Drug-induced gingival overgrowth (DIGO), also referred to as drug-induced gingival enlargement, and previously known as drug-induced gingival hyperplasia, is a side-effect of certain drugs where the gingival tissue is not the intended target organ. The key offending drug classes are anticonvulsants, immunosuppressants, and calcium channel blockers . Gingival overgrowth impedes proper dental hygiene and, apart from the cosmetic damage, causes painful chewing and eating. Therefore, patient education and information about the condition and its management are essential.
Drugs are the most common reason behind gingival enlargement. Drug-induced enlargement is associated with a patient's genetic predisposition and the presence of existing plaque or gingival inflammation . This condition is a side effect seen in patients taking anticonvulsants, immunosuppressants, and calcium channel blockers.
Phenytoin (PHT, or 5,5-diphenylhydantoin), sodium valproate, phenobarbitone, vigabatrin, primidone, mephenytoin, and ethosuximide are some of the drugs that cause gingival hypertrophy. At times, multiple drugs are given together, which could act synergistically and aggravate the condition. Drugs like PHT, phenobarbitone, and primidone are metabolized to 5-(4-hydroxyphenyl) 5-phenyl hydantoin (4-HPPH), responsible for the overgrowth of gingival tissue. Phenytoin is the drug of choice for the treatment of temporal lobe, grand mal, and psychomotor seizures and is the anticonvulsant most associated with gingival enlargements .
Cyclosporin, tacrolimus, and sirolimus are immunosuppressants linked to gingival enlargement, and cyclosporin is the most common of these. Immunosuppressants are frequently prescribed after organ transplantation, such as post renal transplants, and in the treatment of some autoimmune diseases, like rheumatoid arthritis . The incidence of gingival overgrowth has been found in nearly 53% of patients taking cyclosporin after renal transplants . Tacrolimus is less toxic than cyclosporin, causing less hepatic and renal toxicity and less severe gingival overgrowth than cyclosporin . Sirolimus is another immunosuppressant that has shown a predisposition to gingival enlargement .
Calcium Channel Blockers
These include nifedipine, nitrendipine, felodipine, amlodipine, nisoldipine, verapamil, and diltiazem. These drugs are indicated in the treatment of hypertension, angina pectoris, and peripheral vascular disease . Renal transplant patients on immunosuppressants like cyclosporin show a greater propensity to develop gingival hypertrophy when put on nifedipine or diltiazem. However, the extent of hypertrophy is more significant with the former . Combinations of these drugs could act synergistically, causing exaggerated hypertrophy of gingival tissue. Seymour et al. reported the first case of gingival overgrowth attributed to amlodipine in 1994. Lafzi et al. reported gingival hypertrophy in patients receiving 10 mg of amlodipine daily within two months of the onset of treatment .
Studies have shown that drug-induced gingival overgrowth is more commonly seen in male children and adolescents with a more prevalent location in the anterior gingival tissue. Genetic heterogeneity also plays a vital role, and the extent and degree of overgrowth depend on the drug. Phenytoin, cyclosporin, and nifedipine are the most common causes of gingival overgrowth, and phenytoin has the highest prevalence of all. It is estimated that 50% of adults treated with phenytoin experience gingival enlargement, 30% with cyclosporin, and 20% with nifedipine .
In 1996, Seymour et al. postulated the theory of genetic predisposition for the etiopathology of DIGO . This is substantiated by the fact that some individuals develop gingival hyperplasia and some do not whilst on the same drug. The usual inflammatory response of gingival fibroblasts and subsequent proliferation of connective tissue matrix emphasizes the heterogenetic character of the individual’s gingival fibroblasts in response to the inducing drugs. The common mechanism of action at the cellular level of all these three categories of dissimilar drugs appears to be inhibition of cation influx, particularly sodium and calcium ions. Gingival overgrowth is multifactorial . Bacterial plaque appears to be a contributory factor, and the severity of gingival overgrowth is directly proportional to the degree of plaque buildup and plaque-induced inflammation. Decreased cation dependant folic acid (FA) active transport within gingival fibroblasts causes reduced FA uptake by the cells, causing changes in the metabolism of matrix metalloproteinases and inability to activate collagenase. This results in an accumulation of connective tissue and collagen due to a lack of collagenase.
Gingival Fibroblasts and Cellular Folate Uptake
Inducing drugs act as a trigger for the activation and proliferation of gingival fibroblasts, causing an increased connective tissue production of GAGs (glycosaminoglycans). These drugs decrease cellular uptake of folate by genetically predispose fibroblasts. Reduced intracellular folate translates into a decrease in the synthesis or activation of MMPs (matrix metalloproteinases), which are required to convert inactive collagenase to active collagenase, allowing an excess of connective tissue build up. Brown et al. (1991) postulated that bacterial plaque contributes to gingival inflammation, which completes the vicious cycle.
These are more than 20 enzymes that bring about the degradation of connective tissue and tissue remodeling. These include collagenases, gelatinases, and stromelysins. Inhibition of activation of these can result in the accumulation of extracellular matrix and collagen and cause DIGO.
Inflamed gingival tissue exhibits higher levels of interleukin-1 beta (IL-1beta), a proinflammatory cytokine. Likewise, IL-6 causes fibroblastic proliferation and increased production of collagen and GAG synthesis .
Na+/ Ca2+ ion Flux Drug Mechanisms
Fugi and Kobayashi (1990) reported inhibition of Ca2+ uptake within gingival fibroblasts by PHT and several calcium channel blockers (CCBAs). Thomas and Petrou (2013) reported a reduction in Na+ channel availability and, therefore, a decrease in the action potential amplitude. This causes reduced Ca2+ entry, and a decrease in Ca2+ activated K+ channels. All three types of DIGO-inducing drugs act on Ca2+ flux similarly.
The concentrated drug in crevicular gingival fluid or bacterial plaque exerts a direct toxic effect on the gingival tissue. Dental plaque induces inflammation, which causes gingival overgrowth. Inflammation causes the upregulation of transforming growth factor-beta 1 (TGF-beta 1). Hence, control of dental plaque is needed in the treatment and prevention of DIGO over time.
In DIGO, the pathology lies in the connective tissue and not the epithelial cells of the gingiva. There is an excessive accumulation of extracellular matrix-like collagen with varying amounts of inflammatory infiltrates, predominantly plasma cells. Fibroblastic proliferation may not be evident. Erratic columns of collagen fibers are seen interspersed with penetrating epithelial ridges .
Patients with DIGO typically presents with gingival hypertrophy, pain during mastication, and cosmetic disfigurement one to three months after starting treatment with one of the drugs associated with the disease. They will report a past medical history of hypertension, angina, epilepsy, or have received an organ transplant recently.
According to histological and histomorphometric analyses, phenytoin-induced lesions are the most fibrotic. Ciclosporin-induced lesions are more inflamed and show a low fibrotic component, and nifedipine lesions are mixed .
The diagnosis of drug-induced gingival overgrowth is made by clinical examination and the patient's past medical history.
The aim of treatment in DIGO is to alleviate the patient's discomfort, to be able to do simple acts like eating and chewing pain-free, treat the inflammation, reduce the swelling, and give a better cosmetic appearance to the gingiva.
The modalities of treatment are medical and surgical. Medical management is the first line of treatment, and surgery is reserved for recurrences or cases that persist despite good medical treatment.
Discontinuing or changing the medication must be placed under consideration . An alternative to phenytoin includes carbamazepine and valproic acid, which have shown a lower impact in gingival enlargement. Diltiazem and verapamil exhibit lower prevalence of gingival enlargement compared to nifedipine. Cyclosporin substitution is more complicated because there are limited options available. Cyclosporin can be substituted by tacrolimus, and the use of azithromycin in combination with cyclosporin has shown a decrease in the severity of DIGO .Plaque control should be the first step in the treatment of DIGO, correct oral hygiene, and professional plaque removal, including tooth surface cleaning and periodic scaling, which are essential .
Control of inflammation, including non-steroidal anti-inflammatory agents, antibiotics to control infection, and topical antifungal medication like nystatin, may also be utilized. Folate supplementation has also been used .
A sufficient period of six to twelve months should be allowed to elapse after discontinuing the inducing drug before surgery is considered .The surgical methods include gingivectomy and periodontal flap surgery.Electrocautery may be used in difficult cases, children, or where the gingiva is fragile and likely to bleed.
The CO2 laser has a wavelength of 10600 nm; hence, it is readily absorbed by water and therefore is effective in the surgery of soft tissues with high water content like the gingiva. Blood vessels up to a diameter of 0.5 mm can be sealed effectively and provide a dry field for better visibility of the surgical field. A laser is preferred over the scalpel as it has strong bactericidal and hemostatic effects .
In all these conditions, a thorough history, physical examination, and investigations, including biopsy, may be required to confirm the etiology.
Conditions Similar to Gingival Enlargement
If the medication inducing the gingival overgrowth can be changed to a drug that is less associated with this complication, the gingival tissue may return to normal with the aid of adequate plaque control. The gingival enlargement can persist, despite drug substitution and good plaque control, and in this case, surgical management to restore normal gingival contours is performed. These modalities of treatment, although effective, do not always prevent the recurrence of the enlargement. The recurrence of DIGO in surgically treated cases, which are common, may appear as soon as three to six months after the procedure. In general, the results last for at least twelve months .
Some studies indicate that bacterial plaque is a prerequisite for the disease to occur. On the contrary, others believe that the presence of dental plaque is a consequence of the difficulty that the gingival enlargement represents to dental hygiene, which then exacerbates the severity of the overgrowth . In any case, one thing is certain, bacterial plaque does play an important role in the development of DIGO, and patients must be educated about adequate dental brushing and flossing techniques that may be accompanied by chlorhexidine gluconate rinses to control the levels of bacterial plaque. Regular appointments with their dentist must be accomplished to perform professional cleaning of the teeth. These measures can prevent or decrease the rate and the degree at which recurrence occurs.
Since this condition is entirely drug-induced, patient education about the side-effects of these drugs before starting treatment is warranted, and the importance of good dental hygiene should be emphasized . Drug-induced gingival enlargement has a good prognosis and is generally reversible on stopping or substituting the offending drug. An interdisciplinary approach is needed as the primary clinician, the dentist, and the healthcare team should work together to address the patient's signs and symptoms adequately (level V).
|||Marshall RI,Bartold PM, Medication induced gingival overgrowth. Oral diseases. 1998 Jun; [PubMed PMID: 9680902]|
|||Seymour RA,Thomason JM,Ellis JS, The pathogenesis of drug-induced gingival overgrowth. Journal of clinical periodontology. 1996 Mar; [PubMed PMID: 8707974]|
|||Dongari-Bagtzoglou A, Drug-associated gingival enlargement. Journal of periodontology. 2004 Oct; [PubMed PMID: 15562922]|
|||Greenberg KV,Armitage GC,Shiboski CH, Gingival enlargement among renal transplant recipients in the era of new-generation immunosuppressants. Journal of periodontology. 2008 Mar; [PubMed PMID: 18315427]|
|||Sekiguchi RT,Paixão CG,Saraiva L,Romito GA,Pannuti CM,Lotufo RF, Incidence of tacrolimus-induced gingival overgrowth in the absence of calcium channel blockers: a short-term study. Journal of clinical periodontology. 2007 Jul; [PubMed PMID: 17433046]|
|||Nassar CA,Nassar PO,Andia DC,Guimarães MR,Spolidorio LC, The effects of up to 240 days of tacrolimus therapy on the gingival tissues of rats--a morphological evaluation. Oral diseases. 2008 Jan; [PubMed PMID: 18173451]|
|||Cota LO,Oliveira AP,Costa JE,Cortelli SC,Costa FO, Gingival status of Brazilian renal transplant recipients under sirolimus-based regimens. Journal of periodontology. 2008 Nov; [PubMed PMID: 18980514]|
|||Cota LO,Aquino DR,Franco GC,Cortelli JR,Cortelli SC,Costa FO, Gingival overgrowth in subjects under immunosuppressive regimens based on cyclosporine, tacrolimus, or sirolimus. Journal of clinical periodontology. 2010 Oct; [PubMed PMID: 20618547]|
|||Cota LO,Viana MB,Moreira PR,Gomez RS,Cortelli JR,Cortelli SC,Costa FO, Gingival overgrowth in cyclosporine, tacrolimus, or sirolimus-based immunosuppressive regimens and the single nucleotide IL-6 (-174 G/C) gene polymorphism. Archives of oral biology. 2010 Jul; [PubMed PMID: 20430366]|
|||Lafzi A,Farahani RM,Shoja MA, Amlodipine-induced gingival hyperplasia. Medicina oral, patologia oral y cirugia bucal. 2006 Nov 1; [PubMed PMID: 17072250]|
|||Doufexi A,Mina M,Ioannidou E, Gingival overgrowth in children: epidemiology, pathogenesis, and complications. A literature review. Journal of periodontology. 2005 Jan [PubMed PMID: 15830631]|
|||Seymour RA,Ellis JS,Thomason JM, Risk factors for drug-induced gingival overgrowth. Journal of clinical periodontology. 2000 Apr; [PubMed PMID: 10783833]|
|||Dongari A,McDonnell HT,Langlais RP, Drug-induced gingival overgrowth. Oral surgery, oral medicine, and oral pathology. 1993 Oct; [PubMed PMID: 8233439]|
|||Bharti V,Bansal C, Drug-induced gingival overgrowth: The nemesis of gingiva unravelled. Journal of Indian Society of Periodontology. 2013 Mar; [PubMed PMID: 23869123]|
|||Trackman PC,Kantarci A, Molecular and clinical aspects of drug-induced gingival overgrowth. Journal of dental research. 2015 Apr; [PubMed PMID: 25680368]|
|||Samudrala P,Chava VK,Chandana TS,Suresh R, Drug-induced gingival overgrowth: A critical insight into case reports from over two decades. Journal of Indian Society of Periodontology. 2016 Sep-Oct; [PubMed PMID: 29242684]|
|||de la Rosa García E,Mondragón Padilla A, [The effect of mycophenolate mofetil and azathioprine on gingival enlargement associated with cyclosporin A use in kidney transplant patients]. Nefrologia : publicacion oficial de la Sociedad Espanola Nefrologia. 2009; [PubMed PMID: 19820760]|
|||Diesel A,Moriello K, Medical Management of Cyclosporine-Induced Gingival Overgrowth Using Oral Azithromycin in Six Dogs. Veterinary sciences. 2015 Feb 5 [PubMed PMID: 29061926]|
|||Mavrogiannis M,Ellis JS,Thomason JM,Seymour RA, The management of drug-induced gingival overgrowth. Journal of clinical periodontology. 2006 Jun; [PubMed PMID: 16677333]|
|||Dhale RP,Phadnaik MB, Conservative management of amlodipine influenced gingival enlargement. Journal of Indian Society of Periodontology. 2009 Jan; [PubMed PMID: 20376240]|
|||Lu HK,Tseng CC,Lee YH,Li CL,Wang LF, Flutamide inhibits nifedipine- and interleukin-1 beta-induced collagen overproduction in gingival fibroblasts. Journal of periodontal research. 2010 Aug; [PubMed PMID: 20337887]|
|||Camargo PM,Melnick PR,Pirih FQ,Lagos R,Takei HH, Treatment of drug-induced gingival enlargement: aesthetic and functional considerations. Periodontology 2000. 2001; [PubMed PMID: 11551304]|
|||Agrawal AA, Gingival enlargements: Differential diagnosis and review of literature. World journal of clinical cases. 2015 Sep 16 [PubMed PMID: 26380825]|