small bowel
DESCRIPTION
Small BowelTRANSCRIPT
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Small boweltransplantation e the latestdevelopmentsAlan Wiles
Simon Gabe
Stephen Middleton
agents such as alemtuzumab (Campath-1H) in the 1990s,11,12 and
as reported by the international registry,10 (which receives
details of >90% of all cases world wide) is lower (Table 1) but
this survival gap is continuing to close. In the better performing
centres,17,18 survival figures approximate to those on HPN,
particularly for patients given lymphocyte-depleting induction
therapy, whose survival at 1 and 5 years has been reported to be
as high as 90% and 70% respectively.17 Patient survival at the
largest UK adult transplantation centre in Cambridge has also
improved, with 2-year non-oncological survival pre- and post-
2007 of 50% and 100% respectively, associated with a 10-fold
increase in procedures undertaken per year. The larger of the UK
paediatric transplantation centres, in Birmingham, also has
improved results, reporting 69% 3-year survival since 1998 and
31% before this.19 If these improved survival rates are repro-
duced in other centres and prove a match for those of HPN at
10 years, intestinal transplantation may become the preferred
primary treatment for irreversible intestinal failure, rather than
being largely reserved for those who respond poorly to HPN. It
TRANSPLANTATIONAlan Wiles BA DPhil BMBCh MRCP is a Senior Transplantation Fellow at
Addenbrookes Hospital, Cambridge University NHS Trust and has
recently been appointed as a Consultant Gastroenterologist at Queen
Elizabeth Hospital, Kings Lynn, UK. Competing interests: none declared.
Simon Gabe BSc MD MSc FRCP is a Consultant Gastroenterologist at St
Marks Hospital in Harrow, UK. Competing interests: none declared.
Stephen Middleton MA MD FRCP FAHE is a Consultant Physician and
Gastroenterologist at Addenbrookes NHS Trust, Cambridge University
Teaching Hospital, UK. Competing interests: none declared.AbstractIntestinal transplantation has become a routine clinical procedure for
selected patients. Over the last 10 years patient survival figures have
improved considerably and are now approaching those receiving organs
such as liver, lungandheart. Patient selectionhas improvedand immunosup-
pression has been enhanced by the introduction of lymphocyte modulating
antibody therapy combined with less potent maintenance immunosuppres-
sion. The indications for intestinal transplantation remain conservative at
present and largely reserve this procedure for patients who have life threat-
ening complications of parenteral nutrition or require surgical procedures
that make simultaneous or subsequent transplantation advantageous.
However, as survival figures improve the indications are beginning to
broaden to include consideration of quality of life. Survival after transplanta-
tion is approaching that associated with uncomplicated parenteral nutrition
and if this trend continues it may replace parenteral nutrition as the treat-
ment of choice for patients with irreversible intestinal failure. This article
describes the current indications for intestinal transplantation and the
current results of the procedure. Guidelines for referring patients for trans-
plantationassessment and for themanagementof the sick transplant patient
are given. The need to consider referral of patients at an early stage to allow
timely assessment for transplantation is also discussed.
Keywords infections; intestinal; multivisceral; NASIT; nutrition;
transplantation
A brief history of intestinal transplantation
The earliest significant innovations in the technical aspects of
intestinal transplantation are considered to be the canine models
developed by Richard Lillehei in the 1950s1 and 60s,2 and the
vascular anastomotic techniques ofCarrel.3Graft rejection impededMEDICINE 39:3 183the appreciation that thorough preoperative preparation, patient
selection and scrupulous postoperativemanagement are of critical
importance (Figure 1).13 Now, intestinal transplantation can be
considered as a routine component of the management of adult
and paediatric patients with intestinal failure, and is beginning to
replace parenteral nutrition in the long-termmanagement strategy
for many of these patients. Currently, children tend to have better
survival than adults after 5 years (Figure 2).
The current role of transplantation in the management of
intestinal failure
The survival rates of patients requiring home parenteral nutrition
(HPN) range between 86e97% at 1 year, 57e83% at 5 years and
43e71% at 10 years.14e16 Survival following intestinal trans-
plantation (any combination of organs including small intestine),progress but following the introduction of a series of powerful anti-
rejection agents in the late 1980s,4,5 a cluster of reports appeared
describing transplantation of part or all the intestine both in
combination with other organs and as isolated grafts.6e9
However, long-term survival remained modest at best10 until
the introduction of lymphocyte-depleting induction therapy with
Whats new?
C Improved survival figures: 1 year 85%; 5 years 70%
C Survival gap between home parenteral nutrition (HPN) and
transplantation is closing
C Quality of life on home parenteral nutrition HPN can be
improved by transplantation
C National Adult Intestinal Transplantation (NASIT) Forum e UK
forum to discuss all patients before transplantation
C CaMi (Cambridge-Miami) score: first preoperative scoring
system to estimate postoperative survival following intestinal
transplantation
C It is now a requirement that all suitable patients should be
referred (or discussed) for assessment at an appropriate stage
before they lose the opportunity of transplantation 2010 Elsevier Ltd. All rights reserved.
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Su
rviv
al
pro
ba
bil
ity
Years
Logrank p < 0.001 1: 19851989
2: 19901994
3: 19952000
4: 20002004
5: 20052009
0.0 1
2
3
4
5
23
131
409
757
856
4
39
146
196
0
1
25
68
0
1
10
0
0
0
0 20
0.6
0.8
1.0
0.4
0.2
5 10 15
Patient survival following intestinal transplantation in different eras
between 1985 and 2009
Figure 1
Su
rviv
al
pro
ba
bil
ity
Years
Logrank p < 0.584 1: 02
2: 36
3: 717
4: 18-50
5: 51+
0.0 1
2
3
4
5
360
123
116
392
125
100
39
35
100
34
0
0
0
0
0
0 6
0.6
0.8
1.0
0.4
0.2
2 1 3
21
14
8
18
4
4 5
Patient survival following intestinal transplantation according to age
of patient
Figure 2
TRANSPLANTATION
MEDICINE 39:3 184 2010 Elsevier Ltd. All rights reserved.
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C Severe liver disease or progressive disease despite all reme-
dial actions.
(b) Recurrent septic episodes
C IF patients who have severe septic complications (i.e. life-
threatening line infection needing admission to ITU, or
recurrent yeast or candidal infections).
(c) Lack of central venous access
C For isolated intestine: venous access limited to three major
sites.
C For intestine as part of a cluster graft: venous access limited to
four major sites.
2. Very poor quality of life thought to be correctable by
transplantation.
3. Patients with indications for extensive surgery involving partial
or complete evisceration:
Adults
(a) Surgery to remove a large proportion of the abdominal viscera
that is considered untenable without associated multi-visceral
transplantation (e.g. extensive desmoid disease, extensive
severe mesenteric arterial disease requiring intervention).
(b) Localized malignancy considered to be amenable to curative
resection that would necessitate extensive evisceration (e.g.
localized neuroendocrine tumours and cholangiocarcinoma e
particular caution should be exercised with this group).
Children
(a) Surgery that will lead to:
C Terminal gastrostomy
C Terminal duodenostomy
C Ultra short bowel: In children
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isolated intestine liver and intestine multivisceral (liver, intestine, stomach, pancreas) modified multi-visceral (intestine, stomach, pancreas).In addition, patients may undergo renal transplantation and some
centres favour splenic transplantation for immunological reasons.
Patients invariably have an ileostomy, at least initially, to provide
access for ileoscopic surveillance biopsies to detect rejection. A
few centres transplant the large intestine and abdominal wall.
Following surgery it is usual for an ITU stay of 2 or 3 days,
then HDU for 2 or 3 weeks, and finally a less intensive ward stay
for a further 4e6 weeks to establish full enteral nutrition, satis-
factory immunosuppression and resolution of any postoperative
problems such as infection.
Infection is the commonest postoperative complication (Table
3). Rejection is now less of a problem since the introduction of
lymphocyte-depleting agents, but early detection and treatment
remain a pivotal part of the process and surveillance biopsies via
the stoma are undertaken at least three times a week in the first
month. Fluid and electrolyte balance are also frequently chal-
lenging but of critical importance, to prevent the downward
spiral triggered by a confluence of salt and water imbalance,
impaired renal function and sepsis, which may result in multi-
organ failure. At this point, other pre-existing co-morbidities and
the lack of venous access for treatments such as dialysis can
result in inexorable deterioration. The postoperative manage-
ment of these patients is complex and requires a fully integrated
team of consultants from a broad range of specialties who are
well motivated and able to provide prompt consultant-led
expertise. The combination of inducing profound immunosup-
pression and transplanting an organ with very high antigenicity
that also contains a host of potential pathogens produces
Common infections following intestinal transplantation (in the UK)
Location Likely pathogens Clinica l features Diagnosis Treatment
Bacterial Central line related
Superficial
surgical site:
Pneumonia
Abdominal collection/
peritonitis
Staphylococcus aureus
(incl. MRSA)
Escherichia coli
Klebsiella,
Pseudomonas.
Coagulase-negative
Staphylococci:
(IV line infections only)
Brisk deterioration/septic
shock/and organ-specific
features
(respiratory, urinary,
intra-abdominal)
Lower-grade sepsis with
coagulase-negative
Staphylococci
Cause of death in 18%
Blood cultures/pneumococcal/
Legionella urinary antigens
Organ-specific: broncho-
alveolar lavage (BAL);
sputum, urine culture, etc.
Intra-abdominal scans
Initially broad-spectrum
antibiotics then adjust
to include sensitivities
of known organisms.
Need to cover, MRSA
and other potential
hospital-acquired
infections
Fungal Aspergillosis:
Wound, pulmonary,
disseminated,
cerebral
Aspergillus fumigatus Antibiotic-resistant
pneumonia
Aspergillosis is serious,
particularly disseminated,
and intra-cerebral
is usually fatal
Chest CT scan
BAL and trans-bronchial
biopsy PCR
Aspergillosis with
amphotericin/
AmBisome, voriconazole
or caspofungin
Candidal Candidiasis:
oropharyngeal,
genitourinary,
wound related,
line infections.
Candida albicans Antibiotic-resistant
sepsis
Blood and urine culture,
line tip culture.
AmBisome/
caspofungin
Fluconazole if
mild/known to be
sensitive.
Viral CMV looks for colitis, Influenza virus Flu-like illness
ase
ken
um
fec
ase
ula
fec
fec
ase
Nose and throat swabs, Antivirals, depending
TRANSPLANTATIONhepatitis and retinitis.
EBV PTLD late:
>1 year
Respiratory syncytial
virus (RSV) or
parainfluenza
virus 3
Cytomegalovirus (CMV)
Varicella-zoster virus
(VZV)
Herpes simplex virus 1
or 2 (HSV-1/2)
EpsteinBarr virus (EBV)
Human herpes virus 6
(HHV-6)
Adenovirus
Pneumonia
Organ dise
Severe chic
zoster, pne
Systemic in
organ dise
From gland
to PTLD
Systemic in
fever
Systemic in
organ dise
Table 3MEDICINE 39:3 186pox or
onitis
tion,
r fever
tion,
tion,
nasopharyngeal aspirate,
broncho-pulmonary
lavage PCR
on circulating strains
Nebulized ribavirin
Ganciclovir
Acyclovir
Acyclovir
Discuss with virologist
and haematologist
Discuss with virologist
Cidofovir (discuss with
virologist) 2010 Elsevier Ltd. All rights reserved.
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a unique clinical setting, where patients often respond in an
unusual way to infections and treatments.
Which patients should be referred to a transplant centre for
consideration?
The management of all patients with intestinal failure should now
include consideration of the potential role of transplantation. It is
important to make every attempt to treat reversible disease and
thorough intestinal rehabilitation can often restore adequate
enteral nutrition. In the UK, this process is undertaken in regional
or national intestinal failure (IF) centres. The regional (medium-
volume) centres have a nutrition team and clinical staff with
subspecialty interests in the management of intestinal failure
patients. For themore complex patients, especiallywheremultiple
surgical procedures are thought necessary, the UK has two
national IF centres. These centres have specialist medical and
surgical staff that are dedicated to intestinal failure work and have
a high enough volume of these complex patients to build up a high
level of corporate experience. This system is very efficient as it
allows appropriate escalation and concentrates experience of the
less frequent, highly complex patients, who require a very
rounded team of clinicians to manage them effectively. In most
cases, patients fulfilling the criteria for transplantation (Table 2) or
who are approaching this situation (Table 4) should be referred.
Particular attention should be given to those who are likely tomiss
the window of opportunity. These patients often have progressive
disease, which may advance to a point that contraindicates
transplantation or results in death whilst they are on the waiting
list. Examples of this include patients who are rapidly losing
venous access points and those bleeding fromportal hypertension.
Special consideration should also be given to PN-dependent
patients who require transplantation of other organs. They may
benefit from a cluster graft including intestine rather than have
a subsequent intestinal transplantation in the setting of an existing
graft and consequent immunosuppression.
Red-flag indicators for referral for transplant assessment
[In addition to the standard indications for transplantation e Table 2]
Patients with intestinal failure and one or more of the following:
C Abnormal LFTs Persistent elevation of hepatic enzymes may
indicate PN-associated hepatic fibrosis or
cirrhosis
Assessment of liver including biopsy, optimize
HPN and exclude other causes. Refer to or
discuss with national IF or transplant centre
C Frequent line sepsis Patients with three or more episodes of line
sepsis in a year or one episode of life-
threatening sepsis may be candidates for
transplantation particularly if there are other
relative indications
Refer to/discuss with national IF centre
C Ultra-short bowel syndrome Less than 40 cm of jejunum to a stoma is
associated with rapid-onset liver disease
Refer to/discuss with a National IF or
transplant centre
C Co-existing diabetes mellitus with
complication
Diabetic complications are often indications
for pancreatic transplantation and if advanced
increase the risk associated with intestinal
transplantation. Patients may benefit from
early combined transplantation
Refer to transplantation centre for
consideration of combined pancreas and small
bowel transplantation
abd
e in
ion
my
p fo
a-pe
on
nin
s. E
erab
eria
e a
TRANSPLANTATIONa The UK National Desmoid Centre is at St Marks hospital, Harrow, London.
Table 4C Pseudo-obstruction. Complicated by
severe abdominal pain
Patients with intractable
distended small and larg
benefit from transplantat
colectomy and enterecto
a relatively high-risk grou
of intestines reduces intr
subsequent transplantati
Patients without intestinal failure
C Desmoid disease Extensive disease threate
other important structure
intervention may be pref
C Mesenteric vascular disease Extensive mesenteric art
disease involving intestin
intra-abdominal organsMEDICINE 39:3 187ominal pain from
testine may
rather than
and PN. They are
r PN and removal
ritoneal space for
Refer patient to transplant centre
g or damaging
arly surgical
le
Refer to transplantation centre for assessment
or to the national desmoid centrea
l or venous
nd other essential
Refer to transplantation centre for assessment
or to the national desmoid centre 2010 Elsevier Ltd. All rights reserved.
-
given this opportunity at an appropriate stage.
There are certain red flag indicators for referral to a main
centre (Table 4) in addition to the standard indications for trans-
plantation (Table 2). This is not an exhaustive list of high-risk
factors but provides a guide to the type of situation that should
prompt the gastroenterologist to consider referral, to either
a national IF centre or a transplant centre, for further consideration.
Conclusion
Considerable advances over the last 20 years have taken intes-
tinal transplantation from the first procedures that provided only
short-term success to its current status as a routine therapeutic
option for selected patients. Although HPN remains the primary
treatment for most patients with intestinal failure, we approach
the threshold of a new era when intestinal transplantation will be
considered to be the primary treatment for most patients. This
promises to be cost effective and bring with it better quality of life
for patients without reducing their longevity. A key element of
success is appropriate timing of referral to a national IF or
transplantation centre. All gastroenterologists should be aware of
when and how to refer patients, and seek advice early in the
management of the more complex patients. A
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TRANSPLANTATIONWhat is the likely future demand for intestinal transplantation?
The ongoing improvement in postoperative survival brings with it
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Practice points
C The possibility of future intestinal transplantation should be
considered in the management of all intestinal failure (IF)
patients and those with extensive benign intra-abdominal
disease.
C IF patients with significant complications of PN should be
referred for transplantation assessment (National IF or trans-
plantation centre) or at least discussed with a centre.
C Care should be taken not to allow IF patients to deteriorate
past the point when transplantation is possible.
C Sick transplant patients must be treated without delay and
advice should be sought from their transplantation centre
immediately on presentation.
C The early use of appropriate broad-spectrum antimicrobial
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after cardiac transplantation. Thorac Cardiovasc Surg 1995; 43: 352e4.
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11 Middleton SJ, Pollard S, Friend PJ, et al. Adult small intestinal
transplantation in England and Wales. Br J Surg 2003; 90: 723e7.
12 Tzakis AG, Kato T, Nishida S, et al. Alemtuzumab (Campath-1H)
combined with tacrolimus in intestinal and multivisceral trans-
plantation. Transplantation 2003; 75: 1512e7.
13 Middleton SJ, Nishida S, Tzakis A, et al. Cambridge-Miami score for
intestinal transplantation preoperative risk assessment: initial
development and validation. Transplant Proc 2010; 42: 19e21.
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nutrition dependence in adult patients with the short bowel
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17 Abu-Elmagd KM, Costa G, Bond GJ, et al. Five hundred intestinal and
multivisceral transplantations at a single center: major advances with
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18 Nishida S, Levi D, Kato T, et al. Ninety-five cases of intestinal
transplantation at the University of Miami. J Gastrointest Surg 2002;
6: 233e9.MEDICINE 39:3 189agents in sick transplantation patients is essential as they are
most likely to have infection. 2010 Elsevier Ltd. All rights reserved.
Small bowel transplantation the latest developmentsA brief history of intestinal transplantationThe current role of transplantation in the management of intestinal failureWhat does intestinal transplantation involve?Which patients should be referred to a transplant centre for consideration?What is the likely future demand for intestinal transplantation?Why do gastroenterologists need to know about intestinal transplantation?ConclusionReferences