Vol. 115 No.

4 April 2013

Pre-liver transplant protocols in dentistry

Reza Radmand, DMD,a,b Michael Schilsky, MD,c,d,e Simona Jakab, MD,f Mohd Khalaf, DMD,g and
Donald A. Falace, DMD, FDS RCSEdh
Yale New Haven Hospital; Yale School of Medicine; Adult Liver Transplant at Yale New Haven Transplantation Center, New Haven, CT, USA;
UK College of Dentistry, Lexington, KY, USA; and University of Kentucky College of Dentistry, Lexington, KY, USA

The number of adults with end stage liver disease in the U.S., awaiting liver transplantation, has maintained a steady
upward trend in recent years. Concurrently, the survival rate of liver transplant recipients has also been on the rise. To be able
to safely treat this population, dentists should have familiarity with special management requirements of patients with end
stage liver disease. This article reviews the historical background on liver transplantation and provides updated information on
indications and evaluation protocols, treatment considerations in end stage liver disease, clinical dental management
protocols prior to surgical procedures and dental considerations in the pre liver transplant candidates. (Oral Surg Oral Med
Oral Pathol Oral Radiol 2013;115:426 430)

The rst successful human to human liver transplant in

the U.S. that surpassed 1 year survival was performed
by Dr. Thomas Starzl in 1967. It was followed by
historic milestones in procurement and preservation of
cadaveric organs, understanding the immunological
complexities involved in organ rejection and immunosuppression regimens, as well as theological and moral
discussions surrounding organ transplantation and its
initial high mortality rate, questioning the ethical
paradigms of the concept.1 Currently, post-liver transplant survival is around 88% at one year and 72% at
ve years.2,3 Factors contributing to the increase in
success rate of transplant survival are improvements in
immunosuppressive therapy, surgical techniques and
better management of complications.1
In 2008, the number of patients waiting to receive
a liver transplant was close to 16,000, but the number of
liver transplants performed was only over 6000. The
annual mortality for patients on the liver transplant
waiting list for the years 2000-2009 was approximately
a

Section Chief, Hospital Dentistry, Dental Department, Yale New

Haven Hospital, New Haven, CT, USA.
b
Clinical instructor, Yale School of Medicine, Dental Department,
New Haven, CT, USA.
c
Associate Professor of Medicine (Digestive Diseases), Adult
Liver Transplant at Yale New Haven Transplantation Center, New
Haven, CT, USA.
d
Associate Professor of Surgery, Adult Liver Transplant at Yale New
Haven Transplantation Center, New Haven, CT, USA.
e
Medical Director, Adult Liver Transplant at Yale New Haven
Transplantation Center, New Haven, CT, USA.
f
Assistant Professor of Medicine and Hepatology, Yale School of
Medicine, New Haven, CT, USA.
g
Assistant Professor of Oral Medicine /Oral Diagnosis, UK College of
Dentistry, Lexington, KY, USA.
h
Professor Emeritus, Oral Diagnosis and Oral Medicine, University of
Kentucky College of Dentistry, Lexington, KY, USA.
Received for publication Aug 20, 2012; returned for revision Nov 15,
2012; accepted for publication Dec 4, 2012.
! 2013 Elsevier Inc. All rights reserved.
2212 4403/$ see front matter
http://dx.doi.org/10.1016/j.oooo.2012.12.006

426

2000 patients/year.2 The death rate on wait list was 6.6%

nationally in 2009, but up to 20% in regions with donor
shortage where patients are sicker and have higher
MELD (Model for End Stage Liver Disease) score at
transplantation.3 The length of time that patients stay on
the transplant list is dependent on the natural history of
the underlying disease and the rate of its progression, the
United Network of Organ Sharing (UNOS) region in
which the patient is located (different organ donation
rates and population demands), blood type (longer wait
time for blood type O), and if a living donor is available.
According to the Organ Procurement and Transplantation Network and the Scientic Registry of
Transplant Recipients (OPTN and SRTR), the average
time to transplant nationally in 2009 was 382 days.3 This
could create a dilemma for the dental professionals who
are asked to clear the patient. A dentist could see
a patient who will eventually be transplanted after a few
days or several months. In case of a lower MELD score,
or if there is a living donor, there is more time to electively perform needed dental procedures.

INDICATIONS FOR LIVER TRANSPLANT

Liver failure occurs when the liver, gradually over
a course of years or rapidly in a matter of days, loses its
ability to function. If the damage is irreversible, liver
transplantation is indicated. The clinical presentation of
liver disease varies based on the underlying conditions
(viral, autoimmune, metabolic, etc.). Any patient who
has acute liver failure or chronic liver injury that can
lead to end stage liver disease with cirrhosis, hepatic

Statement of Clinical Relevance

The manuscript attempts to familiarize the reader
with organ transplant considerations in patients with
end stage liver disease, and dental management
protocols in the pre-liver transplant candidates.

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Volume 115, Number 4

insufciency and life-threatening complications related

to portal hypertension, should be considered a candidate for liver transplantation.

PRE-TRANSPLANT EVALUATION
In February of 2002, determining priority for organ
allocation for candidates on the waiting list was
changed to the MELD scoring system (for individuals
ages 12 and older). The MELD score is calculated by
using a formula that includes three laboratory values:
INR, serum bilirubin and serum creatinine. The MELD
score predicts 3-month mortality and thereby the
severity of the patients liver disease.2 The score ranges
between 6 and 40, where an MELD score of greater
than 40 translates to a mortality rate of over 71% within
3 months, unless the patient receives a liver transplant
(Table I). Further renements of the model are ongoing
and aim to improve fairness in allocation and survival results. There are certain conditions such as
hepatocellular carcinoma, hepatopulmonary syndrome,
portopulmonary hypertension or metabolic diseases
with higher mortality than as reected by the native
MELD score, when exception MELD points are given.
A patient is usually listed for transplantation when the
MELD score is 15. When the MELD score is less than
15, the one-year mortality post transplant is higher than
the mortality on the wait list. These patients are
considered to be too well for transplantation.3
The process of evaluation of transplant candidacy is
similar among liver transplant centers (Table II). Once
the diagnostic work-up for the prospective candidates
evaluation is completed by the hepatologist, transplant
coordinator and surgeon with consultants in cardiology,
pulmonary, anesthesia, and other subspecialties as
needed, the patient is presented to the candidate selection committee (recipient review committee) for
a decision about the suitability of the patient for
transplantation. This multidisciplinary committee
consists of transplant surgeons, hepatologists, transplant nursing coordinators, psychiatrists, social
workers, cardiologists, pulmonologists, anesthesiologists, hospital dentists and, occasionally, the patients
primary care physician.
DENTAL TREATMENT CONSIDERATIONS
The initial dental consultation is an integral component
of the pretransplantation protocol, aiming to diagnose
and eliminate any sources of existing active infection or
potential for future infection. The evaluation may be
performed either at the bedside, if patient is unable to be
transported, or preferably in an outpatient clinical
setting. After a successful and atraumatic oral surgical
procedure, the patient can be cleared for liver transplant
surgery in 24-48 h, in the absence of any postoperative
complications. If the risk of complications outweighs

MEDICAL MANAGEMENT AND PHARMACOLOGY UPDATE

Radmand et al. 427

Table I. MELD score and 3-month mortality

MELD score

Mortality (%)

>40
30 39
20 29
10 19
<9

71.3
52.6
19.6
6.0
1.9

Adapted from Wiesner et al. United Network for Organ Sharing

Liver Disease Severity Score Committee. Model for end stage liver
disease (MELD) and allocation of donor livers. Gastroenterology.
2003;124(1):91 96.

the benets of dental treatment, it might be best to

postpone the oral surgical procedures until after the
coagulopathy has been reversed, typically 1-2 weeks
after a successful liver transplantation.
The role of dental professionals trained in management of medically complex patients has been recognized in the medical community. With respect to
patients with chronic liver disease, the complexity of
their overall condition brings into attention three
essential aspects of their dental treatment: adequate
hemostasis, infection control and pain management.
Preoperative evaluation of the patients coagulopathy is mandatory, irrespective of the type of dental
procedure that is planned. It should include a complete
blood count (for platelet count, but also to evaluate
hemoglobin/hematocrit if major blood loss anticipated
or use of general anesthesia), as well as prothrombin
time (PT)/international normalized ratio (INR), and
partial thromboplastin time (PTT). Electrolytes and
liver function tests (LFTs) should be evaluated if
intravenous sedation or general anesthesia will be
used.4 A common volatile general anesthetic gas,
sevourane, was shown to increase the peri and postoperative bleeding time.5,6

COAGULOPATHY AND TREATMENT

CONSIDERATIONS
The risk of bleeding in patients with chronic liver
disease is the main reason that surgical procedures may
be delayed or canceled. In addition, bleeding in oral
cavity after dental procedures may precipitate hepatic
coma it is even more important for these patients to
limit bleeding and use aggressive suction to decrease
the amount of swallowed blood, as well as to monitor
them carefully post procedure.
To perform the appropriate dental treatment and
effectively prepare the patient for liver transplant, the
dentist must consider a number of factors in order to
minimize the associated risks. It is reported that many
physicians require a platelet count of greater than
80,000/mL prior to procedures.7 Studies have shown that
any invasive procedure may be performed in patients
with platelet counts of equal or above 50,000 mL, with
very low risk of bleeding.7

MEDICAL MANAGEMENT AND PHARMACOLOGY UPDATE

428 Radmand et al.

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April 2013

Table II. Transplant evaluation process

Event
Referral
Financial screening
Medical evaluation: lab testing

Hepatic imaging
General health assessment
Transplant surgery evaluation
Anesthesia evaluation
Psychiatry or psychology evaluation
Social work evaluation
Financial counseling
Dental evaluation

Pre/post transplant education

Nutritional support
Pharmacy support

Description
To transplant center or hepatologist
Secure approval for evaluation
Assess hepatic synthetic function, electrolytes, renal function, viral serologies, markers of other causes
of liver disease, tumor markers, ABO Rh blood typing; insulin clearance or 24 h urine for creatinine
clearance; urinalysis and urine drug screen
Ultrasonography with Doppler to document portal vein patency and tumor screening, triple phase
computed tomography or gadolinium magnetic resonance imaging for tumor screening
Chest x ray, prostate specic antigen level (males), Pap smear and mammogram (females), colonoscopy
if age 50 years or older or Primary sclerosing cholangitis
Assess technical issues and discuss risks of procedure
Assess perioperative risk
If prior history of substance abuse, psychiatric illness, or adjustment difculties
Address potential psychosocial issues and possible impact of transplantation on patients personal and
social system
Itemize costs of transplant and post transplant care, help develop nancial management plans
To diagnose and eliminate any sources of existing active infection or potential for future infection.
Educate the patient on the importance of maintaining optimal oral care during the long term post
transplant immunosuppression state
Transplant coordinators facilitate the evaluation process and education of patients about liver disease
and transplantation
Assess nutritional status and patient education
Review of medications and potential drug interaction

Presurgical transfusion of appropriate blood products

(Table III) may be necessary based on the extent of the
dental procedure (i.e., possibility of alveoloplasty,
gingival ap manipulation) and the laboratory abnormalities that are contributing to the coagulopathy. After
preoperative transfusion of blood products, a rapid
determination of platelet count (if platelets were transfused) and/or PT/INR (if fresh-frozen plasma was
transfused) should be obtained as close to the surgical
procedure as possible. In addition to preoperative transfusions, transfusion drip is sometimes indicated intraoperatively to obtain maximum efcacy of hemostasis. In
anemic patients the bleeding time could be abnormal with
an increase in bleeding tendency, which seems to be due
in part to an excessive production of nitric oxide, vasodilatation of the endothelial lining and inhibition of
platelet function.8,9 Patients with renal failure may also
experience platelet dysfunction resulting from uremia, in
which case desmopressin or hemodialysis may be
effective in reversing the platelet abnormalities. In some
patients with decompensated liver disease, multi-organ
dysfunction and extensive coagulopathy, the dental team
and the liver transplant team may decide that dental
surgery should take place in an operating room setting.
Hematology consult may be necessary if there is
alloimmunization limiting the effectiveness of blood
transfusions, a history of or predisposition to thrombosis, contraindication to high volume blood products
in a patient with severe uid overload or contraindication to blood transfusions due to religious beliefs. In
patients with malnutrition, vitamin K should also be
given to correct their nutritional decit.

Alternative local anesthesia such as inltration and

intra-ligamental injection may be indicated. Conventional
inferior alveolar nerve blocks may pose an excessive risk
of submucosal hematoma in the pterygomandibular
space, in patients with blood dyscrasias.10,11

LOCAL HEMOSTASIS
The use of local hemostatic agents in exodontia and
soft tissue surgery is of great value in obtaining immediate postoperative hemostasis. In patients with
coagulopathy, the use of local hemostatic agents is an
essential part of dental surgical procedures. Either in
combination or individually, gel-foam (Pharmacia and
Upjohn Company, Kalamazoo, MI) or Surgicel (Ethicon, San Angelo, TX), 5000 U bovine topical Thrombin (BioPharm Laboratories, Inc., Bluffdale, Utah), and
Avitene microber collagen, (Davol, a Bard Company,
Warwick, RI) can be placed in the extraction socket(s)
and sutured with resorbable sutures, such as, 4 0 or
3 0 chromic gut or Vicryl (Ethicon, San Angelo, TX),
preferably with a tapered cutting needle.12 High brinolytic activity in oral cavity suggests a role for antibrinolytics, especially topical epsilon aminocaproic
acid 25% oral syrup which has better topical efcacy
than the tablet form.
PROPHYLACTIC ANTIBIOTIC COVERAGE
Although there are no standard guidelines concerning
antibiotic prophylaxis in pre-liver transplant patients,
preoperative prophylactic antibiotic coverage may be
considered to reduce the incidence of postoperative
infection, based on the extent of the procedure and the

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Volume 115, Number 4

MEDICAL MANAGEMENT AND PHARMACOLOGY UPDATE

Radmand et al. 429

Table III. Blood products and synthetic anti-brinolytic agents

Blood products
Platelets

FFP

RBC

FVIIa

DDAVP

Tranexamic acid
Epsilon aminocaproic
acid

Product description and indication

A unit of pooled platelets in adults is a compilation of approximately 5 units of platelet
concentrates from random donors. In a non alloimmunized patient, this amount could
produce approximately 10,000 platelets/mL, with an approximately 66% efcacy
compared to freshly collected platelets.16 Alloimmunization, may lead to refractoriness
resulting from drug administration such as Vancomycin and Ibuprofen.17 Patients with
low efcacious platelet counts after two or more transfusions, will be classied as having
the diagnosis of refractoriness to transfusion. The etiology of refractoriness should be
investigated in order to identify an immunologic cause due to a non compatible donor.18,19
Fresh frozen plasma: will help to restore coagulation factors and will be administered if INR
is excessively high. A reduction in INR and PTT values on repeat testing is expected. If
the volume necessary to achieve correction of INR is contraindicated, DDAVP (Sano
Aventis, Bridgewater, NJ) and/or recombinant factor VII may be considered (see below).18
Red blood cells: in patients with moderate to severe anemia (approximate average for male
and female adults, <8 g/dL hemoglobin and <24% hematocrit), you may consider RBC
transfusion. Each unit of transfused blood (300 mL) is expected to raise circulating
hemoglobin level by about 1 g/dL. HCT levels above 35% reduces the bleeding time
signicantly by reducing endothelial cells nitric oxide production.8 Treating anemia will
improve bleeding time and therefore patients may require fewer units of platelets.20
Recombinant Factor VII: may be used with the consent of the blood bank/hematology
service for patients who cannot get volume transfused or if there is resistance to correction
in patients with severely elevated INR. Fibrinogen levels must be greater than 100 prior to
the administration of Factor VII. If less, cryoprecipitate may be used to correct the
hypobrinogenemia. Note: Factor VII should not be used electively in patients with
history of venous thrombosis.21,22
Desmopressin: very effective in adhesion and aggregation mediation of platelets to the
vascular subendothelium.23 This is particularly important in patients with moderate Von
Willebrand factor (vWF) deciency.
A synthetic form of amino acid lysine which has an anti brinolytic effect. Its administration
can reduce the need for allogenic blood transfusion peri and post operatively.24
An anti brinolytic agent typically administered to correct excessive postoperative bleeding.
When given orally, it has a rapid gastrointestinal absorption and reaches its peak blood levels
in approximately 2 h. Due to its intravascular stability, amicar can sustain effective plasma
levels of between 24 and 36 h.25 25% oral syrup has better topical efcacy than the tablet form.

severity of the liver disease. Transient bacteremia in

patient with ascites may lead to spontaneous bacterial
peritonitis with additional increase in mortality rate.13
Ampicillin or amoxicillin clavulanic acid or thirdgeneration cephalosporins may be used before dental
procedures in patients with refractory ascites and hypoalbuminemia/severe synthetic dysfunction, although this
is not an ofcial recommendation.

POST PROCEDURE ANALGESIA

As the liver plays a crucial role in drug metabolism,
patients with liver disease are expected to have a significantly diminished capacity to break down and eliminate
drugs. The metabolism of most common analgesics is
through the hepatic route. For patients with chronic liver
disease, alterations in drug dosage and/or administration
intervals need to be made.
Acute or chronic use of acetaminophen in doses less
than 2 g/day is safe in a wide range of liver diseases,14
and acetaminophen should be the rst line analgesic for
these patients. Patients and medical providers tend to
overestimate the risk of acetaminophen-related hepatotoxicity in the context of underlying liver disease.

Cost
$400/U of pooled
platelets

$70 90/U of FFP

$250/U (300 mL)

$1.00/mcg (dosage
of 160 mcg/kg)

$100/21 mg

$1/tablet
$1/tablet $1.13/mL
(elixir)

Although the half-life of acetaminophen in end stage

liver disease patients is prolonged relative to that of
healthy subjects, the cytochrome P-450 activity is not
increased in those taking the recommended doses of up
to 2 g/day.14 The daily dose needs to take into account
combination analgesics that include acetaminophen to
avoid therapeutic misadventures.
The use of non-steroidal anti-inammatory drugs
(NSAIDs) is generally contraindicated given their potential for gastrointestinal bleeding and renal complications
in patients with cirrhosis.
For patients with more severe pain, use of narcotics
could be considered, but narcotics may precipitate
hepatic encephalopathy. A better alternative than narcotics for the relief of moderate to severe postoperative
pain in cirrhotic patients is a different class of analgesics called synthetic opioid agonists such as tramadol.
According to the United States Food and Drug
Administration, in adult patients with liver insufciency
the recommended dose of tramadol is lower, 50 mg
every 12 h, as needed. Cautious use of narcotics is
accepted in cirrhotic patients if acetaminophen and/or
tramadol is not enough.

MEDICAL MANAGEMENT AND PHARMACOLOGY UPDATE

430 Radmand et al.

CONCLUSION
Liver transplantation is the most effective treatment for
many patients with acute or chronic liver failure. Because
of scarcity of organ donors, candidates have to undergo
a rigorous evaluation protocol. A comprehensive dental
evaluation and treatment is an essential part of this process
and poses careful considerations, given the signicant
complications that can occur when performing various
dental procedures. Despite the concerns for such complications, there is very little evidence in the literature to
support the correlation between dental disease and related
post-organ transplant complications or rejections.15 In the
case of end stage liver disease, we can therefore suggest
that if the risk of pre-transplant excessive or uncontrolled
bleeding outweighs the benets of extractions, it might be
best to postpone the oral surgical procedure until after the
coagulopathy has been reversed, typically soon after
a successful liver transplantation.
The data and analyses reported in the 2010 Annual Data
Report of the US Organ Procurement and Transplantation
Network and the Scientic Registry of Transplant Recipients
have been supplied by UNOS and the Minneapolis Medical
Research Foundation under contract with HHS/HRSA. The
authors alone are responsible for reporting and interpreting
these data; the views expressed herein are those of the authors
and not necessarily those of the US Government.

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April 2013

9.

10.

11.

12.

13.

14.

15.

16.
17.
18.

19.
20.

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Reprint requests:
Reza Radmand, DMD
Yale New Haven Hospital
Dental Department
T 231, New Haven, CT 06519, USA
rradmand@gmail.com