Dental management of children undergoing liver transplantation.

Abstract

The number of pediatric liver transplantations undertaken in the US has increased dramatically in recent years. As the survival of liver recipients continues to improve, the dentist will need to be familiar with the management of these patients. This article describes the indications for pediatric liver transplantation, the types of liver transplants, the clinical features of liver disease, and the medical and dental management of children before and after liver transplantation.

Full text

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Pediatric Dentistry – 21:4, 1999American Academy of Pediatric Dentistry 273
Lit er at ur e Review
Dental management of children undergoing liver
transplantation
Evelyn C. Sheehy, BDSc, FDS RCS (Paed), PhD Nigel Heaton, FRCS Peta Smith, BDS, FDS RCS
Graham J. Roberts, MDS, PhD, FDS RCS, MPhil, BDS
Dr. Sheehy is a lecturer in paediatric dentistry, Department of Paediatric Dentistry & Orthodontics, Guy's King's & St
Thomas' (GKT) School of Medicine & Dentistry; Mr. Heaton is a consultant surgeon in charge of Liver Transplant Services,
Institute of Liver Studies, King's College Hopsital; and Dr. Smith is a consultant in paediatric dentistry, GKT School of
Medicine & Dentistry; Dr. Roberts ia professor of paediatric dentistry,The Eastman Dental Institute for Oral Health Care
Sciences, University of London, Department of Paediatric Dentistry, and The Great Ormond Street Hospital for Children,
Maxillofacial and Dental Department, London, England.
Abstract
The number of pediatric liver transplantations undertaken in
the US has increased dramatically in recent years. As the survival
of liver recipients continues to improve, the dentist will need to be
familiar with the management of these patients. This article de-
scribes the indications for pediatric liver transplantation, the types
of liver transplants, the clinical features of liver disease, and the
medical and dental management of children before and after liver
transplantation.(Pediatr Dent 21:273-281, 1999)
P
quently, hepatic tumors.1-3 Patient survival approaches
80%–90% at one year and 64%–78% at five years.2-8
Increasing survival has resulted from improvements in
immunosuppression, intensive care, management of compli-
cations, and surgical techniques.8 The number of liver
transplants undertaken in the US was 2690 in 1990, and 3912
in 1995.9 As the life expectancy of liver recipients continues to
rise with improving survival rates, the dentist will need to be
familiar with the management of these patients. This article
reviews the indications for pediatric liver transplantation, the
types of liver transplants, the clinical features of liver disease,
and the medical and dental management of children before and
after liver transplantation.
Indications for pediatric liver transplantation
(Table 1)
1. Biliary atresia accounts for 40%–70% of pediatric liver
transplants in most centers. It is a condition of unknown
etiology where there is progressive destruction and oblit-
eration of the extrahepatic bile ducts leading to cholestasis,
fibrosis, and cirrhosis.
2. Metabolic disorders associated with cirrhosis such as α-1
antitrypsin deficiency, cystic fibrosis, and Wilson’s dis-
ease, and non-cirrhotic inborn errors in metabolism,
based in the liver with life-threatening extrahepatic com-
plications, such as Crigler-Najjar syndrome, Type I.
ediatric liver transplantation has become an accepted
treatment for end-stage liver diseases, metabolic liver dis-
orders, selected cases of acute liver failure and, less fre-
3. Fulminant hepatic failure due to, for example, viral hepa-
titis or toxic overdose of paracetamol.
4. Cholestatic disorders which may not be immediately life-
threatening but where the quality of life is impaired by
persistent jaundice, pruritus, fatigue, growth retardation,
and osteopenia.
5. Malignant tumors of the liver without extrahepatic me-
tastases.
6. Chronic liver disease leading to decompensated cirrhosis,
for example, autoimmune hepatitis.
Types of liver transplants
The donor organ is matched to the recipient’s ABO blood
group. The types of liver transplants include whole graft, re-
duced-size graft, split-liver graft, living donor graft, and
auxiliary transplantation (Table 2). There has always been a
scarcity of pediatric donor grafts, especially for very young
children. The situation has been alleviated by the use of re-
duced-size grafts, split-liver grafts, and living donor grafts,
which has increased the donor pool and reduced the mortality
on waiting lists. Auxiliary transplantation may be indicated in
metabolic disorders, such as Crigler-Najjar syndrome, Type I,
where the recipient’s residual liver may have sufficient func-
tion to maintain life if the graft fails. Auxiliary transplantation
may also be used in cases with acute hepatic failure where there
is a chance that the patient’s own liver will regenerate. The
dental management of recipients is the same regardless of the
type of liver transplant received.
Clinical features of liver disease
Medical aspects
Clinical features of liver disease vary with the underlying con-
dition (Table 1). Jaundice, anemia, failure to thrive, pruritus,
hepatosplenomegaly, ascites, encephalopathy, portal hyperten-
sion and esophageal varices, coagulopathy, altered drug
metabolism, and propensity to infections may be present. Vi-
tamin D malabsorption, rickets, and osteopenia are important
Accepted May 7, 1999

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274 American Academy of Pediatric DentistryPediatric Dentistry – 21:4, 1999
Liver Disorder DefinitionEtiologyClinical Features Medical &
Surgical
Management
High calorie
protein feed
Fat soluble vitamin
supplements:
(A, D, E & K)
Kasai procedure before
3 months
Liver transplantation
Biliary atresiaProgressive disorder
characterized by absence,
destruction, or obliteration
of the extrahepatic bile ducts
Unknown
? viral/teratogenic
Failure to thrive
Hepatomegaly
Jaundice
Cirrhosis
Portal hypertension
25% have other anomalies
(i.e. atrio-septal defect,
ventriculo-septal defect)
Biliary hypoplasia
Alagille syndrome Absence or reduction
in the number of
intralobular bile ducts
within portal tracts within
the liver substance
Autosomal dominantPersistent cholestasis
Dysmorphic facies
Cardiovascular anomaly
– i.e. pulmonary stenosis
Failure to thrive
Vertebral and digital defects
Mild mental
retardation 30%
+/- Development of
hepatocellular carcinoma
Pruritus
Nutritional support
Liver transplantation if
there is progression
to cirrhosis and portal
hypertension
Fat soluble vitamin
supplements:
(A, D, E & K)
Ursodeoxycholic acid
–retards liver disease
Cholestyramine,
phenobarbital,
& rifampicin for
pruritus (itching)
Metabolic Disorders
α-1 Antitrypsin
deficiency
Deficiency of
α-1 antitrypsin
Autosomal recessive Cholestasis
Ascites
Failure to thrive
Jaundice +/- diminishing
with time
Hepatosplenomegaly
40% develop chronic
liver failure and require
transplantation
Cystic fibrosis Generalized disorder of
exocrine glands
characterized by abnormal
transport of ions across
epithelial surfaces
Autosomal recessiveRespiratory symptoms
Failure to thrive
Liver problems – 20%
of adolescents
Jaundice
Portal hypertension
Bronchodilators &
antibiotics for
respiratory problems
Nutritional support
Vitamin A & E
supplements
Liver transplantation
for end-stage liver disease
Often bilirubin is
normal but liver failure
is more subtle and
there is marked portal
hypertension
Wilson’s diseaseLow serum copper;
copper accumulates in
the brain, liver, kidneys,
and corneas
Autosomal recessiveChronic hepatitis
Cirrhosis
Hemolytic anemia
Neurological symptoms in
the second decade
i.e. mood and behavioral
changes and extrapyramidal
signs
Encephalopathy
Coagulopathy
Liver failure
Renal failure
Penicillamine and/
zinc, to chelate
copper Vitamin B6
supplements Liver
transplantation if
liver failure
Acute liver failureMassive necrosis of the
liver cells or any other
impairment of hepatic
function
Paracetamol overdose
Viral hepatitis:
Non-A, non-B,
Hepatitis A,
Hepatitis B,
Hepatitis C
Halothane toxicity
Intensive care
management
+/- Emergency liver
transplantation
Table 1. Pediatric Liver Disorders8

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Pediatric Dentistry – 21:4, 1999American Academy of Pediatric Dentistry 275
complications of chronic cholestatis in children.8 Bacterial peri-
tonitis and recurrent cholangitis may further complicate the
underlying liver disease.
Dental aspects
Intrinsic green discoloration of the teeth due to elevated serum
levels of conjugated bilirubin in liver disease is well docu-
mented.10-13 Green discoloration may also affect intra oral soft
tissues including the gingivae, the tongue, the floor of the
mouth, and the buccal mucosae. Other findings include enamel
hypoplasia due to metabolic disturbances and delayed eruption
of the teeth.11-14 Enlarged pulp chambers and root canals sec-
ondary to vitamin D deficiency have also been recorded.11,12,14
The prevalence of dental caries in children with end-stage liver
disease would seem to be no greater than in the normal popu-
lation. However, rampant caries has been reported in children
with biliary atresia and was probably due to frequent and pro-
longed bottle feeding.10-12,14,15 Use of numerous sugar
containing oral medications is probably also a contributing
factor.
Medical management
Pre-transplantation
Patients with obstructive jaundice are given oral supplements
of fat soluble vitamins A, D, E, and K. The majority of chil-
dren undergoing liver transplantation are malnourished, more
prone to infection, and have a lower survival. A high calorie
protein feed should be given to treat malnutrition and over-
come fat malabsorption. Nasogastric enteral feeding may be
necessary to ensure adequate nutrition. Children may be given
low dose antibiotics to prevent cholangitis and spontaneous
bacterial peritonitis. Pruritus is managed by cholestyramine,
rifampicin, ursodeoxycholic acid, or phenobarbital, and ascites
by fluid restriction and diuretic therapy. Bleeding from gas-
tric erosions or portal hypertensive gastropathy is reduced by
the administration of ranitidine and if severe, propranolol.
Children with cystic fibrosis are given bronchodilators for the
treatment of respiratory disease. Psychological and emotional
preparation of the child and family prior to liver transplanta-
tion is undertaken.
Post-transplantation
Patients begin immunosuppressive therapy following liver
transplantation to prevent acute rejection. Regimens vary from
center to center but usually consist of cyclosporine (CSA;
Neoral; Novartis), corticosteroids, and azathioprine. An al-
ternative to CSA is tacrolimus (Prograf; Fujisawa), which has
a similar mode of action. Antilymphocytic globulins, includ-
ing monoclonal (i.e. OKT3), and polyclonal anti-T cell
antibodies are used in some centers for induction of immuno-
suppression or in the treatment of severe or intractable rejec-
tion.
Acute rejection occurs usually within the first month after
liver transplantation in 30%–70% of patients and is treated
with high dose steroids.16 Failure to respond to steroids is man-
aged by conversion to tacrolimus or with anti-lymphocyte
globulins. Graft loss due to acute rejection is relatively rare.
Chronic rejection is usually apparent within 12 months of
transplantation and is still a significant cause of graft loss in
children (10%). Some patients respond to tacrolimus but re-
grafting may have to be considered.17 The majority of pediatric
liver recipients remain indefinitely on CSA or tacrolimus.
The most significant long-term complications of CSA and
tacrolimus are nephrotoxicity, hypertension, infection (particu-
larly viral), malignancy, including lymphomas and squamous
cell carcinoma, convulsions, tremor, parasthesia, and hemoly-
sis.18 Other side effects of CSA include arthritis, obesity,
hirsutism, thrombocytopenia, and gingival enlargement. Cor-
ticosteroids, such as prednisolone, have side effects including
diabetes, osteoporosis, muscle wasting, suppression of growth
in children, adrenal gland atrophy, Cushing’s syndrome with
moon face, striae and acne, and modification in tissue reactions
which may result in spread of infection. These side effects are
relatively uncommon in liver recipients as steroids are either
withdrawn or maintained at low doses. Azathioprine (Imuran;
Wellcome) may cause myelosuppression, nodular regenera-
tive hyperplasia, and increased risk of infection and
malignancy.19
The majority of children will have at least one episode of
infection during the recovery phase. Infection is the most fre-
quent complication following liver transplantation, particularly
in the first few months due to the higher levels of immuno-
suppression and although the levels are reduced over time, there
is always a degree of increased risk. Infection may be bacterial,
viral, fungal, or protozoal. Bacterial infections tend to occur
within the first two weeks, particularly associated with chest
and line sepsis.20-22 All patients receive bacterial and antifungal
prophylaxis in the immediate post-transplant period to prevent
infection. The majority of fungal infections are caused by Can-
dida species. Viral infections tend to occur after the second
week. Cyclomegalovirus (CMV) is the most frequent cause of
Type of liver transplant
Whole graft
Reduced size graft
Description
The diseased liver is replaced by a donor liver of the same size
The diseased liver of the recipient is replaced by the right or
left lobe or the left lateral segment of the donor liver
The donor liver is split and the right lobe is used for one
recipient and the left lateral lobe for another recipient
A segment from the liver of a living relative is used to replace
the diseased liver of the recipient
Part of the native liver is replaced by an appropriate part of the
donor organ. The residual liver of the recipient is left in situ
Split-liver graft
Living related graft
Auxiliary transplantation
Table 2. Types of Liver Transplants

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276 American Academy of Pediatric DentistryPediatric Dentistry – 21:4, 1999
significant viral infection in liver recipients and is treated with
ganciclovir. Other viral infections include herpes simplex and
zoster viruses, adenovirus, and Epstein-Barr virus (EBV). In-
fection with EBV may lead to infectious mononucleosis, or
more importantly, a progressive lymphoproliferative disorder
(LPD). Recent reports would suggest that EBV-related LPD
is a particular problem in pediatric liver recipients and is asso-
ciated with excessive immunosuppression.23-25
Vascular complications post-transplantation include hepatic
artery thrombosis which usually requires re-transplantation,
portal vein thrombosis and stenosis, and venous outflow ob-
struction from the graft. Biliary complications are the most
common, occurring in 10%–15% of patients and include leaks
(early) and strictures (late) which may require re-operation, but
seldom lead to graft loss.
Dental Management
Pre-Transplantation
A team approach is required for the dental management of
children prior to liver transplantation. The pediatric dentist
should form part of this team, which should include the
hepatologist, transplant surgeon, general medical practitioner,
nursing staff, including clinical nurse specialists, dietitian, gen-
eral dentist, dental hygienist, psychologist, social worker, and
hematologist. Any potential problems should be discussed with
the hepatologist before undertaking dental care in these chil-
dren. The primary objective must be the elimination of dental
disease prior to liver transplantation in order to reduce the risk
of systemic infection arising from the oral cavity. Clinical and
radiographic examinations should ideally be carried out at the
first appointment. If possible, posterior bitewing radiographs
should be taken in patients where there are approximal con-
tacts, and periapical radiographs of teeth where apical pathology
is suspected. Modified lateral oblique views should be obtained
where bitewing radiographs are not possible. In the mixed den-
tition, a panoramic radiograph should be taken. In the very
fearful or pre-cooperative child, dental and radiographic exami-
nations and treatment will need to be carried out under general
anesthetic at a specialist center.
Emphasis must be on the prevention of dental disease. All
infants with significant liver disease should be evaluated be-
tween 6-12 months of age and advice on oral hygiene, fluorides,
and appropriateness of feeding practices must be given to the
parents or caregivers. The importance of effective oral hygiene,
performed twice daily with a fluoride toothpaste with supervi-
sion by parents or caregivers in children up to seven years,
should be stressed. Frequent scaling and polishing is necessary
in children who are prescribed nasogastric enteral feeding as
they are predisposed to increased calculus deposits on the teeth.
Dietary advice should be given in consultation with the dieti-
tian, but is often difficult as high calorie diets are recommended
in children where there is failure to thrive. The frequent eat-
ing and drinking of sugary foods in between meals should be
discouraged. Fluoride supplements,26 mouthwash or gel, fissure
sealants, chlorhexidine mouthwash or gel, and sugar-free oral
medications are recommended. Professionally-applied fluoride
and chlorhexidine varnishes are useful, especially in the very
young child.
The main problems in dental management of children with
end-stage liver disease or acute liver failure are similar to those
in pediatric cancer patients receiving chemotherapy and
perspective bone marrow recipients.27 These include suscepti-
bility to infection and bleeding tendency. In addition, children
with end-stage liver disease have altered drug metabolism and
the possibility of significant dysfunction of other organs. Psy-
chological and social problems of these patients are also
discussed below.
Susceptibility to infection
Children with severe chronic liver disease may be prone to
systemic bacterial infection or bronchopneumonia. The den-
tal surgeon should remove any potential source of infection in
the mouth that may lead to systemic infection. A radical ap-
proach to treatment is necessary. Pulp therapy, including
pulpotomies and pulpectomies, is contraindicated in primary
teeth. Stainless steel crowns are usually recommended for the
restoration of primary teeth with extensive dental caries. How-
ever, CSA and nifedipine induced gingival enlargement may
be exacerbated by stainless steel crowns which have inadequate
marginal adaptation or in patients with poor oral hygiene.
Children must have prophylactic antibiotic coverage prior
to invasive dental procedures if they have chronic liver failure
as they are prone to spontaneous bacterial peritonitis which car-
ries a mortality rate ranging from 37%–77%.28 Streptococci,
which are normal commensals in the oral cavity, have been iso-
lated from ascitic fluid of patients with spontaneous bacterial
peritonitis, but the source of these bacteria was not stated.28
Bleeding tendency
Bleeding tendency in patients with liver disease is due to
impaired synthesis of vitamin K; reduced or defective synthe-
sis of clotting factors, in particular, factors II, VII, IX and X;
increased consumption of clotting factors; increased fibrinoly-
sis; and thrombocytopenia secondary to portal hypertension
and hypersplenism. Portal hypertension can result in esoph-
ageal varices, which may rupture and hemorrhage giving rise
to anemia. If surgery is required, liaise with the hematologist
and hepatologist. Full blood count, platelet count, and bleed-
ing time should be tested. Clotting time should include
international normalized ratio (INR), prothrombin time (PT),
thrombin time (TT), and activated partial thromboplastin time
(APTT). Blood grouping and cross matching are also required.
The PT or INR may be greater than one and a half times
the normal in patients with severe parenchymal liver disease.
If surgery is undertaken in these patients, fresh frozen plasma
or cryoprecipitate may be needed to replace coagulation fac-
tors. Platelet replacement should be considered prior to surgical
procedures in patients with counts of less than 40,000/mm3.
If a transfusion is required, all procedures which are likely to
cause hemorrhage should be completed during one visit and
should be as atraumatic as possible. The insertion of resorbable
sutures and hemostatic agents, such as microfibrillar collagen
or topically sprayed thrombin, may help to prevent post-ex-
traction hemorrhage. High vacuum suctioning should be used
to prevent ingestion of blood which may contribute to hepatic
encephalopathy in the susceptible patient.13,29-31
Analgesics, such as aspirin and non-steroidal anti-inflam-
matory drugs, should be avoided to reduce the risk of
hemorrhage. Block anesthesia is contraindicated in children
with clotting defects as intramuscular injection may result in
hematoma formation. Intraligamental injection results in a sig-

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Pediatric Dentistry – 21:4, 1999American Academy of Pediatric Dentistry 277
nificant bacteremia and should not be used in patients who are
susceptible to infection.32
Altered drug metabolism
Some drugs which are used in dentistry should be avoided or
used with caution in patients with liver disease (Table 3).33
Unlike renal disease, there are no specific guidelines for dos-
age modifications in liver disease.34 If dental treatment is carried
out under local anesthetic, excessive amounts of lignocaine
must be avoided as it is hepatotoxic. A prolonged half-life of
lignocaine has been reported in adults with chronic liver fail-
ure who were prescribed the drug in tablet form.35,36 General
anesthesia should only be undertaken at a specialist center
where support from all team members is available. Many of
these children require general anesthesia for medical proce-
dures, at which time dental treatment may also be undertaken,
with good planning and a team approach. Nitrous oxide with
pethidine or phenoperidine are the drugs of choice and
isoflurane is preferable to halothane.37
Congenital heart disease
It is necessary to exclude the presence of congenital heart dis-
ease. Twenty to twenty-five percent of children with biliary
atresia have significant dysfunction of other organs, including
cardiovascular defects such as atrio-septal defect or ventriculo-
septal defect.38 Pulmonary stenosis may be present in children
with Alagille syndrome. The cardiologist should be consulted
and prophylactic antibiotics should be given for dental proce-
dures that may cause bacteremia according to the
recommendations of the American Heart Association.39
Psychological and social problems
Children with end-stage liver disease requiring liver transplan-
tation may have enormous psychological problems and their
parents may be, understandably, overprotective. The children
are often dependent, demanding, and have difficulty coping
with even minor procedures. The psychologist may help to
reduce the patients’ fears by providing support and counsel-
ing before or during the dental visit. Patients may still be
resistant to even the most skillful behavior management and
will subsequently need dental treatment under general anes-
thetic prior to transplantation.
Post-transplantation
The immediate post-transplantation period
Patients recover in the intensive care unit following liver trans-
plantation. Some of the patients will be on parenteral nutrition
for up to four or five days post-transplantation as they are un-
able to eat. Patients are particularly prone to bacterial and
fungal infections in the immediate post-transplant period,
which result in considerable morbidity and mortality. Further-
more, potentially harmful changes in the oral streptococcal
flora, with increases in the proportions of Streptococcus oralis
and Streptococcus mitis , have been reported in children who are
receiving parenteral nutrition following liver transplantation40
and bone marrow transplantation.41 These species of oral strep-
tococci are the most frequently isolated bacteria from infections
in immunocompromised and neutropenic cancer patients.42-44
The pediatric dentist, with the help of trained nursing staff and
the dental hygienist, must ensure that an intensive mouthcare
Drug
Antibiotics
Clindamycin
Erythromycin estolate
Tetracyclines
Flucloxacillin
Metronidazole
Ketoconazole
Analgesics
Aspirin
NSAIDs
Opioid analgesics
Paracetamol
Lcoal anesthetics
Lignocaine
General anesthetics
Methohexitione sodium
Thiopentone sodium
Halothane
Muscle relaxants
Suxamethonium
Antihistamines
Sedatives & Hypnotics
Carbenoxolone sodium
Steroids
Comment
Reduce dose
Avoid-may cause idiosyncratic hepatotoxicity
Avoid
Avoid-may cause cholestatic jaundice and hepatitis
Reduce dose in severe liver disease
Avoid-hepatitis-like reaction; accumulation in severe liver disease
Avoid-increased risk of gastro-intestinal bleeding
Avoid-increased risk of gastro-intestinal bleeding & fluid retention
Avoid-may precipitate coma
Avoid large doses-dose related toxicity
Reduce dose in severe liver disease
Avoid or reduce dose
Avoid or reduce dose
Avoid
Avoid in severe liver disease
Avoid-may precipitate coma
Avoid-all can precipitate hepatic encephalopathy or coma
Avoid-sodium and water retention and hypokalaemia
Avoid prednisone; use prednisolone
Table 3. Drugs to Be Avoided or Used with Caution in Liver Disease33