Thoughts on hyaluronidase and The House of God

By Warren R. Heymann, MD
January 15, 2020
Vol. 2, No. 2

I was reminiscing about my internship at Bellevue-NYU forty years ago after reading Stephen Bergman’s (pseudonym Samuel Shem) reflections on the fortieth anniversary of his irreverent, but hilariously accurate, The House of God — a portrayal of resident life in that era. (1) I recall the wisdom of the senior resident (“the Fat Man”) working toward the “big fortoona” to come, but offering profound guidance to his underlings. All of my peers devoured the book with gusto.

One of my patients in the summer of 1979 was an embittered (probably justifiably so), elderly, blind diabetic woman admitted for congestive heart failure. During my examination, I commented that her back felt hard.

“I have scleredema!” she barked.

“You mean scleroderma, don’t you?” I countered.

“No, I mean SCLEREDEMA, you moronic, stupid intern. It’s a complication of diabetes. Didn’t you learn anything in medical school? Look it up! Maybe you’ll figure out a way to help me — although from my first impression of you, I highly doubt it!”

According to Maytin, hyaluronic acid (hyaluronan, HA) is a simple linear disaccharide polymer creating a huge hydrophilic molecule conferring a large volume of hydration, thereby contributing to the turgor and flexibility of healthy skin. HA also has important biological and physiological functions that have been under-appreciated until recently. New research confirms that HA is dynamically produced by most skin cells, not only fibroblasts but also by keratinocytes. For both fibroblasts and keratinocytes, HA plays a regulatory role in controlling cell physiology through interaction of extracellular HA with a major cell-surface receptor, CD44. This interaction mediates intracellular signaling both directly and indirectly, through CD44 interactions with the cytoskeleton and with EGF and TGFβ receptors. Intact HA tends to exert anti-inflammatory effects via CD44, whereas small and mid-sized fragments (oligosaccharides) are pro-inflammatory via Toll-like receptors. Furthermore, degradation of HA by specific hyaluronidases produces HA fragments that can help to regulate inflammatory processes. (2)

Most dermatologists (and patients) will think of fillers when hearing the term HA. Despite its off-label use, every cosmetic dermatologist must have hyaluronidase handy for complications of HA fillers — vascular compromise most emergently, but also superficial placement of the filler, a Tyndall-like effect, or granuloma formation. Hyaluronidase is available commercially (Amphadase, Vitrase, Hylenex) and is delivered by injection. (3) Approved indications include enhancement of subcutaneous absorption of injected drugs, improving resorption of radiopaque agents during subcutaneous urography, and hypodermoclysis (the subcutaneous administration of isotonic infusates to correct short-term fluid and electrolyte balances). (4,5) According to Mo et al: “Adverse effects associated with hyaluronidase treatment are extremely rare. Less than 0.1% of patients respond with hives or angioedema, and there have been no documented cases of anaphylaxis in response to subcutaneous injection. Patch tests for hypersensitivity are recommended for the animal-derived brands of hyaluronidase, and a positive reaction of wheal formation and itching within 30 minutes is a contraindication to its use.” Regarding concern that extensive use of hyaluronidase may break down the body’s own HA and lead to cosmetic defects, the authors cite studies demonstrating that large quantities of hyaluronidase are effective in targeting filler HA, with no appreciable damage to the body’s natural HA. The safety is likely due to rapid turnover of native HA, where one-third of native HA is broken down and rebuilt daily. (3)

As a medical dermatologist, I have never used hyaluronidase, but recent reports suggest that I might. One of the most debilitating manifestations of scleroderma is microstomia; any treatment that could improve mastication, phonation, and oral hygiene would be valuable. Melvin et al reported improvement of microstomia in a 53-year-old woman by hyaluronidase injections, as documented by a diminution of the MHISS (mouth handicap in systemic sclerosis score). (6) Hoesly et al presented two cases of pretibial myxedema, both of whom responded well to hyaluronidase. The first patient had been recalcitrant to clobetasol and pentoxifylline; the second patient had no prior therapy. (4) Eisert and Nast described two cases of severe keloids that were unresponsive to prior surgery. Both patients had impressive results with a combination of intralesional cryosurgery, triamcinolone, 5-fluorouracil, and hyaluronidase. (7) Kiyohara and Tanimura reported the case of a 47-year-old woman with type 2 diabetes and biopsy-proven scleredema. Monotherapy with hyaluronidase injections demonstrated marked improvement over 18 weeks, as documented by MRI scans. (8)

Perhaps other yet unreported indications exist for hyaluronidase; recalcitrant scleromyxedema and granuloma annulare come to mind. When I finally utilize hyaluronidase, I will smile toward the heavens, thanking my first, cantankerous scleredema patient for encouraging me to go back and study.

Point to Remember: Cosmetic dermatologists performing hyaluronic acid filler procedures must have access to hyaluronidase for emergent and other filler complications. Medical dermatologists may wish to borrow some for recalcitrant disorders such as pretibial myxedema, microstomia of scleroderma, and scleredema.

Our Expert’s Viewpoint

Chérie M. Ditre, MD
Director of Cosmetic Dermatology and the Skin Enhancement Center
Penn Medicine at Radnor
Perelman University of Pennsylvania School of Medicine

In this article, Dr. Heymann bridges the gap between medical and cosmetic dermatology which is sorely needed. His delightful article highlights how one aspect of our field helps the other. In this case, his thorough review of hyaluronidase and uses in the medical treatment of scleredema and potentially many others is enlightening. It is a reminder that we can all benefit our patients by removing the stigma of cosmetic versus medical dermatology and learn that by sharing and collaborating we can accomplish more.

1. Bergman S. Basch unbound – The House of God and fiction as resistance at 40. JAMA 2019 Jul 10 [Epub ahead of print]

2. Maytin EV. Hyaluronan: More than just a wrinkle filler. Glycobiology 2016; 26: 553-559.

3. Mo JH, Chapman LW, Cohen JL. A clinical review of common medications used in emergency dermatological situations. Dermatol Surg 2019; 45: 652-657.

4. Hoesly PM, Tolaymat LM, Sluzevich JC, Keeling JH. Pretibial myxedema successfully treated with intralesional hyaluronidase. JAAD Case Rep 2018; 4: 874-876.

5. Lybarger EH. Hypodermoclysis in the home and long-term care settings. J Infus Nurs 2009; 32: 40-44.

6. Melvin OG, Hunt KM, Jacobson ES. Hyaluronidase treatment of scleroderma-induced microstomia. JAMA Dermatol 2019; 155: 857-859.

7. Eisert L, Nast A. Treatment of extensive, recalcitrant keloids using a combination of intralesional cryosurgery, triamcinolone, 5-fluorouracil, and hyaluronidase. J Dtsch Dermatol Ges 2019; May 27 [Epub ahead of print].

8. Kiyohara T, Tanimura H. Diabetic scleroderma successfully treated by topical hyaluronidase injection: Efficacy of magnetic resonance imaging. Clin Exp Dermatol 2019; 44: 584-586.