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09-August-2002, Vol 115 No 1159
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Liver transplantation in New Zealand: the first four
years
Ed Gane, John McCall, Stephen Streat, Kerry Gunn, Mee Ling
Yeong, Sarah Fitt, Dawn Keenan and Stephen Munn
In 1983, the National Institute of Health declared that
liver transplantation was the treatment of choice for end-stage chronic liver
disease.1 Since then, almost 100 000
transplants have been performed in over 200 centres worldwide. The first New
Zealander was transplanted at the Addenbrookes Hospital, Cambridge, UK in 1986.
Over the next 11 years, 134 New Zealanders (including 38 children) were
transplanted in Australia, the United Kingdom and the United States for a wide
variety of acute and chronic liver diseases. Following a favorable wide
consultation regarding the feasibility of a New Zealand Liver Transplant Unit
(NZLTU)2 and a
competitive tendering process, the Government awarded a
three-year contract for 99 assessments and 66 transplants to Auckland Hospital
in June 1997. Patient assessment commenced in December 1997 and transplantations
were performed from February 1998. A second contract, now including children,
has recently been settled with an increase in volumes. This report summarises
the transplant-related activity over the first four years of the
NZLTU.
MethodsA multidisciplinary team
provided all transplant-related care according to a detailed written protocol.
Patients referred for consideration of liver transplantation underwent
assessment of “clinical, psychological and social suitability”
according to a pre-determined consensus protocol (available at http://www.nzliver.org/). NZLTU has adopted
internationally accepted minimal listing criteria for both emergency liver
transplantation for acute liver
failure3–5
and elective liver transplantation for chronic liver
failure6–8
or hepatocellular
carcinoma.9
Contraindications to liver transplantation include significant medical
comorbidities, which would prevent long-term survival, and psychosocial issues,
which would interfere with compliance with long-term immunosuppressive therapy.
The excess mortality observed in elderly recipients is due to nonhepatic
age-related
problems.10
Therefore, although no upper age limit was imposed by NZLTU, candidates over 50
years underwent more rigorous cardiovascular and respiratory
assessment.
Patients referred with acute liver failure were transferred as inpatients to NZLTU for emergency assessment. In the absence of medical or psychosocial contraindications to transplantation, suitable candidates were listed when transplant criteria were met. Patients referred with chronic liver failure or hepatocellular carcinoma underwent a week long outpatient assessment. Wherever possible, patients returned home after listing to wait until a donor organ became available. Those patients who resided more than three hours from Auckland were accommodated locally when top of the waiting list for their specific blood group (see http://www.livers.org.nz/Transplant_House.htm). Patients were reviewed pre-operatively on the transplant ward when a donor organ became available. Patients with worsening encephalopathy, renal failure or hypotension were transferred to the Department of Critical Care Medicine (DCCM) for preoperative management. Following surgery, all recipients were transferred to the DCCM for ventilatory and inotropic support, which were withdrawn as soon as stability and good graft function had been established and patients were transferred to the transplant ward. Primary immunosuppression comprised combination tacrolimus and prednisone, with withdrawal of steroids by three months. Patients with severe renal dysfunction received a modified renal-sparing regimen (lower dose tacrolimus combined with either single IV infusion of anti-IL-2 receptor antibody, or short-term oral sirolimus). Adjuvant immunosuppression for biopsy-proven acute allograft rejection comprised three days of high-dose intravenous corticosteroid therapy or 10 days of antilymphocyte antibody therapy (OKT3 or ATG) for steroid-resistant rejection. When mobile and self-medicating, patients were discharged from hospital to local accommodation and reviewed frequently in the Transplant Clinic. Patients from outside the Auckland region returned home between 6–12 weeks after transplant. Thereafter, patients entered shared care with their local physicians and returned to NZLTU for annual review. ResultsBetween February 1998 and December
2001, 186 patients over 14 years of age were assessed for transplantation at
NZLTU. One hundred and fifty patients (81% of assessments) were listed for
transplantation of whom 15 died waiting (7 with acute liver failure, 8 with
chronic liver disease), 13 were de-listed (Figures 1 and 2) and 14 remain listed
at the time of writing. One hundred and nine liver transplants (including 1
combined heart-liver,11 1 sequential liver-bone
marrow and 5 re-transplants) were performed on 104 patients.
The activity of the unit has
increased steadily over the first four years, from 34 assessments and 13
transplants in 1998, to 67 assessments and 36 transplants in 2001 (Figure 3).
Because of their very narrow window for successful transplantation, critically
ill patients with acute liver failure are prioritised throughout all six
Australasian transplant units. Although there was a net export of donor organs
to Australia in 1998, this trend has reversed since 1999, reflecting the rapid
growth of the New Zealand programme combined with the high incidence of acute
liver failure in this country.
 Figure 3. Annual numbers of New Zealanders over 14
years old who have been assessed for and undergone liver transplantation
(performed at NZLTU since 1998)
Median age at the time of surgery was 50 years (range
14–70 years). Seventy three patients (66%) were male. Seventy one patients
(65%) were European; 13 (12%) Maori; 12 (11%) Pacific Islander (comprising 5
Samoan, 4 Tongan, 2 Cook Islander and 1 Niuean); 8 (7%) Asian (comprising 4
Chinese, 3 Korean and 1 Cambodian); 3 Arabic and 2 Indian. This ethnic
distribution is similar to that of the general
population.12
Patients transplanted have been referred from Kaitaia to
Bluff, with the highest prevalence in Auckland, Gisborne, Bay of Plenty, Hawkes
Bay and Southland regions (Figure 4).
Acute liver failure
Twenty eight patients with acute liver failure were assessed by NZLTU for
emergency transplantation. The aetiologies of acute liver failure are listed
in Table 1. Twenty four met the King’s College listing
criteria but 2 were deemed not suitable because of severe, uncontrolled
psychosis. Of the remaining 22, 2 improved spontaneously, 7 died whilst waiting
a donor organ and 13 were successfully transplanted (Figure 1). The median
waiting time before emergency transplantation was 2 days (range 0–5). All
13 patients were transferred to the DCCM for management of worsening
encephalopathy whilst waiting for transplantation, of whom 8 were ventilated
preoperatively, 6 had continuous intracranial pressure monitoring and 4 had
perioperative haemodiafiltration for acute renal failure.
Figure 4. Residence of 104 NZLTU liver transplant
recipients
 Only one of the 13 patients who underwent emergency liver
transplantation for acute liver failure has died. The others remain well without
residual neuropsychiatric deficit or renal dysfunction.
Table 1. Aetiology of primary liver disease
* Two patients were coinfected with hepatitis B and
hepatitis C
Chronic liver
disease One hundred and fifty eight patients were assessed by NZLTU for
chronic liver disease. The aetiologies of chronic liver disease are listed in
Table 1. The outcomes of all 158 patients are shown in Figure 2.
Of the 158 patients assessed, 138 fulfilled transplant
criteria, of whom 128 have been listed, 20 were considered too early and are
undergoing regular review and 10 were considered unsuitable candidates for
transplantation. By December 2001, 96 of those listed patients had been
transplanted, 14 remained listed, 8 had died whilst waiting, including 1 patient
who died intra-operatively from acute right heart failure prior to liver
implantation. Post mortem examination revealed thrombus in the pulmonary artery
and deep lower limb veins. Eleven patients were removed from the waiting list,
because of tumour progression in 6, medical contraindications in 3, alcoholism
relapse in 1 and voluntarily in 1 patient.
Median waiting time before elective transplantation was 62
days (range 0–320). Between 1998 and 2001, this has increased from 40 days
to 104 days, in parallel with an increase in the numbers of patients waiting
(from 4 patients to 14 patients).
Post-transplant outcome
Kaplan-Meier estimate of patient survival in 104 patients transplanted at
NZLTU (Figure 5) was 94% at 1 year and 87% at 3 years (compared to 88% and 74%
respectively for 7196 North Americans transplanted during this
period).13
Eleven patients have died following transplantation, 1 from cerebellar
haemorrhage, 2 from sepsis (gram negative sepsis in 1, invasive Aspergillosis in
1), 2 from lymphoma, 2 from hepatitis C-induced graft failure and 4 from
recurrent hepatocellular carcinoma.
Figure 5. Kaplan-Meier curve for cumulative probability
of patient and graft survival (1998–2001)
 Only one patient died, from overwhelming gram-negative
sepsis on the sixth post-operative day (post-transplant 90 day mortality, 0.9%).
One patient became paraplegic immediately post-transplant from an intraoperative
epidural haematoma. The early re-operation rate was 17% (10 bleeding, 5 revision
of arterial anastomosis, 3 intra-abdominal sepsis, 2 small bowel obstruction, 1
chest drain injury to liver, and 1 evacuation of epidural haematoma). The
incidence of hepatic artery thrombosis was 3% (2 early, 1 late), biliary leaks
2%, and biliary strictures 14%. Eight patients underwent late re-operations for
other complications of liver transplantation (2 liver resections, 1
Whipple’s operation, 1 bile duct reconstruction, 1 arterial aneurysm, 1
craniotomy, 1 reversal of intestinal bypass, and 1 incisional hernia).
Kaplan-Meier estimate of graft survival in 109 transplants
(Figure 5) at 1 year is 91% and at 3 years is 83% (compared to 81% and 72%
respectively for 7196 North Americans transplanted during this
period).13 Five patients have undergone
retransplantation, 3 for ischaemic cholangiopathy, 1 for chronic rejection and 1
for cholestatic hepatitis C.
Median duration of surgery (including anaesthesia, surgical
preparation and operating time) was 480 minutes (range 300–720). The
median red cell transfusion requirement was 5 units (range 0–32). Median
intensive care length of stay for electively transplanted patients was 2 days
(range 1–17) and total hospital stay was 11 days (range 6–91). Fifty
nine (45%) patients received adjuvant immunosuppression for acute rejection
between 3 and 20 days post-transplant. All received pulse corticosteroid
therapy, of whom 10 failed to respond and received antilymphocyte antibody
therapy (OKT3 in 8, ATG in 2). Two subsequently developed chronic rejection, one
of whom was rescued by a combination of tacrolimus and sirolimus whilst the
other underwent retransplantation.
Post-transplant quality of life has been excellent. Of those
patients who are at least two months post-transplant, 65% are currently employed
outside the home, 15% are homemakers, 7% are unemployed, 7% are retired, 4% are
still convalescing and 1 is currently at secondary school. Only 14% were working
prior to transplantation, because of ill health. One patient became pregnant 18
months post-transplant and delivered a healthy, full-term baby. A more detailed
evaluation of quality of life following transplantation is currently in progress
and will be reported separately.
Specific issues The
most common indication for liver transplantation was hepatitis B-related
end-stage liver disease, which accounted for 31% (58/186) of assessments and 32%
(35/109) of transplants. Acute hepatitis B infection was present in 31% (4/13)
of emergency transplants, and chronic hepatitis B infection in 32% (31/96) of
elective transplants. HBV DNA was detectable in serum prior to transplant in
34/36 patients but was undetectable in one patient with acute hepatitis B and in
one patient with chronic hepatitis B and HDV (delta virus) co-infection. As
antiviral prophylaxis against recurrent hepatitis B infection, all HBsAg+
patients received lamivudine monotherapy (100 mg/day) prior to transplant and
combination lamivudine and monthly intramuscular hepatitis B immunoglobulin (800
iu/month) long-term post-transplant. One patient who had lamivudine-resistant
YMDD variant HBV infection (from HBV polymerase gene mutation) also received
adefovir (5 mg/day) pre- and post-transplant. All 36 patients cleared HBsAg from
serum by 7 days and HBV DNA by 12 months post-transplant. None have developed
recurrent hepatitis B infection.
The second most frequent indication for liver
transplantation was end-stage liver disease secondary to chronic hepatitis C
infection, accounting for 19% (36/188) of assessments and 17% (14/109) of
elective transplants. All HCV+ patients remained viraemic post-transplant and
all had histological features of recurrent hepatitis C in their protocol
one-year allograft biopsy. One patient has recurrent cirrhosis at three years
post-transplant, with diuretic-controlled ascites. Another developed severe
cholestatic hepatitis, leading to graft failure at six months
post-transplant.
Alcoholic liver disease (ALD) was the primary diagnosis in
16 patients referred to NZLTU for transplant assessment. A psychiatrist, social
worker and an alcohol and drug addiction specialist assessed all 16 patients to
determine the risk for post-transplant recidivism. Previous failure to complete
a structured rehabilitation programme, a history of multisubstance abuse, lack
of social support and lack of a period of abstinence are regarded as predictors
of drinking post-transplant.14 Following
assessment, five were deemed unsuitable candidates for transplantation. The
remaining 11 patients were listed and monitored thereafter at the pre-transplant
clinic for evidence of alcohol relapse through direct questioning and regular
measurement of carbohydrate-deficient transferrin levels. One patient resumed
drinking and was removed from the waiting list. None of the 10 patients
transplanted for alcoholic liver disease has returned to drinking
post-transplant. Their median length of pre-transplant abstinence was 11 months
(9–39).
All patients were instructed to avoid alcohol
post-transplant, regardless of primary diagnosis. One patient transplanted for
HBV-cirrhosis and one for HCV-cirrhosis admitted heavy alcohol use at 9 and 30
months post-transplant, although neither developed associated graft dysfunction.
Both have received counselling and are now abstinent.
Hepatocellular carcinoma (HCC) was present in 38/158 (23%)
patients assessed by NZLTU. Thirty seven had underlying cirrhosis (HBV in 23,
HCV in 6, ALD in 4, haemochromatosis in 2 and cryptogenic in 2) whilst one
patient had unresectable fibrolamellar hepatocellular carcinoma without chronic
liver disease. Staging during assessment included helical triphasic CT scanning
or MRI of the liver, CT of chest, and bone scan. Thirty seven met international
criteria associated with low risk of recurrence post-transplant (fewer than 4
tumours, none larger than 5 cm, without vascular invasion or extrahepatic
spread)9 of whom 36 were listed for
transplantation. Tumour staging was repeated every three months. This
demonstrated tumour progression beyond these criteria in five patients who were
subsequently removed from the waiting list. At the time of writing, 30 patients
with HCC have been transplanted. Recurrent HCC was detected in five patients
(10%) after 3, 4, 5, 12 and 29 months and has been fatal in four
patients.
DiscussionBetween 1986 and 1998, only 134 New
Zealanders received liver transplants. In 1996, the annual transplant rate in
New Zealand was 4.6 per
million,15 compared
to 7 per million in Australia,15 12 per million
in UK,16 and 20 per million in
USA.13 This belies a relatively high
liver-related mortality in New Zealand – almost 200 New Zealanders die
annually from end-stage liver
disease.17–21 This largely reflects the
endemic rates of HBV infection in Maori, Pacific Islanders and Asians living in
this country.22,23
The annual total of liver transplants has climbed steadily
since the NZLTU was opened in 1998 (to 10.2 per million in 2001). Because
neither the target population nor the minimal listing criteria have changed
during this period, the increase in numbers must be attributed to removal of
previous geographical economic barriers and medical contraindications to
transplantation. Prior to 1998, patients in need of liver transplantation had to
travel to Australian units for assessment, usually after their families and
local communities had raised sufficient funds. Unfortunately, elective patients
then waited a further 3 to 12 months for the operation then a further 3 to 6
months convalescing post-transplant prior to returning home. The opening of a
liver transplant unit within New Zealand removed many of the financial and
emotional stresses for patients and their families.
In addition, the number of New Zealanders who could benefit
from liver transplantation has increased over this period. Prior to 1997, no New
Zealander had been transplanted for HBV-cirrhosis because of the likelihood of
recurrent HBV infection, which usually progressed rapidly to graft failure and
death. Only a few European and North American units transplanted HBV-cirrhotic
patients, using high-dose intravenous hepatitis B immunoglobulin (HBIG).
However, this therapy is prohibitively expensive (NZ$50 000 per annum,
life-long) and is ineffective in HBV DNA+ patients (33/35 HBsAg+ New Zealanders
transplanted since 1998 were HBV DNA+). The development of lamivudine
represented not only a major advance in the management of chronic HBV infection
but also in the prevention of recurrent hepatitis B following liver
transplantation. Combination low-dose HBIG and lamivudine has provided
affordable, effective antiviral prophylaxis in 98 HBsAg+ Australians and New
Zealanders transplanted on this regimen since
1997.24 Both HBIG and lamivudine are continued
long-term post-transplant. Current studies should determine if and when HBIG may
be withdrawn.25
The numbers of New Zealanders with end-stage liver disease
from chronic hepatitis C infection will double over the next
decade.26 The impact of the current HCV
epidemic has already been felt in other Western countries, where HCV-cirrhosis
has become the leading indication for liver transplantation and now accounts for
40% of transplants worldwide.
Currently, more than 50 000 New Zealanders have chronic
hepatitis B and 25 000 have hepatitis C. Modeling, using conservative
assumptions of the natural history of HBV and HCV, predicts at least 40 New
Zealanders will require liver transplantation each
year.20,21 To meet the rapid rise in demand for
liver transplantation, the contracted volume for NZLTU was increased last year
from 66 adult transplants over three years to 117 over three years. An
additional 20 paediatric liver transplants have been funded over this period.
The combined total of 46 transplants per annum is almost double the minimum
workload recommended by a recent mortality review of 102 European transplant
centres.27
Advances in immunosuppression, organ preservation, surgical
techniques and intensive care have improved the long-term outcome after liver
transplantation, with 5-year survival now exceeding
75%.13,28 Most recipients regain excellent
health within three to six months and return to productive lives, with full
employment and family
life.29 Pregnancies
now pose minimal risk to mother and baby.30
Liver transplantation has become a cost-effective treatment of liver
failure and hepatocellular carcinoma and is comparable to other medical and
surgical interventions.20,31–33 The
contracted unit price includes assessment, donor retrieval, perioperative and
post-transplant care for the first three months and is approximately one third
the cost in the United States and two thirds the current price in Australian
centres.
The only barrier to the continued increase in numbers of
transplants is the limited availability of donor organs. Already there is a
widening gap between the need for transplantation and the availability of donor
organs. During 2001, 51 New Zealanders were listed for liver transplantation but
only 39 cadaveric donors became available.34
Since 1998, the NZLTU waiting times have doubled and waiting list mortality is
now 32% for urgent cases and 10% for elective cases. In addition, 14% of
patients listed with hepatocellular carcinoma have been removed from the waiting
list because of tumour progression. This figure is likely to increase as waiting
times lengthen, thereby reducing the cost-effectiveness of liver transplantation
for patients with hepatocellular carcinoma.35
The current national HBV screening programme will detect an additional
10–20 New Zealanders per annum with early, potentially curable
hepatocellular carcinoma. The NZLTU has adopted a number of strategies to
increase the availability of donor livers, including the use of older donors,
anti-Hbcore+ donors (for HBsAg+ and anti-HBs+ candidates only) and HCV+ donors
(matched to HCV+ candidates). After considerable public debate and peer review,
ethical approval has been granted for live donor liver transplantation for
patients with hepatocellular carcinoma or acute liver failure, ie those patients
with the highest waiting-list
mortality.36
In summary, liver transplantation is now regarded as
preferred management for acute and chronic liver failure and for small
hepatocellular carcinoma. The availability of liver transplantation within New
Zealand has had major medical, social and financial benefits for adult
candidates for liver transplantation, which will soon be extended to paediatric
patients and their families. Outcomes achieved by NZLTU over the past four years
are excellent and comparable to those of much larger units. Specific local
problems of hepatitis B and hepatocellular carcinoma have led to innovative
solutions. The growing gap between donor availability and need is associated
with increasing waiting-list mortality. Further strategies to expand the local
donor pool are urgently needed.
Author information:
Ed Gane, Hepatologist and Associate Professor of Medicine; John McCall,
Transplant Surgeon and Associate Professor of Surgery, New Zealand Liver
Transplant Unit, Auckland Hospital; Stephen Streat, Intensivist and Associate
Professor of Medicine, Department of Critical Care Medicine; Kerry Gunn,
Anaesthetist, Department of Anaesthesia; Mee Ling Yeong,
Histopathologist, Department of Histopathology;
Sarah Fitt, Pharmacist, Department of Pharmacy, Auckland Hospital; Dawn Keenan,
Recipient Transplant Co-ordinator; Stephen Munn, Transplant Surgeon and
Professor of Surgery, New Zealand Liver Transplant Unit, Auckland
Hospital
Acknowledgements: We
acknowledge the very many people who have been involved in the care of these
patients before and after transplantation.
Correspondence:
Associate Professor Ed Gane, New Zealand Liver Transplant Unit,
10th Floor, Auckland Hospital, Auckland. Fax:
(09) 529 4061; email: e.gane@auckland.ac.nz
References:
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