There is no effective product in medicine without pros and cons. Our scientific literature is the forum to describe and discuss its benefits and side effects. We refer to the article by Negri AL et al. “Hypercalcemia secondary to granulomatous disease caused by the injection of methacrylate: a case series” (Clin Cases Mineral Bone Metab 2014;11(1): 444–48). We have read it with interest. The Authors are to be greeted by the publication of four cases relating severe hypercalcemia to granuloma formation after PMMA injection in gluteal regions. It is an interesting hypothesis that a possible overload of macrophages and giant cells contain 1-alpha-hydroxylase, which converts 25 (OH) vitamin D to 1,25-(OH)2 vitamin D, which causes PTH-suppression with consequent hypercalcemia. Four patients within four years may be an alarming sign - since ‘nil nocere’ is paramount especially in filler materials in aesthetic surgery. However, some criticism of the data may be allowed:
Probably, all 4 patients reported had no granulomas (growing tumors!), otherwise they would have had contacted their injectors. They had a normal and expected foreign body reaction. The rate of foreign body granulomas usually years (not months) after PMMA-microspheres injections is about 1 in1000 patients (1).
Of the 4 patients, case 1 had also silicone injected, case 2 had a pre-existing chronic renal failure stage III, case 3 had normal renal function 8 months before, and case 4 was HIV+ and had calcium depositions in glomerular capillaries and tubules compatible with tenofovir toxicity, e.g. 2 of the 4 cases had already decreased renal function.
Granuloma is not like granuloma; it is the body’s reaction to get rid of certain toxins, bacteria, or foreign bodies – with a similar cellular defense but different intracellular reactions. One cannot compare a systemic granulomatous reactions to certain bacteria (tuberculosis, leprosy, candidiasis) with a localized foreign body reaction to inert (!) microspheres.
Contrary to bacteria, fluid silicone, and PAAG, which form phagocytosable microdroplets and are broken down by intracellular enzymes, PMMA-microspheres are solid and kept within macrophages for the rest of patient’s life (2). We therefore doubt whether 1-alpha-hydroxylase plays a role in phagocytosis of PMMA.
The histological picture of case 4 in their article shows no granulomatous tissue at all (Figure 1) but a crude mixture of bone cement (PMMA-microspheres of all sizes) and not the sieved and cleaned microspheres around 40 microns contained today in Newplastic (3), Metacrill (4) and Artecoll/Artefill (2). Case 2 had mainly fat injections; therefore, the biopsy of a lump revealed probably necrotic fat.
Nothing is known about the volume of the injected PMMA. Buttock augmentation with any filler needs a huge amount of injectable, e.g. at least 200 ml, which will stimulate millions of macrophages and giant cells, eventually.
Moreover, was the injected product really PMMA (4) or eventually additional liquid silicone, as the author’s Figure 1 of case 4 suggests? PMMA microspheres cause fast fixation at the injection site (3, 5) while silicone fluid droplets cause little foreign body reaction and therefore can move by gravity to the knees, for example.
MRI should be more valuable to show differences between PMMA and other fillers into muscles. The MRI pattern of PMMA applied is very similar to a normal image with intramuscular strands of PMMA (Figure 2).
Plastic surgeons know as little about hypercalcemia as nephrologists know about PMMA-microsphere injections. We therefore feel that a co-operation with the injectors is mandatory to back the Author’s hypothesis. Correct injected products and volumes, and a clear diagnosis from a filler expert is missing, whether normal nodules with rather few macrophages, or real PMMA-granulomas were present ?
In conclusion: 2 convincing patients and 2 patients with pre-existing inhibited renal function provide not enough data to support the above hypothesis – with its possible consequences.
Figure 1.
Typical PMMA-granuloma with wide spaces between the single microspheres filled with macrophages and giant cells.
Figure 2.
A) MRI of buttock without any filler. B) MRI of buttock with PMMA injection intramuscularly. C) MRI of buttock with liquid silicone injection.
References
- 1.Lemperle G, Gauthier-Hazan N, Wolters M, Eisemann-Klein M, Zimmermann U, Duffy DM. Foreign body granulomas after all injectable dermal fillers. Part 1: Possible causes. Plast Reconstr Surg. 2009;123:1842–63. doi: 10.1097/PRS.0b013e31818236d7. [DOI] [PubMed] [Google Scholar]
- 2.Lemperle G, Knapp TR, Sadick NS, Lemperle SM. ArteFill® permanent injectable for soft tissue augmentation: 1. Mechanism of action and injection techniques. Aesth Plast Surg. 2010;34:267–272. doi: 10.1007/s00266-009-9413-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Nacul AM. Bioplastia na região glútea. In: Yamaguchi C, editor. Procedimentos estéticos minimamente invasivos. Santos; São Paulo: 2005. [Google Scholar]
- 4.Piacquadio D, Smith S, Anderson RA. Comparison of commercially available polymethylmethacrylate-based soft tissue fillers. Derm Surg. 2008;34:S48–52. doi: 10.1111/j.1524-4725.2008.34242.x. [DOI] [PubMed] [Google Scholar]
- 5.Borges Fortes F, Lemperle G, Charrier U. A comparative study among PMMA based fillers commercially available in Brazil. Presented in Primer Consenso Mundial de Bioplastia; Guadalajara, Mexico. 5 y 6 de Diciembre, 2008. [Google Scholar]