Hormones and the gut

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					                                          British Journal of Anaesthesia 85 (1): 58±68 (2000)

                                          Hormones and the gut
                                                         A. Holdcroft

              Imperial College School of Medicine, Hammersmith Hospital, London W12 0HS, UK

                Br J Anaesth 2000; 85: 58±68
                Keywords: hormones, glucagon; hormones, insulin; hormones, somatostatin; gastrointestinal
                tract; cancer; surgery

The heterogeneous hormones produced by the gastrointest-             or metastases also needs to be assessed in order to quantify
inal tract control digestion. They are secreted from cells that      organ dysfunction. For example, pancreatic endocrine
line the lumen of the gut, that is, in the mucosa as well as in      tumours secrete vasoactive substances, leading to haemo-
endocrine organs such as the pancreas. The major secretory           dynamic instability, and block the biliary system, resulting
and motor functions of the peptide hormones of the gut are           in obstructive jaundice. Recent developments in imaging
listed in Table 1. Gut hormones also regulate cell growth. A         technologies, such as the placement of biliary stents, hepatic
few peptides, such as substance P and pancreatic polypep-            artery embolization, radioisotopes of somatostatin for
tide, are recognized as gut hormones but their function is           precise imaging of tumour location by scintigraphy and
uncertain. However, they can be secreted by endocrine                medical therapies to restrict tumour growth with targeted
tumour cells and may be responsible for some of their                chemotherapy, enable improvements in organ function and
systemic manifestations.                                             symptomatic control to be achieved before anaesthesia and
   Signi®cant events in the discovery, localization and              allows surgical targets to be identi®ed in advance. Tumours
management of endocrine neoplasia from the gut are                   limited to one part of the gastrointestinal tract can poten-
summarized in Table 2.18 Initial reports came from biopsy            tially be completely removed by surgery and even palliative
or autopsy. Clinically de®ned syndromes followed. Then               surgery can provide an improved quality of life by reducing
radioimmunoassay methods were developed, which identi-               hormone secretion, thus potentiating the use of somatostatin
®ed gut hormones in 1961. Next, antagonists were                     analogues. If the tumour shows no somatostatin receptors on
synthesized and then markers for gut hormones and                    imaging, histological con®rmation of this can limit the side-
recently, in the 1990s, genetic screening for multiple               effects of somatostatin analogue therapies, which would
endocrine neoplasias (MEN) was developed.7                           otherwise be administered. However, not all patients have
    Endocrine tumours are described as either `non-func-             these types of tumours diagnosed before surgery.
tioning' or `functioning', depending on their endocrine              Anaesthetists should therefore be alert for the rare causes
secretory activity. Excessive hormone production can be              of bronchospasm, such as carcinoid tumours.
characterized by clinical syndromes. The two main
examples are Zollinger±Ellison and carcinoid syndromes.
Therapeutic advances through somatostatin analogues and              Multiple endocrine neoplasia
interferon a (IFNa) have enabled symptom control, though             Patients with MEN have two or more endocrinopathies.
with signi®cant side-effects. Identi®cation of genetic factors       This diagnosis may be dif®cult to make because the
associated with MEN will signi®cantly change clinical                endocrine presentations may occur at different times. In
practice for surgeons and anaesthetists. In the past these           a review of cases from Hammersmith Hospital, second-
tumours were usually diagnosed after patients presented              ary endocrine syndromes (particularly gastrinoma) oc-
with systemic manifestations. In the future, prophylactic            curred in 7% of 353 patients up to 10 years after
elective surgery combined with lifelong surveillance may be          diagnosis of the ®rst syndrome.54 This time interval has
required, perhaps at a young age, in order to prevent tumour         led to one of the main problems in the diagnosis of
occurrence.                                                          MEN.36 Another reason for a lack of recognition and
   The anaesthetic management of patients with abnormal-             understanding of the frequency of this condition has
ities of gut hormone function induced by such tumours                been in the availability of diagnostic tests. It is only in
broadly requires an assessment of endocrine dysfunction              the past 10 years that genetic screening has enabled
(which may complicate anaesthesia and drug therapies),               clinicians to distinguish between the MEN syndromes.
preferably with a standardized battery of tests for gut              These genetically linked lesions are found not only in
hormones. The spread of tumour growth by direct invasion             the endocrine pancreas, the thyroid, the parathyroid and

                    Ó The Board of Management and Trustees of the British Journal of Anaesthesia 2000
                                                                     Hormones and the gut

Table 1 Peptide hormones of the gastrointestinal tract. GIP=gastric inhibitory peptide (glucose insulinotrophic peptide); LOS=lower oesophageal sphincter;
VIP=vasoactive intestinal peptide. *Also occur as neurotransmitters in the plexuses of the gut

Hormone                         Produced by                                 Major function(s)

Gastrin                         Gastric antrum, duodenum                    Acid secretion, contraction of LOS, secretion of glucagon
Secretin                        Mucosa                                      Pancreatic secretion of water and electrolytes
Cholecystokinin*                Mucosa                                      Gall bladder and pancreatic secretion
GIP                             Mucosa                                      Inhibits gastric acid secretion
Motilin                         Mucosa                                      Contraction of LOS
Pancreatic polypeptide          Pancreas                                    Unknown
Peptide tyrosine                Mucosa                                      Decreases gastric acid secretion
Substance P*                    Mucosa, nerves                              Unknown
Neurotensin                     Mucosa                                      Delays gastric emptying
Somatostatin*                   Gastric antrum, pancreatic d cells          Endocrine/paracrine; inhibits secretion of gastrin, secretin, GIP, motilin, pancreatic
                                                                            polypeptide, pancreatic secretion, glucagon, insulin
VIP*                            Nerve cells, endocrine cells                Pancreatic secretion
Glucagon                        Pancreatic a cells                          Stimulates release of insulin and pancreatic somatostatin
Insulin                         Pancreatic b cells                          Anabolic hormone
Histamine                       Mast cells close to parietal cells          Attaches to H2 receptors and sensitizes cell to stimuli such as gastrin
Calcitonin                      Oesophageal tumour                          Not normally produced in the gastrointestinal tract

Table 2 Signi®cant events in the discovery of endocrine neoplasias from the gastrointestinal tract

Type of neoplasm         Date         Event

Carcinoid tumour         1888         Identi®ed at autopsy
                         1907         Oberndorfer introduced the term `carcinoid'
                         1954         Carcinoid syndrome described
Insulinoma               1927         First diagnosed at autopsy
                         1938         Whipple's triad
Gastrinoma               1955         Zollinger and Ellison ®rst described syndrome of recurrent peptic ulcers
                         1960         Gastrin identi®ed as the secretory product of the islet cell tumour in Zollinger±Ellison syndrome
VIPoma                   1958         Verner±Morrison syndrome described
                         1973         VIPoma identi®ed
Glucagonomas             1942         First described
MEN1                     1954         Wermer identi®ed familial occurrence (autosomal dominant) of tumours of pituitary, parathyroid and endocrine pancreas
                         1997         Discovery of multiple endocrine adenomatosis (MEA-1) gene

the pituitary organs but also in the adrenal and in the
intestine, particularly as submucosal duodenal carcinoid                           Pancreatic endocrine tumours
tumours. MEN2A (Sipple syndrome) is associated with                                The endocrine pancreas consists of the islets of Langerhans,
multifocal medullary thyroid cancer and occasional                                 which occur throughout the pancreatic tissue, particularly in
bilateral benign phaeochromocytomas. MEN2B (Gorlin                                 the tail of the pancreas. Within the islets, the a cells occur
or Steinert syndrome) is the rarest, probably because the                          external to the d cells while the b cells lie at the centre.
associated medullary thyroid cancer is most aggressive.                            Hormones from the islet cells are secreted into the blood
MEN1 (Wermer syndrome) is an autosomal dominant                                    stream but also diffuse locally within the islets. The
condition with the gene located on chromosome 11.                                  arrangement and functional interactions of these secretory
Only the pancreatic and duodenal tumours have a strong                             groups within the islets are not fully understood nor can all
tendency to malignancy. Tumours can be functional or                               the clinical manifestations of their secretory tumours be
non-functional; the relative occurrence is shown in Table                          associated with the limited number of hormones identi®ed at
3.20 Tumours can change the expression of peptide                                  present. The a cells, which comprise 20±25% of the islet
secretion and one hormonal secretion may replace                                   cells, secrete glucagon. The b cells occur with the highest
another. Gastrinomas are the most common functional                                frequency (60±80%) and secrete insulin. The d cells are the
pancreatic tumours in MEN1 and tumours should be                                   least common (10±15%) and secrete somatostatin. An
removed only after adequate control of gastric secretion                           unknown proportion of cells secrete pancreatic polypeptide.
by proton-pump inhibitors. Prophylactic pancreatectomy                             The islets are part of the amine precursor uptake and
for MEN1 is not currently indicated, neither is diagnos-                           decarboxylation (APUD) cell system, which takes up amine
tic laparoscopic surgery because lesions are multiple and                          precursors, decarboxylates them to form amines and
preoperative imaging techniques often require supple-                              synthesizes a variety of peptides.50
mentary identi®cation of tumours by manual palpation                                  Tumours of the pancreatic islet cells secrete one or more
and intra-operative ultrasonography.                                               hormones and are termed apudomas. These hormones can


Table 3 Clinical presentations of MEN 1, listed in order of frequency.        frequently, dysphagia presents secondary to oesophagitis. A
*Frequency of diagnoses: from screening (16%) to autopsy (100%)
                                                                              concentration of gastrin of >100 pg ml±1 in a fasting basal
Incidence    Location                                                         state is diagnostic of a gastrinoma. However, anything that
                                                                              decreases gastric acid production can lead to high circulat-
                                                                              ing concentrations of gastrin; this includes drug treatment
                                                                              with H2 receptor antagonists (such as cimetidine) and
                                                                              hydrogen ion (proton) pump blockers (such as omeprazole),
                                                                              as well as diseases such as pernicious anaemia. Thus, to
                                                                              prevent confusion, this type of drug treatment should be
                                                                              withdrawn before diagnostic tests for gastrinoma. If there is
                                                                              any uncertainty, provocative tests with calcium or secretin
                                                                              may be required.
                                                                                 Although medical treatment can control acid secretion,
                                                                              tumour excision for sporadic tumours has a high overall
                                                                              survival rate.34 The role of surgery in Zollinger±Ellison
                                                                              syndrome associated with MEN1 is less clear. Measurement
be ones that are normally secreted by the pancreas, or they                   of serum calcium concentrations and plasma parathyroid
can be non-pancreatic hormones, such as adrenocortico-                        hormone or pituitary hormone studies may con®rm the
trophic hormone. Approximately 75% of apudomas are                            diagnosis of MEN1. In the future, speci®c genetic screening
insulinomas (incidence of one to four cases per million                       may be required because of the difference in prognosis
people). About 20% of apudoma patients will have MEN1                         between sporadic and MEN1 gastrinomas.
and the pancreatic endocrine tumours listed in Table 3 in                        Preparation for surgery requires titration of the dose of
order of frequency, with, in addition, tumours of the                         proton-pump inhibitors, such as omeprazole or lansopra-
parathyroid, pituitary and rarely adrenal cortex.                             zole, to achieve normal basal gastric acid secretion. Oral
   Non-functioning neuroendocrine tumours of the pancreas                     medications are preferred rather than somatostatin, which
may be silent because they produce hormones without                           has to be administered subcutaneously. Antacid prophylaxis
speci®c clinical signs or because they produce peptides in                    with proton-pump inhibitors and H2 receptor antagonists
insigni®cant amounts, or none at all. They are large in size                  should be maintained until surgery. The possibility of
and vascular.5 Resection, even if incomplete, is often                        anaemia from bleeding gastric ulceration must be investi-
associated with prolonged survival and, since these tumours                   gated. A full coagulation screen and liver function tests are
respond poorly to chemotherapy, surgery is the treatment of                   required because alterations in fat absorption may in¯uence
choice.                                                                       clotting factors and hepatic function may be disturbed by
   Strategies to control tumour growth are required if the                    liver metastases. Immediately before and after operation,
tumour is growing quickly or if symptoms are severe. The                      intravenous ranitidine is useful to prevent gastric acid
number of ways of treating such tumours has increased                         hypersecretion from the hypertrophied acid-producing gas-
rapidly over the past decade. Tumour debulking makes                          tric mucosa. A nasogastric tube will be required periopera-
symptoms easier to manage and allows further treatment to                     tively; it should be placed and its position con®rmed at
reduce tumour mass by chemotherapy. Other therapies                           induction of anaesthesia. At exploratory laparotomy, further
include hepatic artery embolization, treatment with soma-                     localization of pancreatic or duodenal gastrinomas may be
tostatin analogues, IFNa, combination therapies with                          required using palpation, transillumination, ultrasound and
somatostatin and IFNa, or occasionally systemic chemo-                        endoscopy. These processes may increase the surgical
therapy or liver transplantation. The rarity and variety of                   exposure required to mobilize these structures and hence
endocrine syndromes have necessitated the development of                      may increase the duration of surgery. Anaesthetic planning
multicentre clinical trials in tertiary referral centres to                   should include preparations to reduce heat loss during
support evidence-based treatments.                                            prolonged surgery.

Gastrinoma                                                                    Insulinoma
Zollinger±Ellison syndrome was described as intractable,                      Tumours of the b cells of the pancreas secrete insulin;
painful, peptic ulcer disease that recurs after surgery unless                patients with such tumours present with episodic symptoms
total gastrectomy is performed. Duodenal, pancreatic or                       of fasting hypoglycaemia, such as dizziness, blurred vision,
rarely ovarian cystadenocarcinoma cells releasing gastrin                     confusion, irritability, tremors and occasionally coma.
cause the clinical syndrome. In the pancreas it is the d islet                Compensatory sympathetic mechanisms lead to sweating
cells which produce gastrin. Diarrhoea and steatorrhoea                       and tachycardia. The differential diagnosis is broad; the
leading to weight loss often occur as a result of excess acid                 causes of hypoglycaemia listed in Table 4 should be
production, which inactivates pancreatic enzymes. Less                        excluded, together with other aetiologies such as cerebro-

                                                             Hormones and the gut

Table 4 Causes of hypoglycaemia to be considered in the differential           coccus and Haemophilus in¯uenzae with Pneumovax and
diagnosis of insulinoma
                                                                               having blood cross-matched for transfusion. Prophylactic
Cause                               Example(s)                                 therapies include antibiotics and possibly somatostatin. In
                                                                               one of the largest studies of insulinomas, although no direct
Drug effects                        Ethanol, quinine and sulphonylureas
Enzyme de®ciencies                  Glycogen storage disease                   deaths were reported, complications of surgery included
Hormone de®ciency                   Addison's disease                          acute myocardial infarction, congestive cardiac failure and
Illness                             Sepsis and liver failure                   paroxysmal atrial tachycardia.13 Assessment of cardiac
Others                              Intense exercise
                                                                               function preoperatively and monitoring and maintenance of
                                                                               cardiac stability perioperatively are prerequisites for anaes-
                                                                               thetic care.
vascular disorders. About 8% of insulinomas are associated                        It is essential that close monitoring of glucose intake and
with MEN1. The diagnosis is made by `Whipple's triad':49                       blood glucose is started the evening before surgery and
(i) symptoms of hypoglycaemia; (ii) a low plasma glucose;                      continued throughout the perioperative period. During this
and (iii) relief of symptoms when glucose is administered                      period of starvation and at operation when the tumour is
and normal glucose levels restored. The diagnosis is made                      handled, glucose 50% solution should be available.
by a fasting plasma glucose of <2.2 mmol litre±1, increased                    Intravenous glucose with potassium should be infused and
insulin (>6 munits ml±1; >40 pmol litre±1), increased C-                       blood glucose, electrolytes and ¯uid input and output
peptide (>0.2 nmol ml±1) and an absence of sulphonylurea                       monitored at least hourly in order to avoid hypoglycaemia,
in the plasma.11 25 The high insulin and C-peptide                             water load and hyponatraemia. On tumour excision, a
                                                                               progressive increase in blood glucose has been described
concentrations con®rm the diagnosis. These two compounds
                                                                               within minutes. Repeated measures of blood glucose and
are formed in equimolar amounts by enzymatic cleavage of
                                                                               maintenance of normal values are more important than the
proinsulin. Measurable C-peptide therefore indicates an
                                                                               observation of rebound hyperglycaemia which used to be a
endogenous source of insulin, in contrast with the use of a
                                                                               marker of complete tumour resection.31
pharmaceutical preparation of insulin that may be used to
                                                                                  The choice of anaesthetic agents for removal of an
mimic the symptoms of an insulinoma.
                                                                               insulinoma has focused on their effects on blood glucose.
   Insulinomas are rare, mainly single, located in the
                                                                               Methoxy¯urane has been used4 because it tends to increase
pancreas and small in size (and thus sometimes dif®cult to
                                                                               blood glucose concentrations. More recently, sevo¯urane
locate); on enucleation, few recur. More radical surgery,
                                                                               has been recommended because it is considered to suppress
including hepatic resection, is required for malignancy in a
                                                                               the spontaneous release of insulin.29 However, the meta-
small number of patients. Medical therapies will be initiated                  bolic pro®le of iso¯urane should be considered an advan-
before surgery. Frequent meals can prevent symptoms.                           tage, particularly if liver blood ¯ow or liver function is
However, drugs that inhibit insulin release are not effective.                 disturbed. Another technique that has been reported not to
These include glucocorticoids, phenytoin and b-adrenergic                      interfere with blood glucose control is general anaesthesia,
blocking drugs. Somatostatin analogues have not been                           using propofol, combined with epidural analgesia.40
proven to be of value in reducing symptoms, perhaps                               Postoperative complications that may alter blood glucose
because octreotide may reduce glucagon in addition to                          homeostasis include diabetes mellitus as a result of pancre-
insulin secretion.                                                             atic insuf®ciency, acute pancreatitis and intra-abdominal
   Diazoxide is a non-diuretic benzothiazide which inhibits                    abscesses. Pancreatic ®stula is a serious complication
the release of insulin from secretory granules of b cells. It                  because it can lead to electrolyte imbalance and the need
may be a therapeutic option in preoperative preparation. Its                   for further surgery.
use is usually restricted to situations where surgery has
failed because it may not block secretion from abnormal
(i.e. non-b) cells. It can also suppress the release of                        Glucagonomas
glucagon and exacerbate symptoms. Besides its unpredict-                       The a cells of the pancreas release glucagon. The two
able ef®cacy, diazoxide also has serious dose-dependent                        clinical diagnostic features of glucagonomas are an
side-effects, causing oedema, sodium retention, hypoten-                       erythematous rash and diabetes mellitus. The rash, present-
sion, cardiac disturbances, weight gain and hirsutism.                         ing in the groin and perineum and then migrating to the
Verapamil, a calcium channel blocker, has been success-                        distal extremities, is known as necrotizing migratory
fully used in long-term therapy when surgery was refused.45                    erythema; it may be treated with zinc ointments.
   Although most tumours are enucleated, the head or tail of                   Stimulation of hepatic glycogenolysis and gluconeogenesis
the pancreas has to be exposed. Resection may sometimes                        results in the metabolic production of glucose and symp-
be required, especially with MEN1, where the head of the                       toms of diabetes mellitus. However, ketoacidosis is rare
pancreas often needs to be removed. The spleen is preserved                    because insulin concentrations are also increased. Tumours
whenever possible but splenectomy may be unavoidable.                          are associated with weight loss, glossitis, stomatitis,
Planning for this will include vaccination against meningo-                    anaemia (probably from bone marrow suppression), reduced


Table 5 The symptoms and signs of VIPomas and their main causes                     very rare. The mediator is vasoactive intestinal peptide
Symptom/sign                Cause(s)                                                (VIP), which should be measured accurately in order to
                                                                                    establish the diagnosis. VIP inhibits gastrin release.
Diarrhoea                   VIP stimulated                                          Pancreatic VIPomas are commonly located in the body
Hypokalaemia                Passive K+ loss in stool; active K+ secretion by
                            colon secondary to hyperaldosteronism                   and tail of the organ while extra-pancreatic VIPomas occur
Hypochlorhydria             Inhibition of gastric mucosal function                  in the autonomic nervous system. The rate of malignancy
Metabolic acidosis          Excess HCO3± loss                                       warrants resection because 40% of VIPomas are benign and
Flushing                    VIP vasodilation
Hyperglycaemia              VIP glycogenolysis (structurally similar to             the others are slow growing, commonly with liver
                            glucagon)                                               metastases. The tumours are vascular and are usually
Hypercalcaemia (tetany)     Hyperparathyroidism, acidosis                           localized on routine imaging. Care should be taken when
Hypomagnesaemia (tetany)    Loss in stool
                                                                                    injecting contrast media because VIP may be released.
                                                                                    Medical treatment includes somatostatin analogues, which
                                                                                    inhibit both VIP release and the secretion of water and
blood amino acid concentrations and diarrhoea. If the
                                                                                    electrolytes from the gastrointestinal tract.
cachexia is severe and the patient is malnourished, nutri-
                                                                                       The primary abnormality is dehydration from stimulation
tional support and supplements for several weeks before
                                                                                    of intestinal secretions with ¯uid losses (rich in potassium)
surgery should be given, otherwise infection and poor
                                                                                    of 3±10 litres day±1. The coexistence of VIPoma and
wound healing are likely to occur postoperatively.
                                                                                    gastrinoma in MEN1, both of which result in diarrhoea,
   A blood glucagon concentration of >50 pg ml±1 and a
                                                                                    should be checked by preoperative investigations and
demonstrable tumour are diagnostic of glucagonoma. The
                                                                                    tumour localization. VIP relaxes smooth muscle and dilates
increase in glucagon should be differentiated from the
                                                                                    splanchnic and peripheral vascular beds; it can induce
increases measured in prolonged fasting or renal and hepatic
                                                                                    hypotension from this mechanism as well as ¯uid losses
failure. The tumour may be primary, in an elderly popula-
                                                                                    from the circulating blood volume. In the past, patients have
tion, or associated with other syndromes such as Zollinger±
                                                                                    died because of a delay in diagnosis rather than from the
Ellison and MEN1 and present in younger patients. The
                                                                                    tumour itself. Resuscitation in a critical care facility has a
majority of patients have liver metastases at presentation.
                                                                                    vital role in the management of such patients. Replacement
Treatment is by debulking and somatostatin analogues,
                                                                                    of ¯uids with central venous pressure monitoring, electro-
which give rapid relief at ®rst but increased dosage may be
                                                                                    lytes (such as potassium and magnesium) and correction of
necessary later. There is an increased incidence of venous
                                                                                    acidosis is the initial step. Blood glucose should also be
thromboses in this disease and prophylactic antithrombotic
                                                                                    maintained carefully. Control of the diarrhoea will then
therapy is appropriate. Once the tumour is excised, symp-
                                                                                    enable surgery to be planned. A positive response to
tomatic relief is achieved.
                                                                                    somatostatin analogues is rapid, occurring within 24±48 h.
                                                                                    If somatostatin treatment fails, other therapies that can be
                                                                                    used include steroids such as methylprednisolone, indo-
                                                                                    methacin (a prostaglandin inhibitor) and metoclopramide.
Tumours of the d cells may release somatostatin and are                             Once cardiovascular stability is achieved, preoperative
often misdiagnosed as adenocarcinomas. Patients with such                           preparation must include H2 receptor blocking drugs to
tumours present commonly with obstructive biliary disease                           prevent rebound gastric acid hypersecretion.2
because many pancreatic tumours are large. Obstructive
jaundice should be relieved by stenting before surgery so
that complications, such as coagulopathies and post-
operative renal failure, are avoided. Other symptoms are                            Carcinoid tumours
usually mild. These include diabetes, from a reduction in                           Carcinoid tumours were ®rst described in 1888 at autopsy
insulin release, steatorrhoea from decreased pancreatic                             from multiple tumours in the distal ileum. They stain with
enzyme secretion and gallstones resulting from stasis within                        silver stains and contain markers of neuroendocrine tissue,
the gall bladder. Somatostatinomas can present in associ-                           such as chromogranin and synptophysin. Within the cells
ation with phaeochromocytomas and von Recklinghausen's                              there are numerous secretory granules containing hormones
disease in the MEN2 syndrome.                                                       and amines including serotonin, corticotrophin, histamine,
                                                                                    dopamine, substance P, neurotensin, prostaglandins and
                                                                                    kallikrein (an enzyme which generates kinins from kinino-
VIPoma                                                                              gen precursors, such as bradykinin and tachykinins). The
Verner±Morrison or WDHA (watery diarrhoea, hypokalae-                               tumours are no longer classi®ed according to origin (fore-,
mia, achlorhydria) syndrome is characterized by profuse                             mid- or hind-gut) but from their histology, site, function and
watery diarrhoea, intestinal ileus, abdominal distension,                           biological characteristics.3 They are commonly located not
confusion, drowsiness, hypokalaemia, achlorhydria, hypo-                            only in the gut (including the stomach, the appendix, the
magnesaemia, metabolic alkalosis and tetany (Table 5). It is                        ileum and rectum) but also in the bronchi and lungs.23

                                                       Hormones and the gut

   Carcinoid cells secrete a variety of amine and peptide              Airway maintenance during anaesthesia for these proced-
hormones, which may be identi®ed biochemically using a                 ures can be a challenge.21
standard battery of tests including high-pressure liquid                  Carcinoid syndrome occurs secondary to the systemic
chromatography for 5-hydroxyindole acetic acid (5-HIAA)                release of secretions either as a result of metastasis in the
and radioimmunoassay for glycogen, VIP, calcitonin,                    liver or from the lung. Bronchial carcinoids can liberate
gastrin, pancreatic peptide and insulin. Bronchial carcinoids          substances directly into the circulation. It has been postu-
can produce an excess of adrenocorticotrophic hormone and              lated23 that when a carcinoid tumour releases active
growth hormone-releasing factor and may present as                     substances into the portal vein, the liver destroys them
Cushing's syndrome or acromegaly. The secretory pattern                until either liver function deteriorates, or shunts between the
of gut tumours can change over time; an anaesthetist should            portal and hepatic veins, or metastases developed. Thus
be aware of this preoperatively in order to interpret                  general release of secretory products from the gastrointest-
investigations. Tumour location is identi®ed by non-speci®c            inal tract is usually prevented until the portal system is
investigations such as computerized tomography, magnetic               bypassed. Substances released by carcinoid tumours
resonance and ultrasound imaging; and somatostatin                     include: serotonin (5-hydroxytryptamine), which is synthe-
receptor scintigraphy or positron emission tomography                  sized from 5-hydroxytryptophan and metabolized to 5-
with 11C-labelled 5-hydroxytryptophan (the precursor of                HIAA, which can be measured in urine; histamine, which is
serotonin) are used for more speci®c localization.                     metabolized and excreted in the urine as tele-methylimida-
Symptomatic tumours are treated with surgery and drug                  zoleacetic acid; tachykinins, such as substance P, neuroki-
therapy. Further diagnostic tests with histology and                   nin A and neuropeptide K, which causes ¯ush and may be an
immunocytochemistry can determine the peptide pro®le of                early indicator of carcinoid disease;33 bradykinins; and
the tumour.                                                            prostaglandins. Table 6 lists these mediators, their clinical
   Gastric carcinoid tumours are divided into various types,           effects and management.28
which have different prognoses. Benign tumours arise from                 Skin manifestations were described in the original report
                                                                       of carcinoid syndrome43 with changing, patchy red and
mucosal cells that synthesize and store histamine. They
                                                                       cyanotic areas, plethoric in nature and ¯ushing of the face
occur as multiple tumours in the fundus or body of the
                                                                       and neck, exacerbated by hot food and spices. This
stomach and have been associated with 2±9% of patients
                                                                       eventually leads to enlarged veins and telangectasia with
with pernicious anaemia, and atrophic gastritis, situations in
                                                                       brown patches of hyperpigmentation on the face, wrist, back
which gastrin concentrations are high. Tumours associated
                                                                       and thighs, similar to pellagra. The pellagra-like signs have
with MEN1 have a higher rate of malignancy. Those
                                                                       been related to niacin de®ciency, because dietary trypto-
composed of a mixture of cell types are solitary and
                                                                       phan is converted into 5-HIAA and can be treated by
metastasize. They produce various hormones including
                                                                       replacement therapy. The ¯ush from pure histamine release
neuroendocrine and exocrine pancreatic secretions.                     differs from this, in that the face swells and lachrymation
   Small bowel carcinoid tumours grow slowly. They can                 occurs. Severe facial oedema has been reported during
present with bowel obstruction from mesenteric ®brotic                 anaesthesia but without airway dif®culty.26
stricture, carcinoid syndrome, gastrointestinal bleeding,                 Common features of carcinoid syndrome are diarrhoea,
diarrhoea and weight loss. Arterial or venous obstruction              from gastrointestinal hypermotility, and ¯ushing, but nei-
by the tumour can lead to abdominal pain (angina)                      ther usually requires resuscitative treatment. Diarrhoea may
precipitated by food. Since carcinoid tumours are the                  persist after surgery for resection of the terminal ileum
commonest small bowel neoplasms, any small bowel                       because of a loss of bile acids. Thus when the patient is
obstruction should alert an anaesthetist to consider this              assessed preoperatively for any complications of surgery,
diagnosis. The anaesthetist must prepare for emergency                 this secondary complication should be considered and long-
anaesthesia with precautions to prevent aspiration of                  term electrolyte abnormalities sought.
stomach contents. During surgery the tumour site should                   It is the respiratory and cardiovascular effects of
be observed (for bleeding or manipulations) and cardiovas-             carcinoid syndrome with which an anaesthetist should be
cular instability treated with therapies, such as octreotide.          familiar because of their severity. Bronchoconstriction,
Gross pathology may reveal a yellow nodule and frozen                  which presents as wheezing and paroxysmal coughing, can
section histology may con®rm the diagnosis.                            be life-threatening and requires prophylactic treatment.
   Bronchial carcinoid tumours can present as a mass,                  Dyspnoea may be present but an underlying cardiac
atelectasis, unilateral lung hyperin¯ation (from a ball-valve          problem should be considered in addition to bronchocon-
action) and with ®lling defects in the airways.32 When major           striction. Right ventricular failure, resulting from endocar-
airways are affected, ¯ow-volume and ventilation-perfusion             dial ®brosis, is a major cause of death in carcinoid
abnormalities can be detected. At thoracotomy, surgery may             syndrome. It is slow in onset and although cardiac oedema
be limited to a bronchial wedge resection or extend to a               is reported, underdiagnosis occurs in clinical practice.23
lobectomy, especially if suppuration has proceeded distal to           Echocardiography can con®rm the presence of right
the tumour or to a tracheal resection for tracheal obstruction.        ventricular dysfunction and tricuspid and pulmonary valve


Table 6 Clinical effects, mediators and treatment of carcinoid syndrome

Clinical effects                        Proposed mediators                        Treatment

Flushing                                Tachykinins (neurokinin A, substance      Somatostatin analogues (others: interferon a, glucocorticoids, phenothiazines,
                                        P, neuropeptide K)                        a-adrenergic block; avoid alcohol)
                                        Histamine                                 H1 and H2 receptor blocking drugs (chlorpheniramine, ranitidine, cimetidine)
                                        Vasoactive peptides (VIP)                 Somatostatin analogues
Hypotension                                                                       Check ¯uids; myocardial depressants, somatostatin analogues, angiotensin,
                                                                                  vasopressin, methoxamine, (epinephrine ± care!)
Diarrhoea                               Serotonin (5HT)                           Somatostatin analogues (others: parachlorphenylalanine, 5HT antagonists
                                        Prostaglandins E and F                    (cyproheptadine, methysergide, ondansetron), loperamide, interferon a)

                                        Bile acid loss                            Cholestyramine
                                        Bacterial contamination                   Doxycyclin
Abdominal cramps                        Small bowel obstruction                   Surgical decompression
(a) wheezing (bronchoconstriction)       Serotonin                                Somatostatin analogues, bronchodilators (care!); (b-adrenergic agonists,
                                         Substance P                              theophylline), chlorpheniramine, nebulized ipratropium bromide
(b) carcinoid heart disease              Growth factors, 5HT(?)                   Valvular replacement (tricuspid, pulmonary), diuretics
Skin lesions (pellagra-like)             Niacin de®ciency                         Nicotinamide
Palpitations (tachycardia, hypertension) Serotonin                                Somatostatin analogues, ketanserin, (others: labetolol, esmolol, increased depth
                                                                                  of anaesthesia)

lesions. These abnormalities are thought to result from the                       effectively inhibits kallikrein22 26 but clinically it is not
episodic circulatory crises associated with liberation of                         so effective.28 46 Antiserotonin antagonists, including non-
active substances from the tumour. 5-Hydroxytryptamine                            speci®c drugs, such as cyproheptadine41 and parachloro-
increases pulmonary artery pressure and intestinal peristal-                      phenylalanine,35 and more speci®c antagonists, such as
sis together with bronchoconstriction.47 Intravenous sub-                         ketanserin (a 5HT2 antagonist15 16 46) and ondansetron (a
stance P in humans causes ¯ushing, tachycardia and                                5HT3 antagonist), have been used to relieve symptoms.51
hypotension9 10 but is not considered to be the main active                       However, the approach based on antagonizing released
chemical responsible for carcinoid syndrome. Endocardial                          hormones has been largely superseded by a preference
®broelastosis has been linked to growth factors.48 Such                           to inhibit hormone release.38 Steroids have been used
activity is part of the function of gut hormones. Sclerosis                       successfully to block substance release but more speci®c
and partial fusion of cusps is the pathological result. It leads                  drugs based on somatostatin have been developed. Steroids
to tricuspid and pulmonary valve incompetence and stenosis                        may be indicated in asthmatic patients.46 Generally, it is
and may even recur in bioprosthetic valves39 used for valve                       only when these somatostatin analogues fail to reduce
replacement. Rarely, ascites and pleural effusion have been                       symptoms adequately that antagonists are used in medical
described. When considering anaesthetic monitoring, such                          treatment. However, H1 and H2 receptor antagonists may be
valve damage may predispose to endocarditis, so pulmonary                         considered for preoperative prophylaxis and during surgery;
artery catheter insertion may be contraindicated.                                 where there is the potential for release of large quantities of
   Left-sided heart disease has also been described.19                            hormones on tumour handling, judicious use of hormone
Carcinoid syndrome can therefore present as a critical crisis                     antagonists should be considered.
in addition to structural heart disease, with bronchoconstric-
tion, tachycardia and hypotension or hypertension leading to
cerebral hypoxia with confusion and coma. These acute                             Principles of management of gastrointestinal
cardiorespiratory events are most common during laparo-                           endocrine tumours
tomies and during or after embolization of liver metastases;                      Experience in managing the complex problems associated
in their differential diagnosis, acute anaphylaxis should be                      with these endocrine tumours is limited mainly to retro-
considered.1 Unfortunately, there is no predictor of                              spective reviews and case reports. Whenever possible,
cardiovascular instability, such as peptide concentrations,                       patients should be treated in tertiary centres with expertise
so vigilance and early intervention are advised.                                  in endocrine surgery, anaesthesia and perioperative critical
   Therapeutic management, as shown in Table 6, targets                           care.
symptoms or more speci®c mechanisms. Methylsergide in
the past was used as a non-selective vasoactive agent, but it
can cause ®brotic heart lesions. Codeine phosphate can be                         Somatostatin
used to treat the diarrhoea, but ¯uid, electrolyte and                            The development of synthetic somatostatin analogues, such
nutritional de®ciencies require replacement. Antibrady-                           as octreotide (Table 7), that are long-acting and inhibit
kinin agents, such as aprotonin, used to be administered                          hormone release rather than block their action has
acutely during carcinoid tumour surgery. In vitro, aprotinin                      revolutionized anaesthetic management, particularly for

                                                                   Hormones and the gut

Table 7 Characteristics of somatostatin and its analogues. *Slow intravenous injection

Characteristics                     Somatostatin                                                  Somatostatin analogues

Number of amino acids               14 or 28                                                      8
Half-life (min)                     <3                                                            80±140
Route of administration             Intravenous* (infusion)                                       Intravenous*, subcutaneous (Octreotide), intramuscular
Receptors activated                 High af®nity for all somatostatin receptor subtypes           distinct binding pro®les (limits diagnosis and therapeutic
Post-infusion rebound hyper-        yes                                                           no
Side effects (for both              Pain at injection site
somatostatin and somatostatin       Inhibition of hormone release (e.g. causing gallstones from
analogues)                            cholecystokinin release)
                                    Reduces motility (presents as ¯atulence, abdominal cramps,
                                    Blocks exocrine function (causes steatorrhoea by inhibiting
                                      pancreas secretion)
                                    Others (e.g. alopecia)

carcinoid, glucagonoma and VIPoma tumours. Somatostatin                           incisions and major tissue manipulations are to be expected,
binds to cell surface receptors, inhibits adenylyl cyclase and                    so the support of intensive care facilities and adequate
enhances potassium conductance, thus decreasing intracel-                         postoperative pain relief are priorities for surgical and
lular calcium ion availability and cellular secretion.44                          anaesthetic management.
Somatostatin analogues do not bind to all somatostatin                               Speci®c types of surgery may be required. The develop-
receptor subtypes; this limits their diagnostic and thera-                        ment of right-sided heart failure in carcinoid syndrome is an
peutic use. In addition, long-term ef®ciency may be reduced                       indication for tricuspid and pulmonary valve replacement.
by receptor down-regulation. Octreotide has to be given                           Signi®cant morbidity and mortality in older patients has
parenterally, for example as 100 mg subcutaneously every                          been described in valvular replacement in carcinoid syn-
8 h, or 100 mg h±1 during surgery. In an emergency a single                       drome.6 Haemodynamic instability can be the result of
dose of 50 mg i.v. before surgical manipulation may suf®ce                        endocrine secretion or treatment with somatostatin, which is
if no preoperative prophylaxis has been given. Another                            a negative inotrope.55 Treatment of hepatic metastases may
bene®cial preoperative effect of somatostatin is an indirect                      be surgical. However, hepatic artery ligature and devascu-
anti-angiogenesis activity that can reduce the size of                            larization have a high mortality and survival from hepatic
metastases. The success of such speci®c therapies has                             transplantation is disappointing. Occasionally, if metastases
enabled more aggressive surgery combined with medical                             are well localized to a lobe, cytoreductive surgery is an
treatments to improve survival rates.42 There is no evidence                      acceptable option. Selective hepatic artery embolization is
to support the postoperative use of octreotide to prevent                         preferred for symptom relief. The acute tumour lysis that
gastrointestinal complications,24 but it may have a role in                       follows can generate severe systemic dysfunction for which
maintaining cardiovascular stability.                                             intensive care management is the preferred option.
                                                                                  Abnormalities of liver function are common and accom-
                                                                                  panied by fever, nausea, vomiting (ileus) and abdominal
                                                                                  pain. Vasoactive peptides can be released and renal failure
Types of surgery
                                                                                  results from contrast load, ¯uid loss and cardiovascular
A broad spectrum of patients present for major gastro-                            disturbances such as hypotension. Prophylactic octreotide
intestinal and hepatic surgery.12 De®nitive resection of the                      and broad-spectrum antibiotics are essential and secondary
tumour is the primary aim in order to secure a potential cure.                    infection or infarction of gastrointestinal structures must be
Prophylactic cholecystectomy eliminates the possibility of                        excluded.
gallstones developing during future octreotide therapy. The
most common procedures for pancreatic endocrine tumours
are pancreatoduodenectomy, distal pancreatectomy and
enucleation; less commonly, resection of metastases is                            Anaesthesia
performed, often combined with medical and oncological                            Preoperative medical therapy with octreotide or a similar
therapies.37 Palliative surgery to debulk tumours or relieve                      somatostatin analogue will provide prophylaxis against the
obstruction may be planned as an elective or emergency                            risk of a carcinoid crisis. It may not prevent an overwhelm-
procedure. In the acute situation, time for preparation of                        ing release of bronchoconstrictors or vasoactive substances
patients with hormonally functioning tumours should be                            during handling of the tumour at surgery. Preparations for
considered essential for optimal care. Large abdominal                            anaesthesia, as summarized in Table 8, involve correction of


Table 8 Preoperative checklist for major pancreatic endocrine surgery


Medical syndromes
  Insulinoma                             Glucose, diazoxide
  Gastrinoma                             Proton-pump inhibitors and H2 receptor blockers preoperatively
  VIPoma                                 Somatostatin analogues
  Glucagonoma                            Somatostatin analogues
  Somatostatinoma                        Somatostatin analogues
  Carcinoid                              Somatostatin analogues, serotonin antagonists
Surgical diagnosis                       Localization, peptide secretion identi®ed
Stomach                                  Nasogastric tube sited at induction
  Emergency obstruction                  Preoperative nasogastric suction and drainage, rapid sequence induction
Large surgical exposure
  Blood loss                             Cross-match, coagulation screen, large-bore cannulae (e.g.13 G), central venous and arterial catheters with direct
                                         pressure monitoring, blood warmers and infusors (capacity 1 litre min±1)
   Potential hypothermia                 Active and passive warming, temperature monitoring (core and periphery)
   Pain                                  Epidural (thoracic) or patient-controlled analgesia, consent for
   Cardiorespiratory                     Facilities for positive end expiratory pressure, blood gases and acid±base measurements hourly perioperatively
System assessments
   Cardiovascular right (left) heart     Prepare for hypo- and hypertension, consider intra-arterial catheter before induction
   disease (carcinoid syndrome)          Echocardiogram, ECG
   anaemia                               Additional iron or transfusion
   bronchospasm (carcinoid)              Somatostatin analogues, steroids, ventilator characteristics
   dyspnoea                              Chest radiograph, echocardiography, blood gases
   coagulation                           Prothrombin time, thrombin time, activated partial thromboplastin time
   biliary obstruction                   Stent, ¯uids, maintain urine output with diuretics/dopamine
   albumin/proteins                      Nutritional assessment
   glucose                               Diabetic assessment and facilities for hourly blood glucose monitoring
   portal hypertension                   Expect increased blood loss
Renal/¯uids                              Normalize electrolytes, catheterize
Risk assessment                          Explain risks, record in patient's notes
Intensive care                           Booked admission
Medications                              Prophylaxis: antithrombosis (after epidural), antibiotics. Cautions in carcinoid: sedatives, drugs releasing histamine,
                                         e.g. morphine, thiopental, atracurium)

¯uid abnormalities and hypovolaemia, maximizing and                               histamine, serotonin or produce a catecholamine response,
quantifying cardiac and respiratory function with electro-                        such as ketamine,8 should be used with caution. For
cardiography, echocardiography, lung function tests and                           example, morphine can release histamine and is relatively
chest radiography, assessing liver function and clotting                          contraindicated during but not after surgery when the
abnormalities (particularly if there are liver metastases) and                    tumour has been removed. Fentanyl is a short-acting
minimizing any medical complication. Surgical assessment                          alternative. Catecholamines, such as epinephrine, can
should have de®ned the type of endocrine dysfunction and                          release serotonin and kallikrein, which activates bradyki-
the site of the tumour and predicted the magnitude of the                         nins. Theoretically, they should be avoided as vasopressors.
surgical intervention and the need for prophylactic im-                           Angiotensin is an alternative agent and can be given by
munization before splenectomy.53                                                  infusion. However, the demand to exclude the use of
  Major cardiovascular and respiratory crises are to be                           epinephrine in carcinoid syndrome was based on experience
expected if the neuroendocrine tumours are functional.                            before prophylaxis with somatostatin analogues and it has
These may be precipitated by induction of anaesthesia,                            been used with effect as an inotropic agent during
surgical manipulations or histamine-releasing drugs. In                           laparotomy and after cardiac surgery.14 27
anticipation of such events, anaesthetic preparation includes                        A review of anaesthetic drugs for carcinoid syndrome has
preoperative medication with anxiolytic and antihistamine                         suggested that the hypertensive response to intubation
drugs and direct monitoring of arterial and central venous                        should be prevented by using a short-acting opioid and
pressures before induction. Large-bore infusion sets should                       etomidate or propofol.47 Succinylcholine has been used
be available for administering warmed ¯uids and blood. A                          safely for rapid sequence induction although hormone
ventilation and breathing system which can accommodate                            release theoretically could be stimulated by fasciculations
high in¯ation pressures is also needed. The choice of                             increasing intra-abdominal pressure. Non-depolarizing neu-
anaesthetic and other drugs should be based on a consid-                          romuscular blocking drugs should be selected on the basis of
eration of the possible medical and surgical problems. The                        their lack of histamine release and ease of reversal.
aim is to maintain cardiovascular stability and not to induce                     Vecuronium is the drug of choice, although in hepatic
bronchospasm. Hence, drugs which are known to release                             failure, atracurium should be considered. Agents for main-

                                                     Hormones and the gut

tenance of anaesthesia primarily should be non-hepatoxic             dramatically improved medical and surgical management
and cardiostable. In addition, where high concentrations of          but have long-term side-effects. Future development of
serotonin can cause drowsiness, agents with a short                  drugs such as calcium channel blockers which act specif-
elimination time should be considered for safe postoperative         ically on gastrointestinal tissues may broaden therapeutic
recovery.28 The choice of regional anaesthesia, particularly         choices in hypersecretion syndromes. Genetic predispos-
in carcinoid syndrome, is controversial because treatment of         ition has identi®ed MEN1 with gastrinoma and MEN2 with
hypotension with catecholamines is contraindicated.17                somatostatin cell tumours. The multidisciplinary care from
However, epidural nerve blocks using incremental or                  surgeons, endocrinologists, gastroenterologists, anaesthe-
infusions of local anaesthetics without epinephrine have             tists, radiologists, pathologists and geneticists necessitates
been administered effectively in a number of patients. They          an agreed management plan in a tertiary centre because of
provide good pain relief to reduce the stress response and           the rare and varied nature of the disorders. Surgery is the
allow mobilization.30 47                                             only approach that can achieve a de®nitive cure. The role of
   Blood loss during surgery depends on speci®c pathology.           the anaesthetist in preoperative preparation, maintenance of
For example, carcinoid tumours induce an intense mesen-              perioperative homeostasis and postoperative high depend-
teric reaction which may not have a focal point of bleeding;         ency or intensive care is one of the main factors in securing
metastatic involvement of major vessels, such as the hepatic         a good prognosis. Future progress in anaesthesia and
and portal vessels, can lead to a blood loss of 1±2 litres           intensive care management to secure this prognosis requires
min±1; the large incision will ooze blood over time and if           a prospective multicentre clinical study to establish evi-
portal hypertension is present blood loss occurs from the            dence-based guidelines.
time of skin incision. These problems can be compounded if
there are coagulation abnormalities. Average blood loss is 2
litres.50 Blood loss can be assessed by weighing swabs and
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