Can chowing down improve pseudoxanthoma elasticum?
By Warren R. Heymann, MD
Oct. 30, 2019
Vol. 1, No. 34
I have diagnosed pseudoxanthoma elasticum (PXE, OMIM # 264800) a few times in my career. The immediate excitement of rendering the diagnosis is quickly tempered by the realization that so far there is no definitive treatment for this devastating disease. PXE is an autosomal recessive disease characterized by ectopic mineralization and fragmentation of the elastic fibers. PXE manifests in the skin (yellow papular lesions with increased skin laxity in flexural areas), eyes (angioid streaks and subchoroidal neovascularization with hemorrhage), and cardiovascular system (peripheral occlusive disease, coronary and cerebrovascular artery disease). There may be marked phenotypic variability between patients. (1) PXE is considered the prototype of heritable ectopic mineralization disorders. Other related diseases include generalized arterial calcification of infancy (GACI) and arterial calcification due to CD73 deficiency (ACDC). GACI is characterized by severe, frequently fatal early-onset mineralization of the cardiovascular system. ACDC occurs in the elderly, mostly affecting arteries in the lower extremities. These three conditions, PXE, GACI, and ACDC, caused by mutations in ABCC6 (ATP-binding cassette, subfamily C, member 6), ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1), and NT5E (5'-nucleotidase ecto), respectively, are categorized by reduced levels of inorganic pyrophosphate (PPi) in plasma. Because PPi is a powerful antimineralization factor, reduced levels of PPi are postulated as pathogenic for ectopic mineralization in these disorders. (2) According to Devriese et al: “Arterial calcification disorders are the consequence of an imbalance in the metabolic pathway of inorganic pyrophosphate (PPi), a physiological inhibitor of ectopic tissue mineralization. ABCC6 encodes an ATP-binding cassette protein of unknown precise function although its inactivation reduces plasma levels of PPi. ENPP1 encodes an enzyme that converts ATP to AMP and PPi. The loss of ENPP1 results then in a decrease of AMP, PPi, and adenosine extracellular concentration. NT5E encodes CD73, an enzyme converting AMP into adenosine and inorganic phosphate (Pi). The tissue non-specific alkaline phosphatase (TNAP) degrades PPi. TNAP activity is upregulated in CD73 deficiency, decreasing extracellular adenosine and PPi levels, and provoking premature arterial ectopic calcification.” (3) Managing PXE focuses on a healthy lifestyle, including a low-cholesterol diet, aerobic exercises, and avoidance of smoking. Patients should be advised to avoid aspirin and other blood thinners unless essential, as well as contact sports and other activities that increase the risk of eye trauma. Patients should be encouraged to avoid calcium supplementation and excessive ingestion of milk products which could result in progression of the disease. (4) Because mouse models of PXE have shown that elevated levels of magnesium result in decreased calcification, a randomized, double-blind study of 44 patients with PXE with oral administration of magnesium oxide was performed. The authors demonstrated a trend toward diminished elastic fiber calcification, although these findings were not statistically significant. (5) The obvious question is whether oral administration of PPi can be beneficial for PXE patients. The answer may have been discovered serendipitously. Pomozi et al inadvertently discovered that modulating dietary PPi can be effective in reducing calcification in ABCC6-/- mice. This finding was prompted by a change in institutional rodent diet. The new chow was enriched in PPi, which increased plasma PPi, and significantly reduced mineralization in ABCC6-/- mice. The authors also found that dietary PPi is readily absorbed in humans. Their findings suggest that consumption of food naturally or artificially enriched in PPi could possibly mitigate calcification progression in PXE. The authors state that the FDA designates PPi as a safe food additive, currently being used as a preservative. (6) More studies are warranted, and in fact, clinical trials on orally administered PPi in patients with PXE are underway. The possibility that a food additive could have such a profound effect on PXE is scintillating. More food for thought — could it be valuable for other disorders such as calciphylaxis?
Point to remember: The food additive inorganic pyrophosphate (PPi) may be valuable in heritable ectopic mineralization disorders such as PXE. Although more research is warranted, the serendipitous discovery of this finding in mice (because of an institutional change in rodent chow) reminds us of Louis Pasteur who stated that “chance favors the prepared mind.”
Our expert’s viewpoint
Jouni Uitto, MD, PhD
Professor and Chair, Department of Dermatology and Cutaneous Biology
Jefferson Medical College, Philadelphia
As summarized by Dr. Heymann, the unifying pathomechanistic finding in PXE, GACI, and ACDC is the reduced plasma level of PPi, and consequently low PPi/Pi ratio, which allows ectopic mineralization of soft connective tissues to ensue. Consequently, supplementation of diet with PPi intuitively makes sense. However, PPi has a very short half-life in plasma, and it is unclear in what quantities and how frequently it should be taken by the patients to effectively counteract the mineralization phenotypes. In this context, we have tested the efficacy of bisphosphonates, particularly etidronate, a stable structural and functional analogue of PPi, for its efficacy in preventing ectopic mineralization. Our preclinical animal studies revealed that etidronate is effective in preventing the mineralization in mouse models of PXE and GACI, and recent early clinical trials have shown its efficacy against vascular mineralization in patients with PXE. These are the first clinical indications that there may soon be a treatment for PXE, a currently intractable disorder.
Van Gils M, Nollet L, Verly E, Deianova N, Vanakker OM. Cellular signaling in pseudoxanthoma elasticum: An update. Cell Signal 2019; 55: 119-129.
Li Q van de Wetering K, Uitto J. Pseudoxanthoma elasticum as a paradigm of heritable ectopic mineralization disorders. Am J Pathol 2019; 189: 216-225.
Devriese M, Legrand A, Courtois MC, Jeunemaitre X, Albuisson J. Pseudoxanthoma elasticum with prominent arterial calcifications evoking CD73 deficiency. Vasc Med 2019 Jun 4:1358863X19853360. doi: 10.1177/1358863X19853360. [Epub ahead of print]
Kellen R. Lebwohl MG. Pseudoxanthoma elasticum. In Lebwohl MG, Heymann WR, Berth-Jones J, Coulson I (eds). Treatment of Skin Disease, fifth Edition, Elsevier, 2018, pp 695-696.
Rose S, On SJ, Fuchs W, Chen C, et al. Magnesium supplementation in the treatment of pseudoxanthoma elasticum: A randomized trial. J Am Acad Dermatol 2019 Feb 28. pii: S0190-9622(19)30348-2. doi: 10.1016/j.jaad.2019.02.055. [Epub ahead of print]
Pomozi V, Julian CB, Zoll J, Pham K, et al. Dietary pyrophosphate modulates calcification in a mouse model of pseudoxanthoma elasticum: Implication for treatment of patients. J Invest Dermatol 2019; 139: 1082-1088.
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