Hyaluronidase for Filler Reversal: Understanding Patient Concerns and Safety

Patient satisfaction with hyaluronidase sits at around 50% on RealSelf, dramatically lower than the 94% satisfaction rate for filler treatments themselves, which demands an explanation if we’re going to guide our patients effectively through these decisions. This gap between patient expectations and outcomes with filler reversal creates anxiety for both practitioners and patients, especially when online communities discuss potential complications without the context needed to understand what’s actually happening at a biochemical level.

Understanding what hyaluronidase actually does starts with the fundamentals of how enzymes work in the body, and this knowledge helps us have better conversations with anxious patients who’ve read concerning things online.

How hyaluronidase works at the molecular level

Hyaluronidase is an enzyme, which means it’s a complex three-dimensional protein that performs a very specific chemical reaction at the molecular level. Enzymes are biologic catalysts, and their specificity defines how they function in the body through a lock-and-key mechanism where the protein shape allows reactions only at precise molecular sites.

In the case of hyaluronidase, it takes a water molecule and reacts it with hyaluronic acid to break it down into monosaccharides at one specific type of chemical bond called a beta 1,4 bond which occurs between monosaccharides. Our bodies contain over 75,000 known enzymes because they are highly specialized, with one enzyme performing one chemical reaction through this precise protein-substrate interaction.

This specificity is a core way that enzymes work, and they do not react with multiple different chemicals or else our bodies simply would not function properly. Hyaluronidase is an enzyme we already have in our systems, with our own bodies making several versions of the enzyme, and without it our lymphatic systems would clog up with hyaluronic acid so we would no longer be able to drain and clean fluids from the extracellular space.

The enzyme is also a key part of the process of conception, as the sperm itself produces hyaluronidase to dissolve the hyaluronic acid which is the last barrier to pass through before a new life begins. Animal versions of this enzyme have been used for over 60 years to help absorption and dispersion of drugs in subcutaneous tissue, to break down hematomas, and to dissolve dermal filler, usually coming from the testicles of sheep, cows, and pigs.

To reduce reaction rates due to subtle differences, we have become better at purifying animal versions as well as developing a synthetic human version which is much more compatible with our systems.

Five growing indications for hyaluronidase use

There is a growing number of indications to dissolve dermal filler in aesthetic practice, and understanding these helps frame why we need this enzyme despite the relatively low satisfaction ratings. Filler-induced blindness represents the most extreme indication, where hyaluronidase has been used successfully for remission, and dissolving as a result of overfilling is going up generally across the field.

We are all using high volumes of filler and have already been doing this at scale for 10 to 20 years, which creates a patient population where migration has become a growing problem. There is a subset of patients whose fillers may last for many years without staying put, with diffusion along with some additional water attraction that begins to degrade the appearance over time.

The tendency to solve lost definition by adding more dermal filler is probably the worst thing you can do long-term, and this compounds the problem substantially. We know from studies that some filler can last up to 12 years, and there’s a cohort of patients where waiting simply does not work because their lymphatics may be blocked in some cases, most obvious in the tear trough area.

This is compatible with what we know from animal studies where they knock out the hyaluronidase gene and see similar effects. The point is clear: so long as we use hyaluronic acid fillers, we will also need hyaluronidase as an essential tool in aesthetic practice.

Theories about why satisfaction ratings are low

The most interesting discussion centers on how the SMAS could potentially be affected by hyaluronidase, based on surgical experience in over 3000 lip lifts where the SMAS appears to shrink in size and its ability to hold moisture in some patients. When saline is injected, it does not seem to hold the same volume as it would in other patients who’d not had a reversal, with the SMAS appearing to lose its puffy nature.

There is a possible depletion in the SMAS as a result of using hyaluronidase in a small number of patients, though this leads to a conclusion that hyaluronidase can have a lifelong effect which we cannot make with any certainty. Thought-provoking as this experience is, we cannot draw a causal relationship between this observation and hyaluronidase without a structured study with data to interrogate.

Personal experience is evidence but it’s the lowest form of evidence, and these patients having surgical lip lifts already creates a selection bias since we don’t know if these patients were accommodating for a weaker SMAS with lip filler and then having reversals to have surgery. We also have the problem of confirmation bias, where humans tend to look to confirm their theories, so it’s highly likely that in cases where the SMAS looks thinner the correlation gets noticed while normal SMAS cases get disregarded even though they may also have had hyaluronidase in the past.

The theory itself is easy to destroy even if there was a correlation, because what if hyaluronic acid itself caused a down regulation in natural hyaluronic acid production? After years of HA use and then dissolving it, you could be left with exactly the same clinical picture without the enzyme being at fault, since the suppression of natural hyaluronic acid would produce exactly the same clinical appearance.

This is often the problem with hypotheses presented as conclusions – they are easy to come up with and hard to disprove, which means they can spread as memes for years before the truth eventually catches up.

Reassuring evidence about hyaluronidase effects

Dr. Gabriela Casabona’s experiment observed the effect on the skin of hyaluronidase and showed a decrease in resistance to a pinch test that was dose dependent and lasted only for 48 hours before a complete return to baseline. What we can conclude from this experiment is that hyaluronidase is breaking down probably the natural hyaluronic acid, which is then being remanufactured and replacing itself in the skin about 48 hours later.

This gives us confidence that the enzyme performs its specific function and the body recovers normally through its natural processes.

Understanding why patients are unhappy with reversal

We need to tease out why a minority of patients are so unhappy after hyaluronidase, and there are a number of potential options that can be divided into issues of perceptual or real physical changes, or a combination of both. The first option is that hyaluronidase really is causing a physical problem in a minority of patients, while the second is that hyaluronidase is used in conditions where it’s very easy to create the perception of a long term problem.

The third possibility is that there are real changes which you would expect to occur in any reversal, which then cause an additional long term shift in perception that becomes the real problem patients experience. Some people suggest that filler has stretched their face and when it’s dissolved it is worse than ever, something that seems quite unlikely unless you’re using extremely large volumes.

The second theory involves acclimatization to an overfilled state and then a reversal to normal which simply feels much worse than normal because it is so shocking to lose so much volume so quickly. Even with a bounce back of endogenous HA after the initial trauma, this could still cause a shift in perception that persists.

We also have the psychological explanation, which recognizes that these patients who seek reversal are already more likely to be on the dysmorphic end of the spectrum and more easily traumatized by small changes which are expected to be normal, then persisting in an unhappy state for a long time after treatment.

The nocebo effect comes into play here as well, which is the idea that if you go into a procedure expecting the worst you are most likely to experience more side effects. When humans go in expecting a bad outcome, they tend to notice the bad side effects and ignore the positives because that’s simply how our brains work.

With growing online communities discussing these side effects without the moderation of opposing views, clinicians should be warned about treating patients who already believe that hyaluronidase dissolves normal tissue, since this level of uncertainty is a red flag for poor outcomes. Some of the patients in the RealSelf testimonials actually reference having dysmorphia in their testimonial, and regardless of any potential physical effect long term, dysmorphic patients will be overrepresented in these experiences simply because having a reversal usually implies you are significantly unhappy with your appearance after a treatment.

Hyaluronidase red flags in patient consultations

When patients discuss hyaluronidase, you should follow a fundamental medical principle to intervene with discretion since we are not omniscient and it is possible that new evidence could emerge showing that there are cases where long term effects are due to hyaluronidase. You should act as if this could be true even if you’re not yet convinced, approaching the treatment with appropriate caution.

Dive straight into your patient’s health beliefs in the consultation without dismissing them, letting them talk about everything they’ve read on the subject and then systematically sharing what your understanding is. If they believe something which is not compatible with the treatment, you should not offer it at all.

An anxious patient with a self-loathing attitude to their appearance, a belief that hyalase can cause your face to collapse, and a history of treatment with dissatisfaction should be handled very carefully, erring on the side of no treatment. These conversations require time and care because the patient’s psychological state may be more important than the physical aspects of the treatment itself.

The importance of independent information

For transparency, this information comes from a completely independent perspective without any connection to pharmaceutical companies or manufacturers. Unlike many of the famous voices in aesthetic medicine who are paid representatives of drug manufacturers or pharmacy companies (often termed KOLs or key opinion leaders), this analysis comes from someone who makes most of their income by educating practitioners about complications.

There is no interest in minimizing this issue since the focus is on seeking out the truth as best as possible, shedding light on this important matter, and although we may disagree with certain conclusions, the goal remains being on the side of patients through open and honest discussion where disagreement is part of a healthy process. Information on this topic continues to be gathered, and perspectives may change completely in time if more evidence emerges that changes our understanding of how hyaluronidase affects tissue long-term.

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