Successful Dental Implant Placement in a Liver Transplant Survivor: Literature Review and Case Report

by Pouran Famili, D.M.D., M.D.S., MPH, Ph.D.; Omer Farooq Akmal, D.D.S

Abstract:
Twenty-five years after federal regulation through the United Network for Organ Sharing established criteria governing utilization of scarce donated body parts and individual access to healthy and viable organs, safe almost routine organ transplantation is the norm. Authors explore clinical decision-making in medical management for dental implant placement in immunocompromised transplant survivors, and report the case of a five-year liver recipient (male Caucasian, age 50) requiring daily tacrolimus FK506, seeking treatment at the medical center-associated dental school for failed root canal and crown at non-restorable tooth #9.

Implant placement successful, and subsequent full prosthetic restoration and loading achieved. Two years post-op, the implant remains well functioning and stable in oral bone with no sign of infection, inflammation or loss. This dental implant placement team followed the specific medical directive of the University of Pittsburgh transplant team regarding routine antibiotic prophylaxis for our mutual patient.

Clinical Relevance. Long-term organ transplant survival is realistically a modern clinical expectation. Knowledge of recommendations for the dental medical management of the immunocompromised patient, posed in theory by some writers a decade ago, is clinically imperative in the contemporary implant practice. It is common practice to place implants in organ transplant survivors with no decrease in positive outcomes. Success is best assured by detailed prior consultation with the transplant team.


Replacement of failing body parts through the surgical transplantation of healthy organs was one of the major medical and scientific accomplishments of the Twentieth Century, made possible by the medical intuition of immune system functioning and the development of immunosuppressive drugs. The United Network for Organ Sharing, the private nonprofit domestic national organ procurement and transplantation system, records 183,222 persons living with functioning transplanted organs at the close of 2007,1 an increase 56.6 percent over the previous 1999 transplant-survivor census. Between 2007 and 2008, the database records an overall but small decrease in the number of organs transplanted (1.1 percent) or recovered for transplant (1.57 percent) yet the waiting list grows by nearly four percent to more than one hundred thousand individuals. Ironically, it is the common success of organ transplantation that is largely responsible for the general decline in available organs between 2002 and 2007.1

Initial attempts at liver transplantation were performed with heterotopic grafts in which extra liver tissue was spliced alongside the diseased organ, with generally poor outcomes. The procedure has now largely been replaced by orthotopic liver transplantation, in which a failed liver is completely removed from the patient’s body and a healthy donor liver wholly embedded in its place. Most liver transplant survivors return to a regular lifestyle six months to a year after a successful surgery.

The National Transplant Act of 1984, legislation passed in the mood of the era to regulate the utilization of scarce donated organs and establish criteria governing individual access to healthy and viable organs, created both the United Network for Organ Sharing and the scientific registry and database of the Organ Procurement and Transplantation Network, tracking organ donorship, harvesting, surgical re-placement, success, and survival. With the achievement of cyclosporine in the early 1980s making transplantation of organs other than kidneys suddenly feasible, individual demand far outstripped supply, precipitating concern that those who could best afford U.S. transplantation technology would take advantage over others. Daily insulin can replace a pancreas, dialysis can replace kidneys, but people in liver failure need even a little piece of transplanted liver, to regenerate and grow. While only two percent of people waiting for liver transplant need one because of cancer, other liver-wrecking conditions like hepatitis, alcohol abuse, and drug-induced cholestasis (blockage in the flow of bile) are rampant enough that the Organ Procurement and Transplantation Network could count 72,731 active waiting list candidates on their website, current to real time on a Friday afternoon in April 2012. The United Network for Organ Sharing utilizes the Model of End-stage Liver Disease3 to make a three-point assessment of the severity of the recipient liver disease, based on serum creatinine, bilirubin, and INR (International Normalized Ratio), for the allocation of scarce available organs.

National liver transplant statistics1 show 1,713 liver transplants in the United States in 1988, multiplying one hundred times to 110,730 liver transplants cumulatively by the end of 2010 in this country alone, with liver transplants peaking in 2006. As many as 91 percent of living-donor liver recipients can anticipate survival for a year and 79 percent can anticipate life five years after transplant.

REVIEW OF LITERATURE
Review of 4000 consecutive patients receiving nearly 5000 liver allografts2 in the first eighteen years of the University of Pittsburgh liver transplant program (1981-1998) divides success into three eras coinciding with anti-rejection pharmacology: the clinical introduction of cyclosporine, the advent of Orthoclone OKT3 (Ortho, Raritan NJ) and Viaspan (Dupont, Wilmington DE), and finally tacrolimus. Actuarial survival was 48 percent for the entire Pittsburgh program in the period, and significantly better in children, females, and after 1990.2 One review3 suggests that as much as 30 percent of the liver transplant literature has been written since 1997, and that contraindications have been so widely resolved that few remain as universal exclusions. While what are considered prohibited cases vary with the transplant center undertaking the procedure, routine expected contraindications include uncontrolled infection, HIV seropositivity, advanced hepatic or extrahepatic malignancy, and active substance abuse. A (2005) comprehensive survey of dental care protocols among U.S. organ transplant centers undertaken by colleagues here at the University of Pittsburgh4 assessed regimens regarding pre-transplant dental clearances, pre-transplant cancellations or post-transplant sepsis related to dental infections, and protocols for antibiotic prophylaxis for post-transplant dental procedures. A number of responding transplant centers reported cancellations or postponement of a transplant or post-transplantation sepsis related to dental infections, and 83 percent of responding transplant centers requested routine antibiotic prophylaxis, 77 percent indicating they would request routine antibiotic prophylaxis in all dental procedures, whether invasive or not. Those authors called for standardized protocols for pre- and post-transplantation dental care, in their remarks similar to a 2000 recommendation from the Institute of Medicine.4 The vast majority of the transplant centers preferred the 1997 American Heart Association guidelines for preventing bacterial endocarditis as adequate antibiotic prophylaxis.4 Still another review of the subject of routine antibiotic prophylaxis5 takes the position that the decision is one reasonably best made on a case-by-case basis in consultation with the transplant center and the surgical team.

As medical science advances, the number of patients living with transplanted organs will increase exponentially, as will survival time. Transplant survivors will necessarily seek other kinds of medical treatment, including dental implants, and dentists will more frequen
tly need to create treatment plans for the gamut of dental procedures for individuals living with increasingly complex medical conditions bolstered by fragile natural immune systems and a pharmacy of immunosuppressive medications. It is not the transplant but the actions of a patient’s medications and current medical status that may contradict the placement of a dental implant in any individual. Best evidence-based dentistry regarding absolute medical contraindications to implant therapy6 concludes that because both ionizing radiation and chemotherapy disrupt host defense mechanisms and hematopoiesis and the individual on such regimens cannot mount an appropriate wound-healing response, dental implant placement in individuals receiving ionizing radiation or chemotherapy is flatly prohibited. Very early in the development of transplant medicine (1987), dental implantologist Richard Marx7 cautioned against dental implant placement earlier than at least six months after the end of radiation, and that has remained over time as a normally reliable guideline in the profession.

CASE REPORT
Fifty-year old Caucasian male with history of portal hypertension was diagnosed with endstage liver disease secondary to primary sclerosing cholangitis prior to being scheduled for liver transplant in May 2004. Donor liver allograft was 23 years, all serologies negative. Several years later (2008), the same liver transplant survivor presented at the University of Pittsburgh School of Dental Medicine with a fractured crown at tooth position #9, originally placed (1999) five years prior to the transplant. Intraoral exam from 1999 revealed generalized mild gingivitis and a then-fractured crown on the tooth at that point also, with a history of even earlier root canal treatment. Prior to 2008, the patient’s treatment at the dental school had included re-treatment of the root canal, internal bleaching, and post and core placed along with porcelain-fused-to-metal crown on tooth #9. When the liver transplant survivor presented in Nov. 2008 to the academic private practice of the author, tooth #9 had become completely non-restorable and the decision was made to extract the tooth and replace the dentition with an implant-supported restoration. The former pack-a-day smoker had been tobacco-free fifteen years and alcohol-free a reported ten. At the time of implant placement, our liver transplant survivor was regularly ingesting a regimen of prescribed medications that would affect dental implant placement and restoration. Medications were mesalamine (5-aminosalicylic acid) [Asacol™, Proctor and Gamble, Cincinnati OH] 400 mg oral three tablets/twice a day; Prograf™ capsule (tacrolimus) one mg by mouth three tablets in the morning, two tablets in the evening (Astellas Pharma US Inc., Deerfield IL); and acyclovir capsule 200 mg by mouth twice/day. By the end of dental implant therapy, our patient also was taking ferrous sulfate 325 mg (65 mg iron) one tablet by mouth twice daily. The patient’s liver transplant team was consulted prior to treatment-planning the dental implant surgery, the transplant team clearing the patient for the implant procedure and subsequent restoration.

On April 23, 2009, the patient was premedicated with 2g amoxicillin and tooth #9 was surgically extracted under two percent lidocaine. A removable partial appliance from the patient’s private dentist was inserted to function as a temporary prosthesis replacing #9 during the post-op healing period. Follow-up radiograph at four months to assess for proper healing prior to implant placement revealed the area had healed well, visible trabeculation at the extraction site was evident, and on August 24 the liver transplant survivor was scheduled for implant placement one month later.

On the day of implant placement surgery (09-17-2009) our patient was again premedicated with 2g amoxicillin one hour prior to the procedure and the surgical area anesthetized with two percent lidocaine. A full-thickness soft tissue flap was raised to allow for proper visualization of the alveolar crest, and a 2-mm twist drill (NobelBiocare, U.S. and international) was used to create the initial osteotomy to 13mm. The osteotomy was subsequently expanded to 4.3x13mm, and a NobelReplace™ Tapered Groovy titanium implant of the same dimensions was placed according to the manufacturer’s protocol. Primary stability of 35Ncm was achieved, a cover screw was placed, the flap was consequently replaced and sutured with 4.0 vicryl and a radiograph of the area of the dental implant taken. These radiographs show the extraction socket four months after the tooth was removed (Fig. 1) and the implant securely situated one month after placement (Fig. 2). Figure 3 shows the restoration functionally loaded approximately two years post-implant placement.

During dental implant placement our patient reported only minimal discomfort, requiring pain medication 800mg ibuprofen only the day of dental surgery and the day after. Sutures were removed at post-op one week, and uncovery was six months later (April 2010) without incident. The patient has been followed-up at standard dental implant maintenance intervals almost two years. The implant remains well functioning and stable in the oral bone, with no indications of infection, inflammation, or dental implant loss.

MEDICAL MANAGEMENT AND TREATMENT, WITH COMPLICATIONS
Although the introduction of cyclosporine marked a turning point in organ transplantation, one of the side effects of the drug is proliferative gingival overgrowth, in some cases precipitating gingival hyperplasia so severe that transplant patients would be troubled in their efforts to chew. Speech, aesthetics, and even tooth eruption may be affected.8,9 Overgrowth characteristically begins as thickening in the gingival margin progressing to the interdental papilla and finally filling the interproximal spaces, in extremely severe cases covering the crowns of teeth. Hyperplastic tissue becomes soft, red, edementous, and bleeds easily due to the accumulation of plaque. Along with the psychosocial implications of organ transplantation and survival, physical side effects related to the pharmacokinetics of the anti-rejection course of therapy may influence patient compliance with the overall prescribed treatment regimen, resulting potentially in the most serious post-transplant complications. Fundamentally any point of oral infection is significant in the immunocompromised transplant survivor. Tacrolimus, in contrast to cyclosporine, is now routinely accepted as not associated with gingival overgrowth among adult transplant recipients.10,11 Research by this author8 at this institution among the first transplant recipients to be given the medication, earliest showed that transplant survivors taking the third-generation anti-rejection drug FK506 (tacrolimus) after receiving their new organ would not develop gingival hyperplasia.

Our particular patient, transplanted in 2004 and being a reasonably healthy and fairly young individual with an excellent personal survival prognosis, is a product of a well-established post-transplant tacrolimus anti-rejection protocol. In the dental clinic, our patient post-dental implant placement was instructed in meticulous oral hygiene, demonstrated consistent compliance with periodontal recall appointments, and never presented with any indication of oral infection or hyperplastic gingiva, or any other periodontal or general dental complication.

During the healing period post-implant placement and functional loading, while we were monitoring the stability of the dental implant to conform to Marx’ definition of implant success, our patient did experience a medical complication. Routine blood-testing charted August 18, 2010, showed MCV increased at 71, and RDW high at 16.4. The conclusion noted was that gradually worsening MCV
was likely related to iron deficiency. Results of this blood testing and this conclusion probably precipitate the subsequent addition of the ferrous sulfate iron supplement. Otherwise at the final charting before our summary begins (May 25, 2011) and three months before the patient’s fiftieth birthday, review of systems is completely negative.

PRONOSIS

Dental implications and significance
Transplant survivors have fewer and less complex medical-dental management issues than individuals needing transplants,12 yet the goal for dental treatment remains to manage an immunocompromised patient, as indefinite long-term immunosuppressive therapy is required to avoid organ transplant rejection. The prime directive of managing an immunocompromised patient entails precautions to avoid bacteremia from oral sources, which can then lead to systemic infections. [A good, broad discussion of the immunosuppression issues of graft-versus-host-disease (GVHD) is found in Goldman 2006.13 The text most-often cited as the authoritative source is the chapter on organ transplantation in Little and Falace, Dental Management of the Medically Compromised Patient, Mosby 1997).] Other authors have suggested adhering to the American Heart Association’s guidelines for prophylactic antibiotic coverage14,15 while still others maintain that prophylaxis for liver transplant patients is only requisite for those with active infections, or those being prescribed an increased dose of immunosuppressants.16 Specific secondary consideration needs to be made for patients undergoing steroid therapy in addition to the regimen of immunosuppressants. While the ADA has recommended that steroids may require supplementation prior to invasive therapy,17 such clinical decisions should be made only in conjunction with the patient’s treating physician and the transplant team. Our review of the literature has indicated only a few prospective reports of the placement of dental implants in immunocompromised liver transplant survivors,18,19 including most recently a German report of dental health among solid organ transplant survivors,20 and several attempts at summarizing guidelines or transplant center protocols for dental implant placement.3,4,12-16,20-24 At least two early reviews by regional dental associations25,26 discuss for general dentists the dental care of the transplant patient, and a recent comprehensive Canadian review27 takes the position that routine antibiotic prophylaxis is not established in the evidence, but should be made on a case-by-base basis after discussions with the patient’s medical team. Anecdotes report general success, in one case detailing longitudinal follow-up ten years18 and the second19 describing an individual circumstance where multiple implants were placed, surviving five years and counting. In our clinical experience we attribute the overall successful resolution of the dental implanting surgery, with subsequent full prosthetic restoration and loading, achieved without medical or anesthetic complication, to consistently following the transplant team recommendation for premedication with 2g amoxicillin in the dental office one hour before any dental procedure.

Implications for dental management of the immunocompromised patient
Given the developing literature on guidelines, the impetus to establish transplant-survivor dental management protocols inside transplant centers of national significance, and the accumulating prospective reports of success, dental implant placement in long-term organ transplant survivors is increasingly a clinical decision of managed risk. The current case describes the successful rehabilitation of an edentulous span in a liver transplant recipient via dental implant placement. Compared to the transplanted heart, lung, and kidney, the liver is far less susceptible to chronic rejection but like most other allografts, a transplanted healthy liver will be rejected unless immunosuppressive drugs are used for the rest of the survivor’s life. Our patient was medicated with tacrolimus FK506 on an anti-rejection regimen pioneered in the University of Pittsburgh liver transplant program, for four years prior to the placement of the dental implant and has been continuing tacrolimus to the current date now, three years after placement and restoration of the dental implant and counting. No serious adverse effects of the immunosuppressive therapy have been noted. Nearing the 10-year survival marker, with life expectancy somewhat better than 50 percent, the patient’s three-year post-op radiograph of the dental implant stable in oral bone with restoration in place shows the generally clinically acceptable range of bone loss post-placement to the first thread. The patient claims no unfavorable or undesirable issue of function or aesthetics with the implant device, its surgical placement or subsequent prosthetic restoration, and clinically the implant is fully integrated in oral bone.

This report supports the hypothesis that an individual recipient of a transplanted healthy liver allograft, despite consistent high-dose immunosuppressive therapy, can be successfully rehabilitated using dental implants. Positive clinical results treating this long-term liver transplant survivor were assisted by prior clinical medical consultation with the transplant team to supervise management of the medical condition before dental implant placement and during all the obligatory subsequent appointments of prosthetic rehabilitation. OH


Pouran Famili is Professor, Chair, Director of the Residency Program, Department of Perio­dontics and Preventive Dentistry, University of Pittsburgh School of Dental Medicine.

Omer Farooq Akmal graduated in 2012 from the Department of Periodontics and Preventive Dentistry, University of Pittsburgh School of Dental Medicine.

Neither author has any potential, perceived, nor real conflict of financial interest to disclose relative to the material of this report.

Corresponding author, institutional mailing address contact for all:

Pouran Famili D.M.D., M.D.S., MPH, Ph.D., Professor, Chair, Director of the Residency Program, Department of Perio­dontics and Preventive Dentistry, University of Pittsburgh School of Dental Medicine, B94 Salk Hall 3501 Terrace Street, Pitts­burgh, Pennsylvania 15261, 412-648-8598, 412-648-8594 fax pof@pitt.edu, secondary contact [assistant] email: rav3@pitt.edu 412-648-9997.

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