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Review Article

Drug‑induced gingival overgrowth:

A critical insight into case reports from
over two decades
Pramod Samudrala, Vijay Kumar Chava, Tanguturi Sri Chandana,
Rachakonda Suresh

Department of Abstract:
Periodontology, Drug‑induced gingival overgrowth (DIGO) is a well‑recognized adverse effect of certain systemic medications.
Narayana Dental Calcium channel blockers, anticonvulsants, and immunosuppressants are frequently implicated drugs in the
College and etiology of DIGO. Drug variables, plaque‑induced inflammation, and genetic factors are the three important
Hospital, Nellore, factors in the expression of gingival changes after systemic medication use. Careful clinical examination and
Andhra Pradesh, India thorough history taking form the basis for diagnosis of DIGO. Histopathological examination is often neglected;
however, it is an important aid that helps in differential diagnosis. Cessation or change of drug and meticulous
plaque control often leads to regression of the lesion, which however might need surgical correction for optimal
maintenance of gingival health. The purpose of the present article is to review case reports and case series
published in the last two decades and to assimilate and compile the information for clinical applications such as
diagnosis and therapeutic management of DIGO.
Key words:
Anticonvulsants, calcium channel blockers, dental plaque, drug‑induced gingival overgrowth, genetic factors,
immunosuppressants, oral hygiene

Access this article online

Website:
www.jisponline.com INTRODUCTION with speech and mastication. The clinical
characteristics common to all DIGOs include a

C
DOI:
10.4103/jisp.jisp_265_15
ertain gingival diseases that are modified
substantially by the use of systemic
Quick Response Code:
medications are now well recognized. In the
1999 international workshop for a classification
of periodontal diseases and conditions,
“drug‑influenced gingival enlargements” have
been identified and added as a subcategory
under the section “dental plaque‑induced
gingival diseases.”[1] Drug‑influenced gingival
enlargement has been defined as “an overgrowth
or increase in size of the gingiva resulting in
whole or in part from systemic drug use.”[2]
variation in the inter‑ or intra‑patient pattern of
enlargement; a tendency to occur more often in the
anterior gingiva; a higher prevalence in younger
age groups; onset within 3 months of drug use;
and no association with attachment loss or tooth
mortality. Moreover, the clinical lesions and their
histological characteristics are indistinguishable
among the gingival enlargements induced by one
drug to another.[7] Age and other demographic
variables, drug variables, concomitant
medications, periodontal variables, and genetic
factors are the known risk factors for DIGO.[3]

Anticonvulsants such as phenytoin and Although adequate literature is available in the

immunosuppressants such as cyclosporine form of case reports and case series, a lacunae
and calcium channel blockers (CCBs) are still exists in assimilation and compilation of
frequently implicated as drugs that cause this knowledge for clinical application. Hence,
Address for
gingival overgrowth.[3] In addition, drugs such as
correspondence:
Dr. Pramod Samudrala, sodium valproate[4] and erythromycin[5] induced This is an open access article distributed under the terms of the
Department of gingival enlargements have also been reported Creative Commons Attribution‑NonCommercial‑ShareAlike 3.0
License, which allows others to remix, tweak, and build upon
Periodontology, in the past. Although the chemical nature of the
the work non‑commercially, as long as the author is credited
Narayana Dental three drug groups is different, they have a similar and the new creations are licensed under the identical terms.
College and Hospital, mechanism of action at the cellular level, where
Chinthareddypalem, For reprints contact: reprints@medknow.com
they inhibit intracellular calcium ion influx. Thus,
Nellore, all these drugs, despite being dissimilar, have a
Andhra Pradesh, India. How to cite this article: Samudrala P, Chava VK,
common side effect upon secondary target tissue
E‑mail: pramodsamudrala@ Chandana TS, Suresh R. Drug-induced gingival
gmail.com such as gingival connective tissue.[6]
overgrowth: A critical insight into case reports from
over two decades. J Indian Soc Periodontol; doi:
Submission: 07‑08‑2015 Drug‑induced gingival overgrowth (DIGO) is
10.4103/jisp.jisp_265_15.
Accepted: 21‑02‑2017 usually esthetically disfiguring and interferes
© 2017 Indian Society of Periodontology | Published by Wolters Kluwer - Medknow 1
[Downloaded free from http://www.jisponline.com on Friday, September 15, 2017, IP: 36.79.172.174]

Samudrala, et al.: DIGO: A review of case reports

in the present article, an attempt is being made to review case

reports and case series of drug‑induced gingival enlargements
to outline the different drugs that induce gingival overgrowth,
their varied clinical presentations, possible pathogenic
mechanisms involved, their diagnosis and therapeutic
managements.

MATERIALS AND METHODS

A thorough Medline/PubMed search was done for articles

published from January 1993 to December 2014 using the
search terms “gingival enlargement,” “gingival overgrowth,”
“gingival hyperplasia,” “drug‑induced,” “drug‑influenced,”
“medication‑induced,” “medication‑influenced,” and “DIGO”
in various combinations. The search has been carried out by
two separate investigators and then compared, analyzed,
discussed, and agreed upon by the entire team of investigators
before inclusion of the articles in the study.

Only human case reports and case series of DIGOs published
in English were considered for inclusion in the article.
Exclusion criteria
1. Studies published in languages other than English
2. Reports of gingival enlargements in nonhuman
subjects (DIGO reports in animals)
3. Exclusive review of literature articles
4. Exclusive histopathological analysis without clear reporting
of the case
5. In vitro studies
6. Epidemiological studies, including prevalence studies,
case–control studies, cohort studies, and therapeutic
efficacy studies.
7. Reports of gingival enlargement with any etiology other
than “drug‑induced” or of uncertain etiology.
Inclusion criteria
1. Case reports and case series publications of DIGO involving
human subjects
2. Articles published in English alone between January 1993
and December 2014.
RESULTS
The primary literature search identified 1757 potential articles.
However, by thorough screening of titles and abstracts,
and further full text reading, only 86 relevant articles could
be identified, which included case reports and case series
presentations of DIGOs. Altogether, the number of cases
analyzed was 119 [Figure 1].
Reported cases of gingival enlargements were induced by
different drugs; CCBs (50/119 – of which amlodipine‑25;[8‑28]
nifedipine‑13; [26,29‑40] verapamil‑4; [41] felodipine‑2; [42,43]
nisoldipine‑1;[44] manidipine‑1;[45] and unspecified CCBs‑4[46]);
phenytoin (11/119); [47‑57] cyclosporine (31/119); [35,46,58‑75]
phenobarbital (4/119);[76‑78] sodium valproate (3/119 ‑ including
one report of congenital drug‑induced gingival
hyperplasia);[79‑81] d‑penicillamine (2/119);[82] combination oral
contraceptive pill‑lynestrenol and ethinyl estradiol (1/119);[83]
vigabatrin (1/119).[84] Cases of gingival enlargement after
combination drug therapy have also been reported; a
Figure 1: Schematic representation of “literature search”
combination of cyclosporine and CCBs (11/119);[35,46,85‑88]
phenytoin and phenobarbital (4/119);[54,89‑91] and a combination
of phenytoin, cyclosporine, and CCBs (1/119).[92]
Two cases of DIGO around dental implants have been reported;
one associated with nifedipine use,[37] and other with phenytoin
use.[57]
DISCUSSION
Gingival overgrowth is a frequently encountered, unrelated
adverse effect resulting from intake of certain systemic drugs.
An understanding of the underlying factors and mechanisms
involved might be needful in prevention and therapeutic
management of DIGO. Seymour et al. in 1996[93] suggested that
DIGO is multifactorial and that three factors are significant
in its expression. They are drug variables, plaque‑induced
inflammatory changes in the gingival tissues, and genetic
factors.
Drug variables
From the reported cases in the last two decades assessed in this
review, it has been clear that CCBs, cyclosporine, and phenytoin
are the attributing drugs for a majority of DIGO cases.
Cyclosporine is an immunosuppressant reportedly used
in kidney/heart/liver transplant patients to prevent organ
rejection.[35,60,61,64‑70,72,74,75] It has also been used for treating
aplastic anemia,[58,60,73] psoriasis,[62] and Behcet disease.[71]
Cyclosporine is known to alter the metabolism of gingival
fibroblasts and also upregulates specific growth factors such
as platelet‑derived growth factor B, thereby causing adverse
gingival changes such as overgrowth.[6] Cessation of the drug
or its substitution by another drug is a definitive step in the
management of cyclosporine‑associated gingival overgrowth.
Mathur et  al. in 2003 [65] reported regression of gingival
overgrowth in a renal transplant patient after cessation of
cyclosporine. Similarly, V’lckova‑Laskoska in 2005[62] reported
virtually complete reduction of gingival enlargement after
cessation of cyclosporine in a patient under treatment for
psoriasis.

2 Journal of Indian Society of Periodontology - Volume XX, Issue XX, Month 2017
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Samudrala, et al.: DIGO: A review of case reports
However, abrupt cessation of an immunosuppressant
might lead to severe complications such as failure of organ
transplantations. Hence, substitution of cyclosporine by a
better alternative has been suggested. Kennedy and Linden in
2000[72] and Hernández et al. in 2003[66] reported rapid reduction
in gingival overgrowth after cyclosporine withdrawal and
its conversion to tacrolimus in organ transplant patients.
Similarly, Gonçalves et al. in 2008[60] reported that DIGO in a
9‑year‑old renal transplant patient under cyclosporine therapy
recurred even after surgical correction and thorough practice
of plaque control measures, which however regressed on
change of medication from cyclosporine to tacrolimus without
any need for further surgical intervention. Furthermore,
Macartney et al. in 2009[59] reported that gingival enlargement
in a child with severe aplastic anemia under cyclosporine
therapy did not respond to intensive dental intervention.
Significant improvement in gingival hyperplasia could only be
achieved after the immunosuppressive therapy was changed
to tacrolimus.
Besides cessation and change of drug, short‑term
administration of azithromycin was reported to improve
cyclosporine‑associated gingival hyperplasia by Wahlstrom
et  al. in 1995[75] and Strachan et  al. in 2003.[67] Azithromycin
may improve the symptoms of cyclosporine‑induced
gingival overgrowth by inhibiting cyclosporine‑induced cell
proliferation and collagen production and also by activating
matrix metalloproteinases in cyclosporine‑treated fibroblasts.[94]
However, Nowicki et  al. in 1998[74] reported only a partial
regression of gingival hyperplasia with azithromycin in
cyclosporine‑treated renal transplant patients and could not
find any further improvement with repeated azithromycin
administration. In addition, Vallejo et  al. in 2001[73] reported
no improvement in cyclosporine‑induced gingival hyperplasia
in spite of administering azithromycin. They further
reported complete remission of gingival hyperplasia, only
after withdrawal of cyclosporine and its replacement with
tacrolimus. Thus, certain cases of cyclosporine‑induced
hyperplasia are resistant to azithromycin and this could
probably be explained on the basis of varying fibroblast
subpopulations in different individuals. Drug substitution by
alternative immunosuppressants such as tacrolimus remains
to be current definitive viable option in the management of
cyclosporine‑associated gingival hyperplasia.
CCBs are therapeutic agents that are used in the management
of heart diseases, particularly hypertension. CCBs affect
calcium metabolism by reducing Ca2+ cell influx, which in turn
reduces uptake of folic acid and leads to reduced production
of active collagenase.[95] Among CCBs, nifedipine is the most
frequently implicated drug, inducing gingival overgrowth.[95]
However, in the last two decades, more cases of gingival
overgrowth have been reported after amlodipine use than
nifedipine (25 cases of amlodipine as against 13 cases of
nifedipine). Low doses and short‑term administration of CCBs
might also induce gingival hyperplasia as suggested by Lafzi
et al. in 2006[21] and Joshi and Bansal in 2013.[10] Furthermore,
a case report by Sunil et al. in 2012[29] suggests that severity of
the enlargement is dose dependent.
Changes of drug and meticulous oral hygiene are important
aspects in the management of CCB‑associated gingival
Journal of Indian Society of Periodontology - Volume XX, Issue XX, Month 2017 3
overgrowth. Aldemir et al. in 2012[12] reported a case of gingival
overgrowth in a hypertensive patient under amlodipine
therapy, in which, change of medication resulted in regression
of the overgrowth within 3 months without any need for
surgical intervention. Joshi and Bansal in 2013[10] reported
that gingival overgrowth in a hypertensive patient under
amlodipine therapy showed drastic improvement within
1.5 months after change of drug. Similarly, Ramsdale et  al.
in 1995[36] reported gingival hyperplasia in a patient with
heart disease under long‑term nifedipine therapy, which
disappeared completely within 6 months after cessation of
nifedipine use. On the contrary, D’Errico and Albanese in
2013[8] reported a case of gingival overgrowth in a hypertensive
patient under amlodipine therapy, where changing drug and
execution of a professional oral hygiene treatment did not
allow resolution of the hyperplasia. Only surgical excision
of the overgrowth permitted resolution of the case. Leaving
the two extremities apart, majority of cases were managed by
change of drug and meticulous plaque control, which resulted
in moderate regression of the lesion. This was followed by
surgical correction of gingival tissues for optimal gingival
health and maintenance.
Phenytoin is the most commonly prescribed anticonvulsant
agent in the management of epilepsy. Phenytoin‑induced
gingival overgrowth is the earliest known DIGO; first case of
which was reported in 1939 by Kimball.[96] Phenytoin affects
metabolism of certain fibroblast subpopulations, intracellular
calcium metabolism, reduces folic acid uptake and metabolism,
leading to production of inactive collagenase; thus, leading to
gingival overgrowth.[6]
Although rare, besides gingival hyperplasia, phenytoin
is also known to induce mucosal hyperplasia in denture
wearers.[97] Dhingra and Prakash in 2012[89] reported a rare
case of enlargement of mucosa in partially edentulous alveolar
ridges despite not using any denture, after combination therapy
of phenytoin and phenobarbital for epilepsy. Chee and Jansen
in 1994[57] reported a case of peri‑implant tissue hyperplasia
after phenytoin therapy for epilepsy.
The management of phenytoin‑induced gingival overgrowth is
similar to that of other DIGOs. Withdrawal and change of drug,
meticulous oral hygiene maintenance, conservative nonsurgical
approach followed by surgical intervention if necessary are
the sequential steps in the treatment of phenytoin‑associated
gingival hyperplasia.
Polypharmacy can have an effect on DIGO. Majority
of conditions need a combination therapy, particularly
organ transplant patients receiving immunosuppressants
are frequently administered CCBs to prevent serious
life‑threatening complications. However, such concomitant
medications have a significant synergistic effect on gingival
changes and increase the chances of recurrence.[98]
Plaque‑induced inflammatory changes
Majority of DIGO cases are reported in patients with poor
oral hygiene maintenance. However, whether plaque is a
contributing factor to gingival hyperplasia or a consequence of
gingival hyperplasia is not yet clearly outlined. Nevertheless,
the clinical and histological picture of gingival enlargement
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Samudrala, et al.: DIGO: A review of case reports
and the medical history of the patient led some investigators
to diagnose the enlargement as a combination of inflammatory
and DIGO.[4] Addition of inflammatory component to the
gingival overgrowth, thus complicates the diagnosis and also
the management of DIGO.
Nonsurgical management of DIGO includes professionally
delivered scaling and root planing as well as instructing and
reinforcing oral hygiene maintenance measures to the patient.
This, in conjunction with drug change, may totally eliminate
the overgrowth or might at least partially result in regression
of the lesion, allowing for an easy surgical correction.[99]
Genetic factors
Genotypic variation among individuals was attributed to the
observed inter‑individual variability in the expression and
presentation of gingival hyperplasia after using systemic
medications. Gingival fibroblasts exhibit marked functional
heterogeneity in response to various stimuli.[93] This probably
could explain why, not all individuals subjected to medications
inducing gingival hyperplasia show gingival changes.
Babu et  al. in 2013[47] evaluated drug metabolizing enzyme
cytochrome P450 2C9 gene polymorphism in an epileptic
patient under phenytoin therapy who presented with
generalized gingival enlargement. The pharmacogenomic
study of the patient revealed that the patient was a homozygous
mutant of CYP2C9 which prompted them to substitute the
drug. Similarly, Charles et  al. in 2012[13] reported a case of
amlodipine‑induced gingival hyperplasia associated with
MDR1 3435C/T gene polymorphism. This gene polymorphism
was suggested to alter the inflammatory response of the
gingival tissues to the drug. Thus, pharmacogenomic studies
might be useful in determining the effects of a drug and also
help in prompting the physician to choose correct dose of drug
or other alternatives.
The analysis of case reports in this article also revealed
the importance of histopathological examination of the
DIGO lesions. Kim et  al. in 2002[69] reported two cases of
cyclosporine‑induced gingival overgrowth. However, the
histopathological examination of the excised gingival tissues
was suggestive of plasma cell granuloma composed of
mature plasma cells. Thus, a careful differential diagnosis
from malignant plasmacytoma had to be made in those
cases. Another report by Rolland et  al. in 2004[64] presented
two cases of gingival overgrowth in heart transplant patients
under cyclosporine therapy. The histologic picture of the
excised tissue showed diffuse lamina propria infiltration by
large malignant‑appearing lymphoid cells. Subsequently, a
diagnosis of posttransplant lympho‑proliferative disorders
was suggested.
In yet another report, Yoon et al. in 2006[22] presented a case
of gingival enlargement in a patient who had been under
long‑term amlodipine therapy. Histopathological examination
of an incisional gingival biopsy of the lesion revealed neoplastic
cells. Further immunohistochemical study yielded a diagnosis
of myeloid sarcoma. Later, a bone marrow biopsy was
performed and the diagnosis was changed to acute myeloid
leukemia. Unfortunately, the patient never showed remission
and died 4 months after initial diagnosis. da Silveira et al. in
2007[90] reported a case of gingival enlargement in a patient
4 Journal of Indian Society of Periodontology - Volume XX, Issue XX, Month 2017
under long‑term phenytoin and phenobarbital therapy who
also presented a peripheral calcifying epithelial odontogenic
tumor which could be confused with fibrous hyperplasia.
Vishnudas et al. in 2014[28] reported a gingival enlargement after
amlodipine use, which on histopathological examination was
identified as plasma cell granuloma. These above reported cases
clearly signify the importance of histopathological examination
of gingival tissues in the diagnosis and management of DIGO.
Significant findings of the review
1. Besides gingiva, drug‑induced hyperplasias of edentulous
mucosa and peri‑implant mucosa have also been
reported (although rare)
2. Azithromycin therapy for cyclosporine‑induced gingival
enlargement is not a definitive management module
3. Tacrolimus is the best alternative substitute (available till date)
for cyclosporine as an immunosuppressant to avoid/treat
gingival hyperplasia
4. Meticulous oral hygiene maintenance is a critical factor in
regression of DIGO
5. Persisting enlargement after drug cessation/substitution
and meticulous oral hygiene maintenance might require
surgical excision
6. Histopathological examination of all persisting enlargements
is mandatory to evaluate malignant changes
7. Incidence of DIGO is believed to be influenced by genotype
of the individual. This signifies the need for transformation
to the concept of personalized medicine to prevent
DIGO. Further research is, however, needed for such
transformation in medicine to be practiced
8. Treatment recommendations as in Figures 2 and 3.
CONCLUSION
DIGO is a multifactorial adverse effect of taking certain
systemic medications. Although exact pathogenic mechanisms
are not yet completely understood, the drug variables,
dental‑plaque induced inflammatory changes, and genetic
variables are frequently listed as important risk factors for
DIGO. Careful selection of drug and its dose for particular
medical conditions by medical practitioners might be helpful
in preventing drug‑related adverse effects. In cases, where
using drugs that induce gingival overgrowth is unavoidable,
Figure 2: Treatment recommendation flowchart for cyclosporine‑induced
drug‑induced gingival overgrowth
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Samudrala, et al.: DIGO: A review of case reports
Figure 3: Treatment recommendation flowchart for calcium channel blocker/
anticonvulsants‑induced drug‑induced gingival overgrowth
dental referral, thorough plaque control, reinforcement of
oral hygiene maintenance instructions to the patient might
be helpful in preventing as well as controlling the severity of
the lesion. An in‑depth knowledge of pharmacokinetics of the
drugs, their adverse effects, pathogenic mechanisms involved
in DIGO and their varied clinical presentations helps the dental
practitioner in therapeutic management of DIGO. In addition,
coordination between medical and dental practitioners is
essential for successful management of DIGO.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
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