The British Society of Gastroenterology - GutGut, 1972,13, 836-857 TheBritish Society...

Gut, 1972, 13, 836-857

The British Society of Gastroenterology

The 33rd annual general meeting of the British Society of Gastroenterology was held at Aviemore,Inverness-shire from 28 to 30 September 1972 under the Presidency of Professor W. I. Card. Theprogramme included a very large number of communications of which the abstracts follow, andsymposia on 'A new look at gastritis' and 'Gastrooesophageal reflux and its complications'. TheSir Arthur Hurst Memorial Lecture on 'Gut hormones-milestones and signposts' was given byMorton I. Grossman. A general report and a note on the annual business meeting, which wasattended by honorary, senior, and ordinary members, is on page 858.

Hepatic Damage from Overdose of Paracetamol

R. P. H. THOMPSON, R. CLARK, R. A. WILLSON, V.BORIRAKCHANYAVAT, B. WIDDOP, R. GOULDING, andR. WILLIAMS (Liver Unit, King's College Hospital andPoisons Unit, Guy's Hospital, London) The in-creasing use of paracetamol as an analgesic has beenfollowed by an increased incidence of overdoses.We have seen 46 patients during two years; 42 whotook more than 13 g developed liver damage, and14 died in hepatic failure. The prothrombin ratioand bilirubin level usually became abnormal within24 hours, but peak levels were not reached untilthree to six days. An unusual finding was an initialunconjugated hyperbilirubinaemia. Hepatic his-tology at four to 26 days showed centrilobularreticulin collapse, congestion, and necrosis ofvarying extent, but with considerable recovery atthree months, except in one in whom considerablefibrosis persisted. Coagulation tests were improved byintensive therapy with heparin and fresh-frozenplasma, and their effect is being assessed in a con-trolled trial.A new approach to therapy was studied in pigs.

Paracetamol administered to hepatectomized animalswas completely cleared from the blood when passedin vivo through a column of activated charcoal. Thismay be an easy and effective method for removingthis drug if the patient is seen early.

Factors Influencing Human Gallstone Dissolution inMonkey, Dog, and Human Bile

G. D. BELL, D. JUNE SUTOR, B. WHITNEY, AND R.DOWLING (Departments of Medicine and Radio-diagnosis, Royal Postgraduate Medical School.Ducane Road, London W12, and CrystallographyUnit, Department of Chemistry, University College,London) The influence of bile composition and of

size and cholesterol and calcium content of gall-stones on rates of dissolution has been studied invitro and in vivo.

Selected human gallstones, removed at surgery,were analysed chemically and by x-ray diffractionand then exposed to flowing bile of rhesus monkeyswith an intact enterohepatic circulation'. Rapidgallstone dissolution was associated with (1) highgallstone cholesterol content; (2) bile undersaturatedwith cholesterol; (3) high surface area: weight ratio.

In vitro studies with dog bile showed that thepresence of a radioopaque outer rim of calciumdelayed gallstone dissolution.Of 10 gallstone patients treated with chenodeoxy-

cholic acid (0'75-1 5 g/day for three months)cholesterol solubility improved in nine. After sixmonths' treatment, of two patients with radiolucentgallstones, complete gallstone dissolution occurredin one, and a significant reduction in stone size inthe second.

Reference

'Dowling, R. H., Mack, E., Picott, J., Berger, J., and Small, D. M.(1968). J. Lab. clin. Med., 72, 169-176.

Malignancy in Relatives of Patients with AdultCoeliac Disease

P. L. STOKES, P. ASQUITH, J. H. WATERHOUSE, AND

W. T. COOKE (The General Hospital, Birmingham, B46NH) Previous reports have shown that patientswith adult coeliac disease have an increased incidenceof malignancy especially of lymphoma and cancer ofthe gastrointestinal tract'. As adult coeliac diseasefrequently occurs in more than one member of afamily it seemed appropriate to examine the familiesof patients with this disease to assess the incidenceof malignancy.A family history was obtained from 80 patients

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The British Society of Gastroenterology 837

with well documented adult coeliac disease. Dataobtained by questionnaire were later confirmed ineach case during a personal interview. Particularattention was paid to the causes of death of relativeswith recourse to death certificates where possible,and to the Birmingham Regional Cancer Registryfor confirmation of cancer and other deaths. Thedeath of any family member was not included foranalysis if the cause of death, age at death, or year ofdeath were not definitely known.From this information years-at-risk were obtained

for all relatives and deaths from cancer and othercauses noted. Computer programmes have beendeveloped to provide the expected numbers of deathsfrom cancer of all sites and within each degree ofrelationship using the mortality rates of the Registrar-General2. Preliminary results show that the numbersof deaths from cancer in first degree relatives of thepropositi are greater than expected (p = 0 01) andfurther analysis is continuing.The significance of these findings is discussed with

emphasis upon the inheritance of the disorder and thepredisposition to malignancy.References

1Harris, 0. D., Cooke, W. T., Thomson, H., and Waterhouse, J. H.(1967). Malignancy in adult coeliac disease and idiopathicsteatorrhoea. Amer. J. Med., 42, 899-912.

2Cancer Statistics for England and Wales 1901-1955. General RegisterOffice.

Essential Fatty Acid Deficiency Secondary to IntestinalMalabsorption

M. PRESS, H. KIKUCHI, AND G. R. THOMPSON (Depart-ment of Medicine, Royal Postgraduate MedicalSchool, London) Malabsorption of essential fattyacids (EFA) must inevitably lead to EFA depletionsince inadequate intake cannot be overcome by anincreased rate of synthesis, as occurs with non-essential fatty acids. This paper reports an in-vestigation into the fatty acid pattern of plasmalipids in a group of patients with steatorrhoea.The fatty acid composition of lecithin, tri-

glyceride, and cholesterol ester in fasting plasma wasdetermined by GLC. The percentage of linoleic acid(18:2) in each of these fractions was significantlylower in 23 malabsorbers (15, 8, and 30%) than in 14controls (27, 17, and 49 %, p < 001). These changes.indicative of EFA depletion, were more severe inpatients who had undergone intestinal resectionthan in those with malabsorption due to adultcoeliac disease or other causes, even though thefaecal fat excretion of the three groups was similar.The classical picture of EFA deficiency, character-ized by the appearance of an abnormal fatty acid

(20: 3 w 9) in plasma lecithin, was found in only threepatients, all of whom had undergone intestinalresection. This was successfully treated by theintravenous administration of Intralipid.The reason why resected patients are so prone to

EFA deficiency is uncertain, but these observationsmay have clinical implications. EFA deficiency causesdiarrhoea and dermatitis in human infants andgallstones in hamsters: its possible role should beconsidered in the pathogenesis of the waterydiarrhoea and increased incidence of gallstonesfound after intestinal resection in man.

Effects of Cholecystokinin on Colonic Motility andSymptoms in Patients with the Irritable Bowel Syn-drome

R. F. HARVEY AND A. E. READ (Department ofMedicine,Royal Infirmary, Bristol) It has been shown thatmany patients with 'functional' food-induced painhave an abnormally marked colonic motor responseto eating' and this may be important in the pro-duction oftheir symptoms2. Little, however, is knownof the mechanisms involved in this response.The effect of intravenous administration of

cholecystokinin (CCK) on motor activity of thesigmoid colon was studied in 20 patients withabdominal pain believed to be due to the irritablebowel syndrome. Intraluminal pressure changeswere recorded on a Devices M19 recorder, usingminiature balloons3 placed 20-25 cm from theanus. After placing of the balloons, the patientsrested quietly for at least 60 minutes, and were thengiven a slow intravenous injection of normalsaline. Following this, motility was recorded for 30minutes. CCK (6 CHR units/g/hour) was then givenover a 10-minute period and motility recorded for afurther 30 minutes. Motor activity during these two30-minute periods was compared by measuring thepercentage duration of pressure waves, their meanamplitude, and a motility index (multiple of theother two indices).

All three parameters of motor activity increasedafter CCK administration (% activity 22-2 to 33 7,P<0-025; mean amplitude 9-0 to 11 1 cm H20,NS; motility index 244 to 397, 0 05<P<010) butthese increases were almost entirely confined topatients whose pain was usually precipitated byeating. In this group of eight patients the changeswere much greater (13-7 to 41-3%, P<0 001; 4 9 to12-3 cm H20, p<0-02; 71 to 497, p<0-02), and fourof these eight patients developed a severe attack oftheir usual pain after CCK administration, at a timewhen markedly increased motor activity was seen.These results suggest that the abnormally increased

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838 The British Society of Gastroenterology

postprandial colonic motor response in patients with'functional' food-induced pain may be mediated bycholecystokinin.

References

'Connell, A. M., Avery Jones, F., and Rowlands, E. N. (1965).Motility of the pelvic colon. IV. Abdominal pain associatedwith colonic hypermotility after meals. Gut, 6, 105-112.

sH{oldstock, D. J., Misiewicz, J. J., and Waller, S. L. (1969). Observa-tions on the mechanism of abdominal pain. Gut, 10, 19-31.

'Atkinson, M., Edwards, D. A. W., Honour, A. J., and Rowlands,E. N. (1957). Comparison of cardiac and pyloric sphincters. Amanometric study. Lancet, 2, 918-922.

An Animal Model for Diverticular Disease

J. HODGSON (introduced by B. N. BROOKE) (St.Georges Hospital, Tooting, SW17) An animalmodel using rabbits has been devised (Hodgson,1972). After intracolonic activity before and afterneostigmine was measured, eight rabbits continuedon normal pellet diet and eight rabbits were put on apseudo-human diet of white bread, butter, milk, andsugar supplemented by Complan. Four months laterpressures were measured again.

Pressures fell in the normal rabbits but rose inthose on the special diet. The mean pre-dietaryresting colonic motility index (CMI) of 147 rose to1,287 (p< 0-05). After neostigmine the mean pre-dietary CMI rose from 8, 153 to 27, 569 (p < 00025).Normal mean daily faecal weight was 80 g; on

the special diet it was 3 g. Normal transit time was24 hours; on the special diet it was 48 hours.Neostigmine caused the regular occurrence of

temporary intertaenial diverticula in the contractedcolon of the special diet rabbits similar to thosedemonstrated by Painter (1962) in humans.

It is suggested that the colon, fixed only by thetaeniae, can contract onto itself or contained faeces.In low residue states, contraction continues for alonger period than normal and may become per-manent (Williams, 1965). More force is exerted by thehypertrophied muscle on a low faecal colume and,such increased pressure would eventually lead to theformation of diverticula.References

Hodgson, J. (1972). Brit. J. Surg., 59, 315.Painter, N. S. (1962). M.S. thesis, London.Williams, I. (1965). Brit. J. Radiol., 38, 437-443.

Study of Carcinoembryonic Antigen (CEA) inGastrointestinal Cancers

A. K. SINGH (introduced by B. CREAMER) (St. Thomas'sHospital, Department ofHaematology, London) Thediscovery of a tumour specific antigen, demonstra-

tion of its presence in the plasma of patients withgastrointestinal cancers, and the subsequent develop-ment of a quantitative measurement of the CEA inplasma has given rise to considerable optimism aboutthe availability of a simple technique likely to beuseful in the diagnosis and the assessment of treat-ment of gastrointestinal cancers. The present studywas carried out to evaluate the role of CEA in thediagnosis of gastrointestinal cancers and examineits importance in assessing the efficacy of therapyand evaluate its possible function in early detectionof recurrence of the disease. Plasma CEA levels weremeasured in a radioimmune assay system in normalsubjects, patients with gastrointestinal cancers, andin related disorders. The findings show that CEAlevel is raised in the majority of patients with GIcancer and, thus, appears to be a useful diagnosticadjunct. It is, nevertheless, also shown that normallevels of plasma CEA do not exclude the presence ofa malignant tumour of the gastrointestinal tract.Raised levels of plasma CEA were also found incertain liver diseases and megaloblastic and irondeficiency anaemias in the absence of a demonstrablemalignancy of the GI tract. Considerably elevatedCEA-like activity has also been observed in ap-parently normal gastric juice.The physico-chemical nature of the CEA has been

examined. Column chromatography has shown thepresence of CEA activity in more than one fractionwhich appear to differ in their molecular size;similar studies have been carried out on gastricjuice and plasma. Additional observations haveshown an immunological resemblance between theCEA and blood group substances. It is likely thatCEA may represent an incomplete or atypicalblood-group substance-like product of the malignanttissues.

In view of these findings the values and limitationsof the routine measurements of CEA level inpatients with gastrointestinal disorders will bediscussed.

Immunoglobulin Measurements in Jejunal Secretionsof Patients with Adult Coeliac Disease and Derma-titis Herpetiformis

D. B. L. MCCLELLAND, R. R. SAMSON, R. C. HEADING,R. St.C. BARNETSON, AND D. J. C. SHEARMAN (Gastro-intestinal Section of the University Department ofTherapeutics and the University Department ofDermatology, Royal Infirmary, Edinburgh) Jejunalimmunoglobulin levels have been studied in normals(17), adult coeliac disease (8) and dermatitis herpeti-formis (15) by immunodiffusion methods. Immuno-globulin levels in controls were similar to those

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already published (Douglas, Crabbe, and Hobbs,1970). In adult coeliac disease (ACD) and dermatitisherpetiformis (DH), IgA levels were very high andusually exceeded 30 mg/100ml in ACD and 50mg/100ml in DH. In five patients with DH, IgAlevels exceeded 100 mg/100 ml. In both ACD andDH, IgG levels were very low but IgM levels wereraised in DH.

Since the IgA levels in ACD and DH were muchhigher than previously reported, studies were carriedout to confirm the validity of the immunodiffusionmethod for jejunal IgA. There was no interferencefrom trypsin complexes (McClelland, Parkin,Samson, and Shearman, 1972). Although trypticdigestion may lead to an apparent increase in IgGlevels, it did not affect secretory IgA levels. Inaddition, the molecular weight distribution of IgAin jejunal aspirate has been studied by Agarosefiltration and density gradient ultracentrifugation.

It is concluded that the method used for themeasurement of jejunal IgA levels is valid and thatvery high levels of IgA occur in the jejunum indermatitis herpetiformis as well as in adult coeliacdisease.

References

Douglas, A. P., Crabbe, P. A., and Hobbs, J. R. (1970). Gastro-enterology, 59, 414.

McClelland, D. B. L., Parkin, D. M., Samson, R. R., and Shearman,D. J. C. (1972). Gastroenterology, 62, 693.

The Association between the Large Lymphocyte andthe Small Intestine

A. R. MOORE AND J. G. HALL (introduced by J. C.GOLIGHER) (University Department of Surgery, TheGeneral Infirmary, Leeds) It has been shown thatabout 30% of the large lymphocytes (immuno-blasts) that appear in the thoracic duct of rats, afterantigenic stimulation of their foot pads, 'home' tothe lamina propria of the small intestine1' 2.We have studied the entry of immunoblasts into

'free' grafts of syngeneic foetal small and largeintestine implanted subcutaneously as described byZinzar et a13, and also the entry of xenogeneicimmunoblasts into normally situated small in-testine.

Histological studies show that implanted foetalintestine grows with a perfectly preserved structure.

After intravenous injection of 5-IODO-2 dexoyuri-dine labelled immunoblasts, the specific radioactivityof the 14 implants of foetal small intestine (corre-sponding to the number oflabelled immunoblasts perunit length of small intestine) averaged 75% (SE6 5) of the normal adult in situ small intestine.

Therefore although the foetal small intestine wasisolated from the normal anatomical and en-

vironmental influences it received a similar share ofimmunoblasts.Although the entry of xenogeneic immunoblasts

into the small intestine was somewhat less than entryof syngeneic cells the Dhenomenon was qualitativelysimilar. The localization of radioactivity in immuno-blasts in intestinal tissues was confirmed withautoradiographs.The possible importance of this primary asso-

ciation between the large lymphocyte and thelamina propria of the small intestine is discussed inrelation to the immune defences of the smallintestine and the diseases of this organ.

References

'Gowans, J. L., and Knight, E. J. (1964). Proc. roy. Soc. B., 159,257.

2Hall, J. G., and Smith, M. E. (1970). Nature, 226, 262.3Zinzar, S. N., Svet-Moldavsky, G. J., Leitina, B. I., and Tumyan,

B. G. (1971). Transplantation, 11, 499.

Circulating Immune Complexes in Ulcerative Colitisand Crohn's Disease

D. P. JEWELL, I. C. M. MACLENNAN,AND S. C. TRUELOVE(Nuffield Department of Clinical Medicine, Oxford)When certain IgG antibodies combine with targetcell antigens, determinants on the antibody moleculebecome available to react with receptors on thesurface of non-immune lymphocytes. The inter-action between such lymphocytes and the sensitizedtarget cell leads to target cell destruction. Immunecomplexes are able to inhibit this form of cytotoxicityby competing for the receptor sites on the lympho-cyte surface (MacLennan, 1972).

Using Chang liver cells labelled with 51Cr andsensitized with anti-Chang antibody as target cells,it has been found that serum from patients withulcerative colitis or Crohn's disease inhibits thecytotoxicity or normal human lymphocytes to agreater extent than control sera. The difference isstatistically significant. Inhibition of cytotoxicityshowed a positive correlation with the clinicalseverity of the disease and, in the case of ulcerativecolitis, with the degree of inflammation seen onsigmoidoscopy. There was no correlation withserum IgG concentrations.The inhibitory factor was found in the globulin

fraction following ammonium sulphate precipitationand, by fractionating the serum on Sepharose 6B,it was eluted in fractions of higher molecular weightthan monomeric IgG but lower than that of IgM.These fractions, nevertheless, contained IgG mea-sured by immunodiffusion. The inhibitory factor inpatients' sera is therefore likely to be an immunecomplex containing less than five molecules of IgG.

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Reference

MacLennan, J. C. M. (1972). Competition for receptors for immuno-globulin on cytotoxic lymphocytes. Clin. exp. Immunol., 10,275-283.

Salazopyrin Metabolism in Ulcerative Colitis

K. M. DAS, M. A. EASTWOOD, J. P. A. MACMANUS, ANDW. SIRCUS (Gastrointestinal Unit, Western GeneralHospital and University of Edinburgh) Thoughsalicyl azo sulphapyridine (salazopyrin, SASP) iswidely used in the treatment of chronic inflammatorybowel disease, our knowledge of its metabolism islargely obtained from normal volunteers'.We have studied 20 patients with ulcerative

colitis, admitted to our Unit during the intro-duction ofsalazopyrin. Salazopyrin takes two to threedays to reach a steady serum concentration, whereasits sulphapyridine metabolite takes three to sevendays.

These patients have been followed for six monthsto one year and the serum concentration of salazo-pyrin and sulphapyridine metabolites are main-tained at the concentration at discharge providedthat the dosage remains the same. In addition, 68patients in this steady 'state' have been studied atrandom to give a range of serum concentrations ofSASP and its principle serum metabolites, freeacetylated and hydroxylated sulphapyridine (SP).

Total sulphapyridine concentration, rather thansalazopyrin or constituent sulphapyridine concentra-tion equated best with remission. Ninety per cent ofoutpatients in remission had serum total SP con-centrations in excess of 20 ,ug/ml. Yet 60% ofoutpatients with active colitis had concentrations oftotal SP of less than 20,ug/ml. Aserum concentrationof total sulphapyridine of more than 20 ,ug/mlappears to be best achieved with 3 g of salazopyrin/day.

Reference

'Schrbder, H., and Price-Evans, D. A. (1972). Gut, 13, 278-284.

Pathogenesis of Secondary Hyperoxaluria in IlealResection

V. S. CHADWICK, K. MODHA, AND R. H. DOWLING(Department of Medicine, Royal PostgraduateMedical School, London W12) Hyperoxaluria (andoxalate renal stones) may complicate ilealresection'. 2. To investigate the mechanism for thissecondary hyperoxaluria, three hypotheses weretested. The first, that bile salt glycine, spilling intothe colon because of ileal dysfunction, is liberated bybacterial deconjugation, converted to glyoxylate,

absorbed and oxidized to oxalate, was tested byfeeding cholyl glycine-1-_4C. Results show thatwhile breath 14CO 2/24 hours was markedly increasedafter ileectomy (44% ± SEM 2 3) compared tocontrols (4% ± 07), both groups excreted only0 003 % of the dose as urinary oxalate/24 hours, thusexcluding bile salt glycine as the oxalate precursor.

Secondly, in ileal resection, the increased demandon hepatic glycine for bile salt conjugation might bemet by increased conversion from glycollate throughglyoxylate with an associated increase in oxalateproduction from glyoxylate. However, after intra-venous 14C-glyoxylate, the conversion to bile saltglycine, CO2 and urinary oxalate was the same incontrols and resection patients.

Thirdly, since enhanced absorption occurs afterresection3, 14C-oxalate was fed to 10 controls, sevenileectomy patients without, and seven with, hyper-oxaluria. The percentage of the dose in urinaryoxalate/36 hours was 28, 29, and 52% respectively.

In conclusion, increased oxalate absorptionexplains, at least in part, hyperoxaluria afterileectomy.

References

'Hofmann, A. F., Thomas, P. J., Smith, L. H., and McCall, J. T.(1970). Gastroenterology, 58, 960 (Abstr.)

'Dowling, R. H., Rose, G. A., and Sutor, D. J. (1971). Lancet, 1,1103-1106.

3Dowling, R. H., and Booth, C. C. (1966). Lancet (2), 146-147.

Carcinoma of the Biliary Tract Associated withUlcerative Colitis

JEAN K. RITCHIE AND P. R. HAWLEY (St. Mark'sHospital, London) In 1954, Parker and Kendallreported a case of a biliary tract tumour in a reviewof necropsy material from patients with ulcerativecolitis. Since that time, there has been an increasingnumber of papers dealing with the rare coexistence ofthese two conditions amounting, according to someauthors, to a definite association.

This study presents in detail eight new cases, onlytwo of which have been mentioned briefly in earlierpublications by one of the present authors.

In the cases described, the diagnosis of ulcerativecolitis is authenticated in seven cases by histo-pathological reports of the excised colon and in theremaining patient by clinical and radiologicalevidence. Operative, necropsy, or histological datasubstantiate the diagnosis of malignant biliary tracttumour in all cases.The present report shows that this association can

occur not only in patients treated medically forulcerative colitis but also many years after procto-colectomy.A definitive survey of the literature is included;

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particular attention has been paid to the managementof the ulcerative colitis (medical or surgical) as wellas to the location of the tumours within the biliarytract.

References

Parker, R. G. F., and Kendall, E. J. C. (1954). The liver in ulcerativecolitis. Brit. med. J., 2, 1030-1032.

Ritchie, J. K. (1971). D.M. thesis, University of Oxford.Ritchie, J. K. (1971). Ileostomy and excisional surgery for chronic

inflammatory disease of the colon: A survey of one hospitalregion. Part II The health of ileostomists. Gut, 12, 536-540.

Abscess and Fistula in Crohn's Disease

D. M. STEINBERG, W. T. COOKE, AND J. A. WILLIAMS(Nutritional and Intestinal Unit, General Hospital,Birmingham B4 6NH) Abscess and/or fistulaeoccurred in 18% of patients in a retrospective surveyof 360 cases of Crohn's disease followed up for amean of 13 years. This incidence is less than in otherreported series' 2 3 and the possible reasons for thisare discussed.

ABSCESSAbscesses can occur spontaneously but usuallyfollow operation, sometimes many years later.Simple drainage of a superficial abscess almostinevitably has resulted in an external fistula. Deepabscesses are optimally treated by major excision.

FISTULAExternal fistulae comprised the largest group,usually following drainage of a superficial abscess.The majority of cases followed previous operation.There was a high incidence after appendicectomy(30%), bypass (13%) or diagnostic laparotomy(10%). The incidence was low after major resection(5 %) which represented over 80% of the total opera-tive experience in the series.

Fistulae do not close spontaneously and minorsurgery has a poor record with a high recurrencerate. Major excision surgery with en bloc excision ofthe fistula and affected bowel has produced goodresults with minimal morbidity and mortality.

CONCLUSIONS1 In a large series of Crohn's disease the incidence offistula and abscess has been low, possibly as the resultoftimely surgical excision before complications occur.2 The results of the surgical treatment of fistulaecompare favourably with early reports of immuno-suppressive drugs.References

'Atwell, T. D., Duthie, H. L., and Goligher, J. C. (I 965). The outcomeof Crohn's Disease. Brit. J. Surg., 52, 966-972.

"Schofield, P. G. (1965). The natural history and treatment of Crohn'sDisease. Annals Royal College of Surgeons (Eng), 36, 258-279.

3Edwards, H. (1969). Crohn's disease, an enquiry into its nature andconsequences. Annals of The Royal College of Surgeons (Eng),44, 121-139.

Observations on Experimentally Induced Colonic Pain

J. A. RITCHIE, G. M. ARDRAN, AND S. C. TRUELOVE(From the Nuffield Department of Clinical Medicine,Radcliffe Infirmary, Oxford, and the Nuffield Insti-tute for Medical Research, Oxford) Inflation of aballoon in the pelvic colon regularly produced pain,but its location and the degree of inflation requiredvaried from one individual to another.

In most instances, the pain was felt either in thehypogastrium or in one or other of the iliac fossae,but sometimes it was anorectal and occasionally wasfelt in the back or in other areas of the abdomen. Afew subjects experienced pain in different areas withrepeated inflations or at different volumes of inflation.

Patients with diverticular disease or irritable colonsyndrome were liable to develop pain at much lowerlevels of inflation than normal subjects. For example,only one out of 16 normal subjects developed pain at60 ml inflation whereas more than half of the patientsdid so. The mean diameter of the balloon inflated to60 ml was significantly less in patients with theirritable colon syndrome than in normal subjects; itwas narrower still in patients with diverticulardisease.

Observations on the mechanism of pain productionsuggest that increased tension in the wall of the gutis a crucial factor. However, the relationship oftension to the pain was different in the three clinicalgroups and this will be discussed.

Effect of Vagotomy and Pyloroplasty on the Inter-digestive Myoelectrical Complex of the Stomach

I. H. KHAN AND B. S. BEDI (University Department ofSurgery, Western Infirmary, Glasgow) There isgood evidence of a close relationship between theelectrical activity and the contractions of thestomach. Szurszewskil first identified a caudadmoving band of large amplitude action potentials inthe small bowel of fasted dogs. Carlson et a12 latershowed that this interdigestive myoelectrical com-plex was controlled by the extrinsic nerves. Thepresent experiments were designed to study theeffect of vagotomy and pyloroplasty on the myo-electrical complex of the stomach in dogs.

Three mongrel dogs were used. Electrical activitywas detected in healthy conscious dogs by usingchronically implanted Ag-Ag Cl electrodes. Pro-longed recordings of the electrical activity showedperiods with no action potentials (phase I) followed

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by periods (phase II, III, and IV) with actionpotentials. Each cycle (phase I-IV) lasted for 105minutes and regularly recurred as long as the record-ings were made (average eight hours). All dogswere studied for at least two months after vagotomyand a minimum of 10 myoelectrical complexes wererecorded, in each dog, before and after vagotomy.

Pyloroplasty had no effect on these electricalcomplexes.Vagotomy in dogs with previous pyloroplasty

completely disrupted the regularly recurring com-plexes.

Reduction in the frequency of the pacesetterpotential by an injection of insulin was abolished byvagotomy.

These experiments suggest that the vagus controlsthe myoelectrical complexes of the stomach.

References

'Szurszewski, J. H. (1969). A niigrating electric complex of the caninesmall intestine. Amer. J. Physiol., 217, 1757.

'Carlson, G. M., Bedi, B. S., and Code, C. F. (1972). Mechanism ofPropagation of intestinal interdigestive myoelectric complex.Amer. J. Physiol., 222, 1027.

The Two- to Four-Year Clinical Results of HighlySelective Vagotomy (Parietal-Cell Vagotomy) with-out a Drainage Procedure for Duodenal Ulcer

D. JOHNSTON, J. C. GOLIGHER, C. N. PULVERTAFT, ANDB. E. WALKER (Leedsl York Gastric Follow-up Clinic)and E. AMDRUP AND H-E. JENSEN (Surgical Department1, Kommunehospitalet, Copenhagen, andthe Universityof Arhus) Two years ago, we reported to theSociety that the early results after highly selectivevagotomy (HSV) were most encouraging, and lastyear we reported that it abolished postvagotomydiarrhoeal.We have treated 350 patients by HSV in the past

45 months, without operative mortality. There hasbeen one proven recurrent ulcer, a gastric ulcerassociated with gastric stasis. Three other patientswere subjected to re-operation because of suspectedrecurrence, but no ulcer was found. Thus, to date,the incidence both of recurrence and of gastricretention is less than 1 %.Two hundred and six patients were reviewed, one

year, and 105 patients, two years after HSV, theresults being compared with those recorded inpatients after vagotomy with drainage (V-D) orpartial gastrectomy. Results in the two centres werein agreement. Results after selective V-D and truncalV-D were pooled, because they differed only slightly.Comparing HSV with V-D, respective incidences

were:-diarrhoea, 3% and 20% (p< 001); bile

vomiting, 0% and 10% (p < 002); dumping, 6% and14% (p <0-05); perfect, Visick grade I clinicalresults, 62% and 40% (p < 0-02); and 'fair' (Visickgrade III) results, 6% and 19% (p < 0'02).Two to four years after operation, patients are

faring significantly better after HSV than aftervagotomy with a drainage procedure.

Reference

'Humphrey, C. S., Walker, B. E., Pulvertaft, C. N., Goligher, J. C.,and Johnston, D. (1971). Gut, 12, 866.

Is a Pyloroplasty Necessary with Proximal GastricVagotomy?

R. J. CLARKE, B. M. JAFFE, B. J. CLENDINNEN, AND J. A.

WILLIAMS (The General Hospital, Birmingham, TheDepartment of Surgery, Washington University, St.Louis, USA, and The Royal Infirmary, Bristol)Holle concluded, from experimental work indogs', that a pyloroplasty is always necessary withproximal gastric vagotomy (PGV) both to drain thestomach and to prevent excessive gastrin release andso excessive gastric secretion. This prospective trialassesses gastric acid secretion, serum gastrin, andgastric emptying in 20 patients before and threemonths after either PGV with (+ P) or without(- P) pyloroplasty.Acid secretion was measured after fasting, in

response to insulin and to pentagastrin. Serumgastrin concentrations were measured by radio-immunoassay after fasting, insulin, and a standardmeat extract drink. Gastric emptying of a hypertonicfluid meal was measured by double sampling dyedilution2.Acid secretion after insulin was reduced by 98%

following PGV- P and 93% following PGV+ P andafter pentagastrin by 67% following PGV - P and74% following PGV+ P. Fasting gastrin levelsincreased by 56% after both operations. While thegastrin response to insulin was similar after both, theresponse to meat extract was twice as great afterPGV- P. Gastric emptying is faster after than beforeoperations, but PGV +P causes significantly morerapid gastric emptying than PGV- P.

CONCLUSIONSAfter PGV the omission of a pyloroplasty results inmore normal gastric emptying at the expense of anincreased gastrin response to protein. It does notaffect basal or maximal acid output.

References

'Kiempa, I., Holle, F., Bruckner, W., Welsch, K. H., Handle, H., andvon Wolff, A. (1971). Arch. Surg., 103,713.

'George, J. D. (1968). Gut, 9, 237.

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Lysolecithin: A Factor in the Pathogenesis of GastricUlceration?

A. G. JOHNSON (Department ofSurgery, Charing CrossHospital Medical School, London) The regurgita-tion of bile salts into the stomach has been proposedas a cause of gastric ulceration. The phospholipid,lysolecithin, which is formed in the duodenum whenphospholipase A in pancreatic juice hydrolyses thelecithin in bile, is also a strong detergent and highlytoxic to cell membranes. This study was designed todetermine whether in the night gastric juice of gastriculcer patients, lysolecithin occurs in sufficientconcentration to cause mucosal damage.A nasogastric tube was positioned at 9.30 pm by

a non-fluoroscopic method (Hassan and Hobsley,1968) and 10 ml samples taken at two hourlyintervals throughout the night. Lysolecithin wasmeasured by silicic acid column chromatography(Borgstrom, 1957), and its purity confirmed by thin-layer chromatography.

Twenty-seven patients were studied. The mean ofthe concentrations of all night samples for gastriculcer patients (212 ,ug/ml) was significantly higher(p< 001) than for normal control patients (23,ug/ml). Duodenal ulcer patients had normal orslightly raised levels (mean 69 ,ug/ml). The valuesfound in gastric ulcer patients with peak levels up to1369 ,tg/ml are in the range that causes considerablegastric mucosal damage under experimental con-ditions (Davenport, 1970) and it is concluded thatlysolecithin may be as important or more importantthan bile salts in the aetiology of gastric ulceration.

References

Borgstrom, B. (1957). Acta chem. scand., 11, 749.Davenport, H. W. (1970). Gastroenterology, 59, 505-509.Hassan, M. A. and Hobsley, M. (1968). Gut, 9, 728.

The Effect ofAntral Acidification on Gastric SecretionStimulated by Pentagastrin

M. H. WHEELER AND A. P. M. FORREST (Department ofClinical Surgery, The Royal Infirmary, Edinburgh)There is some evidence that an antral inhibitoryhormone and a nervous mechanism might beinvolved in the antral inhibition of gastric secretion.Such mechanisms might be relevant to both themedical and surgical management of duodenal ulcer.It has been suggested that preservation of an in-hibitory reflex is an advantage of the operation ofhighly selective vagotomy.A series of experiments have been performed in

dogs to seek evidence for the existence of an antralinhibitory action not related to the control ofendogenous gastrin release. Dogs were prepared with

innervated antral and either innervated or dener-vated fundic pouches. Two series of tests werecarried out in which submaximal doses of penta-gastrin were infused intravenously and the acidsecretory response was monitored. The antralpouches were perfused atpH 7-0 andpH 1 0 either inseparate tests or in the course of a single test. Therewas no evidence of inhibition of acid or pepsinsecretion.As in these studies acid secreted by the main

stomach could enter the duodenum, the duodenalinhibitory mechanism might have confused theinterpretation of results by masking antral inhibition.Further antral acidification tests were thereforeperformed during which acid from the mainstomach was diverted to the exterior by means of agastric fistula. Again, no inhibition of gastricsecretion occurred.

These studies provide no support for either ahormonal or neuronal antral inhibitory mechanismactive against pentagastrin.

Gastric Metabolism of Histamine'

C. F. CODE, W. E. R. GREEN, H. D. RITCHIE, J. F.SCHLEGEL, AND J. C. KENNEDY (Mayo Clinic andMayoFoundation, Rochester, Minnesota, and Surgical Unit,The London Hospital, London, England) Recog-nizable products of histamine metabolism werecompared in gastric juice collected from Heidenhainpouches in conscious dogs and from completelyisolated and perfused canine stomachs. The experi-ments were designed to determine which productsof histamine metabolism detectable in the gastricjuice are the outcome of processes occurring in thestomach alone. 14C-labelled histamine was adminis-tered continuously, intravenously to the pouch dogsand intraarterially to the isolated stomachs. Allgastric juice secreted by the pouches and the isolatedstomachs was collected and the proportions ofhistamine, N-methylhistamine (NMH), N-dimethyl-histamine (NDMH), 1-4 methylhistamine (1-4MH), imidazoleacetic acid, 1-4 methylimidazole-acetic acid, acetylhistamine, and histaminol weredetermined by two-dimensional thin-layer chromato-graphy after preparation of extracts of the juice. Allof the primary products of histamine methylation,NMH, NDMH, and 1-4 MH, were present in thesecretion of the isolated stomach in proportionssimilar to those in the juice from the pouches of theintact animals, while all of the other products wereabsent, or nearly so, in juice from the isolatedstomach. Methylation is thus the sole route ofmetabolism of histamine in the stomach of dogs.This finding supports the concept that methylation

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in the stomach provides a mechanism for control ofsecretion.

'This investigation was supported by grants from the Wellcome Trust,England, and the John A. Hartford Foundation, Inc., U.S.A.

Shock in Acute Pancreatitis and Hypovolaemia

P. FARRELL, P. FITZGERALD, 0. FITZGERALD, K.MCGEENEY, C. GEOGHEGAN, AND A. HEFFERNAN(Department of Surgery, Medicine, and Therapeutics,University College, Dublin) Shock in acute pan-creatitis is indicative of a poor prognosis. In acutepancreatitis in dogs with hypotension, angiotensinII levels fell from 30 pg/ml to 6i4 pg/ml. Bothparameters returned to normal on recovery. In acutepancreatitis without hypotension, angiotensin IIremained stable, suggesting the activity of anangiotensinase in the shock of acute pancreatitis.

Trypsin when complexed with the plasma proteaseinhibitor alpha2-macroglobulin possesses esteraseactivity (TPE). We have shown that this TPE invitro behaves as an angiotensinasel. With shock incanine acute pancreatitis TPE activity rises.

In canine hypovolaemia hypotension results in arise in angiotensin II levels (16 pg/ml to 24 pg/ml).This reverts to normal on volume replacement. Therewas a concommitant moderate rise in plasma TPEactivity.

Systemic kinin release in the shock of canine acutepancreatitis has not been shown2. We conclude thatTPE acting as an angiotensinase in vivo may formpart of the aetiology of the shock in acute pan-creatitis.

References

'FitzGerald, O., and McGeeney, K. (1970). Gut, 11, 1060.'Ofstad, E. (1970). Scand. J. Gast., 5, Suppl. 5.

A Simultaneous Combined Pancreatic Test

S. NUNDY, J. H. BARON, J. S. M. BEALES, R. HEAF, J. P.LAVENDER, N. O HIGGINS, AND E. PEARSE (Depart-ments of Surgery, Diagnostic Radiology, and Diag-nostic Cytology, Royal Postgraduate Medical School,London) To study pancreatic disease we havecombined five standard procedures which can beperformed in one morning and are without sideeffects: (a) near maximum bicarbonate and enzymeoutput, (b) maximum 75Se output, (c) scan, (d)cytology, (e) hypotonic duodenography.The patient fasts overnight and a double-lumen

Dreiling tube is passed into the duodenum whichis aspirated for three hours (12 x 15 min). Afterbasal aspiration for 30 min a secretin-pancreozymintest is performed with an intravenous infusion of

0-25 u/kg-h secretin (GIH) and 16 u/kg-h pancreazy-min (GIH) for 90 min and a single intravenousinjection of 7"Se selenomethionine 3 ,uci/kg is given.The pancreas is scanned with a gamma camera.Propantheline 30 mg is injected intravenously at theend of the above tests and a hypotonic duodeno-gram is performed using a standard double-contrasttechnique. The duodenal aspirates are analysed forvolume, bicarbonate concentration, tryptic activity,and 75Se counts; Papanicolou smears are made.Four groups of patients have been studied: no

pancreatic disease, acute pancreatitis (four weeksafter the acute episode), chronic pancreatitis, andcarcinoma of the pancreas.

In our first 50 patients: (a) a single secretion testhas been of little value in distinguishing betweendifferent pancreatic diseases. (b) The cytologicalexamination was most accurate and pancreatic scanleast accurate. (c) The combined test distinguishedpatients without pancreatic disease from those withchronic pancreatitis and those with carcinoma of thepancreas.

An Appraisal of 75Se-Selenomethionine Scanning as aTest of Pancreatic Function: A Comparison with theSecretin-Pancreozymin Test

JOAN BRAGANZA, MAIR CRITCHLEY, H. T. HOWAT, H. J.TESTA, AND H. B. TORRANCE (Clinical Division ofGastroenterology and the Department of MedicalPhysics, Manchester Royal Infirmary, ManchesterM13 9WL) Photoscans of the pancreas after theincorporation of 76Se-selenomethionine are inter-preted in terms of both anatomy and function.Though the position of the pancreas and its dis-tortion and involvement by tumours are now welldefined, the assessment of the functional capacity ofthe pancreas by scanning remains empirical, beingusually gauged by comparing the photoscan with theobserver's appreciation of a normal scan. Fewattempts have been made to correlate the photoscanobtained in pancreatic disease with reliable tests ofpancreatic function.

In over 100 patients with and without pancreaticdisease the isotope uptake in pancreatic scans,objectively determined, has been compared withpancreatic function assessed by the secretin-pancreo-zymin test, developed and used extensively in ourdivision. The volume of duodenal juice after secretinstimulation shows a poor correlation to the uptakeof 75Se selenomethionine. In chronic pancreatitis andcancer of the pancreas, photoscans correlate wellwith maximal bicarbonate concentration and post-secretin output of bicarbonate but less well withamylase output.

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An Evaluation of a Breath Test to Detect Altered BileAcid Metabolism

0. JAMES, J. E. AGNEW, RUBY LYDFORD, AND A. D.BOUCHIER (Department of Medicine and Physics, TheRoyal Free Hospital, London) Recently a test hasbeen described" 2'3 claiming to be a convenientand reliable method of detecting bacterial deconju-gation of bile acids. The test might therefore bethought to be useful in the investigation of bacterialovergrowth syndromes of the small bowel. In thetest 14CO 2 specific activity of breath samples obtainedafter a meal containing cholylglycine-l-14C aremeasured at intervals for up to 24 hours.We report an evaluation of the breath test on 70

persons, including 20 normal subjects; from thisgroup a normal range of '4C02 specific activity hasbeen constructed. The patients comprised fourprincipal groups: inflammatory bowel disease, ilealresection, recurrent cholangitis, and primary biliarycirrhosis, together with a range of other gastro-intestinal and hepatic conditions.Markedly abnormal results were found in patients

with terminal ileal resection, Crohn's disease,gastro-colic fistula, bacterial overgrowth syndrome,and recurrent cholangitis. Minor abnormalities inthe test, not previously described, have been foundin primary biliary cirrhosis.The shape of the 14CO2 specific activity time curves

and the reproducibility of the test will be discussed,and the results compared with the small bowel flora,radiology and other findings.

References

'Hofmann, A. F., Thomas, P. J., Smith, L. H., et al. (1970). Gastro-enterology, 58, 960.

'Sherr, 1H. P. et al. (1971). New Engl. J. Med., 285, 656-661.'Fromm, H., and Hofmann, A. F. (1971). Lancet, 2, 621-625.

Bile Salt Absorption following Small Bowel Resectionin the Rat

P. M. PERRY, JUNE WHITE, AND R. H. DOWILING(Departments of Medicine and Surgery, RoyalPostgraduate Medical School, Ducane Road, London,and St. Bartholomew's Hospital, London) Theenterohepatic circulation (EHC) of bile salts (BS)ensures adequate concentrations of BS in thejejunum for the digestion and absorption of fat. Inturn, this bile salt EHC is largely maintained byactive BS reabsorption from the ileum and to a lesserextent by passive BS diffusion from jejunum andcolon. Intestinal absorption depends on the numberof epithelial cells and since small bowel resectioncauses mucosal hyperplasia (particularly in theileum) we looked for (a) increased BS diffusion from

jejunum and colon as compensation for loss of activetransport following ileectomy, and (b) supranormalBS absorption by residual ileum after proximal smallbowel resection.

Bile salt absorption was measured using an in vivorecirculation perfusion system in bile fistula sham-operated control rats and in animals three to sixmonths after either proximal or distal small bowelresection. 14C monomer and micellar cholate andtaurocholate absorption were measured both byfall in luminal BS concentration and by cumulativeisotope excretion in bile.Our results show: (1) in control rats, the ratio of

ileal to jejunal to colonic BS absorption (per unitlength of intestine) is 9:2. 5 :1; (2) after ileal resection,colonic absorption did not change but jejunal cholate(P< 0-05) and taurocholate (p< 0-01) absorption wereboth significantly increased; (3) following jejunec-tomy, active BS transport by hyperplastic ileumbecame supranormal, with expansion of the BSpool.

It is concluded that following ileal resection,compensatory increases in jejunal bile salt absorptionpartially conserve the EHC. Ileal mucosal hyper-plasia produced by jejunectomy increases bile saltabsorption.

Why are Primary Bile Acids Present in CholerhoeicDiarrhoea?

M. A. EASTWOOD, J. M. FINDLAY, R. MACRAE, AND W. D.MITCHELL (Wolfson Gastrointestinal Laboratory,Gastrointestinal Unit, Western General Hospital andUniversity of Edinburgh) We have recently shownthat in patients who have ileal resection (I.R.) theirfaeces contain mainly primary bile acids andcholesterol'. An understanding of this phenomenonmay affect management.

There may be several reasons. We had anticipatedthat transit time would be rapid, thus modifyingbacterial activity. In eight patients (I.R.) the meantransit time2 (plastic markers) was 58 hours (range25-120 hours). In eight normals the mean transittime was 61f4 hours (range 24-124 hours). The valueof the use of plastic markers for transit time studiesin diarrhoeal states was examined. Polyethyleneglycol (water soluble) and chromium sesquioxide(solid phase) were administered for seven days.Recovery patterns suggest no 'streaming' effectsjustified the use of plastic markers.

In these patients the faecal extraction of bile acidsis markedly increased. The homogenate from normalfaeces was incubated anaerobically with tauro-cholate, glycocholate, and taurochenodeoxycholicacid. Whilst it was not possible to influence decon-jugation at 15 mM it was possible to abolish 7a-

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dehydroxylation at concentrations found in diar-rhoeal stool (> 4mM).

It would appear that the presence of primary bileacids is due to inhibition of bacterial activity by bileacids rather than through altered transit time.

References

Mitchell, W. D., and Eastwood, M. A. (1972). Scand. J. Gastroent., 7,29-32.

'Hinton, J. M., Lennard Jones, J. E., and Young, A. C. (1969). Gut,10, 842-847.

A New Technique for Examining Intestinal Biopsies

B. L. CHAPMAN, K. HENRY, F. PAICE, J. S. STEWART, ANDN. F. COGHILL (Medical Department, West MiddlesexHospital, Department of Morbid Anatomy, RoyalPostgraduate Medical School, and MRC CyclotronUnit, Hammersmith Hospital, London) A newtechnique for measuring changes in the architectureof the small intestinal mucosa has been developed.Current techniques measure only single dimensions,or involve indices dependent on villous structure.They usually have overlapping ranges of values forcontrol and flat mucosae, and at best only a three-fold difference between the mean values.We have used a modification of the technique of

quantitative colour television image analysis tomeasure the areas occupied by the surface and cryptepithelial cells in proximal jejunal biopsies. Fromthese measurements the ratios of surface to cryptcell areas were calculated. The mean ratio was 2-2in 12 control mucosae. In 12 untreated flat coeliacmucosae the mean ratio was only 0 25. This nine-fold difference, which was statistically highlysignificant, was greater than that for any measure-ment previously reported.The technique was used to measure the progressive

changes in the mucosae of coeliac patients treatedwith a gluten-free diet. The surface-to-crypt arearatio gradually increased in patients who kept to astrict diet. In some, a change was detectable at threeor seven days. In both control and abnormalmucosae, the area ratios correlated very closely withthe most accurate of the conventional measurements,the surface cell height.

Cell Production Rate in Mucosa of Untreated CoeliacDisease

N. A. WRIGHT, A. J. WATSON, A. R. MORLEY, D. R.

APPLETON, AND JANET M. MARKS (Departments ofPathology, Medical Statistics and Dermatology,University of Newcastle upon Tyne) We havealready established that the mitotic index in duodeno-jejunal crypt-cells is elevated in untreated coeliac

disease, and that the production rate of crypt cells isincreased x 5 to x 61,2. The validity of this conclusiondepends on the assumption that there is no signifi-cant change in mitotic duration, a parameter uponwhich the value of the mitotic index heavily depends.

Mitotic index =mitotic durationcell-cycle duration

A shortened division cycle seems inherently moreprobable and has been postulated by others3.Our earlier observations have been extended by

using a stathmokinetic technique with vincristine.We have studied a patient with morphologicallynormal mucosa and another with the flat mucosaand total villous atrophy of untreated coeliacdisease (associated in this instance with dermatitisherpetiformis). We find a small increase in mitoticduration in the coeliac mucosa but cell-cycle time ishalved. These parameters have not hitherto beenreported in coeliac disease. We also confirm that cellproduction rate is increased x 5 to x 6 and thatcrypt-cell migration rate is increased. These findingsare in keeping with the existence of a hyper-productive mucosal state in untreated coeliac disease.

References

'Wright, N. A., Watson, A. J., Morley, A. R., Appleton, D. R., andRobinson, D. C. (1972). 'Analysis of mucosal cell kinetics inthe small intestine using peroral biopsy specimens: comparisonof normal and flat mucosae in children'. (In press). Het Ned.Tschr. v. Geneesk.

'Watson, A. J., Wright, N. A., Morley, A. R., Appleton, D. R., andMarks, Janet M. (1972). 'Small-intestinal crypt-cell kinetics inthe coeliac syndrome'. (In press). Het Ned. Tschr. v. Geneesk.

'Winawer, S. J., and Lipkin, M. (1970). 'Proliferative abnormalities inthe gastrointestinal tract'. In Modern Trends in Gastroenter-ology-4, p. 68. Ed. by W. I. Card and B. Creamer. London:Butterworths.

Two Types of 'Coeliac' Disease?

R. E. BARRY AND A. E. READ (Department ofMedicine,University of Bristol) Although an associationbetween malignant abdominal lymphoma andmalabsorption has been known since 1937, it was notuntil shortly after the introduction of peroraljejunal biopsy in 1956 that some cases of lymphomawith malabsorption were shown to have the 'flat'jejunal biopsy characteristic of coeliac disease. In1962 Gough, Read, and Naish suggested thatmalignant lymphoma may occur as a complication ofcoeliac disease, a suggestion subsequently supportedby the publication of a study of a large series of casesof coeliac disease by Harris, Cooke, Thompson, andWaterhouse (1967).We have recently studied the mucosal dynamics of

the small bowel in the presence of malignancy andestablished the mechanism by which architecturalchanges may be produced. Because of the association

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between coeliac disease (in which profound changesin the mucosal architecture occur) and malignancyof the lymphoreticular type, we have investigated 15cases previously diagnosed as adult coeliac diseasewho presented with malabsorption and subtotalvillous atrophy.

Studies of the mucosal dynamics as indicated by(1) epithelial cell (DNA) loss rate and (2) mucosalthickness and mitotic index suggest that thesepatients fall into two distinct groups, the mucosalchanges in each group being produced by differentmechanisms. The subsequent progress of thesepatients in their response to a gluten-free diet anddevelopment of grave complications suggest that thedistinction between the two groups has directclinical relevance. It is suggested that a considerationof mucosal dynamics in 'coeliac disease' is of con-siderable value in prognosis.

References

Gough, K., Read, A. E., and Naish, J. (1962). Intestinal reticulosis as acomplication of Idiopathic Steatorrhoea, Gut, 3, 232-239.

Harris, 0. D., Cooke, W. T., Thompson, H., and Waterhouse,J. A. H. (1967). Malignancy in adult coeliac disease. Amer. J.Med., 42, 899-912.

Change in Jejunal Structure and Function in Derma-titis Herpetiformis: Effect of Gluten-free Diet andCorticosteroids

PARVEEN KUMAR, D. B. A. SILK, M. L. CLARK, AND

M. DAWSON (Departments of Gastroenterology andMedicine, St. Bartholomew's Hospital, London)Although there are similarities between coeliacdisease and the enteropathy associated with derma-titis herpetiformis (DH), there is controversy over theresponse of the latter to a gluten-free diet. Predni-solone has recently been shown to improve themucosal structure in coeliac disease'. We havetherefore investigated the response of DH entero-pathy, both in terms of structure and function, toeither gluten withdrawal or corticosteroid therapy.The function studies performed using a double-lumen perfusion technique2 were undertaken becauseof the claim that the lesion in this condition ispatchy3.

In the four patients studied so far we have shown asignificant increase in surface cell heights and villousheights with a corresponding decrease in mucosalthickness. Absorption of glucose (from a 56 mMsolution), and the amino acids glycine and alanine(from a mixture of glycine and alanine as well as thedipeptide glycylalanine) showed a dramatic improve-ment after treatment. Bicarbonate absorption (froma 35 mM solution) showed a less striking improve-

ment, thus confirming our previous findings thatbicarbonate absorption is a more sensitive index ofjejunal function. The patients who secreted sodiumand water in response to the above solutes beforetreatment, showed an improvement and in some casesa reversal of their secretory state.

References

'Wall, A. J., Douglas, A. P., Booth, C. C., and Pearse, A. G. E. (1970).Gut, 11, 7-14.

'Sladen, G. E., and Dawson, A. M. (1970). Gut, 11, 947-954.'Brow, J. R., Parker, F., Weinstein, W. M., and Rubin, C. E. (1971).

Gastroenterology, 60, 355-361.

Ilntestinal Permeability in Coeliac Disease

I. S. MENZIES (Department of Clinical Chemistry, St.Thomas's Hospital, London) (introduced by B.CREAMER) Lactulose (,B 1-4 galactosido-fructose) isneither hydrolysed by the human small intestine normetabolized significantly, and is quantitativelyrecovered from the urine after intravenous injection'.The amount reaching the urine after ingestiontherefore reflects the state of intestinal permeability.Muller2, using an oral loading technique, found nodifference in urinary lactulose excretion betweennormal subjects and patients with coeliac disease.However, because intestinal permeability temporarilyincreases when hypertonic solutions are ingested",this test was re-evaluated in relation to the tonicity ofingested solution, and different conclusions wereobtained.The excretion of lactulose, as measured by

quantitative paper chromatography, was estimatedin 20 healthy adults during five hours after both anisotonic (5g lactulose in 100 ml water) and a hyper-tonic (5g lactulose + 40g sucrose in 100 ml water)load. The excretion following the isotonic load was23 5 ± 22 mg and following the hypertonic load was25 7 ± 17-4 mg (mean ± 2 standard deviations). In23 patients with coeliac disease, six of whom wereuntreated, the excretion of lactulose was greater thannormal in 90% after the hypertonic load, but in only25% after the isotonic load. All the untreated casesshowed abnormal permeability following the hyper-tonic load.

In conclusion, the hypertonic lactulose test showedconsiderable potential as a screening procedure, andthe isotonic test correlated well with the severity ofthe disease.

References

"Menzies, I. S. (1972). Biochem. J., 126, 19-20 P.2MOller, M., Walker-Smith, J., Shmerling, D. H., Curtius, H.-CH.,

and Prader, A. (1969). Clin. Chim. Acta, 24, 4549.

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Gluten Enteropathy in Vitro: A Culture System for theStudy of Coeliac Disease.

J. D. MITCHELL, P. BHATHAL, H. CORNELL, AND R. R. W.TOWNLEY (introduced by c. C. BOOTH) (University ofMelbourne, Departments ofPaediatrics andPathology,and the Gastroenterology Unit, Royal ChildrensHospital, Melbourne, Australia) The purpose of thisstudy was to develop an in-vitro system for inves-tigating coeliac disease. Small slices of singleduodenal biopsies were maintained in vitro for 24hours and used to study the effect on epithelial cellultrastructure of the addition to the culture mediumof a digest of gluten (peptic-tryptic-cotazyme (PTC)digest of gliadin): The culture medium was Eagle's(basal) medium containing foetal calf serum (10%),glucose to 2 mg/ml, antibiotics, and sodium bi-carbonate. Tissue slices were placed in roller tubeson a slowly rotating drum situated inside anincubator at 37°C. A constant flow of a gas mixtureof 95% 02 and 5% CO 2 maintained the atmospherewithin the incubator.

CULTURESCultures of duodenal biopsy tissue from two normalcontrols and an infant with mucoviscidosis werecompared with cultures of tissue from one youngadult and two children with untreated coeliacdisease. Individual slices of each biopsy specimenwere maintained in medium alone and in mediumto which 5 mg/ml PTC gliadin had been added.Tissue slices from five of the individuals studiedwere cultured in triplicate pairs and from one coeliacinfant as only a single paired culture.

RESULTSResults, based on an ultrastructural comparison oftissue before and after culture for 24 hours, indicatedthat 5 mg/ml PTC gliadin specifically inhibitedmaintenance of coeliac epithelial cell morphology inthis in-vitro system. Mature enterocytes of non-coeliac origin maintained their ultrastructuralcharacteristics both in the presence and absence ofthe gluten fraction. Coeliac tissue cultured in mediumalone had epithelial cell morphology which tended,if anything, to approach the normal appearance asseen in treated coeliac disease. However, whencultured for 24 hours in medium containing PTCgliadin, coeliac enterocytes showed marked loss ofmicrovilli with marked blunting and fusion of thoseremaining. Epithelial cell height was reduced andvariable intracellular ultrastructural changesoccurred.

This system shows promise as an in-vitro model forthe study of coeliac disease and has the advantagethat portions of a biopsy obtained primarily fordiagnostic purposes can be used.

Vagotomy and Gastrin Secretion

D. BYRNES AND T. SCRATCHERD (Wolfson Gastro-intestinal Laboratories and Teaching and ResearchCentre, Western General Hospital and University ofEdinburgh) It has generally been assumed thatgastrin release during insulin-induced hypoglycaemiais mediated solely by the vagus nerves. The presentstudy was undertaken to determine if gastrinsecretion during hypoglycaemia was abolished bysurgical vagotomy.Using a sensitive radioimmunoassay gastrin

estimations were determined on serum samples takenbefore and during insulin-induced hypoglycaemiafrom 11 patients, six months after surgical vagotomy.The gastric contents were continuously aspiratedduring the procedure. Studies were also performedon dogs to determine the gastrin response to hypo-glycaemia following cholinergic and adrenergicblockade.

Following 'complete vagotomy' (six patients)serum gastrin levels were significantly elevated(130 ± SE 35 pg/ml, normal 49 ± SE 8 pg/ml). Adecrease in mean gastrin concentration occurredduring the basal hour (130 ± SE 35 to 98 ± SE 31pg/ml). After administration of insulin there was alatent period of 30 minutes followed by a consistentrise in serum gastrin above the basal level. A similargastrin response during hypoglycaemia was observedin two patients with histologically proven gastri-nomas.These studies demonstrate a non-vagal release of

gastrin during insulin-induced hypoglycaemia. Pos-sible mechanisms for this release will be discussed.

Antral G-cell Hyperplasia with HypergastrinaemiaProducing a Zollinger-Ellison Syndrome

R. Y. WILSON, B. E. BOYES, B. H. STAGG, M. R. LEWIN,JULIA M. POLAK, A. G. E. PEARSE, I. W. DYMOCK, ANDD. J. COWLEY (Departments ofSurgery and Medicine,University Hospital of South Manchester, Depart-ment of Surgery, University College Hospital,London, and Department of Histochemistry, RoyalPostgraduate Medical School, London) It hasrecently been postulated that some patients with theZollinger-Ellison syndrome have hypergastrinaemiaand hyperplasia of the antral G-cells but no tumour.This subgroup has been classified as Z-E syndrometype I1. We have treated such a patient by vagotomyand antrectomy with subsequent return of fastingplasma gastrin and acid secretion to normal.A 17-year-old male had a four-year history of

duodenal ulcer confirmed radiologically. Gastricsecretion tests showed acid hypersecretion (BAO13-6 m-equiv/h, basal acidity 92 m-equiv/l, PAO

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pentagastrin 47T8 m-equiv/h). Fasting plasma gastrinwas 8 350 pg/ml (normal 50-170 pg/mi). Pancreasscan and angiography showed no abnormalities.At laparotomy duodenal ulceration was confirmed

but no pancreatic or other tumours were found.Truncal vagotomy and antrectomy was performedwith distal pancreatectomy. Immunofluorescentstaining showed hyperplasia ofG cells in the resectedantrum but with a normal pancreas and duodenum.

Since operation he has been symptom-free andtwo months later fasting plasma gastrin was <50pg/ml and the acid secretion was reduced by 92%(BAO 0-45 m-equiv/h, PAO pentagastrin 4-8 m-equiv/h).

This report confirms that type I Z-E syndrome is aclinical entity and suggests that it may be treated by aless radical operation than total gastrectomy.

Reference

'Polak, J. M., Stagg, B. H., and Pearse, A. G. E. Gut, in press.

Acid Secretion, Plasma Gastrin Levels and theDiagnosis of the Zollinger-Ellison Syndrome

M. R. LEWIN, B. H. STAGG, AND C. G. CLARK (Depart-ment of Surgery, University College HospitalMedical School, London) Fasting plasma gastrinlevels have been determined by radioimmunoassayfor 75 patients with suspected Zollinger-Ellisonsyndrome. Fifty-two patients had gastrin levelswithin the normal range (50-170 pg/ml), and 23patients had gastrin levels in the range 800-9 500pg/mi. A diagnosis of Zollinger-Ellison syndromewas confirmed in 16 of the latter, the remaining sevenpatients being lost to follow up. Acid secretion studieswere carried out on the majority of patients, and thesecretory patterns evaluated to determine theirusefulness in the diagnosis of the syndrome.The patients could be divided into three main

groups. Group 1 consisted of23 patients referred witha short history of severe dyspepsia associated withhigh acid secretion and/or multiple ulceration.Group 2 consisted of 39 patients referred withrecurrent ulceration after previous surgery. Group 3consisted of nine patients with a variety of symptoms,some of which occur in the Zollinger-Ellisonsyndrome. Hypergastrinaemia was observed ineight patients in group 1 and 15 patients in group 2,but in none of the group 3 patients. Acid secretorypatterns were suggestive of the disease in less than50% of the patients with the Zollinger-Ellisonsyndrome, but the radioimmunoassay gave un-equivocal results.

The Relationship between the Rate of GastricEmptying and Release of Insulin after PartialGastrectomy and in the Idiopathic Lag StorageCurve

G. H. TOMKIN AND A. M. CONNELL (Royal VictoriaHospital, Belfast, and Division of Gastroenterology,University of Cincinnati, Cincinnati, Ohio) In arecent paper' pyloroplasty, but not partial gastrec-tomy, was associated with raised insulin levels after aglucose load, suggesting that a major insulinreleasing factor(s) in the antrum was removed bypartial gastrectomy.

This study examines the relationship betweengastric emptying, glucose absorption, and insulinrelease in (1) controls, (2) newly diagnosed milddiabetics, (3) patients with an 'idiopathic' lagstorage curve, and (4) patients with a lag storagecurve after partial gastrectomy.

RESULTSGroup 4 emptied faster than group 1 (t = 3-5P<0-01). There was no difference between theemptying times of groups 1 and 3 (P>0-05). Theinsulin response to the glucose load was greater ingroup 4 than in group 3 (t = 3-26, P<0-05) and ingroup 4 but not in the other groups and the insulinresponse correlated with the emptying rate (r=0-94, p<0-005).

These studies demonstrate that the idiopathic lagcurve is not related to rapid gastric emptyingwhereas there is a correlation between insulinrelease and rate of emptying in the postgastrectomypatients. Removal of the antrum is not associatedwith a diminished insulin response after a glucoseload. It is concluded that insulin stimulation bygastrointestinal releasing factor(s) depend on thelength of time that glucose is in contact with the bodyof the stomach and/or the upper small bowel.

Reference

'Breuer, R., Moses, H., Hager., J., and Zuckeman, L. (1972).Gastroenterology, 62, 1109-1119.

A Radioimmunoassay for Secretin Using AntibodiesRaised to Pure Natural and Synthetic Hormone

J. D. TEALE, K. D. BUCHANAN, AND G. HARPER(introduced by A. H. G. LOVE) (Department ofMedicine, The Queen's University of Belfast)A radioimmunoassay for secretin has been estab-lished. lodination of synthetic secretin (Squibb) tospecific activities of 40 to 75 mCi/mg has beenachieved using a modification of the procedure ofHunter and Greenwood (1962). Antibodies wereraised using as little as 5 ,ug of pure natural secretin

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(Jorpes) in the unconjugated form and adsorbedonto carbon (Boyd and Peart, 1968). Higherantibody titres were achieved by immunization with25 ,ug of unconjugated synthetic secretin or 30 to 90,ug of natural hormone conjugated to ovalbumin.

Standard curves were constructed and purenatural, synthetic and crude (Boots) hormonepreparations were found to inhibit binding of thelabelled hormone to antibodies. Antisera fromanimals immunized with either natural or syntheticsecretin showed equal reaction with both natural andsynthetic standards. The immunoassay could detectan absolute amount of 40 pg of secretin in buffersolution. No cross-reaction was observed withinsulin, pancreatic and gut glucagons, gastrin, andcholecystokinin-pancreozymin.

Immunoreactive secretin has been detected inacid-alcohol extracts of duodenum and upper andmid parts of jejunum of pig. None was found in thestomach, pancreas, liver, spleen, lower jejunum,ileum, and colon.References

Boyd, G. W., and Peart, W. S. (1968). Lancet, 2, 129.Hunter, W. M., and Greenwood, F. C. (1962). Nature (Lond.), 194,

495.

Secretin and Pancreozymin Effect on SalivaryAmylase Concentration in Man

H. MULCAHY, 0. FITZGERALD, AND K. F. MCGEENEY(Department of Medicine & Therapeutics, UniversityCollege, Dublin 4) During serum enzyme evocativetests using secretin and pancreozymin (PZ-CCK) arise in salivary amylase concentration was observed.

Fasting subjects were given secretin IV 1-5 units/kg, and following a 30-minute interval 1-5 units/kgPZ-CCK. Saliva was collected before secretin(control period) and then at 30-minute intervals, atotal of five samples being taken from each subject.In each of seven subjects a rise in salivary amylaseconcentration was noted following administrationof secretin. This rise was augmented in each case byPZ-CCK.

In pure parotid saliva an increase in amylaseconcentration in response to the two hormones wasalso observed.The parotid duct of fasting subjects was covered

with a Curby cup and the basal secretion collected forone hour. Secretin and PZ-CCK were given asbefore and parotid saliva was collected at 30-minuteintervals. A rise in amylase concentration in responseto secretin was again augmented following PZ-CCK.The maximum rise observed was 50% of the restingvalue (5 x 105 iu).From our experiments on the conscious human, it

would appear that the gastrointestinal hormones

exert an effect on the composition of human saliva,unlike the situation in the dog".

Reference

'Clendinnen, B. G., Reeder, D. D., Warren, D., Davidson, M. D., andThompson, J. C. (1970). Arch. Surg., 101, 596.

Double-contrast (Air-contrast) Radiology of theStomach and Duodenum

W. G. SCOTT-HARDEN (Cumberland Infirmary, Carlisle)This paper describes our experience of routinedouble-contrast radiology of the stomach andduodenum. The decision to replace the traditionalbarium meal by air-contrast studies six years ago wasthe result of critical assessment of the shortcomingsof the traditional method, by endoscopy in patientsnot submitted to surgery, and by the findings atlaparotomy.The traditional barium meal relies upon tangential

irregularities and irregularities en face demonstratedby palpation at the time of screening. Both areincreasingly difficult to achieve when the stomachlies obliquely and become impossible when it ishorizontal. Furthermore an error of observation atthe time of screening is too often irretrievable bystudy of the film series.The double-contrast method suffers none of these

difficulties and it has been proved that minute ulcersare demonstrable. Progress of an ulcer to completehealing can be defined and the mucosal characteris-tics of malignancy are clearly demonstrable.The double-contrast technique must be simple to

permit routine use within the work load of theNational Health Service. A simple method isdescribed.

This contrast method has also been used through-out this period in the acute bleed with very obviousadvantage and illustrations of these cases areincluded in this paper.

References

Notes and activities (1972). Gastroenterology in Japan: report on aspecial meeting of the Japanese Gastroenterological Society,March, 1972. Gut, 13, 328.

Solanke, T. F., Kumakura, K., Maruyama, M., and Someya, N.(1969). Double-contrast method for the evaluation of gastriclesions. Gut, 10, 436442.

Enterokinase Levels in Intestinal Mucosa fromNormal Subjects and Patients with Coeliac Disease

J. F. WOODLEY AND ROSALEEN KEANE (introduced byC. F. MCCARTHY) (Department of Biochemistry,University College, Galway, Ireland) Enterokinaselevels were measured in peroral biopsy specimens ofintestinal mucosa from coeliac patients and from

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normal and symptomatic controls. The levels ofenterokinase were compared with those ofsucrase andlactase, expressed as specific activities (mIU/mg ofprotein). The results were divided on the basis ofanatomical location, ie, duodenal or jejunal, and onhistological appearance, ie, normal or total villousatrophy. In the series of biopsies from the duodenum,15 with normal histology and 10 showing a 'flat'mucosa, typical of coeliac disease, were analysed.The biopsies from the coeliac patients had levels ofsucrase and lactase which were 75% lower thannormals, whereas there was no significant reductionin the enterokinase levels. Results from jejunalbiopsies showed a similar trend. In the 33 normal andnine coeliac biopsies studied, the sucrase and lactaselevels were reduced 80-90% in the coeliac samples,with no significant change in the enterokinase levels.

These results do not support the hypothesis(Holmes and Lobley, 1970; Nordstrom and Dahl-qvist, 1971) that enterokinase is a 'brush border'enzyme like sucrase and lactase, but would be con-sistent with the idea that it is adsorbed to the cellmembrane after secretion.

References

Holmes, R.. and Lobley, R. W. (1970). J. Physiol. (London), 211, 50-51.

Nordstom, C., and Dahlqvist, A. (1971). Biochim. Biophys. Acta, 242,209.

Enterokinase in Human Duodenal Juice FollowingSecretin and Pancreozymin and its Relationship toBile Salts and Trypsin

S. MOSS, R. W. LOBLEY, AND R. HOLMES (Department ofGastroenterology, The Royal Infirmary, Manchester)Enterokinase has been localized to the brush borderof the epithelial cell of small intestinal mucosal,and it is also present in fluid aspirated from theduodenum in humans. Both bile salts and trypsinrelease enterokinase from guinea pig brush bordersin vitro, and it has been suggested that in vivoenterokinase is released from the brush borders ofintact epithelial cells by the action of bile salts2 andof trypsin3 present in duodenal fluid.The duodenum was intubated in humans and the

amount of enterokinase in aspirated juice estimatedafter removing trypsin by gel filtration. Following theadministration of both secretin and pancreozyminthere was a significant rise in the output of entero-kinase in duodenal juice similar to that observed foralkaline phosphatase, but only negligible amounts ofdisaccharidases were detected. The postsecretin risein enterokinase output also occurred when bile saltlevels remained low, and in one patient with completebiliary obstruction enterokinase output rose fol-lowing secretin stimulation although bile salts were

undetectable throughout. Duodenal fluid from apatient with pancreatic atrophy contained virtuallyno trypsin, yet the rise in enterokinase output stilloccurred after secretin and pancreozymin stimula-tion.Thus the rise in output of enterokinase in duodenal

juice after secretin and pancreozymin stimulation isindependent of bile salt concentration, and does notappear to require the presence of trypsin.

References

1Lobley, R. W., and Holmes, R. (1970). The localization of entero-kinase to the brush border membrane of guinea pig smallintestine. Gut, 11, 1059.

'Hadorn, B., Steiner, N., Sumida, C., and Peters, T. J. (1971). In-testinal enterokinase: mechanisms of its 'secretion' into thelumen of the small intestine. Lancet, 1, 165.

"Nordstrom, C., and Dahlqvist, A. (1971). Intestinal enterokinase.Lancet, 1, 1185-1186.

Clinical Relevance of Endoscopic Retrograde Cholan-gio-pancreatography

P. B. COTITON AND J. S. M. BEALES (St. Thomas'Hospital, London) Endoscopic cannulation of thepapilla of Vater has succeeded in 80 out of our first100 attempts, and relevant retrograde cholangio-grams and/or pancreatograms have been obtained in72 patients. In many patients where cannulationfailed, duodenoscopy alone provided useful visual orhistological diagnostic information. Significant com-plications have so far been confined to two cases ofsepticaemia (successfully treated). However, theprocedure is not simple and requires the cooperationof endoscopist, radiologist, assistant, and patient forup to one hour. Is it worth while?Where preoperative diagnosis is sought in a

patient with obvious obstructive jaundice, trans-hepatic cholangiography (in experienced hands) issimpler and better. In the differentiation of medicalfrom surgical jaundice, however, the retrograderoute may be equally valuable since both normal andabnormal duct systems can thereby be outlined. Thisis also the case in patients with biliary type symptoms,particularly after cholecystectomy, in whom stand-ard intravenous or infusion cholangiography hasfailed.Much remains to be learnt concerning the range

of normality, and the specificity of abnormality inpancreatic duct radiographs. Retrograde pancrea-tography promises to be a useful guide to theoperative approach in patients with known chronicpancreatitis, for instance in the localization ofstrictures; however, similar strictures may be seen incarcinoma.

Pancreatography has not yet been shown to bemore discriminating than already available diagnostictests in patients with suspected pancreatic disease.

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The Natural History of Hepatitis-associated (Aus-tralia)-antigen (HAA)-positive Chronic Liver Disease

F. J. DUDLEY, P. J. SCHEUER, AND S. SHERLOCK(Departments ofMedicine and Pathology, Royal FreeHospital, London) Fifty-nine patients with HAA-positive chronic liver disease have been studied.Onset was varied. Continued hepatic injury afteracute hepatitis was documented in 30 (51 %). Sevenothers (12 %) gave a history of acute hepatitis butwere asymptomatic for a variable period beforechronic liver disease was diagnosed. The other 22(37%) had no history of acute hepatitis and pre-sented as chronic liver disease.

Corticosteroid therapy was commonly used earlyin the course of the original episode of acutehepatitis. Its subsequent withdrawal and reintro-duction was often associated with exacerbations andremissions of disease activity. Such therapy markedlyaccentuated natural fluctuations in activity. Patientswith established cirrhosis also improved both sympto-matically and biochemically from steroid therapy.

Six patients presented initially as primary liver cellcarcinoma and all have died. Thirty-three otherpatients have been followed for an average of 23months (range six-99). Three have died, two fromcomplicating primary liver cell carcinoma, and onefrom haematemesis and hepatocellular failure. Onlytwo other patients have shown any clinical orbiochemical deterioration during the follow-upperiod. The other 28 (85 %) have either improved orremained static.

Liver biopsies of all 59 patients were reviewed.Diagnoses included acute hepatitis with possibletransition to chronic hepatitis, chronic persistent,lobular, or aggressive hepatitis, cirrhosis, and primaryliver cell carcinoma. Excluding patients with cancer,follow-up biopsies were available in 21 patients,seven showing a significant change in the type ofhepatitis, usually toward a more active lesion.

Asymptomatic Liver Disease in Australia-antigen-positive Blood Donors

I. L. WOOLF, B. E. BOYES, I. W. DYMOCK, P. H. RENTON,AND F. STRATTON (Department ofMedicine, UniversityHospital ofSouth Manchester, and the National BloodTransfusion Service, Manchester) Routine testingof donor blood for the hepatitis-associated antigenand antibody has been carried out for some time.Twenty-two donors were found on this routinescreening to be HAA positive. These have beenreviewed clinically and in some cases more detailedinvestigations carried out. Three of the donors hadreceived either blood or plasma. Three had beenextensively tattooed and six had had contact with

hepatitis. Three donors became antigen negativeduring the period of review.

Six of the 22 had abnormal liver function tests.Bromsulphthalein retention tests were carried out onnine donors and in four abnormal retention wasfound. In nine donors liver biopsy was performed andin only two was histology considered normal. Theabnormalities encountered were a chronic aggressivehepatitis in two donors, chronic persistent hepatitisin two donors, focal parenchymal necrosis in twodonors, and a resolving viral hepatitis in one donor.Twelve donors were found to have the antibody to

Australia antigen and in two of these the liver func-tion tests were mildly abnormal. One liver biopsy wascarried out and the histology was within normallimits.

Australia Antigen in the Urine of Patients with AcuteAustralia-antigen positive Hepatitis and their House-hold Contacts1

E. J. L. HEATHCOATE, A. TSIANIDES, AND SHEILASHERLOCK (Department of Medicine, Royal FreeHospital, London, England) The Australia antigenwas looked for in concentrated urine samples usingthe complement-fixation test. Twenty-three patientswere studied during their acute hospital admission;only four showed urinary antigen. However, 15of these patients and their household contactswere studied at monthly intervals for six months,dating from the time of the hospital admission,and 13 showed transitory urinary antigen, onlyone having been positive whilst in hospital.Sixty per cent of the 43 household contacts alsodeveloped Australia antigen in their urine during thistime but none had clinical or biochemical evidence ofhepatitis. Urines from 50 healthy controls were foundto be negative.

In summary, Australia antigen may be detected inthe urine of patients with acute, Australia-antigen-positive hepatitis, most commonly during the periodof their convalescence, when the antigen was nolonger present in the serum. Despite no evidence ofrecent hepatitis a high proportion of householdcontacts also had Australia antigen in their urine.

1This work was supported by a grant from the Medical ResearchCouncil, England.

Hepatitis-associated, Antigen-induced LymphocyteTransformation in Chronic Hepatic Disease

N. PETTIGREW AND R. I. RUSSELL (Departments ofPathology and Gastroenterology, Royal Infirmary,Glasgow) Recent work has demonstrated that

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lymphocytes from patients who have recovered fromhepatitis-associated, antigen-positive hepatitis can betransformed when stimulated in vitro by hepatitis-associated, antigen-positive sera (Yeung Laiwah,1971).This finding has been confirmed. The trans-

formation was expressed as the ratio of 3H-thymidineuptake in triplicate cultures of lymphocytes in thepresence and absence of antigen. The mean lympho-cyte transformation ratio (with SD) in a series of 12normal control subjects was 1-31 + 023; in sixpatients with a history of serum hepatitis 2-97 ±0-98; in nine patients with biopsy-proven primarybiliary cirrhosis 1 20 ± 036; and in five patients withchronic active hepatitis 1 30 ± 0-52.

In seven chronic alcoholic patients with hepaticdisease, the mean ratio was 2-07 ± 058. Alcoholicswithout hepatic disease behaved like normal controls.The lymphocyte transformation ratio was sig-

nificantly different from that of normal individualsin the patients who had recovered from serumhepatitis (t = 5 6; P<O001) and in the chronicalcoholic patients with hepatic involvement (t=3-9; P<0O01).These observations suggest that serum hepatitis

virus may be important in the pathogenesis ofalcoholic liver disease.

Reference

Yeung Laiwah, A. A. C. (1971). Lymphocyte tranaformation byAustralia antigen. Lancet, 2, 470-471.

Serum Alkaline Phosphatase Isoenzymes in LiverDisease

T. W. WARNES, PAULINE M. HINE, AND G. H. KAY(Department of Gastroenterology, Manchester RoyalInfirmary) Alkaline phosphatase isoenzymes wereseparated by heat, urea, and L-phenylalanine in-hibition tests, and the results compared withacrylamide gel disc electrophoresis, on whichintestinal and origin bands may be found, inaddition to the main band. Band width and positionwere measured and expressed in such a manner thatthe results could, for the first time, be placed on asemiquantitative basis, thus permitting a statisticalanalysis. The main 'bone' band is significantly slowerand broader than the 'liver' band, whilst two mainbands are seen in normal serum.An intestinal band was found in 50% of normals,

in only 19% of patients with bone disease, and in 45%of patients with liver disease. When the latter groupwas analysed, an intestinal band was found in 55%of patients with an intrahepatic lesion, but in nopatient with an extrahepatic lesion.

In contrast, an origin band, which was found in

80% of the liver disease group, was present in bothintra- and extrahepatic lesions. This origin band wasfound in only 7% of patients with bone disease, andin no normal subject.The liver isoenzyme can often be demonstrated in

the serum of patients with liver disease who havenormal liver function tests, including a quantitativelynormal alkaline phosphatase concentration, andalkaline phosphatase isoenzyme studies represent asensitive and specific new test of hepatocellularintegrity.

The Diagnosis of Gilbert's Syndrome: Role of theReduced Caloric Intake Test

D. OWENS AND S. SHERLOCK (Department ofMedicine,Royal Free Hospital, London) The effect of a 400calorie diet for 72 hours on plasma bilirubin con-centration was studied in 12 normal subjects, 10 withGilbert's syndrome, in 12 patients with chronic liverdisease, and in three with haemolytic anaemia.There was a significant increase in the unconju-

gated bilirubin concentration in both normal subjectsand in patients with Gilbert's syndrome. It occurredwithin 24 hours of starting the diet. Continuation foranother 48 hours was not associated with furtherincrease in the bilirubin concentration. The increasewas significantly higher in Gilbert's syndrome than innormal subjects. There was no significant increase inthe patients with chronic liver disease and in the threepatients with haemolytic anaemia.The cause of the elevation is unknown. It may be

related to decreased hepatic glucuronyl transferaseactivity which was shown to be present in sevennormal rats fasting for 72 hours.

Intestinal Blood Flow and Sodium Transport

A. H. G. LOVE, J. G. W. MATTHEWS, AND N. VEALL(Departments of Medicine and Surgery, The Queen'sUniversity of Belfast, and the Radioisotopes Division,MRC Clinical Research Laboratories, Harrow,Middlesex) Intestinal blood flow not only suppliesthe metabolic needs of the mucosa but also trans-ports absorbed materials. The relationships betweenabsorption and blood flow are poorly defined. Norelationship between net sodium absorption andtotal blood flow has been demonstrated (Goldbergand Fine, 1945).

In the present study in dogs using small bowelperfusion bidirectional sodium ion fluxes were.measured using double isotope labelling. Total bloodflow to the intestine was measured using an electro-magnetic flow meter. 133xenon clearance from theintestine was recorded as an estimate of functionalblood flow.

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The mean transit times of sodium tracer andxenon from the lumen to the blood were almostidentical at varying blood flow rates. At low flowrates bidirectional sodium fluxes were depressed butnet absorption was not impaired until blood flow fellbelow 10% of control values.

It appears that the relationship between bi-directional sodium fluxes across the intestinalmucosa and functional blood flow is closer thanpreviously suspected. This may be important in thepathogenesis of diarrhoeal states.

Reference

Goldberg. M., and Fine, J. (1945). J. clin. Invest., 24, 445-450.

The Effect of Intravenous Prostaglandin F22, on SmallIntestinal Function

J. H. CUMMINGS, G. J. MILTON-THOMPSON, J. A. BILLINGS,A. N. NEWMAN, AND J. J. MISIEWICZ (Medical ResearchCouncil Gastroenterology Unit, Central MiddlesexHospital, London, and Royal Naval Hospital, Haslar,Gosport, Hants) Oral and parenteral prostaglandinsmay cause diarrhoeal 2 but the effect of circulatingprostaglandins on small intestinal function has notbeen studied.We have measured the net movements of water

and electrolytes, the transit time and motor activityin the small intestine of 13 normal male volunteers.Using a three-lumen tube, the intestine was perfusedwith an isoosmotic solution before and duringintravenous administration of PGF22,. Intraluminalpressures were recorded with open-ended tips andtransit with a dye injection technique.

In six out of seven jejunal studies at doses of 0-28to 0-81 ,tg/kg/min of PGF22, no significant change innet movements of water and electrolytes werenoted. In one jejunal study at the highest dose netwater and electrolyte secretion into the lumen wasobserved. However, jejunal motility was inhibited atthe two highest doses.By contrast, in four out of six ileal studies in a

similar range of doses, significant net secretion offluid into the lumen occurred (P<0-01). Pressureactivity was inhibited (P<0001) but transit timesremained unchanged.These results suggest that circulating prosta-

glandins affect water and electrolyte transport, andthe motility of the small intestine. They also indicatethat the ileum is more sensitive and that motilityand absorption are affected independently.

References

,Misiewicz, J. J., Waller, Sheila L., Kiley, Nancy, and Horton. E. W.(1969). Effect of oral prostaglandin El on intestinal transit inman. Lancet, 1, 648-651.

'Matuchansky, C., and Bernier, J. J. (1971). Effects of prostaglandinE1 on net and unidirectional movements of water and electro-lytes across the jejunal mucosa in man. Gut, 12, 854.

The Effect of Glucagon and Secretin on Salt and WaterTransport in the Human Jejunum

T. HICKS AND L. A. TURNBERG (Division of Gastro-enterology, Manchester Royal Infirmary) The in-fluence of glucagon and secretin on salt and watertransport in the human jejunum was investigated inhealthy volunteers using a triple-lumen tubeperfusion technique. Intravenous infusions ofglucagon (0-7 ,,g/kg/hour) significantly reducedabsorption of NaCl, by an average of 0-29 m-equiv/hour/cm and of water by 2 ml/hour/cm of jejunumand in some subjects this resulted in a net secretion.The mean transit time was increased t y 100%, meanjejunal diameter by 50 %, andjejunal volume by 130%in response to glucagon. Higher doses ofglucagon didnot increase its effects on transport or motility. Allsubjects developed marked diarrhoea, while thosegiven doses greater than 3 p,g/kg/hour also developednausea and vomiting.

Intravenous infusions of physiological doses ofpure secretin (0 5 ug/kg/hour) influenced ion trans-port only in the most proximal jejunum (90 cm fromteeth) where it reduced absorption of NaCl by amean of 0 3 m-equiv/hour/cm of jejunum and it wasineffective in the mid jejunum (120 cm from teeth).Higher doses did not increase its effect on theproximal jejunum. Transit times were not clearlyaltered by secretin.The possible relevance of these findings to the

physiological control of jejunal ion transport and tothe diarrhoea associated with some pancreaticadenomata will be discussed.

Absorption of Amino Acids and Peptides in Man

D. B. A. SILK, D. PERRETT, AND M. CLARK (Departmentsof Gastroenterology and Medicine, St. Bartholomew'sHospital, London) Absorption of peptides mayoccur either by hydrolysis at the brush borderfollowed by absorption of the released amino acids,or by direct uptake of the peptide into the cell withsubsequent intracellular hydrolysis.Using a double-lumen perfusion technique in man,

we have studied the absorption of the amino acidsglycine and alanine and their two dipeptidesglycyl-alanine and alanyl-glycin>.

Alanine was asborbed faster than glycine from anequimolar amino acid mixture. Glycine was absorbedfaster from both dipeptides than from the aminoacid mixture, and this was greatest when the dipep-tide glycvl alanine was perfused. Alanine, on the

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other hand, was absorbed at comparable rates fromall three solutions. Free amino acids were seen in thelumen during perfusion of both dipeptides-higherconcentrations of both glycine and alanine werepresent during perfusion with alanyl-glycine.These results suggest that by altering the amino

acid configuration, the dipeptides are handleddifferently. This difference in handling would becompatible with both suggested modes of peptidetransport. On the one hand, direct uptake ofglycylalanine with minimal hydrolysis at the brushborder; on the other hand alanyl-glycine transportprobably involves both superficial hydrolysis anddirect uptake.

The Effect of Salazopyrin on Water and ElectrolyteTransport in the Human Colon Measured in vivo andin vitro

J. HARRIS, E. Q. ARCHAMPONG, AND C. G. CLARK(Department of Surgery, University College HospitalMedical School, London) One of the principalfunctions of the human colon is to absorb water andelectrolytes from its lumen. Its ability to do this ismarkedly impaired in both ulcerative colitis andCrohn's disease so that the large intestine becomesless absorptive and more secretory in function'.To study the action of salazopyrin on the net

transport and unidirectional fluxes of sodium,potassium and water, two methods of investigationhave been used: (1) the in-vivo technique of Duthie etal (1964)2, and (2) a modification3 of an in-vitroprocedure described by Ussing and Zerahn (1951).Measurements have been made in 18 patients (10controls, four ulcerative colitis, and four Crohn'sdisease).Both the in vivo and in vitro studies show that

control subjects absorb sodium and water andsecrete potassium into the lumen. In ulcerativecolitis and Crohn's disease net secretion of sodiumand water is found and potassium secretion isincreased. The addition of salazopyrin to the testsolution significantly increases the absorption ofsodium and water from the healthy colon but has noeffect on potassium transport. The effects of salazo-pyrin are even more marked on the diseased bowel,for in all cases net sodium and water secretion isconverted into net absorption within 10 minutes.These changes are accompanied by an alteration ofthe unidirectional fluxes across the mucosa.

These results suggest that salazopyrin, in additionto its immunosuppressive action, also has a localdirect effect on both healthy and diseased colonicepithelial cells.

References

'Harris and Shields (1970). Gut, 11, 27.2Duthie et al (1964). Gastroenterology, 47, 525.'Archampong et al (1972). Brit. J. Surg., 59, 314.

Comparison of Bowel Function after Colectomy andIleostomy or Ileorectal Anastomosis for InflammatoryBowel Disease

C. R. NEWTON (introduced by J. E. LENNARD-JONES)(Research Department, St. Mark's Hospital, London)A large fluid effluent from the small bowel canbe a problem after colectomy for inflammatorybowel disease. This study was carried out to see ifpatients with a large output differed from those witha smaller output in gut transit time or biochemicalcomposition of the effluent, and if the output afterileostomy differed from that after ileo-rectalanastomosis. Transit times were determined withpolythene shapes, and 24-hour ileostomy or stooloutputs were weighed, homogenized, and analysedfor pH, dry weight, sodium, potassium, calcium,magnesium, chloride, lactic acid, short chain fattyacids (with D. Gompertz, Royal PostgraduateMedical School, London), and faecal fat.

Twenty-eight inpatients were studied after colec-tomy and ileostomy and 19 after ileo-rectal anas-tomosis for inflammatory bowel disease. Theaverage ileostomy output was 697 g/24 hours, whichwas significantly greater than the average stooloutput of414 g/24 hours after ileo-rectal anastomosis(p < 0-05). Average daily sodium losses were 92m-equiv after ileostomy and 45 m-equiv afterileo-rectal anastomosis (p < 0-02). The mean sodiumconcentration in the ileostomy effluent was 127m-equiv/l as compared with 113 m-equiv/l afterileo-rectal anastomosis (p < 005) and conversely,the potassium concentration was 11 8 m-equiv/l afterileostomy and 21 2 m-equiv/l after ileo-rectalanastomosis (p < 0 05). Similar results were obtainedin 21 unselected, healthy outpatients, 11 with ileo-stomy and 10 with ileo-rectal anastomosis, who hadhad a colectomy for ulcerative colitis more than sixmonths previously. In both ileostomists and patientswith ileo-rectal anastomosis, 24-hour outputscorrelated with transit times and sodium andchloride losses but not with pH, potassium, calcium,magnesium, lactic acid, short chain fatty acid, orfaecal fat excretions.

These results suggest that a large fluid effluent isassociated with rapid transit and inadequateabsorption of sodium chloride and water. Ileo-rectalanastomosis may confer a biochemical advantageover ileostomy due to the sodium and water ab-sorbing capacity of the rectal remnant.

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856 The British Society of GastroenterologyDoes Oral Metoclopramide Increase Cardiac SphincterPressure?

J. B. DILAWARI AND J. J. MISIEWICZ (Medical ResearchCouncil Gastroenterology Unit, Central MiddlesexHospital, London) Oral metoclopramide (Maxolon)is frequently prescribed for heartburn. Althoughintravenous metoclopramide increases the loweroesophageal sphincter (LES) pressure in normalpeople', it is not known what is the magnitude andduration of response following oral administrationto patients with heartburn or regurgitation. We havemeasured pressures in the oesophagus, the LES, andthe stomach of 23 such patients before and after theingestion of a placebo (five patients) or 10 mg ofmetoclopramide (18 patients).

Intraluminal pressures were measured withperfused open-ended tips, positioned so that twotips were in the gullet, one in the LES, and thefourth in the stomach. Pressures were recorded for30 minutes before and for 90 minutes after, the drug.The placebo had no effect. Oral metoclopramide

raised the LES pressure (p <001 to < 0 001) within30 minutes in all but two of the patients. Although inindividuals at the time of maximal effect the LESpressure rose two or more times above basal for0 to 80 minutes (mean 22 ± 6 min), the averageincrease in the group amounted to only 6 mm Hg.Amplitude of oesophageal peristaltic waves wasincreased whilst gastric activity was stimulated inhalf the patients. These results suggest that oralmetoclopramide increases the cardiac sphincterpressure.

Reference

'Heitman, P., and Moller, N. (1970). The effect of metoclopramide ongastroesophageal junctional zone and the distal esophagus inman. Scand. J. Gastroent., 5, 621-625.

The Interpretation of Colonoscopic Biopsies ofPolypoid Lesions in the Large Bowel

R. H. RIDDELL AND T. MUTO (introduced by B. C.MORSON) (St. Mark's Hospital, London) Of over800 colonoscopic biopsies examined histologically atSt. Mark's during the past 18 months, 250 have beenfrom polypoid lesions. In addition, over 50 excisionbiopsies of polyps have been examined since theintroduction of the colonoscope diathermy snare.The success of these biopsies in the diagnosis ofpolyps and the relative merits of the differentcolonoscope biopsy forceps are discussed.The majority of single polyps sampled proved to be

adenomatous, but metaplastic, inflammatory, andbenign lymphoid polyps were frequent. Lymphoidpolyps of the terminal ileum nmust be distinguished

from chronic inflammatory bowel disease. Onesubmucous lipoma and a single case of malignanttransformation of an adenomatous polyp were seen.Cases with multiple adenomas, metaplastic polyps,or Peutz-Jeghers polyps were also examined.

It is concluded that accurate differential diagnosisof colonic polyps is possible from biopsies obtainedusing the available biopsy forceps. The use of spikedforceps was helpful for sampling large polyps butless desirable for small polyps. There are alsolimitations on interpretation of colonoscopic biopsiesand not all frank carcinomas biopsied actuallyshowed unequivocal carcinoma on forceps biopsy.Close correlation between the clinician, radiologist,and pathologist is never better exemplified than inthese cases.

Comparative Study of the Principal Gastric Glyco-proteins Isolated from Gastric Aspirates of Normal,Neoplastic, and Foetal Gastric Mucosae

J. SCHRAGER (The Group Laboratory, Royal AlbertEdward Infirmary, Wigan) Proteolysed four normal,20 neoplastic, and six foetal gastric mucosae wereinvestigated. The procedures of isolating the glyco-proteins and the determination of their carbohydrateand amino acid composition and the method usedto study structural features of the isolated glyco-proteins have been described1.2 3.The carbohydrate and amino acid composition of

the glycoprotein isolated from the normal gastricmucosae was virtually the same as the principalgastric glycoprotein obtained from gastric aspirates.Galactose, fucose, glucosamine, and galactosaminewere present in approximate molar ratios of 4:3:3:1.Superimposed on the basic common structure wereadditional sugar residues associated with blood groupspecificity which was the same as that of the hosts'red cells.The acid hydrolysates of the 20 glycoproteins

isolated of extracts from gastric neoplastic mucosaecontained the same range of sugars but also revealedsignificant differences: (a) The quantitative rela-tionships of the carbohydrate components of theneoplastic glycoproteins showed variations dividingthe samples investigated into four groups, eachgroup with a distinctive and constant carbohydratecomposition:Group 1 galactose/glucosamine/galactosamine

= 1:1:1 (1 case)Group 2 galactose/glucosamine/galactosamine

= 2:1:1 (1 case)Group 3 galactose/glucosamine/galactosamine

= 3:2:1 (9 cases)Group 4 galactose/glucosamine/galactosamine

= 4:3:1 (9 cases)

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(b) The blood group specificity of 11 out of the 20cases investigated differed from that of the hosts' redcells.The extracts of the gastric mucosae from the two

foetuses 16 weeks and the four foetuses 20 weeks oldshowed the same carbohydrate composition whichhad the same quantitative relationship as the neo-plastic glycoproteins of group 1 (1:1:1) and group 2(2:1 :1) respectively. The amino acid composition ofall foetal glycoproteins were similar to that of thenormal and neoplastic glycoproteins.

It is suggested that the mutation of the normalmucous cell to a neoplastic cell has changed theenzymic system synthesizing the glycoprotein, thechange consisting in the varying losses of the numberof repeating units glucosamine-galactose dividingthe specimen investigated into groups with respect tothe number of units composing the carbohydrateside-chains, the groups differing in one or multipleunits of the disaccharide glucosamine-galactose(except group 1 which differed from group 2 by onlyone galactose residue).

The change in the blood group specificity involvedall four blood groups. It is interesting to note that thechange from blood group 0 to A would involve theintroduction of a new enzyme linking the terminalgalactosamine to the carbohydrate side chain.The results of this investigation would suggest that

the foetal mucous cell at 16 and 20 weeks aftergestation has not yet developed the full complementof enzymes needed to synthesize the complete sidechain hence its shortness and difference from thenormal glycoprotein.

References

'Schrager, J., and Oates, M. D. G. (19A). The carbohydrate com-ponents of hydrolysates of gastric secretion and extracts frommucous glands of the gastric body mucosa and antrum.Biochem. J., 106, 523.

'Schrager, J., and Oates, M. D. G. (1971). The isolation and partialcharacterisation ofthe principal gastric glycoprotein of'Visible'Mucus. Digestion, 4, 1-12.

'Schrager, J., and Oates, M. D. G. (1971). The isolation and composi-tion of the major glycoprotein from human gastric aspirates.Gut, 12, 559-569.

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The British Society of Gastroenterology - GutGut, 1972,13, 836-857 TheBritish Society...

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