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833
Letters
to use local anaesthetic spray to the throat. If
the patient requests sedation or if terrified a
titrated dose of midazolam is given. Endoscopy
without sedation is successfully practised by
my registrars and has the advantage that it is
possible to talk to the patients immediately
after the endoscopy, and they are allowed home
within the hour.
There have been no deaths or major injuries
on my unit relating to patients undergoing
upper gastrointestinal endoscopy since 1976. It
is my impression that, apart from patient
safety, instruments get damaged less. Keeping
the patient's conscious cooperation by sympathetically talking the instrument down also
protects the endoscope. Many of my patients
come back for several repeat endoscopies.
R D KINGSTON
Department of Clinical Studies,
Trafford General Hospital,
The statement that 'there is little doubt that
endoscopic stenting is the treatment of choice'
(for hilar lesions) is provocative. Some primary
bifurcation lesions are resectable' (a few even
prove to be benign), and I am not convinced
that percutaneous interventions are obsolete.'
The careful randomised study by Speer et al'
certainly showed endoscopic stenting to be
safer than percutaneous intervention at the
Middlesex and London Hospitals - but those
data have yet to be confirmed in other institutions. It may be that two expandable stents
placed percutaneously via small transhepatic
catheters would be more effective than one
placed endoscopically from below; stenting
both sides of a bifurcation lesion endoscopically is rarely possible. In addition, combined percutaneous-endoscopic manipulation
is often necessary in managing difficult problems, as the Middlesex group have reported.4
Davyhulme,
ManchesterM31 35L
PETER B COTTON
Division of Gastroenterology,
Duke University Medical Centre,
Box 3341, Durham
NC 27710, USA
SIR,-Mr Kingston and Drs Clark and Goy
suggest contrasting means of improving the
safety of endoscopy. While most would agree
that the option of not using sedation should be
considered more frequently, this option is
clearly not possible in all patients. Nevertheless, the avoidance of sedation when possible in
'at risk' patients, such as those with acute
gastrointestinal bleeding, should be encouraged.
From our experience the 'interventionist'
approach of intensive monitoring and oxygen
supplements is not yet likely to find favour
among most British gastroenterologists. These
interventions all have opportunity costs both in
resources and time and, until there is some
evidence of their being both effective and
appropriately applied to 'at risk' groups, then
recommendations as to their routine use seem
premature. Indeed, is there evidence that
patients having routine upper endoscopies with
supplementary oxygen suffer significant 0,
desaturation and would therefore also need
pulse oximetry?
The purpose of our survey was to make a
preliminary assessment as to whether an appreciable problem existed. Our survey suggests a
striking number of serious adverse outcomes
occur, and studies, sponsored by the British
Society of Gastroenterology, are now in progress to identify which patients are at risk and
the most useful interventions.
R F A LOGAN
T K DANESHMEND
Department of Public Health Medicine
andEpidemiology, University Hospital,
1 Cotton PB. Management of malignant bile duct
obstruction. J7ournal of Gastroenterology and
Hepatology 1990; 5: 63-77.
2 Boerma J. Research into the results of resection of
hilar bile duct cancer. Surgery 1990; 108: 572-80.
3 Speer AG, Cotton PB, Russell RCG, et al.
Randomised trial of endoscopic versus percutaneous stent insertion in malignant obstructive jaundice. Lancet 1987; i: 57-62.
4 Dowsett JF, Vaira D, Hatfield ARW, et al.
Endoscopic biliary therapy using the combined
percutaneous and endoscopic techniques.
Gastroenterology 1989; 86: 1180-6.
Reply
Queen's Medical Centre,
Nottingham NG7 2UH
Palliation of malignant obstructive jaundice
- surgery or stent?
SIR,-I would like to comment on Hatfield's
excellent brief leader (Gut 1990; 31: 1339-40).
Although he was reviewing methods for palliation, it might have been appropriate to mention
the frequent difficulty in proving that a patient
has an incurable lesion. Both histological
confirmation of malignancy, and irrefutable
evidence of unresectability, are sometimes
hard to obtain short of operation.' An argument in favour of surgical palliation is that
these doubts can be laid to rest; the morbidity
of surgery is very low if carefully selected
patients are managed by an expert surgeon and
perioperative team.
SIR,-We read with interest the leading article
in Gut (1990; 31: 1339-40) which discussed the
relevant merits of surgical bypass and endoscopic stenting for the palliation of malignant
biliary obstruction. While we would agree with
Dr Hatfield that endoscopic stenting achieves
good biliary decompression with a low procedure related mortality and morbidity, there
are several points in his article which cannot
remain unchallenged.
Firstly, we strongly contest the notion that
cholangiocarcinoma of the proximal common
bile duct or its confluence (Klatskin tumour)
should automatically be managed by stenting.
This tumour is characteristically slow growing
and often metastasizes late. Because of these
features surgical resection often produces good
longterm palliation and occasional cure. The
resection rate of hilar cholangiocarcinoma is
increasing worldwide with a corresponding fall
in morbidity and mortality when performed in
specialist units. ' A median survival of two years
is expected, and the five year survival in recent
series has reached a creditable 17%.' Quality of
survival for the vast majority of these patients is
excellent. Another serious consequence of
stenting high biliary strictures without exploratory surgery is that the diagnosis is not proved.
It has been shown that, despite sophisticated
imaging techniques, the diagnosis of Klatskin
tumour will be incorrect in up to 30% of cases.3
Immediate endoscopic stenting will therefore
lead to the mismanagement of both benign
biliary strictures and some highly curable
malignant lesions, such as papillary adenocarcinoma.
With regard to low bile duct obstruction due
to malignancy, two points need to be made.
Firstly, the best bypass procedure is a Rouxen-Y choledochojejunostomy, not the operations mentioned in Dr Hatfield's article. Moreover, the standard Whipple pancreaticoduodenectomy can be performed with an operative
mortality of less than 5%,4 and excellent
palliation accompanies this procedure. Five
year survival rates of 30% for cholangiocarcinoma and 15% for pancreatic cancer have
been reported.4 These results far exceed the
median survival of five months quoted from the
Middlesex trial.
In summary, endoscopic biliary stenting is a
new and exciting procedure for the palliation of
malignant biliary obstruction, but its exact role
has yet to be defined. We would agree with Dr
Hatfield that it is the treatment of choice for the
high risk surgical candidate and for patients
with obvious advanced malignant or metastatic
disease. Resectional surgery, however, remains
superior for achieving effective longterm
palliation, and appropriate patients at least
deserve the opinion of a specialist surgeon
before being referred for stenting. Medical
nihilism should be discouraged, and physicians
should remember that the decision to stent
limits the patient's survival to a few months.
Routine stenting, therefore, rests very uncomfortably with us.
A J RUSSELL
M REES
Hepatobiliary U'nit,
Basingstoke District Hospital,
Basingstoke,
Hants RG24 9.NA
Correspondence to: Mr M Rees.
1 Cameron JL, Pitt HA, Zinner NIJ, Kaufman SL,
Coleman J. Management of proximal cholangiocarcinomas by surgical resection and radiotherapy. AmJ7 Surg 1990; 159: 91-7.
2 Boerma EG. Research into the results of resection
of hilar bile duct cancer. Surgery 1990; 108: 57280.
3 Wetter LA, Pellegrini CA, Way LW. Differential
diagnosis of Klatskin tumours: preoperative
diagnosis is often incorrect [Abstract]. 3rd W'orld
Congress on Hepato-Pancreato-Biliany Surgeiy
1990; 2 (suppl): 119. London: HPB Surgery.
4 Michelassi F, Block GE. Improved results following radical operations for pancreatic adenocarcinoma [Abstract]. 3rd W'orld Congress on
Hepato-Pancreato-Biliary Surgery 1990: 2
(suppl): 46. London: HPB Surger.
Reply
SIR, -In response to the letters from Professor
Peter Cotton and Messrs Russell and Rees
concerning this leading article we would like to
comment with particular reference to hilar and
low bile duct strictures.
Hilar strictures
The evidence that cholangiocarcinoma is a
uniformly slow growing tumour is at variance
with our own experience' in a large group of
over 100 patients with Klatskin tumours in
whom the median survival is only 12 weeks. A
few patients have prolonged survival admittedly, but such patients survive with resective
surgery, radiotherapy, or stenting alone. While
we agree that specialist units are necessary, it is
important to note the median age of patients in
the above series was 75 vears, less than 15%
being under the age of 60 years. The goxo
results in Boerma's review could merely be due
to patient selection and age. Probably our
experience and referral pattern is different and
this is an excellent example of the widely
quoted 'apples and oranges' phenomenon described by Peter Cotton.:
We agree that diagnosis can be difficult, but
spontaneous benign strictures in this region are
extremely rare and papillary lesions are easily
distinguished by their different radiological
appearance. Our policy is to attempt to obtain a
histological diagnosis in those patients where
endoscopic retrograde cholangiopancreato-
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Letters. Book reviews
834
graphic brush cytology has proved negative by
using a fine spring-loaded Tru-cut needle
Biopty gun (Biopty TM, Radiplast, Uppsala),
percutaneously under ultrasound guidance.
The use of self expanding metal stents was
alluded to in the leading article, and a primary
indication would be those patients with nonresectable hilar cholangiocarcinoma in whom
good survival might be expected. There is no
evidence that the optimum route of insertion
for these metal stents is via the transhepatic
route, and there are many advantages in
placing metal stents endoscopically.
Low strictures
Messrs Russell and Rees failed to reference
Roux en Y choledochojejunostomy as the
preferred procedure for biliary drainage, for
there is none except surgical history. In fact,
conventional choledochoduodenostomy is an
adequate bypass and this has the added advantage of easing endoscopic procedures later if
nodes or tumour growth around the porta
hepatis occlude the bile duct.
We agree that there are a few figures
suggesting an improved survival after radical
resection, but numbers are small and very few
centres achieve a 5% mortality, and cures are
rare. The improved survival may merely in-
dicate the improved selection.
We agree with Professor Cotton that difficulties do arise in the management of a few
patients for whom resective surgery may be the
correct approach. The patients are best cared
for in a unit which has a specialist team of
interventional endoscopists, radiologists, and a
pancreatobility surgeon.
In the article routine stenting was not
advocated; in fact, it was clearly pointed out
that clinicians now have to take a mature
approach in their decision making, and have to
balance the patient's condition and likelihood
of survival before deciding on a surgical or an
endoscopic approach to palliation. Clearly,
there are going to be some patients who look fit
and well, and in whom some form of surgical
palliation may be appropriate to reduce the
need for admissions, which would be necessary
in the patient stented endoscopically. At the
other end of the spectrum there are those
patients over the age of 70 years in whom a
simple stenting procedure seems a very suitable
alternative to any form of surgical palliation,
particularly, when we know that most patients
die jaundice free with their original stent in
situ.
A R W HATFIELD
R C G RUSSELL
Department of Gastroenterology,
Middlesex Hospital,
London WIN8AA
1 Polydorou AA, Cairns SR, Dowsett JF, et al.
Palliation of proximal malignant biliary obstruction by endoscopic endoprosthesis insertion.
Gut 1991, 32: 685-9.
2 Cotton PB. Endoscopic management of bile duct
stones: (apples and oranges). Gut 1984; 25: 58797.
Ultrastructural demonstration of histamine
in human enterochromaffin like celi granules
SIR,-We read with great interest the paper by
Lonroth et al.' By using imnmunohistochemical
methods in light microscopy in normal volunteers, the authors showed that in addition to
mast cells some gastric endocrine cells contained histamine. These cells were located
exclusively in the fundus, constituted 44% of
the total number of endocrine cells in the
oxyntic mucosa, and stored neither 5 hydroxy-
M VIVARIO
E LOUIS
P GAST
J BONIVER
Department of Gastroenterology and
Department of Pathologic Anatomy,
University ofLtige,
CHU Sart Timan B-4000 Liege,
J DELWAIDE
J BELAICHE
R COURTOY
100
nm
_
.
Ultrastructural histamine demonstration in
enterochromaffin like cell secretory granules on
human fundus biopsy section. The 5 nm gold
particles are located in the electron dense granules
and inside a typical vacuolated granule (original
magnification x60,1O0).
tryptamine nor somatostatin. These endocrine
cells were supposed to be enterochromaffin like
cells.
To study this hypothesis, we tried to demonstrate histamine (HA) in the enterochromaffin
like cells by an immunocytochemical method
in electron microscopy. Ultrastructural
analysis of fundic sections, indeed, allow
enterochromaffin like cells to be distinguished,
with their typical secretory granules, from the
other gastric endocrine cells.2 This study was
done in a patient with pernicious anaemia,
hypergastrinaemia (>1000 pg/ml), and micronodular hyperplasia of argyrophilic cells (Grimelius argyrophil technique). Fundic mucosal
biopsy specimens were obtained during gastroscopy, fixed in 4% glutaraldehyde in phosphate
buffer at 20°C, dehydrated in ethanol, and
embedded in Epon 812. Ultrathin sections
were cut and mounted on gold grids. They
were incubated for four hours in 1/200 diluted
polyclonal guinea pig anti-HA antibodies (Peninsula ref 61069) at room temperature and
rinsed in phosphate buffer and in distilled
water. The grids were then incubated for one
hour in a 5 nm gold particle conjugated
antiguinea pig immunoglobulin (Biocell
EMGAG5), 1/20 diluted in phosphate buffer
solution. Finally, the grids were rinsed in
water, dried, and contrasted with uranyl acetate in ethanol.
The efficiency and the specificity of the
immunocytochemical reaction were first
checked on rat peritoneal mast cell (PMC)
sections. Normal rat PMC granules were
shown to contain HA while, after in vitro
incubation in a poly-L-lysine (secretagogue)
solution,3 the PMC granules no longer contained HA.
In the human biopsy sections few mast cells
were present around the gland. They were
shown to contain HA in their uniformly
electron dense granules. The enterochromaffin
like cells were identified ultrastructurally.
Most of these cells contained granules positively marked by the anti-HA immunocytochemical reaction (Figure). This reaction was
reproduced several times on many sections of
the same biopsy specimen with concordant
results. The control sections were incubated
either with anti-HA neutralised by HA
followed by the immunogold reaction, or with
immunogold reagent alone. They were both
negative except a light aspecific background.
The results of this study are in agreement
with Lonroth's conclusions: the histaminecontaining endocrine cells ofthe human fundus
are enterochromaffin like cells. The role of
these cells in the physiology of histamine
mediated acid secretion should be explored.
Further studies should determiine if the cell
granules release histamine under the influence
of gastrin.
Belgium
Correspondence to: Dr Jean Delwaide.
1 Lonroth H, Hakanson R, Lundell L, Sundler F.
Histamine containing endocrine cells in the
human stomach. Gut 1990; 31: 383-8.
2 Hakanson R, Bottcher G, Sundler F, Vallgreen S.
Activation and hyperplasia of gastrin and
enterochromaffin-like cells in the stomach.
Digestion 1986; 35 (suppl 1): 23-41.
3 Courtoy R, Boniver J, Simar LJ. Cytochemistry of
mouse mast cell reaction to polylysine. Histochemtistry 1980; 66: 49-58.
Reply
SIR,-Dr Delwaide and colleagues have with
this report further confirmed that the enterochromaffin like cells of the human fundus
indeed contain histamine. In the human gastric
mucosa these cells are confined to the oxyntic
gland area, which also presents a higher
histidine decarboxylase activity than the nonacid producing pyloric gland region.' Patients
with hypergastrinaemia of different origin also
have a higher histidine decarboxylase activity
together with an increased density of enterochromaffin like cells in the oxyntic gland
area.2' In addition, pentagastrin infusion is
followed by a release of histamine and by a
substantial increase in histidine decarboxylase
activity in the oxyntic gland mucosa of healthy
volunteers. These penragastrin induced events
do not occur in the pyloric gland region.4
In conclusion, all this circumstantial
evidence together with the results presented by
Dr Delwaide and colleagues favour the view
that the enterochromaffin like cells of the
human stomach store histamine, release the
amine on proper stimulation, and have the
capacity to synthesise histamine.
H LONROTH
University of Goteborg,
Department ofSurgery II,
S-413 45 Goteborg, Sweden
1 Lonroth H, Lundell L, Rosengren E. Histamine
metabolism of the human stomach - a study on
the regional distribution of the amine and
enzyme activities. ScandJ Clin Lab Invest 1989;
49: 23-31.
2 Cattan D, Roucayrol AM, Launay JM, Callebert J,
Charasz N, Nurit Y, et al. Circulating gastrin,
endocrine cells, histamine content and histidine
decarboxylase activity in atrophic gastritis.
Gastroenterology 1989; 907: 586-96.
3 Bordi C, Cocconi G, Togni R, Vezzadini P, Missalo
G. Gastric endocrine cell proliferation; association with Zollinger Ellison syndrome. Arch
Pathol 1974; 98: 274-8.
4 Ldnroth H, Lundell L, Rosengren E, Olbe L.
Histamine metabolism of the human gastric
mucosa - effect of pentagastrin stimulation.
Gastroenterology 1990; 98: 921-8.
BOOK
REVIEWS
Textbook of secretory diarrhea. By Emanuel
Lebenthal and Michael E Duffey. (Pp 456;
illustrated; $132.) New York: Raven Press,
1990.
Although secretory diarrhoea is not everyone's
cup of tea, I approached this book with some
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Reply
A R W Hatfield and R C G Russell
Gut 1991 32: 833-834
doi: 10.1136/gut.32.7.833-c
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