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Chapter 9
a linear scale from 1 to 7 (always aware to never
aware). A score of 4 or above suggests IAH. The
Clark method asks eight questions to document
the patient's exposure and responses to moderate
and severe hypoglycaemia, and again a score of 4
or more suggests IAH.
a composite HYPO score based on 4 weeks of
glucose values.
81
Ryan etal. have described
83
They suggest that this provides
a more objective assessment of the metabolic
instability of an individual patient and allows
pre- and post-transplant comparison. Patients
should be assessed by a multidisciplinary team
consisting of a diabetologist, transplant surgeon,
dietician and a diabetes nurse specialist. This will
ensure an optimum insulin regimen and dietary
compliance and that the patient is fully informed
about the likely outcome of islet transplantation
and the risks involved, principally post-transplant
immunosuppression.
Islet isolation
Donor factors contributing to successful islet
isolation have been documented by Lakey et al.
(Table 9.2).
from older donors with a higher body mass index
(BMI) should result in a significantly higher islet
yield. O'Gorman et al. have suggested a scoring
system from 1 to 100 to give a numerical assessment
of the likelihood of successful isolation from a
specific donor pancreas.
only predict successful isolation and do not take into
from younger donors are functionally better.
UK, a sharing scheme was introduced in December
2010 where patients for SPK transplantation and
islet transplantation are placed on a common waiting
Table9.2 • Donor-related variables predicting isolation
84
This paper suggests that pancreases
85
These studies, however,
86
In the
success
list and pancreases offered on a named patient basis.
Multiple donor and recipient factors are taken into
consideration, allowing islet and whole pancreas
recipients equal access to suitable organs.
Most of the outcome data on islet transplantation
are based on organs from brain-dead donors
(DBD); however, there is growing evidence that
pancreases from donation after circulatory death
(DCD) can produce transplantable preparations
and good outcomes. Most of the data on DCD
islet transplantation are from the Kyoto group
and although long-term graft survival is obtained,
insulin independence is less common.
87–91
It is critical that the pancreas for islet isolation is
retrieved with the same care as that for whole pancreas
transplantation and that cold ischaemia time is
minimised, ideally to under 8 hours.
92
Pancreases
should be transported rapidly and the staff in the
isolation laboratory should be ready to begin the
isolation immediately. It has been demonstrated that
suspending the explanted pancreas in a bilayer of
oxygenated perfluorocarbon (PFC) and University
of Wisconsin (UW) solution during or after
transport allows satisfactory islet preparations to be
obtained from suboptimal pancreases and may even
increase yields from pancreases with long ischaemia
93,94
times.
expand the donor pool by improving islet isolation
from DCD pancreases and older donors.
PFC-based preservation may also help
95
The semi-automated process for islet isolation that
is used in most laboratories was described by Ricordi
etal. in 1989.
96
This involves digestion of the pancreas
using a combination of collagenase enzyme and
mechanical dissociation of the pancreas in the Ricordi
chamber (
Fig.9.4). A number of new enzyme blends
have been developed for human isolation, including
collagenase NB1 (Serva), Liberase MTF (Roche) and
C1 collagenase HA (Vitacyte). Each of these differs
slightly in the enzyme blend and manufacturing
process but promises to deliver more consistent,
better-quality islet yields. The preparation is then
Variable P value R value Odds ratio
Donor age (yr) <0.05 0.18 1.10
Body mass index <0.01 0.19 1.30
Local vs distant
<0.01 0.21 7.04
procurement team
Min. blood glucose <0.01 −0.24 0.68
Duration of cardiac
<0.01 −0.17 0.81
arrest
Duration of cold
<0.05 −0.13 0.86
storage
Reproduced from Lakey JR, Warnock GL, Rajotte RV, etal.
Variables in organ donors that affect the recovery of human
islets of Langerhans. Transplantation 1996;61(7):1047–53. With
permission from Lippincott, Williams & Wilkins.
Figure9.4 • Ricordi chamber.
162
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Pancreas and islet transplantation
purified on a continuous density gradient using
a COBE 2991 cell separator, resulting in a packed
cell volume of only 1–2 mL (Fig. 9.5).97 Although
unpurified preparations can be used (particularly in
autotransplants), the risk of portal vein thrombosis,
portal hypertension and disseminated intravascular
coagulation (DIC) is increased.
98–101
After isolation and purification, it is now standard
practice to place the islet preparation in culture for
12–48 hours. There are compelling data that this
does not adversely affect islet graft function and
does in fact increase purity of the preparation.
102
Extended culture up to 48 hours can also be used to
assess the viability of an islet graft, particularly after
DCD isolation.
The number of islets in the preparation is
documented in terms of islet equivalents (IEQ).
This counting method adjusts for the fact that
islets vary greatly in size, and cell viability stains
such as fluorescenediacetate/propidium iodide and
SytoGreen/ethidium bromide are used to determine
the viable beta-cell mass.
103
The minimum release criteria in the UK for an islet
preparation are:
• >200 000 islet equivalents
• >70% viability
• >30% purity
• Gram-stain negative
• Endotoxin-negative
It is accepted that these criteria are subjective
and open to observer variation and error. Some
assessment of the ‘quality’ of the preparation should
also be made. Experienced islet laboratory staff
can comment on the morphology of the cells, the
integrity of the islets and whether or not there is
evidence of central necrosis within the islets. Islet
oxygen consumption rate and beta-cell ATP content
show good correlation between product testing and
invivo islet function in animal studies, and may be
useful in the future, but are time-consuming and
expensive. The Minnesota group has demonstrated
good correlation between marginal mass islet
transplants in diabetic nude mice and outcome of
human islet transplants from the same donor.
Modern islet isolation facilities must comply
with current good manufacturing practice (cGMP).
The facility must be purpose-built to comply with
regulatory authorities, which in the UK comprise the
Human Tissue Authority (HTA) and the Medicines
and Healthcare products Regulatory Authority
(MHRA). These regulations are designed to ensure
that each laboratory produces a safe, consistent
and traceable product, by influencing the structural
design of the laboratory, the documentation of
standard operating procedures and of individual
isolations, and training of members of the isolation
team. Modern islet isolation is therefore expensive
and requires a large number of staff to cover a 24/7
on-call rota. In the UK, a hub-and-spoke model
exists, whereby three isolation facilities provide
islets for transplantation in seven centres.
The islet transplant
In the original Edmonton protocol, >11 000 IEQ/kg
were required to achieve insulin independence and
therefore at least two islet infusions are normally
required.
matched with the potential recipient, but the need
for close tissue matching is not clear. There is no
evidence that closely matched preparations have a
better outcome; however, it is likely to be beneficial
to avoid repeated common mismatches as recipients
may, in the event of graft rejection, become sensitised
to multiple common alloantigens.
vein of the recipient under local anaesthetic and
sedation in the radiology suite.
introduced under ultrasound and videofluoroscopy
74
Islet preparations are blood group
The islets are normally infused into the portal
105
A 4-Fr cannula is
104
a b
Figure9.5 • Islets stained red with dithizone before (a) and after (b) purification.
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163
Chapter 9
into the main portal vein and the islet preparation
infused under gravity feed over a period of 15–20
minutes (
Fig. 9.6). Portal venous pressures are
measured during the infusion process and if there
is a significant rise, the infusion should be stopped
until the portal pressure falls. The islet preparation is
heparinised (35 U/kg patient body weight) to reduce
the risk of portal vein thrombosis. This should ideally
be done by experienced interventional radiologists
and the track of the cannula occluded on withdrawal
to reduce the risk of bleeding. The infusion into
the portal vein can also be carried out by surgical
cannulation of an omental vessel or the umbilical
vein. The intraportal site for islet embolisation was
recognised to be the most efficient location for
islet implantation in the rodent, with the benefit of
high vascularity, proximity to islet-specific nutrient
factors and physiological first-pass insulin delivery
to the liver.
106
While many different sites have been
tried for islet implantation, the optimal site appears
to be through portal venous embolisation. Attempts
to embolise the spleen have led to significant lifethreatening complications of splenic infarction,
rupture and even gastric perforation.
107,108
More
recently, reports of experimental implantation of islets
into the gastric submucosa have shown improved
vascularisation of the graft.
109
Recent developments
in encapsulation technology have stimulated interest
in using alternative sites. Encapsulation devices
protect the islets from immunological attack while
allowing insulin to be secreted.
110
Such devices have
been implanted subcutaneously, intramuscularly
and into the omentum, but with limited clinical
application to date.
After infusion into the liver, the islets undergo a
process of angiogenesis, which takes 14–21 days.
Interestingly, this is often reflected in the reduced
need for insulin in islet graft recipients around
3–4weeks post-transplant.
Immunosuppression and
outcomes
All seven patients in the original Edmonton
experience were insulin-independent at 1 year
post-transplant; however, follow-up of this cohort
revealed that only 10% remained free of insulin
at 5 years.
strategies have been reported in an attempt to
improve these long-term outcomes. T-cell-depleting
agents such as antithymocyte globulin (ATG),
anti-CD3 and alemtuzumab (campath/anti-CD52)
have been used as alternative induction therapy and
combined with agents such as etanercept/tumour
necrosis factor (TNF)-α or mycophenolate mofetil/
tacrolimus as maintenance therapy.
have published data from the Collaborative Islet
Transplant Registry on 677 patients receiving 1375
islet infusions between 1999 and 2010.
data demonstrated a significant improvement in
long-term insulin independence in the 2007–2010
era compared to earlier years (
insulin independence approaching 50%. This report
also documented that patients who received T-celldepleting agents combined with TNF-α inhibition
had better 3- to 5-year insulin independence rates
(62% vs 43%). More recently, data from the UK and
the US clearly demonstrate that islet transplantation
provides protection from severe hypoglycaemic
episodes, restores awareness of hypoglycaemia and
improves glycaemic control.
111
Alternative immunosuppression
112
Barton etal.
113
These
Fig.9.7), with 3-year
114–116
a b
Figure9.6 • Islet infusion into the portal vein.
164
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Pancreas and islet transplantation
% Insulin independence
Year of islet transplant
1 year
70
60
50
40
30
20
10
0
1999-2002 2003-2006 2007-2010
Figure9.7 • Improvement in long-term insulin
independence after islet transplantation from 1999 to
113
2010.
2 year
3 year
Serious adverse events after islet transplantation
are either related to the infusion procedure or the
immunosuppression. The more serious procedurerelated complications of segmental portal vein
thrombosis and bleeding have been reported in 4%
and 10%, respectively.
117,118
The risk of portal vein
thrombosis can be minimised by heparinisation
of the recipient and by using only low-volume,
high-purity preparations. Bleeding from the liver
puncture can be avoided by using a fine-bore
cannula and by ablating the track in the liver using
coils, thrombostatic agents or a coagulative laser.
Leucopenia, neutropenia and sepsis have all been
described after islet transplantation.
119
A reduction
105
in estimated glomerular filtration rate has been
described in islet transplant recipients in the long
term post-transplantation, but reports of clinically
significant renal impairment are rare.
113
One of the biggest challenges in islet transplantation
is monitoring the graft. No reliable investigations
exist to monitor graft function or detect acute
rejection. Experimental studies in rats suggest that
islets labelled with superparamagnetic iron oxide
(SPIO) nanoparticles can be monitored using
magnetic resonance imaging (MRI) scanning and
that loss of the islet-related MRI spots correlates
with rejection.
120
Metabolic studies such as the
C-peptide response to a glucose challenge may give
an indirect indication of ongoing graft mass but as
yet cannot aid in predicting acute rejection.
121
Organ
retrieval
IBMIR
Engraftment
Rejection
Figure9.8 • Barriers to long-term islet graft function.
Autoimmunity
CIT
Isolation
where there have not been the physiological changes
associated with brain death may be beneficial for islet
isolation, and techniques such as using extracorporeal
membrane oxygenation (ECMO) circuits in the
donor may result in islets that are protected from
ischaemic change. There is no doubt that minimising
the time between cross-clamp in the donor and
beginning the isolation process in the laboratory
improves the islet yield and long-term graft function,
requiring that pancreases must be transported rapidly
to the laboratory and the isolation process started
immediately. Improvements in isolation techniques
have seen an increase in the average number of islets
that can be produced per isolation with resultant
improvements in graft survival.
There is an immediate blood-mediated inflammatory reaction (IBMIR) to the islet graft as soon
as the islets are infused into the portal vein. Platelets
bind to the surface of the islets and leucocytes
infiltrate the graft. This contributes largely to the
early loss of islets post-transplantation, which can
be as high as 60% of the graft.
122
Strategies such as
heparinisation of the recipient and ongoing insulin
therapy may help to abrogate this process.
is known about the engraftment process of human
islets within the liver. Transient elevation of liver
enzymes is very common post-islet transplantation
and it is interesting that the use of anti-inflammatory
agents such as TNF-α blockers appears to improve
graft survival.
Islets as a cell therapy
123
Little
Barriers to long-term function
Figure 9.8 illustrates the multiple factors that
contribute to islet death and subsequent graft failure.
The organ retrieval process and subsequent cold
ischaemia time (CIT) have a significant negative
impact on the outcome of islet isolation. The
increasing use of pancreases from DCD donors
The shortage of organ donors coupled with the
increased demand for islets has led to much research
into alternative sources of insulin-producing cells
that would be renewable and not depend solely
on the availability of human cadaveric donors.
The use of fetal or adult porcine islets for human
xenotransplants has been explored; however, the
high levels of immunosuppression required and
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165
Chapter 9
the risk of transmission of porcine endogenous
infections means that xenotransplantation is still
some way in the future.
Stem cells are capable of both self-renewal
and multilineage differentiation. They have the
potential to proliferate and differentiate into any
type of cell and to be genetically modified invitro,
thus providing a renewable source of cells for
transplantation. Several potential strategies exist for
developing a replenishable supply of beta cells. One
of these is through directed differentiation of human
embryonic stem cells (hESCs).
124
Functioning beta
cells have been produced using this technology but
concerns have been raised around the reproducibility
of these processes and the potential for these cells
to develop into teratomas. In 2006, Takahashi and
Yamanaka described a technique whereby adult
somatic cells could be de-differentiated and then
induced to develop into different cell types.
They used a cocktail of four transcription factors
to produce these induced pluripotent stem cells (iPS
cells), and many groups have now reproduced this
work and developed cells of multiple lineages using
this technology. The Melton group from Cambridge
demonstrated that, in vivo, three transcription
factors are required for beta-cell development,
namely Ngn3, Pdx1 and MafA.
126
encouraging steps forward in the development
of stem-cell-derived islets but there are still issues
around upscaling of cell numbers and the potential
for residual de-differentiated cells to produce
tumours in the recipient. Recent developments in
large-scale beta cell production invivo are grounds
for optimism and an exciting prospect is the
potential existence of stem cells within the pancreas
that could develop into new beta cells or with the
potential to transdifferentiate non-endocrine tissue
125
into functioning islets.
127–129
These are
Key points
• As of the end of 2010, over 35 000 pancreas transplants have been performed worldwide. In the
USA alone there are more than 100 000 patients with functioning transplants; around 10 000 of these
are pancreas allografts.
• The outcome following pancreas transplantation has improved considerably in the last 10–15years.
It is now comparable to the outcome for other solid-organ transplants.
• The number of pancreas transplants reached a peak in 2004. Activity has been declining in the USA
since then in all three categories. An overall decrease of 20% was observed in 2010, compared with
2004. The largest decrease was observed in the PAK category (55%), followed by PTA (30%) and
SPK (8%).
• Pancreas transplantation activity in the UK has followed a different pattern, with a much sharper
increase in activity between 2000 and 2007, followed by a more modest decline since then.
• Despite the reduction in activity, pancreas transplant outcomes have remained at least as good in the
last decade.
• Induction immunosuppression with biological agents is used in pancreas transplantation more
often than any other solid-organ transplant. Tacrolimus/MMF combination is the basis of the most
commonly used maintenance immunosuppression protocols. Steroid minimisation or avoidance is
gaining momentum.
• Over the last 15years, enteric drainage has gradually replaced bladder drainage as the preferred
technique for the management of exocrine secretions in pancreas transplantation.
• Portal venous drainage, introduced in the mid-1990s, has not gained increasing popularity. It is used
in just under a fifth of SPK and PAK transplants, and in 10% of PTA transplants.
• Evidence regarding the influence of pancreas transplantation on diabetic complications and life
expectancy is not available from prospective controlled trials. Nevertheless, accumulating evidence
from many studies strongly suggests that successful pancreas transplantation has a favourable
influence on diabetic complications and survival prospects for patients.
• Islet transplantation is now considered as ‘standard of care’ for patients with type I diabetes and
severely impaired awareness of hypoglycaemia.
• The long-term outcomes of islet transplantation have improved significantly over the last 10years,
with insulin independence at 3years approaching that of whole pancreas transplantation.
• Immunosuppression with T-cell-depleting agents appears to give the best long-term graft survival.
166
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Pancreas and islet transplantation
Recommended video:
• Pancreas and islet cell transplant – https://youtu.
be/z_mb9_FHdgI
Full references available at http://expertconsult.
inkling.com
Key references
35. Papadimitriou JC, Drachenberg CB. Distinctive
morphological features of antibody mediated
and T-cell mediated acute rejection in pancreas
allograft biopsies. Curr Opin Organ Transplant
2012;17:93–9. PMID: 22227719.
This publication provides an authorative review of
the histological criteria for acute pancreas allograft
rejection and the mechanisms leading to graft injury.
36. Mittal S, Page SL, Friend PJ, et al. De novo
donor-specific HLA antibodies: biomarkers of
pancreas transplant failure. Am J Transplant
2014;14(7):1664–71. PMID: 24866735.
In a multivariate analysis of 433 pancreas transplants
at the Oxford Transplant Centre, development of de
novo donor specific antibodies (DSA) emerged as a
strong independent predictor of pancreas graft failure
(hazard ratio 4.66, P < 0.001).
57. The Diabetes Control and Complications Trial
Research Group. The effect of intensive treatment
of diabetes on the development and progression
of long-term complications in insulin dependent
diabetes mellitus. N Engl J Med 1993;329:977–
86. PMID: 8366922.
This paper provides good evidence that better
blood glucose control reduces the risk of
progression of retinopathy.
74. Shapiro AM, Lakey JR, Ryan EA, et al. Islet
transplantation in seven patients with type 1
diabetes mellitus using a glucocorticoid-free
immunosuppressive regimen. N Engl J Med
2000;343(4):230–8. PMID: 10911004.
This publication from the Edmonton group
demonstrated that long-term insulin independence
can be achieved with islet transplantation
and paved the way for the modern era of islet
transplantation.
96. Ricordi C, Lacy PE, Scharp DW. Automated
islet isolation from human pancreas. Diabetes
1989;38(Suppl. 1):140–2. PMID: 2642838.
This paper was the first to describe the semi-automated
technique of human islet isolation – a technique that is
still used by islet laboratories worldwide.
113. BartonFB, RickelsMR, AlejandroR, etal. Improvement in outcomes of clinical islet transplantation:
1999–2010. Diabetes Care 2012;35(7):1436–45.
PMID: 22723582.
Data from the CITR is presented in this paper
that demonstrates improved outcomes after islet
transplantation over three eras, with a 3-year insulin
independence rate after islet transplantation of >40%
in the current era.
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167
10
10
The spleen and adrenal glands
Brendan Visser
Geoffrey W. Krampitz
Introduction
The spleen is a wedge-shaped secondary lymphoid
organ present in all vertebrates. The word spleen
originated from the Greek language, which was then
translated into Latin and Middle English and then
into its current English form. The Roman anatomist
Galen identified the spleen as the source of black bile,
one of the major humors of the body, and a major
subsidiary organ of the liver. In antiquity, the spleen
was thought to be the seat of spirit and courage
or such emotions as melancholy and anger. The
immunological and haematopoietic functions of the
spleen have only recently been appreciated. Given
the immunological consequences of asplenism, the
indications for complete surgical resection have
evolved and given rise to spleen-preserving and
spleen-conserving approaches.
Anatomy and embryology
The spleen is the largest reticuloendothelial organ,
being approximately the size of a clenched fist
and normally weighting 150–250 grams.
spleen is shaped like a cupped hand situated in
the left hypochondrium. It has two surfaces, the
diaphragmatic surface that is smooth and convex
and is in contact with the diaphragm, and visceral
surface that is irregular and concave and has
impressions contacting the fundus of the stomach,
left kidney, splenic flexure of the colon and tail of
the pancreas. The spleen is an intraperitoneal organ
that is suspended by multiple ligamentous folds of
peritoneum, namely, the gastrosplenic connecting the
1
The
hilum of the spleen with the greater curvature of the
stomach, the splenorenal connecting the hilum of the
spleen to the left kidney and containing the splenic
vessels and tail of the pancreas, and the phrenicocolic
connecting the left colic flexure and diaphragm
to the diaphragmatic surface of the spleen.
spleen forms from the cephalic aspect of the lateral
plate mesoderm during the fifth week of gestation.
Multiple aggregations of mesodermal cells condense
to form a single organ. In up to 11% of individuals,
one or more of these aggregates of splenic tissue fails
to condense, and instead forms an accessory spleen,
or splenule.
results from infiltration of cells from the yolk sac
wall and near dorsal aorta that continues to produce
red blood cells into the second trimester. Although
the haematopoietic function of the spleen normally
ceases in the fifth month of gestation, lymphocyte
and monocyte generation persists throughout life.
The spleen derives its major blood supply from the
splenic artery, which emanates from the abdominal
aorta as a branch of the coeliac trunk, traverses a
tortuous course along the superior border of the
pancreas, giving rise to the left gastroepiploic artery
and short gastric arteries before dividing into multiple
branches that enter the hilum of spleen (
The arteries ramify throughout the organ radially
into splenic arterioles that branch into penicillar
arterioles that ultimately terminate in splenic cords
Fig. 10.1). Here, the reticuloendothelial cells and
(
splenic macrophages come in intimate contact with
blood and its contents as it percolates through the
splenic cords and across walls of the splenic sinuses.
Owing to the large amount of infiltrating blood, the
red pulp is a principal site of blood filtration, where
3
The haemopoietic function of the spleen
2
The
Fig.10.1).
168
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The spleen and adrenal glands
Hilu
Spleni
vei
White pulp
Spleni
artery
Capsule
Trabecula
Vascular
sinusoi
White
Artery
Vei
Arterioles and
capillaries
c
c
n
s
Figure10.1 • Gross anatomical features of the spleen. The spleen is a cupped hand-shaped retroperitoneal organ with
diaphragmatic and visceral surfaces. The spleen derives its major blood supply from the splenic artery, which divides
before entering the hilum of spleen into multiple branches that ramify throughout the organ radially into splenic arterioles
that branch further into penicillar arterioles that ultimately terminate in splenic cords. The major vascular outflow from the
spleen occurs via coalescence of the open sinuses via reticular trabeculae into the splenic vein, which exits via the hilum
of the spleen.
Modified from © 2006 Pearson Education, Inc., publishing as Benjamin Cummings, In: Elaine N. Marieb, Katja Hoehn,
Human Anatomy & Physiology, 7th edition. Fig. 20.6a,b.
ageing blood cells are destroyed via programmed
cell removal.
4
Scattered throughout the red pulp are
local expansions of lymphocytes that appear as white
Fig.10.2). White pulp is closely associated with
pulp (
central arterioles that are surrounded by periarterial
Splenic artery
Splenic vein
lymphatic sheaths containing T lymphocytes.
Surrounding the T lymphocytes are follicles that
contain B lymphocytes. In response to antigen
presentation, these B lymphocytes become activated
and produce antibodies that play a significant role
Capsule
Trabecula
Venous
sinuses
Splenic
cords
Central
artery
Red pulp
Germinal
center
Red pulp
Periarteriolar
lymphoid
sheath (PALS)
Primary follicle
Marginal zone
pulp
169
d
n
Figure10.2 • Microscopic anatomical features of the spleen. The red pulp of the spleen is the principal site of blood
filtration where reticuloendothelial cells and splenic macrophages come into intimate contact with the blood and its
contents as it percolates through the splenic cords and across walls of the splenic sinuses. The white pulp of the spleen
is local expansions of lymphocytes scattered throughout the red pulp. White pulp is closely associated with central
arterioles and their surrounding periarterial lymphatic sheaths that contain T lymphocytes, which are surrounded by
clusters of B lymphocytes. Between the red and white pulps is a marginal zone that contains antigen-presenting cells
crucial for initiating lymphocyte activation.
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Chapter 10
in opsonisation of extracellular organisms including
encapsulated bacteria. Between the red and white
pulps is a marginal zone that contains antigenpresenting cells crucial for initiating lymphocyte
activation. The association of lymphoid and myeloid
cells in the red and white pulp makes the spleen a
principal site of intersection between the innate
and adaptive immune systems.
1
The major vascular
outflow from the spleen occurs via coalescence of
the open sinuses via reticular trabeculae into the
splenic vein, which exits via the hilum of the spleen
and courses medially to converge with the superior
and inferior mesenteric veins to form the portal vein.
The spleen is invested by two fibrous capsules,
the outer tunica serosa that is derived contiguous
with the peritoneum and invests the organ except
at the hilum, where the peritoneum reflects into the
phrenicocolic and gastrosplenic ligaments, and the
tunica albuginea that invests the entire organ and
at the hilum is reflected inward along the vessels to
form sheaths from which the trabecular framework
of the spleen emanates.
Indications for splenectomy
Trauma
The spleen’s juxtaposition in the left upper abdomen
to the 9th, 10th and 11th ribs renders it extremely
vulnerable to injury during blunt or penetrating
trauma. Haemodynamically unstable patients should
undergo emergency laparotomy and splenectomy
without delay. Patients who are haemodynamically
stable should undergo abdominal computed
tomography (CT) with intravenous contrast to
evaluate the extent of splenic injury, which will
guide further management. The grading criteria
for splenic injuries is shown in Table10.1.
operative management, including bedrest, telemetry
5,6
Non-
monitoring, haemoglobin/haematocrit laboratory
monitoring every 6 hours, and documented
hourly serial abdominal examination for 24 hours
following injury, has become the standard of care
for haemodynamically stable patients with low to
moderate grade injuries (grade I–III) in the absence
of evidence of active extravasation on initial
contrast-enhanced CT.
7
Failure of non-operative
management, defined as hypotension or evidence
of ongoing haemorrhage requiring operative
intervention, is associated with hypotension on
presentation, grade III injury with contrast blush,
or grade IV/V injuries.
operative management failures occur within 72 hours
of injury.
9
Increasingly, spleen-preserving selective
angioembolisation is used following failure of nonoperative management.
8
Ninety-five per cent of non-
10
All patients undergoing
splenectomy or at high risk for splenectomy should
receive vaccinations for encapsulated bacteria prior
to discharge from hospital.
Haematological
The most common indication for splenectomy is for
patients with immune thrombocytopenic purpura
(ITP). ITP is an autoimmune disorder characterised
by antibody-induced platelet destruction by splenic
macrophages.
glucocorticoids or intravenous immunoglobulin
and platelet transfusions. More recently, rituximab
and thrombopoietin-receptor agonists have been
introduced into the traditional armamentarium.
Splenectomy is indicated for medically refractory
15
Thrombotic thrombocytopenic purpura (TTP)
ITP.
is an autoimmune disorder caused by antibodies to
ADAMTS13 that results in altered von Willebrand
factor homeostasis leading to thrombotic
microangiopathy.
defined as the pentad of fever, thrombocytopenia,
11,12
ITP is initially treated with
16
TTP classically has been
13,14
Table10.1 • Spleen injury scale (1994 revision)
Grade Injury type Description of injury
I Haematoma Subcapsular, <10% surface area
Laceration Capsular tear, <
1 cm parenchymal depth
II Haematoma Subcapsular, 10–50% surface area; intraparenchymal, <5 cm in diameter
Laceration Capsular tear, 1–3 cm parenchymal depth that does not involve a trabecular vessel
III Haematoma Subcapsular, >50% surface area or expanding; ruptured subcapsular or parenchymal haematoma;
intraparenchymal haematoma ≥
5 cm or expanding
Laceration >3 cm parenchymal depth or involving trabecular vessels
IV Laceration Laceration involving segmental or hilar vessels producing major devascularisation (>25% of spleen)
V Laceration Completely shattered spleen
Vascular Hilar vascular injury with devascularised spleen
Advance one grade for multiple injuries up to grade III.
170
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The spleen and adrenal glands
microangiopathic haemolytic anaemia, renal
dysfunction and neurologic symptoms, although
presentation of these symptoms is highly variable.
Acutely, TTP is treated with plasmapharesis, which
results in remission in more than 80% of cases.
Patients who are refractory to plasmapharesis or who
develop recurrence of disease require splenectomy.
17
Hereditary spherocytosis (HS) is an autosomal
dominant or recessive abnormality of erythrocytes
caused by mutations in membrane structural proteins.
These mutations lead to cytoskeletal instability that
results in altering the normal biconcave erythrocytes into
pathognomonic spherocytes that are osmotically fragile
and prone to rupture. Cells with these dysfunctional
proteins are degraded in the spleen leading to anaemia,
jaundice, and splenomegaly.
16
A common complication
of HS is cholelithiasis from pigmented stones.
Splenectomy is curative, and concurrent cholecystectomy
should be performed if indicated.
Other disorders of erythrocyte structure include
sickle cell anaemia and thalassaemia. Sickle cell
anaemia (SCA) is an autosomal recessive disease
caused by mutations in haemoglobin subunit betaglobin, which leads to reductions of the elasticity
of the protein under conditions of low oxygen
tension that result in deforming of the erythrocyte
into a sickle shape. A major feature of SCA is
painful episodes of sickle cell crisis complicated by
vaso-occlusive phenomena, aplastic or haemolytic
anaemia, as well as splenic sequestration. Splenic
sequestration can lead to hypersplenism and
ultimately splenic infarction. Treatments include
blood transfusion and hydoxycarbamide with
splenectomy for refractory cases.
18
Thalassaemias
are a group of genetic disorders that lead to abnormal
ratios or absence of haemoglobin subunits. Betathalassaemia results in an excess of alpha-globin that
forms insoluble tetramers that precipitate within
the erythrocyte interfering with erythropoiesis, cell
maturation and function, leading to anaemia. Alphathalassaemia results in an excess of beta-globin that
also forms tetramers, which, under conditions of
stress, precipitate leading to anaemia. Treatment of
thalassaemia includes blood transfusion and iron
chelation therapy.
19
Splenectomy is indicated in high
transfusion-dependent patients with hypersplenism.
Autoimmune haemolytic anaemia (AIHA) is a disorder
caused by antibodies directed against erythrocytes
leading to Fc or complement-mediated haemolysis in
the spleen. AIHA can be primary, idiopathic or secondary
to another underlying illness (lymphoproliferative
disorders and other autoimmune disorders) or drug
reactions. Treatment includes immunosuppressive
therapies (corticosteroids, rituximab, azathioprine) and
splenectomy in refrac tory cases.
Felty syndrome comprises a triad of rheumatoid
arthritis, splenomegaly and neutropenia.
Approximately 1–3% of all patients with rheumatoid
arthritis are affected by Felty syndrome. Increased
mortality is associated with recurrent infections due
to neutropenia secondary to decreased granulogenesis
and increased peripheral destruction of granulocytes.
Although the exact cause of Felty syndrome is
unknown, it is thought to be an autoimmune disorder
associated with HLA-DR4, rheumatoid factor and
antinuclear antibody. Neutropenia can be effectively
treated with disease-modifying anti-rheumatic drugs.
Splenectomy results in immediate improvement of
neutropenia in 80% of patients.
20
Neoplastic
A number of neoplasms may require splenectomy.
Traditionally, Hodgkin’s lymphoma was staged by
laparotomy and splenectomy, although this is no longer
routine. Haematological malignancies such as nonHodgkin’s lymphoma, hairy cell, chronic myelogenous
leukaemia and chronic lymphocytic leukaemia
may present with symptomatic splenomegaly and
pancytopenia that may require splenectomy in selected
patients. Primary splenic angiosarcoma is a rare and
aggressive malignant neoplasm arising from splenic
vascular endothelium. It is associated with a very
poor prognosis, and splenectomy is the only chance of
21
The most common primary sources of splenic
cure.
metastasis are breast, lung, colorectal, ovarian and
melanoma. Splenectomy may be indicated in the event
of oligometastatic disease. Although metastases to the
spleen are usually asymptomatic, they may occasionally
lead to splenomegaly or spontaneous rupture.
Infectious
Infectious diseases involving the spleen may
require splenectomy. Hydatid disease caused by
Ecchinococcus granulosus in the spleen has been
reported. Hydatidosis is treated with albendazole
and en bloc resection of the parasitic cysts.
Splenectomy must be performed without rupturing
the cyst to avoid disseminated disease and potential
anaphylactic reaction. Albendazole is an effective
adjuvant therapy in the treatment of hydatid cyst.
22
Bacterial splenic abscesses that are multiloculated,
not amenable to percutaneous drainage, or that
have failed to resolve with percutaneous drainage
and antibiotics may require splenectomy.
Splenectomy
Open
Open splenectomy can be performed with the patient
in the supine position with arms extended and using
a midline or left subcostal incision depending on the
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171