroid had effectively eliminated the serum ACE, it had not been so effective at reducing the extra-renal production of 1,25-dihydroxyvitamin D.

Patient B had an ACE value which was low-to-normal, regardless of ACE genotype, and a ratio of 1.29, which also indicated minimal inflammation. The symptomatic Hypervitaminosis D was due to Vitamin D supplementation within a Calcium preparation which had been prescribed for this patient’s osteoporosis.

Patients C,D and E all have high D-Ratios. Patient E had been counseled about exposure to sunlight, and, although still intermittently symptomatic with Hypervitaminosis D, had clearly managed to minimize those symptoms by reducing her 25-hydroxyvitamin D production. As a result, her 1,25-dihydroxvitamin D assay was essentially normal even though the high D-Ratio indicates significant granulomatous activity.

Bacteria induce Sarcoid Inflammation

For nearly a century, optical microscopy has allowed us to observe the non-necrotic granuloma of Sarcoidosis, but we found nothing that would induce the macrophage biochemistry to produce the excessive 1,25-dihydroxyvitamin-D levels which perpetuate the sarcoid granuloma. Recently, ‘Rickettsia Helvetica’ (gram-negative) bacteria have been found in biopsy samples from Swedish sarcoid patients8. Electron microscopy of the Rickettsia bacteria, at an 84,000 magnification, has shown that this bacteria can live and multiply within the cells of sarcoid granuloma8, one of the most inhospitable environments in the body. Whenever pathology indicates some ‘empty’ granuloma we should now assume a bacterial pathogenesis.

Therefore, as part of any treatment regimen for sarcoidosis, it is essential to ensure that all possibility of gram-negative bacteria living in the granulomatous tissue has been precluded. We have found the careful use of non-generic low-dose Minocin9 in combination with high-dose ARB therapy1 represents an appropriate intervention.

Allergies

The patient should also be removed from any environment where the pulmonary lymphocytes might become activated by allergens or inhaled foreign matter. Either might cause the release of Gamma Interferon, a Th1 cytokine that has also been proven to potentiate the release of 1,25-dihydroxyvitamin D, and the subsequent proliferative differentiation to macrophages and giant cells.

Remove Vitamin D from the diet

All sources of exogenous Vitamin D must be eliminated if the body’s production of 25-hydroxyvitamin D is to be brought down to levels which allow very little 1,25-dihydroxyvitamin-D to be generated within the granuloma.

Many food products are enriched with Vitamin D. Particularly check the labeling on milk, breakfast cereals, diet supplements and vitamin preparations. Natural medications can also a significant source of Vitamin D, and, in the absence of a reliable list of ingredients, such medications should be discontinued.

Stay indoors, away from bright lights

Once all Vitamin D has been removed from the diet, sunlight remains as the major catalyst leading to the proliferation of sarcoid granuloma1.

The patient should be instructed to stay indoors for the duration of any therapy aimed at inducing remission.

Additionally, the eyes have a complete Renin-Angiotensin system10. Yet little is known about the effects of optical exposure, even though the optic nerve connects the eyes directly to the brain. Our experience is that protection of the eyes is just as critical to inducing remission as is remaining indoors. The patient should wear sunglasses in all but the darkest of indoor environments. "Zeiss Skylet Fun" is a suitable indoor lens.

If there is a need to venture outdoors then thick clothing must cover all exposed skin, mandating the use of gloves and hats, and dark sunglasses, such as the Alpine varieties which use leather side-pieces designed to block out stray peripheral glare. When driving, or in direct sunlight, a polarized clip-on should be used in addition to the sunglasses, in order to increase the attenuation. "Zeiss Skylet Sport" is a minimally dense (90%) prescription lens that is suitable for mounting into Alpine frames.

Computer screens are usually too bright, and must be adjusted to match the density of the sunglasses being worn indoors.

Don’t overdo it

As the D-Ratio becomes lower (<3.0) the patient will become less sensitive to sunlight. At this point the indoors isolation can be relaxed, as the body needs to be able to synthesize at least a minimal level of 1,25-dihydroxyvitamin D.

At this time we are uncertain whether exposure to the sun and diet supplementation are equivalent methods of supplying the body’s need for basal 25-hydroxyvitamin D. Initial indications point to diet supplementation as being the preferred source.

Discussion - when do we declare "Remission!"

Recall that "one or more microbes behaving in a non-infectious fashion in a genetically predisposed individual, trigger the sarcoidosis granulomatous response".

Our genes rarely change, and therefore absolute remission from a sarcoid event is highly unlikely. There is always the possibility of a relapse, and the patient should be educated to be alert for the early symptoms of relapse. These include fatigue, somnolence, chronic abdominal discomfort, difficulty swallowing, and muscle pain.

Bacteria are the most likely cause of relapse. An organism which has managed to hide in soft tissue during the Minocin therapy can again become an active driver of sarcoid inflammation. Mercola’s 9 low-dose Minocin therapy has minimal side-effects, and can be repeated whenever relapse is suspected. The antibiotic duration and frequency will have to be assessed on a case-by-case basis.

Remission is characterized by symptomatic relief, together with 1,25-dihydroxyvitamin D assays which remain in the low to normal range, and a D-Ratio close to normal (1.25). When all indicators have reached these levels any systemic inflammation is self-limiting, and should not progress to sarcoid granuloma.

----------------------------------------------------------------------

References:

1. Marshall FE, Marshall TG: The Angiotensin Hypothesis: how sunlight feeds the run-away inflammation of Sarcoidosis. In press

2. Reichel H, Koeffler HP, Barbers R, Norman AW: Regulation of 1,25-dihydroxyvitamin D3 production by cultured alveolar macrophages from normal human donors and from patients with pulmonary sarcoidosis. J Clin Endocrinol Metab 1987 Dec;65(6):1201-9 [Medline]

3. Scadding JG: Sarcoidosis, with special reference to lung changes. BR Med J 1950; 1: 745-753

4. Inaba M, Yukioka K, Furumitsu Y, Murano M, Goto H, Nishizawa Y, Morii H: Positive correlation between levels of IL-1 or IL-2 and 1,25(OH)2D/25-OH-D ratio in synovial fluid of patients with rheumatoid arthritis. Life Sci 1997;61(10):977-85 [Medline]

5. Brot C, Jorgensen NR, Sorensen OH: The influence of smoking on vitamin D status and calcium metabolism. Eur J Clin Nutr 1999 Dec;53(12):920-6 [Medline]

6. McGrath DS, Goh N, Foley PJ, du Bois RM: Sarcoidosis: genes and microbes--soil or seed. Sarcoidosis Vasc Diffuse Lung Dis 2001 Jun;18(2):149-64 [Medline]

7. Ohta M, Okabe T, Ozawa K, Urabe A, Takaku F: In vitro formation of macrophage-epithelioid cells and multinucleated giant cells by 1 alpha,25-dihydroxyvitamin D from human circulating monocytes. Ann N Y Acad Sci. 1986; 465:211-20 [Medline]

8. Nilsson K, Pahlson C, Lukinius A, Eriksson L, Nilsson L, Lindquist O: "Presence of Rickettsia helvetica in granulomatous tissue from patients with sarcoidosis". J Infect Dis 2002 Apr 15;185(8):1128-38 [Medline]

9. Mercola JM: Physician’s protocol for using antibiotics in Rheumatic disease. Presented at 32nd International Congress of the Great Lakes College of Clinical Medicine, Baltimore, Maryland, September 25, 1999

10. Wagner J, Jan Danser AH, Derkx FH, de Jong TV, Paul M, Mullins JJ, Schalekamp MA, Ganten D: Demonstration of renin mRNA, angiotensinogen mRNA, and angiotensin converting enzyme mRNA expression in the human eye: evidence for an intraocular renin-angiotensin system. Br J Ophthalmol 1996;80(2):159-63 [Medline]


(C)Copyright 2002 Trevor G and Frances E Marshall, All Rights Reserved




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Remission in Sarcoidosis
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Right arrow Articles by Marshall, T. G.
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Related Collections
Right arrow CLINICAL:
Molecular Medicine

Right arrow Rheumatology:
Other Rheumatology

Right arrow Respiratory Medicine:
Other respiratory medicine

Right arrow NON-CLINICAL:
Basic sciences


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