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·DIFFUSE LESIONS
OF THE STOMACH
An Account uith Special Reference
to the I alue of Gasinıc Biopsi
BY
IAN I WOOD
MD (Melbourne) FRCP FRACP
Assistant Director of the Walter and Eliza Hal Institute
of Medical Research Royal Melbourne Hospital and
Head of the Clinical Research Unit of the Royal
Melbourne Hospital and the Walter and Fliza tlalt Inst tute
AND
LION I TAIT
MB BS BSc (lelbourne)
Pathologist to the clinical Research Unit of the Royal
Melbourne Hospital and Walter and Elza Hall Institute
Melbourne Victoria Australia
LONDON
EDWARD ARNOI D (PUBLISHERS) LTD

·©1) Ilood and L I Taft 1998
Tirst published 1993
Vade and printed on Creat B itain by
illam Closes and Sms limited Loni in I Beccles

·TO
I NI BURNET, TRS
WHO OFTEN TOLD LS THAT
NEW NOWLEDGE FOI LOW ED CLOSELY
IN THE WAKE OF A
New IECINIQUE

·No text on this page.

·I 1 I 2 11 CONTENTS Chapter Page METHODS OF INVESTIGATION Problems of the early investigators Symptomatology and clinical investigation Test meal examination 3 Radiology 4 Gastroscopy 5 Gastric biopsy 6 Technique of gastric biopsy with the flexible gastric biopsy tube 7 Preparation and staining of biopsy specimens for microscopic examination The appearance of the normal gastric biopsy 13 The indications for gastric biopsy using the flexible tube 15 Complications of gastric biopsy with the flexible tube 16 Gastric cytology 17 ACUTE GASTRITIS Structural changes Symptomatology Aetrology 22 Treatment 23 3 CHRONIC GASTRITIS 24 Structural changes 24 Symptomatology of chronic atrophic gastritis 33 Aetiology of chronic atrophic gastritis 37 Relationship of chronic gastritis to peptic ulcer 45 Relationship of chronic gastritis to carcinoma Relationship of chronic gastritis to anaemia Treatment 51 2 18 18 20 46 48 11 ·V111 CONTENTS Pa e Chapter + DIFFUSE GIANT HYPERTROPHIC GASTRITIS 53 57 5 GASTRIC ATROPHY PERNICIOUS ANAEMIA AND SUBACUTE COMBINED DEGENERATION OF THE CORD Structural changes of gastric atrophy and per nicious anaemia Symptomatology of gastric atrophy and pernicious 57 anaemia 61 Aetiology of gastric atrophy and pernicious anaemia 64 The relationship of the gastric changes to pernicious anaemia subacute combined degeneration of the cord and other megaloblastic anaemias 66 Can pernicious anaemia be diagnosed in the pre sence of normal acıd secretion and normal appearance of the gastric biopsy > 68 Definition of pernicious anaemia 69 Treatment of gastric atrophy pernicious anaemia and subacute combined degeneration of the cord 69 EPILOGUE 72 REFERENCES 73 INDEL 82 ·PRETACE In 1946 our Clinical Research Unit was formed by Sir Mac farlane Burnet FRS Director of the Walter and Eliza Hall Institute to work in the Institute and in the wards of the Royal Melbourne Hospital Diseases of the gastro intestinal tract were chosen for study and we soon encountered middle aged or elderly patients who had suffered from flatulent dyspepsia for many years They exhubited diffuse epigastric tenderness and an absence of the usual causes of dyspepsia such as ulcer cancer gallstones and pancreatitis We first studied the gastric secretions and found them to be depleted and in 1948 ne developed the technique of gastric biopsy using a flexible gastric biopsy tube designed in the unit (Wood Doig Motteram and Flughes 1949) Now some 10 years after our study began we are privileged to present our collected observations in this book Much of the data has been selected from our published papers which have appeared in Australia Englınd and the United States of America We have added a limited number of observations made by other workers in this field many of whom have generously helped us over the years Our special thanks are due to Dr Avery Jones and Professor Magnus in England Dr Walter Palmer and Lieutenant Colonel Eddy Palmer in the United States of America and in Australia to members of the Medical Staff of the Royal Melbourne Hospital particularly Dr W E hing Mr J O Smith Mr Grayton Brown Dr E Graeme Robertson Dr D C Cowling and finally and most gratefully to our many colleagues who have worked in our Clinical Research Unit over the years particularly Dr R Doig Dr S Weiden Dr R Motteram Dr J Funder Dr E Finckh Dr R Joske and Dr I Mackay together with their technical assistants Miss E Davis and Miss E Larle Mir E Matthaer of the Melbourne University and Mr R Ingles of the Royal Melbourne Hospital kindly helped with the photography The title Diffuse Lestons of the Stomach has been u ed to include diffuse gastritis in its acute and chronic forms gastric atrophy and that rare disease diffuse giant hypertrophic gastritis It naturally includes pernicious anaemia and excludes the localised lesions of

·PREFACE
X
peptic ulcer and cancer although some reference is made to their
relationship to gastritis
All the studies have been undertaken in adults as no children
are treated in the Hospital It may well be that some of the lesions
seen in adult life have begun during childhood or even in the
prenatal period

·CHAPTER 1 METHODS OF INVESTIGATION In later years Problems of the early investigators For many centuries physicians considered dyspepsia was fre quently caused by diffuse inflammation of the stomach "The celebrated Broussais (1831) initiated widespread belief in the occurrence of chronic phlegmasiae or inflammations of the stomach by reporting observations which he made while military surgeon to the army of Napoleon However many factors confused early investigators in this field especially their failure to appreciate the gross changes which took place in the gastric mucosa soon after death recourse was made to the study of specimens obtained at surgical operation but even here considerable changes were found to be brought about by the manipulations by the surgeon An apprecia tion of these problems created a wave of disbelief in the prevalence of gastritis especially in its chronic stage Moreover even when physicians did accept its presence they were loath to accept it as a cause of chronic dyspepsia A challenge to this disbelief came at the turn of the present century led by the splendid studies of Faber (1935) who prevented post mortem digestion of the gastric mucosa by introducing formalın immediately after death But this post mortem material could still be criticised on the grounds that structural abnormalities might first appear during the terminal illness (see Chapter 3) There was an urgent need for fresh undamaged specimens of gastric mucosa which could be placed immediately in a fixative solution and prepared for histological examination Moreover it would be of considerable value of these specimens were obtained with minimal discomfort and risk to the patient for this would enable a comprehensive study to be made not only in health and disease but also over a number of years in the same in dividual It is our sincere belief that the technique of gastric biopsy first ·2 METHODS OF INVESTIGATION described in our Unit in 1949 has made a liberal contribution to this urgent need In this chapter the methods used in our studies are discussed Symptomatology and clinical investigation In addition to the history and physical examination it may be necessary to employ a fractional test meal ray by barium meal and even gastroscopy and gastric biopsy to establish the diagnosis of gastritis and exclude other diseases with similar clinical features Clinical history The taking of a comprehensive history is of considerable importance It may call for much time and patience from the physician but the information is rewarding The family history social history and the nature of past illnesses may be of value In taking the history and making the physical examination it should be constantly recalled that diffuse lesions of the stomach have to be differentiated from gastric and duodenal ulcer cancer of the stomach chronic pancreatitis and other diseases involving the upper portion of the abdomen Pure functional dyspepsia will always present a problem in diagnosis often true gastritis is present with considerable functional overlay Pain and discomfort The nature site and duration of the dis comfort should be ascertained together with its provocation by food physical exertion or mental stress The type of food which causes pain is of interest-pickles pastry and sherry are often incriminated The relief of pain by alkalis dilute hydrochloric acid or food should be ascertained Diet The appetite and the quality and quantity of the food consumed should be recorded together with the general eating habits In lustralia as indeed in many other parts of the world the consumption of alcohol is often excessive and this may cause gastric disturbances due either to its direct effect on the gastric mucosa or to its influence on the diet Physical examination In carn ing out the general physical examination the local signs of gastric disease should be noted and also a special search should be made for lesions elew here in the hody which may be associated with ga tritis as they may share in a common aetiolog, I hus hepatomegaly and peripheral neuritis may suggest alcoholism and malnutrition ·VIETHODS OF INVESTIGATION 3 There may be premature greying of the hair atrophy of the tongue recurrent stomatitis haemorrhagic gums carious teeth or complete dental extraction anaemia purpura pigmentation or vascular spiders in the skin cardiac enlargement and tachycardia from vitamm deficiency and finally Peripheral neuritis or early igns of subacute combined degeneration of the cord Examination of the upper abdomen may reveal the diffuse epigastric tenderness of gastritis in contrast to the more local tenderness of peptic ulcer gall bladder disease or perhaps cancer A mass in the epigastrium may be hepatic enlargement hy datid disease or cancer of the stomach Rarely it may be a tumour of the body of the pancreas or enlargement of the retroperitoneal glands A more laterally placed mass may be caused by a palpable gall bladder splenic enlargement or a renal tumour Test meal examination The histamine test meal is a most satisfactory method of determining gastric secretion and thereby obtaining some evidence a to the state of the gastric mucosa There is good correlation between the test meal and the findings at gastric biopsy as is clearly shown in fig 1 (Wood et al 1949 Joske et al 1995) (see Chapter 5) Case Distribut on 75 No m ! 50- Limts 25 Withi wwww Supericial 75 Gastritis EL At ophc Gtritis 50 251 75 50- 25-1 Mamsen Gastrie 75 At ophy 50 25 its >60 21 60 1 20 0 Mar mum ed acid Iter Hist mne Fig I The elutions) ip bit een tie finden son gastric bropsy and !) la tamine test mal With the in raen the inflammatory r action and atrophy of the gastric mucosa there 13 a cor esponding fall the secret on of acid There were 27, biopsi s within normal fun ts 296 showing supe ficial gastrit 172 atrophc gastritis and 41 gastric atrophy (Data from Joshe Tinckh and Wood 1995) In most of our series a standard subcutaneous dose of o9 mg of histamine acıd phosphate was used This stimulus produced a satisfactory rise in acid in normal controls and high levels in cases ·4 METHODS OF INI ESTICATION of duodenal ulcer, but without producing unpleasant histamine effects in the patient Before giving histamine the stomach was emptied by passing a fine stomach tube such as the Rehfuss model, and then after giving histamine it was emptied at half hourly intervals for one and a half hours In some cases of sus pected pernicious anaemia the maximum secretory response was evoked by hay s method (1953) when an antihistamine drug was given to counter the general systemic effects of a liberal dose of histamine (04 mg histamine acid phosphate per 10 kg body weight) as the antihistamine drugs do not inhibit the histamine stimulus to gastric secretion Hypoglycaemia caused by intravenous insulin stimulates gastric secretion by way of the vagus nerve and an insulin test meal (insulin 15 units intravenously) is of value after vagotomy to assess the degree of completeness of the nerve section An overnight test meal reveals the resting secretion over a long period continuous gentle suction or 2 hourly aspiration being used The tubeless test meal in which the excretion of uropepsin is estimated after histamine stimulation has not been used in this series as it is less accurate than the direct measurement of gastric secretion (Levy and Levine 1996) however it is of value as a screening test for lowered gastric secretion The plasma pepsinogen level may be a guide to gastric secretion Iloar and Browning (1996) claim that it is superior to urinary pepsinogen determination A tubeless test meal using cation exchange resins may also be used as a screening test for anacıdıty (Rechtschaffen and Wein garten 1957) Radiology The radiological examination is of considerable value in the diagnosis of localised lesions of the stomach and duodenum notably peptic ulcer cancer diverticulum and prolapse of gastric mucosa through the pylorus Flowever the value of radiology in detecting diffuse lesions of the stomach is mostly confined to the rare disease diffuse giant hypertrophic gastritis (see Chapter 4) It is of little value as a method of detecting chronic atrophic gastritis or gastric atrophy (Joshe et al 1993) Furthermore in our experience the diagnosis of hypertrophic gastritis based on the findings of pronounced gastric rugae has been prosed by ·METHODS OF JESTIGATI0N 5 biopsy to be incorrect except in diffuse giant hypertrophic gas tritis After considerable experience Eddy Palmer (1954) has reached a somewhat similar opinion to that held in our unit Gastroscopy Most patients in our series were examined by gastroscopy "The technique consists of spraying the throat with local anaesthetic (cocaine 19 ml of 3 per cent with adrenalin i 10 000) preceded by basal sedation with chlorpromazine 50 mg omnopon 20 mg and hyoscine o 4 mg The stomach is emptied by gravity using a large bore stomach tube and elevating the foot of the examination Couch The Hermon Taylor gastroscope was used in 95 per cent of our last 200 gastroscopies as it has a controllable lower segment which affords a good view of most localised lesions However in elderly patients especially in females over the age of 60 the less bulky Cameron model (Schindler design) was used to reduce the hazard of pharyngeal or oesophageal perforation We encountered only one such perforation in 661 gastroscopies "The patient recovered after drainage of a paraoesophageal abscess which developed in spite of ugorous treatment with antibiotics hatz et al (1996) described a massive pneumoperitoneum after gastroscopy This subsided with conservative treatment Gastroscopy may show congestion mucopurulent exudate and some petechial haemorrhages and even erosions in acute gastritis and during the acute relapses in chronic gastritis In pernicious anaemia with gastric atrophy the atrophy may be observed in the body of the stomach especially in the upper segments where the underlying veins are revealed However gastric biopsy has provided evidence that gastroscopy often fails to determine whether chronic gastritis is present Thus Joske et al (1995) reviewed 258 instances where gastric biopsy had been performed within 2 weeks of the gastroscopy often at the In 164 instances where gastroscopy reported the gastric mucosa to be normal gastric biopsy revealed normal gastric mucosa in only 87 instances whereas superficial gastritis was present in 56 atrophic gastritis in 26 and gastric atrophy in 5 Although these findings could be partly due to a sampling error in the gastric biopsies the study does emphasise the limitations of gastroscopy as a method of diagnosing chronic gastritis same time ·6 METHODS OF INVESTIGATION Gastric biopsy In 1948 one of us (I J W) observed that fragments of gastric mucosa of sufficient size for microscopic examination might be obtained during a histamine test meal when vigorous suction was exerted through the stomach tube during the collection of the gastric juice Moreover it was found that better fragments were obtained when negative pressure was exerted and then the tube was suddenly jerked out so as to dislodge a fragment "These fragments could be fixed immediately in formalın embedded in paraffin cut and stained However they contained mostly super ficial epithelium Our initial observation was subsequently found to have been recorded by Linhorn in 1894 and later by Hawksley in 1939 who subsequently heard of Einhorn s classical observation (Hawksley and Cooray 1948) The dezelopment of the flexible gastric biopsy tube Our findings of such fragments stimulated the development in our unit of the flexible gastric biopsy tube which now has been used by the unit in carrying out 1736 successful biopsies It has also been used in its present or a modified form by other workers in many parts of the world notably by ID Palmer (1990) in the United States of America who has made many excellent contributions to the knowledge of gastric histopathology Others who have made valuable studies with this biopsy tech nique either in the form described or with a modified model include Badenoch and Richards (1993) Rubins et al (1993) Coghill and Williams (1955) Ldwards and Edwards (1956) Markson and Davidson (1996) and Shiner and Doniach (1957) Chez alter Jackson and gastric biopsy I he credit must be given to Chevalier Jackson the dozen of endoscopists for first using gastric biopsy under direct vision and establishing it as a valuable and safe method of intestigating diseases of the stomach In 1906 he first performed gastric biopsy using forceps through his rigid oesophagoscope and later stated In malignant diseases a specimen may be taken with little risk in fungating conditions but in flat ulcerations suspected of malignancy the biting out of the edge of the ulcer though very easy of accomplishment is unjusti fiable (Jackson 1907) His work prosed of considerable value and in 1935 he and his son reported The taking of tissue through the open tube gastroscope is casily done and hundreds of cases without a single complication have demonstrated its freedom from ·VETHIODS OF INTESTIGATION 7 danger when done with proper precautions (Jackson and Jackson 193) In 1937 Schindler described the flexible gastroscope a momen tous discovery in the field of gastroenterology Later Hermon Taylor designed a gastroscope with a controllable lower segment which afforded the operator a more extensii e text of the stomach Schindler s discovery led to the development of the operating gastroscope containing a channel through which forceps can be manipulated under direct vision Now many but by no means all of the technical difficulties have been overcome following the researches in the United States of America by Renamore (1940) kenamore Scheff and Womach (1946) Benedict (1948) and Tomenius (195) Most of our studies described in this book were made with our flexible gast ic biopsy tube the Hermon Taylor gastroscope or the Benedict operating gastroscope Each instrument has its oun particular virtues and limitations For diffuse lesions of the stomach the flexible gastric biopsy tube obtains one or two satisfactory fragments of gastric mucosa with minimal inconvenience to the patient In contrast to this the Benedict operating gastroscope is more bulky and may cause considerable discomfort during and after the examination Hou ever it enables fragments of mucosa to be obtained under direct vision from most parts of the stomach although fragments from antral lesions are difficult to obtain This type of instrument is thus essential for obtaining tissue from local lesions such as ulcer We have used the Benedict operating gastroscope on 53 occasions after preliminary inspection with the Hermon Taylor instrument Successtui biopsies were obtained on 40 Occasions and there were no complications or carcinoma Technique of gastric biopsy with the flexible gastric biopsy tube The technique of gastric biopsy using the flexible gastric biopsy tube designed in our unit is described in detail as this method is most suitable for studying diffuse lesions of the stomach This procedure has been the piece de resistance of our work The examination can be made on out patients so long as they are not unduly debilitated or anaemic Simi hey

·METHODS OF INVESTIGATION
mu
Fig 2
Fler ble gastric b psi suhe
Top illustration Ih complete bi pss tub with op ratin, hand and war (t P
1 ft) lat ral tube le ding to an thaust pump (top) length ftub ith hste
marks at le els 1 I and III and the op ating he j flor) (B)
Cettre ell est att m Operating head with t minal scre
(1 ft)rmi d allor ni
the cyl ndrical hlad to be thrust do n and uns te edfm the p rating
This enables the biopsy fragment to be btain (*11)
The cutting eda
Lotser illustrat Operating head assembled
Iາຄ.
drical knife blade is si il le throuch the later Ihr
(th

·YETHODS OF INVESTIGATIO 9 biopsy tube consists of a length of coiled Bou den wire covered by plastic tubing to render it airtight (fig 2) (Wood et al 19494 and B Doig and lood 19,2) * At the lower end a steel cylinder is attached which houses a cylindrical knife blade with a proximal cutting edge The end of the chnder is closed sith a terminal screw and its side is pierced by a countersunk circular lateral hole id inch in diameter through which a fragment of gastric mucosa may be sucked The fragment is then cut off by pulling up the cylindrical knife past the lateral hole by means of a length of wire which traverses the tube to emerge through a vacuum tight gland at the proximal end Suction is applied with a pump through a lateral tube which emerges close to the proximal end The overall length of the biopsı tube is 100 centimetres and levels I II and III are marked to 5) and 63 cm respectively from the lateral hole in the operating head Technique The patient is examined fasting and no sedative is gwen The pharynx is anaesthetised by a gargle with 1, mi of 3 per cent cocaine with adrenalin i 10 000 A fine stomach tube is passed into the stomach with the patient sitting The stomach is then completely emptied by the patient lying prone on a couch which is inclined to an angle of 30 with the head dou nmost and by applying suction to the tube with a 20 cc syringe while it is slowly withdrawn Should air or fluid remain in the stomach the chance of obtaining a fragment of mucosa is greatly diminished The flexible gastric biopsy tube is then passed with the patient lying on his left side the passage through the pharynx being aided by vigorous swallowing Rarely the tip is arrested by spasm at the cardia and this can usually be overcome by encouraging deep breathing and swallowing If still arrested it may pass if the patient sits erect or it may be necessary to administer an inhalation of amyl nitnte The tube is introduced past marh I till mark II approaches the lips The fragment is then cut off by (a) forcing down the blade by means of the control wire to open the lateral hole (b) immediately exerting negative pressure by means of the exhaust pump to suck in the fragment (c) firmly pulling up the blade The tube is then withdrawn 2-4 cm and rotated 180 in order to engage a new area of gastric mucosa and the cutting is repeated to obtain a second fragment * This flexible gastric biopsy tube is manufactured by Drug Houses of Australia Ltd Alfred Place Velbourne Victoria Australia ·IO METHODS OF INVESTIGATION The tube is removed for inspection and the patient instructed to lie still The fragments of gastric mucosa are located by removing the terminal screw forcing out the cylindrical knife blade and unscrewing the blade The fragments will be found either inside the cylindrical knife blade or more frequently within the steel cylinder which houses the blade They are dislodged from the cylinder by directing a current of air down the tube The fragments are immediately fixed in 10 per cent formol salıne thus providing excellent material for histological examina tion The instrument is immediately cleaned by Alushing 1 through with a liberal quantity of water and then drying with a stream of air The tube can then be sterilised with Zephiran I 100 and the knife blade with alcohol The instrument is then placed in a sterile cloth bag It is essential that the knife blade be sharpened after every five operations After the biopsy has been performed the patient has complete rest lying down for a period of 4 hours Sips of milk are given after 1 hour and a light meal at the end of 4 hours Out patients are then sent home to rest arrangements being made for them to be driven home shey return to full work on the following day but within 48 hours thev visit the Hospital for a medical inspection to exclude haemorrhage In our cases gastric biopsy was usually a painless procedure on rare occasions a minor dull burning sensation was experienced but this was usually caused by vigorously thrusting the tube too far into the stomach thus everting pressure on the greater curature for it was immediaten relieved by withdrawing the instrument 2-3 cm After the operation was completed a few patients had minor epigastric discomfort for 12-24 hours but the significance of this was difficult to assess as most of them were being investi gated for a similar complaint In general it may be sard that gastric biopsı performed with the flexible gastric biopsy tube is not a major undertaking Vost patients are quite prepared to have it repeated at intervals of 1 or 2 vears The efficiency of gastric biopsy e ith the flexible tube The efficiency of this method is shown by the combined experience of a number of operators in our unit Between the years 1948 and 1997 there were 1949 attempts at gastric biopss with the flexible tube and 89 per cent were successful The unsuccessful attempts were duc to failure to obtain a suitable fragment in 6 per cent and the ·METHODS OF INVESTIGATION II obtaining of oesophageal mucosa in 5 per cent The 1736 success ful biopsies were carried out on 1046 patients many patients haung more than one biopsy Thus in one patient 15 successful biopsies were carried out over a period of 8 years Sampling error As the area of mucosa examined in a single biopsy is so small it is inevitable that a sampling error occurs To minimise and measure this error usually 2 fragments of mucosa are obtained from different portions of the body of the stomach with each passage of the biopsy tube Joske et al (193) found that of 726 cases in 738 per cent the appearances in the 2 frag ments were similar while in 26 2 per cent there were sufficient differences between the fragments to suggest that the changes were patchy Similarly of 123 patients in whom senal gastric biopsies were carried out 764 per cent showed substantial agreement in histology while 23 6 per cent did not Some of the latter were due to known local lesions (uicer carcinoma) and in others they were related to the changing course of the illness Studies of operation and autopsy material reveal that gastritis usually involves the body of the stomach fairly diffusel (Hebbel 1949 Williams 19,0) Furthermore it has been found that the re uits of the histamine test meal and the biopsy appearance are related in that the lower the gland content of the section the lower the acıdıty and output of the gastric juice (Funder and Weiden 1992) Preparation and staining of biopsy specimens for micro scopic examination The fragment of gastric mucosa obtained by the flexible biopsy tube consists of a disc of tissue approximately 2 mm in diameter and o 5 mm in depth (fig 3) Immediate fixation is carried out in 10 per cent formal saline for 6 to 12 hours It is then prepared for paraffin embedding in the routine manner It is essential to obtain vertical sections of mucosa Should difficulty be experienced in achieving this the fixed specimen may be cut perpendicularly to the surface with a sharp scalpel and appropriately placed in the molten paraffin during embedding Sections 5 x in thickness are cut mounted and stained with eosin and haematorylin haematorylin and Mayer s mucicarmine for detecting alterations in the mucus secreting cells and the tri chrome stain of Motteram (1921) which is a modification of that

·12
METHODS OF INVESTIGATION
used by Bowie and Vineberg (193)) The trichrome stain is most
informatie as it clearly identifies the chief and parietal cells It
is used as follows
--
Fig 3 Amalg strieb psi / agnient obtained with the flexible gastric biopsy
tube to sho the spe imen of mu osa obtained (eosin and h ematorylin ~ +5)
Reagents for trichrome stain
1 Pepsinogen stain Stoch solution
Methyl volet 6B (1 per cent in aqueous solution)- 100 ml
Orange G (o 5 per cent in aqueous solution)100 ml
Vir allow to stand overnight centrifuge and wash the pre
cipitate 6 times
Dissolve the precipitate in 100 ml ubsolute
ethyl alcohol
For use take 2 parts of the stock solution and add one part of
distilled water The stock solution is quite stable in a well
stoppeted bottle
2 Ponceiu-fuchsın--phloxine
Ponceau de vilıdınc (1 per cunt in aqueous solution)-G mi
Acid fuchsin (1 per cent in aqueous solution)-2 ml

·METHODS OF INVESTIGATION 13 Azophloxine (o 5 per cent in aqueous solution)- 2 ml Acetic acid (1 ml glacial acetic acid in 1500 ml water)–88 ml 3 Methyl green (1 per cent in aqueous solution) Staining method for trichrome stain 1 Pepsinogen stain-70 ininutes in a Coplin jar 2 Decolourise with 70 per cent ethyl alcohol until the violet colour remains in the chief cells only 3 \lash with water 4 Ponceau--fuchsin-phloxine—10 seconds Wash with water 6 Methyl green--ho seconds 7 Differentiate rapidly with 95 per cent ethyl alcohol 8 Dehydrate with absolute alcohol 9 Tylol 10 Mount in Canada balsam Results of trichrome stain Pepsinogen granules purple parietal cell cytoplasm red Paneth cell granules dark red nuclei bluish green goblet cell mucus green The appearance of the normal gastric biopsy Detailed accounts of gastric cytology have been given by Bensley (1928) Plench (1932) and Maximow and Bloom (1952) Microscopic examination of biopsy fragments from the body of the normal stomach shows the mucosa to consist of a dense aggrega tion of regular branched tubular glands opening through a neck into the foreolae gastrıcae or gastric pits (fig 4) The epithelium of the pits and glands is supported by a basement membrane formed by a condensation of the lamına propria the glands extend ing down to the muscularis mucosae The average depth of the processed section from the surface to the inner aspect of the muscularis mucosae is o 54 mm (Joske et al 1955) The pits extend down into the mucosa for a distance of one third to half of its depth and their lumen (10-40 44) may be wider than that of the glands The superficial epithelium lining the surface of the mucosa and extending into the pits consists of a single layer of regular tall columnar epithelium with small round or oval basal nucle and a pale eosinophilic cytoplasm containing a theca of mucigenic granules which stain with mucicarmine Goblet cells are not present in the normal gastric mucosa Smaller mucigenic cells are also present in the necks of the glands Mucus ·14 METHODS OF INVESTIGATION may be visible in the lumen of the pits forming an adherent layer on the superficial epithelium Bensley (1928) found mitoses in the cells lining the bases of the pits so that replacement of the rapidly shedding gastric epithelium probably occurs by multiplication of the cells in these areas This is bome out by the progressive differentiation in the cells from the depths of the pits to the surface, sometimes becoming more pro nounced during recovery from injury (Motteram 1951) TVe have not encountered obvious mitoses in the bropsy specimens prepared by our technique but [ Palmer (1954) has reported an excellent example in a case of acute alcoholic gastritis The parietal or acid secreting cells are more numerous in the superficial portion of the glands polyhedral in shape with the deeper cells tending to be displaced laterally from the lumen of the gland Their cytoplasın 15 eosinophilic The pepsinogen secreting or chief cells are more numerous in the deeper portion of the glands cuboidal or lou columnar in shape with basal nucles and granular cytoplasm Argentaffine cells are not seen in sections stained in the manner described above In the antrum and pyloric areas the pits are deeper and the glands here consist of coiled tubules lined by low columnar or cuboidal cells with basal nuclei and a pale granular cytoplasm which stains with mucicarmine They resemble the Brunners glands of the duodenum Interstitial cellularity is more pro nounced The glands in the region of the cardia are similar in appearance to the glands of the antrum The lamına propria is a delicate reticulum containing a few fibroblasts plasma cells and lymphocytes Capillaries and lymphatics in this area are occasionally apparent in the sections Occasionally a small lymph follicle is present in the deeper portion of the mucosa In the antrum interstitial cellular infiltration is more pronounced The muscularis mucosae forms a lamına at the base of the glands sending an occasional fibre up into the lamına propria between the glands In the biopsy the circular and longitudinal fibres are not seen as such because of the random orientation of the fragment In some biopsies the connectie tissue and small vessels of the submucosa can be seen Artefacts due to the suction of the biopsi cylinder include small extravasations of red cells under the superficial cpithelium and the aspiration of epithelial or gland cells into the lumen of the glands or pits In abnormal specimens both these phenomena are more ·Fug 4 Normal gastric mucosa in a gastric biopsy With the trichrome staid the panietal (red) and chief cells (purple) are easily distinguished in the glands (Trichrome stain x 80 ) Fig 5 Chronc atrophic ga Iritis zith moderate atrophy Patchy intestin metaplasia with goblet cells in the superficial epithel um The gastric pits are d storted th glands are reduced in number and cont in non spec fic cells The famna poprials nfiltrated with inflarnmatory cells ('Trichrome stain x 80 ) Fug 6 Gast ic alt phy. The bropsy shows d ffuse int stinal metaplasia and compl te atrophy of the glands (Trichrome stain x 110 ) ·14 METHODS OF INVESTIGATION may be visible in the lumen of the pits forming an adherent layer on the superficial epithelium Bensley (1928) found mitoses in the cells lining the bases of the pits so that replacement of the rapidly shedding gastric epithelium probably occurs by multiplication of the cells in these areas This is borne out by the progressive differentiation in the cells from the depths of the pits to the surface, sometimes becoming more pro nounced during recovery from injury (Motteram 1991) We have not encountered obvious mitoses in the biopsy specimens prepared by our technique but I Palmer (199+) has reported an excellent example in a case of acute alcoholic gastritis The parietal or acıd secreting cells are more numerous in the superficial portion of the glands polyhedral in shape with the deeper cells tending to be displaced laterally from the lumen of the gland Their cytoplasm is eosinophilic The pepsinogen secreting or chief cells are more numerous in the deeper portion of the glands cuboidal or los columnar in shape with basal nuclei and granular cytoplasm Argentaffine cells are not seen in sections stained in the manner described above In the antrum and pyloric areas the pits are deeper and the glands here consist of coiled tubules lined by low columnar or cuboidal cells with basal nuclet and a pale granular cytoplasm which stains with mucicarmine They resemble the Brunner s glands of the duodenum Interstitial cellularity is more pro nounced The glands in the region of the cardia are similar in appearance to the glands of the antrum The lamina propria is a delicate reticulum containing a few fibroblasts plasma cells and lymphocytes Capıllaries and lymphatics in this area are occasionally apparent in the sections Occasionally a small lymph follicle is present in the deeper portion of the mucosa In the antrum interstitial cellular infiltration is more pronounced The muscularis mucosae forms a lamına at the base of the glands sending an occasional fibre up into the lamına propria between the glands In the biopsy the circular and longitudinal fibres are not seen as such because of the random orientation of the fragment In some biopsies the connective tissue and small vessels of the submucosa can be seen Artefacts due to the suction of the biopsy cylinder include small extravasations of red cells under the superficial epithelium and the aspiration of epithelial or gland cells into the lumen of the glands or pits In abnormal specimens both these phenomena are more ·Fig 4 Vormal gastric mucosa in a gastric biopsy With the trichrome stain the panieta) (red) and chief cells (purple) are easily distinguished in the glands (Tnchrome stain x 80 ) F85 Chronic atrophic gastritis aith mod rate at ophy Patchy intestinal metaplasia with goblet cells in the superficial epithelium The gastric pits are distorted the glands are reduced in number and contain non specific cells The lamina propria is infiltrated with Inflammatory cells (Trichrome stain x 80 ) Gastric at ophy. The biopsy shous diffuse intestinal metaplasia and komplete atrophy of the glands (Trichrome stain x 110 )

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·METHODS OF INI ESTIGATION 15 pronounced and may reflect actual changes of this nature or the more ready production of such changes in the abnormal mucosa The indications for gastric biopsy using the flexible tube Gastric biopsy is of considerable value in determining the cause of chronic dyspepsia where neither ray nor gastroscopy reveals an ulcer or cancer Ilere a biopsy may aid in the diagnosis by showing active chronic gastritis with considerable atrophy of the parietal and chief cells Actue chronic gastritis may be the sole cause of the symptoms and signs It must be appreciated however that the biopsy per se does not exclude cancer Biopsy may also indicate gastritis as being the cause of chronic iron deficiency anaemia from continuing blood loss This blood loss is usually in minimal quantity but from time to time there may be a frank melaena and even a haematemesis Gastric biopsy may also aid in the diagnosis of subacute combined degeneration of the cord where examination of the peripheral blood and bone marrow reveals no clear evidence of pernicious anaemia and where the estimation of serum vitarnın B12 15 not available or is rendered valueless by previous injections of vitamin B, The more elaborate absorption tests following the oral administration of 5 cobalt labelled vitamin B, is also informative in these circumstances (Booth and Mollin 1956 Witt 1956) Gastric biopsy is contra indicated when there is clinical evidence of a bleeding tendency supported by laboratory tests Also neither gravely ill patients nor patients with severe anaemia should be examined in this way-the latter should first be treated by transfusion or other suitable means to relieve their anaemia This applies to cases of megaloblastic anaemia where the cause is in doubt Should it be true pernicious anaemia the gastric atrophy will remain unchanged in spite of full treatment with vitamin B, (Finckh and Wood 1953) (astric biopsy will also aid in determining the cause of achlor hydria for there is a close correlation between the gastric biopsy findings and the histamine test meal (fig 1) Thts was first shown by Wood Doig Werden and Moore (1949) and more recently by Shiner and Doniach (1997) who found good correlation between gastric biopsy and the secretion of acid and pepsin ·16 METHODS OF INVESTIGATION Complications of gastric biopsy with the flexible tube Haemorrhage into the lumen of the stomach was the only complication encountered in our series There was no evidence of gastric perforation-the instrument was designed to cut down to the muscularis mucosae and no deeper and this was confirmed by extensive preliminary trials on the bench using fresh specimens of stomach removed at operation Gastroscopy performed im mediately after biopsy revealed a minute lesion usually covered by blood clot, at the most there was minimal bleeding There was no evidence of persistent ulceration as judged by the absence of pain X ray examination gastroscopy or examination of the mucosa when subtotal gastrectomy for duodenal ulcer was per formed one week or more after the biopsy was taken However a small superficial healing lesion could usually be observed in a stomach resected 1 or 2 days after the biopsy Using the same model of the flexible gastric biopsy tube and working with cats Gunter (1950) made detailed observations on the rate of healing of the gastric mucosa after biopsy and found that a single layer of regenerating epithelium just covered the lesion in 3 days and experience with humans indicated a similar rate of healing Haemorrhage sufficient to cause symptoms of anaemia haemate mesis or melaena or a pronounced fall in haemoglobin occurred in only 10 of 1947 attempted biopsies 87 per cent of the latter pro viding suitable fragments of gastric mucosa Most haemorrhages occurred within 12 hours of the biopsy and caused weakness sweating and pallor followed by the passage of a melaena stool Rarely there was a small haematemesis Limited blood transfusion was required in only 2 of the ro patients ; of these was severely and chronically ill with subacute combined degeneration of the cord and bladder sepsis There were no fatalities In our series haemorrhage has been much less frequent since patients have been kept at strict rest in bed for 4 hours after making the biopsy and since biopsy has not been undertaken in patients showing the bleeding diathesis Markson and Davidson (1956) encountered 2 cases of haemate mesis in 111 gastric biopsies performed with the flexible tube one an elderly male with hypertension and renal insufficiency the other a middle aged female with untreated pernicious anaemia Both responded to blood transfusion Using a modification of the ·METHODS OF INVESTIGATION 17 flexible tube Rubin et al (1953) reported haemorrhage in 2 of over 200 biopsies and Coghill and lilliams (1955) recorded haemate mesis in 9 (2 i per cent) of 1189 attempted biopsies on 437 patients and also one case of perforation of the oesophagus C Palmer and Smith (1953) reported 2 patients who developed a submucosal haematoma but recovered with conservative treatment Shiner and Doniach (1957) performed 127 successful biopsies without any complications and there were few failures to obtain a suitable fragment The best results are obtained by gentle handling of the instrument till it is in position by keeping the head of the instrument stationary while the negative pressure is applied and the knife blade firmly pulled up ensuring that the knife is sharpened frequently and arranging that after the biopsy the patient has absolute rest for 4 hours And finally gravely ill patients and patients with a bleeding tendency should not be subjected to biopsy Such measures should reduce the complications to less than i per cent Severe complications should be rarely encountered Gastric cytology Because of our interest in gastric biopsy we have only had limited experience with the study of gastric washings Un doubtedly this method is of value in the detection of gastric cancer and even pernicious anaemia when it is performed by pathologists shilled in this procedure (11assey and Rubin 1954 Crozier et al 1956) ·CHAPTER 2 ACUTE GASTRITIS Structural changes Surely the most dramatic accounts of acute inflammation in the stomach have come from Beaumont (1833) who described the hyperaemia mucus patches erosions and diminution in secretion in the gastric fistula of Alexis St Martin follow ing strong alcoholic beverages and other dietary trauma and during acute febrile episodes These studies have been paralleled in the modern era by Wolf and Wolff (1943) who demonstrated that psychic stimule in their patient Tom produced acute inflammatory changes in the mucosa of his gastric fistula Gastroscopic appearances in acute gastritis have been recorded by Schindler (1922) and E Palmer (1991) while haematogenous gastritis in fatal infections has been found by Limtrup (1929) and Nyfeldt and Vamtrup (193-) using the technique of Faber (1935) of early post mortem fixation of the stomach with formalın The gastric mucosa may be damaged by various chemical bacterial and physical factors nervous stimuli and interference with blood supply The nature of the noxious stimulus its severity duration and portal of entry into the stomach modify the changes occurring in the mucosa Vlaintenance of the normal gastric epithelial lining is a dynamic process and simple increase in the rate of regeneration of the cells may cope with increased loss of cells due to some damaging agent without actual ulceration but a point is reached when necrosis and desquamation occur too rapidly for immediate regeneration to occur and erosions or more severe ulceration appear The changes characteristically involve the mucosa diffuseli with areas of pronounced hyperaemia rendered patchy by muco purulent exudate mucosal oedema and submucosal petechiae When damage is severe erosions ulceration and even corrosion of the gastric wall may occur The microscopic changes in acute gastritis have been described in 18 ·ACUTE GASTRITIS 19 biopsy material by Palmer (1991) and Motteram (1991) Increased regeneration of cells is reflected by the presence of irregu larity of the cell size nuclear size and staining poor cytoplasmic differentiation and arrangement of the superficial epithelial cells These cells may be stratified with indistinct cell borders and containing little or no secretory material in their cytoplasm The changes are often clearly seen occurring in the depths of the pits There is oedema of the superficial lamına propria which contains increased numbers of plasma cells and lymphocytes and many polymorphonuclear cells ( polymorphs ) which penetrate the epithelium Haemorrhages may occur into the interstitium The overall appearance in some cases may resemble chronic superficial gastritis Fig 7 ct tega titis G stric biopsy from a m le pati nt aged 57 Vea s 3 days fter se er alcoholic bout followed by haemat mesis Nec ot c superfi1 epithel I c lls ae is ble in the su f ce mu u Thy are regulr in height nd show poor cell outlin In many the mu gent theca is abs nt The la inap pa i oedemn tou and infiltrated th pla ma c lls lymphocytes and pol morph (on and b ematovylın x600) More intense stimuli result in frank necrosis of cells which become desquamated into the lumen of the pits and the lining mucus along with migrating inflammatory cells (fig 7) 'These necrotic foci may desquamate to leave small erosions or even ·20 ACUTF GASTRITIS penetrate the muscularis mucosae to become a frank ulcer Williams (1950) considered that erosions were initially produced by the rupture of mucosal capıllaries through the superficial epithelium The most severe erosi e processes penetrate the gastric wall following necrosis of all coats When damage to the stomach has been confined to the super ficial epithelium of the ridges and pits surface regeneration is probably always complete (E Palmer 1951) However it is unlikely that regeneration of damaged glandular cells can occur to the same extent and these cells may permanently disappear or be replaced by non specific or mucus secreting epithelium termed pseudopyloric glands Damage to the submucosa muscle and serous coats may be followed by the formation of granulation tissue and even deformity of the organ particularly in the antral region Symptomatology Acute gastritis of minor severity is frequently encountered in clinical medicine the symptoms lasting from a few hours to 2 or 3 days Anorexia nausea occasional vomiting and diffuse epigastric discomfort and tenderness are the outstanding features In a severe case the onset is usually sudden with pronounced epigastric pain persistent nausea and vomiting perhaps with traces of blood on occasions there may be a profuse haematemesis The patient is weak thirsty drowsy and soon shows the effects of toxaemia dehydration and electrolyte depletion He is pale with sunken eyes inelastic skin rapid pulse lou blood pressure muscular cramps and excessive thirst The urine is scanty de ficient in chlorides and may contain a trace of albumen The temperature may be subnormal at first and later elevated There may be constipation or diarrhoea The abdomen is usually sunken but later may become distended The tenderness is diffuse with maximum intensity in the epigastrium The nature and duration of the symptoms are largely determined by the cause of the acute gastritis Thus in acute staphylococcal food poisoning due to the ingestion of staphylococcal enterotoxin the gastric symptoms predominate whereas in acute staphylococcal gastro enteritis and in Salmonella infections the intestinal symptoms predominate with diarrhoea and generalised abdominal tenderness E Palmer (1991) made a valuable study of the stomach in ·21 ACUTE GASTRITIS acute exogenous (staphylococcic) gastroenteritis due to inges tion of food heavily contaminated by staphylococci and their torins He investigated 42 previously healthy male subjects aged between 17 and 47 years 38 of whom had been involved in of 3 major outbreaks of 'food poisoning On most of them a gastric biopsy was performed with a modified flexible gastric biopsy tube and followed with gastroscopy The subjects were examined in this way at intervals varying between 5 and 580 hours after the onset of the symptoms These symptoms usually consisted of vomiting retching chills fever and perhaps some circulatory collapse Sıx patients were examined in the acute stage 5-12 hours after the onset and all showed abnormal gastroscopic appearances the majority having hyperaemia oedema erosions petechiae and purulent exudate The same 6 patients were sub jected to gastric biopsy during the acute stage and s showed pronounced histological changes the remaining patient was examined 5 hours after the onset of symptoms and showed no histological change but at gastroscopy there was congestion of the mucosa The essential histological lesion in these 5 early biopsies u 25 congestion and oedema followed by necrosis of cells at the junction of the pits and glands the damaged cells then being extruded to the surface with exfoliation and erosion Regeneration of the epithelium was accompanied by interstitial inflammatory cell infiltration Twenty four patients were subjected to gastric biopsy and an abnormal gastric mucosa was present in 5 of 6 examined in the first 12 hours all of 4 examined between 20-40 hours 4 of 7 examined between 50-82 hours and o of 7 examined between 92-220 hours These splendid studies of E Palmer would therefore suggest that in relatively young individuals a single severe attack of acute gastritis causes considerable inflammatory changes in the gastric mucosa and this is followed by complete healing It may be that of the attacks were frequent of the subjects were older or if greater numbers had been studied then evidence of the persisting changes of chronic gastritis would be forthcoming No studies of gastric secretion were reported in E Palmer s series but it is anticipated that there would have been a depression of acid and pepsin secre tion during the acute phase with a retum to normal les els with the subsidence of the inflammatory changes ·22 ACUTE GASTRITIS E Palmer (1994) has also studied the acute gastric symptoms and the gastroscopic and biopsy findings in cases of acute alcohol ism (see Chapter 3) He concluded that following an acute alcoholic bout there was evidence of acute gastritis, but that usually there was complete resolution However it is our experience that if the alcoholic bouts are severe and often repeated then persistent change may be estab lished the mucosa changing from acute superficial gastritis to chronic atrophic gastritis and perhaps after the course of many years even to gastric atrophy The factor of chronic malnutrition also plays a part (Joske and Turner 1952) (erde infra) Aetiology A number of chemical dietary bacterial as well as psychic stresses may produce acute gastritis The corrosive action of agents such as caustic soda phenol and mineral acids gives rise to an acute corrosive gastritis in which the stomach wall may per forate Should the patient survive healing with fibrosis and distortion of the stomach occurs In Australia the commonest dietary irritants implicated in acute gastritis are the strong alcoholic beverages Motteram (1951) illustrated the histological features of the gastric mucosa of a patient from whom a gastric biopsy was obtained 3 days after a haematemesis brought on by a severe bout of alcoholism Necro tic surface epithelium was present with replacement by actively proliferating epithelial cells growing out from the pits while red cell extravasations were visible in the lamina propria (fig 7) Finckh et al (1952) examined the gastric biopsies of alcoholics Abnormal gastric mucosa was found in 18 or these superficial gastritis was present in 14 and atrophic gastritis in 4 Of the cases with superficial gastritis 5 showed subsequent resolu tion suggesting that the lesion had been acute and reversible Later similar figures were obtained in our unit by Joske et al (1955) who found 31 out of 95 gastric biopsies obtained from alcoholic subjects showed evidence of gastritis Williams (1956) found similar changes in a group of 25 alcoholics submitted to gastric biopsy He also carried out animal experiments which suggested that alcohol consumed in the concentrations found in fortified wines and spirits may cause haemorrhage erosions and ulceration especially if taken on an empty stomach 39 chronic ·ACUTE GASTRITIS 23 Ny feldt and Vimtrup (1932) examined the stomach of children dying of diphtheria and found evidence of acute gastritis Thus was considered to be due to circulating diphtheria toxın for when the stomachs were fixed soon after death and subsequently ex amined there was no evidence of diphtheritic bacterial invasion Thomsen (1925) produced gastritis in dogs by the injection of diphtheria torin Vimtrup (1929) also found acute gastritis at the post mortem examinations of patients dying from influenza and pneumonia As previously stated E Palmer (1991) performed gastroscopy and gastric biopsy on 42 patients with acute staphylococcal food poisoning and observed the gastritis beginning some hours after the onset of symptoms and usually disappearing within 2 to 4 days without residual damage to the mucosa Treatment The treatment of acute gastritis depends on the cause and severity of the attack In the commonest form which is associated wath mild food poisoning rest free fluids and probably a saline purge is all that is required The severe attacks may be associated with a specific bowel in fection and the causal psganism should be sought by culture of a fresh specimen of stool Transfer to liospital is essential Antt biotics and sedatives together with the intravenous infusion of electrolytes glucose and perhaps blood or serum may be indicated As the patient improves increasing oral feeding is gren ·CHAPTER 3 CHRONIC GASTRITIS Structural changes Reports of chronic inflammatory changes in the gastric mucosa were criticised and discredited for many years on the grounds that they were caused by post mortem autodigestion Satisfactory post mortem material was first obtained by Faber and Bloch (1900) using intraperitoneal injection of formalın immediately after death The pathology of chronic gastritis has since been amply demonstrated by Faber (1935) The results of the examination of specimens of stomach obtained at operation were recorded by honjetzny (1928) but have been criticised by Schindler (1947) Schindler et al (1939) and Sanders and Mecray (1941) showed that acute erosions of the mucosa could develop during the actual resection of the specimen Schindler and Ortmayer (1942) obtained stomach biopsies through an abdominal incision but of course this procedure is unsuitable for routine use Chronic inflammatory lesions were described in biopsy frag ments obtained through oesophageal tubes by Swalm et al (1936) while henamore et al (1946) Benedict (1948) and d Almeida (1948) recorded similar findings in mucosal biopsies The use of a flexible gastric biopsy tube (Wood et al 1949A) has enabled serial biopsies to be made on patients with chronic gastritis im mediate fixation of the fragments ensuring freedom from autolysis In chronic gastritis there is a wide variety and a continuous spectrum of structural changes Attempts to classify these changes into different types tend to overlook the variations of distribution severity and activity which may occur in the same patient ou er a period of time A relationship to the clinical features of gastritis is best achieved by classifying according to alterations in the thickness of the mucosa the concentration of chief and parietal cells and the extent and activity of the inflammatory processes Thus three main types of gastritis can be recognised 24 ·severe CHRONIC GASTRITIS 23 I Superficial gastritis Here there is superficial inflammation of the mucosa without atrophy of the glands The mucosa is of normal width and while the inflammatory changes may be slight moderate or severe the lesion is capable of complete resolution However the changes may persist as a chronic superficial gastritis or with recurrences may progress to atrophic gastritis 2 Atrophic gastritis There is a more diffuse inflammation of the mucosa showing varying degrees of activity coupled with slight moderate or severe atrophy of the specific parietal and chief cells usually leading to a decrease in the width of the mucosa While the inflammatory changes may resolve to some degree there are permanent changes in the epithelial structures and only partial regeneration of the parietal and chief cells occurs Recurrent exacerbations of inflammation lead to a atrophy which may closely resemble primary gastric atrophy (see Chapter 5) 3 Gastric atrophy This is the classical change seen in per nicious anaemia and subacute combined degeneration of the cord It is included here for the sake of completeness as this change may result from the subsidence of the inflammatory changes in a severe case of atrophic gastritis or alternatively it may be due to a primary atrophy of the mucosa This is discussed later together with the histological picture (see Chapter 5) Diffuse grant hypertrophic gastritis This is a further rare variety which is described in Chapter 4 It probably represents a different disease to chronic gastritis Macroscopic appearance in chronic gastritis There may be little alteration from normal appearance In severe cases the mucosal surface may appear granular or mammillated the mucosa thin and the rugae small (fig 8) The granularity may be the result of oedema cellular infiltration lymphoid infiltration or cystic change in the ep structures However the degree of distension of the stomach must always be considered when estimating mucosal thickness and the size of rugae—lack of appreciation of this has led surgeons gastroscopists and radiologists to make an erroneous diagnosis of hypertrophic gastritis (fig 9) Hebbel (1949) found wide variation in the distribution of chronic gastritis Local changes were common in the antrum and along the lesser curvature and the presence of changes in these sites was not necessarily indicative of more diffuse changes in the mucosa However he claimed that changes along the greater curvature ·26 CHRONIC GASTRITIS * Fig 8 Chronic atrophic gastritis Stomach obtained post mortent from a male patient aged 6-4 years i ith severe chronic atrophic gastritis previously proven by Lastric biopsy The mucosa 18 smooth finely granular or slightly nodular i he rugae are flattened and have largely disappeared an appearance which may have been caused by terminal gastric dilatation (natural size) Fig 9 Vormal g stric nucosa en contracted stomach fixed soon after death The rugae are full and regular lth distension of the stom ch they becom less pominent ( natural size) ·ficial gastritis CHRONIC GASTRITIS 27 occurred usually as part of a more diffuse process in the body of the stomach Vicroscop c appearances in chronie gastritis The changes in the gastric biopsy may range from slight superficial increase in plasma cell infiltration of the lamina propria to gross alteration in the epithelial structure disappearance of the specific glands and in filtration and replacement by mesenchymal elements These appearances are best considered under the headings of super and atrophic gastritis although there is no clear dividing line between the two Superficial gastritis The most constant feature is the presence of inflammatory cells in the superficial regions of the lamina propria Where there is only a slight increase of plasma cells unaccompanied by superficial epithelial changes this may be considered to be within physiological limits The pathological range is considered to be reached when there is more pronounced plasma cell infiltration polymorphonuclear cells are seen migrating singly or in groups from the lamına propria to penetrate the super ficial cpithelium and lie in the pits or superficial mucus (fig 10) Some red cells may be extras asated into the superficial lamina propria and there is lymphocytic infiltration of the deeper layer (fig 11) In acute exacerbations of the gastritis superficial epithelial cell damage is sometimes evident as groups of poorly staining cells in the adherent mucus (hig 7) but a more common feature is the evidence of cell regeneration in the form of irregular or smaller flattened cells Sometimes these epithelial cells are stratified and show indistinct cell borders poor differentiation and little or no ecretory material in their cytoplasm the nuclei vary in size often being large and hyperchromatic These changes are sometimes most pronounced in the pats where there is dilatation or cystic change lengthening tortuositv and distortion due to extension of the regenerating cells down into the glands as well as up to the surface Sometimes this is due to obstruction of the lumen of the pit The basal two thirds of the mucosa are normal and the total width of the mucosa is unchanged Should it be possible to remove the damaging agent the mucosa may return to a normal appearance in 2 to 3 weeks The histological appearance of chronic superficial gastritis may be identical with that of acute gastritis Chronicity of the lesion ·28 CHRONIC GASTRITIS Fig 10 Acre supe fir al gastritis sho ving intensive polymorphonuclear in filtration of the lamina propria with penetration of the superficial epithelium by the polymorphs (eosin and haematoxılın X 400) Fig 11 Gast ic biopsy st Aling superficial gust its The superf cual epithelium 19 flattened and regular There is infiltration of the superficial lamina propria bi plasma cells and polymorphs There are some lymphocyt : deeper n the lamina propna (eosin and haematoryIn x 150) ·CHRONIC GASTRITIS 29 is only established by the duration of the symptoms or more convincingly by repeated biopsy when persistent superficial gastritis or perhaps progression to atrophic gastritis is seen Atrophic gastritis In atrophic gastritis the changes in the superficial portion of the mucosa are identical with those in super ficial gastritis but the inflammatory changes now extend to involve the lower two thirds of the mucosa with slight (fig 12) moderate (fig s) or severe atrophy of the glands (figs 13 14 15) The average depth of the mucosa in the processed section varies from 047 mm in gastritis with slight atrophy to o 45 mm in those with severe atrophy (Jo ke et al 1995) Groups of plasma cells and polymorphs are seen in the super ficial lamina propria while lymphocytes are more prevalent in the deeper areas where they may be aggregated into follicles near the base of the mucosa Occasionally fat cells develop close to these follicles (fig 16) The intervening areas of lamına propria contain a delicate connective tissue network which may be oedematous but dense collagenous fibrosis does not occur Sometimes these mesenchymal elements replace the glands completely and often separate the fibres of the muscularis mucosae which becomes thickened (fig 17) The irregularities of the superficial epithelium extend into the glands and the chief and parietal cells are partially or wholly re placed by mucus secreting or non specific cells arranged in coiled pseudopyloric glands a form of post inflammatory metaplasia of the epithelium (fig 18) Another form of metaplasia is to an intestinal type of gland (Magnus 1937) which is characterised by the appearance of a superficial epithelium containıng tall columnar cells with a darkly staining surface interspaced with goblet cells (fig 18) They are arranged to form a crypt with argentaffin cells and at the base Paneth cells The Paneth cells contain coarse eosinophilic re fractile granules which stain a dark red with the trichrome stain (fig 19) By means of silver stains argentaffin cells can be de monstrated lying laterally in these crypts (fig 20) (Magnus 1937) This metaplasia is patchy in character more confined to the pits and usually seen to occur abruptly in a single high power field (fig 21) In spite of these atrophic changes in the glands the mucosa may not be decreased in depth owing to infiltration with infiammatory cells and oedema

·30
CHRONIC GASTRITIS
Tig 12
Gastric biopsy shouin, chronic gastritis aith slight atrophy of the glinds
(trichrome stain x 150)
F 13 Cronic al opi gast its till setere atrop!
A female aged 64 years
with recurrent abdominal pa n anaemia and achlorhydria for 22 yet fulloning
an episode of gross malnutr tion Castric bi psy showing se ere inflmmatory
in liration of the lamina propria with polymo phs plasir a cells and lymph St
A lymph foll cle has formed at the right the specific glands h ve almost com
pletely disappeared Dur ng the ensuing 8 years s cial biopsis and test m als
remained unchanged eosin and haematorslin x 150)

·CHRONIC GASTRITIS 31 Fug 14 Chromc at ophuc gast ills Castra bopsy from same case as fig 13 The biopsy shows distortion and elongation of the pits disappearance of most of the glandul tubules and a severe inflammatory inhltration of the la ina propr a (trichrome stain x 150) F8 15 Ciromc atrop! gast fis showing cystic change in the pits ps udops loric metaplasia of the glands (eosin and haematorylin *150) ith

·32
CHRONIC GASTRITIS
Fig. 16
Chronic atropluc gastritis Lymphoid tissue and fat are replacing the
specific glands (cosin and haematorylin x 180)
15
Fig 17 Chome gast its There is splintering and th cken ng of the muscl
mucosae by inflammatory cells (eosin and haematorslin * 180)

·CHRONIC GASTRITIS 33 With gross atrophy of the glands and post inflammatory meta plasia the end result resembles primary gastric atrophy Differen tiation between atrophic gastritis and gastric atrophy is made on the histological characteristics (Table 3 Chapter 5) Symptomatology of chronic atrophic gastritis The symptoms of chronic atrophic gastritis are distinctive and show but little variation from patient to patient The patient is usually a female over 40 years of age Doig and Wood (1952) found a female male ratio of 5 4 and this female predominance was increased when the alcoholics were excluded The patients discomfort varies from a sense of excessive fullness in the epi gastrium especially after taking food to a dull burning pain The site of her distress is diffusely situated in the epigastrium In contrast to peptic ulcer where the patient usually demonstrates the site of the pain and tenderness by pressing in deeply with the tips of the fingers she rubs the epigastrium from side to side with the flat of her hand saying This is where I have the discomfort (or the pain) across here Rarely pain may also be felt in the back and thus may mimic a penetrating ulcer chronic pancreatitis or cancer Like gastric ulcer the pain of gastritis most frequently occurs immediately after taking food or within half an hour It is paradoxical that although most of the patients have hypo chlorhydria or achlorhydria their discomfort is relieved by taking alkaline powder Hydrochloric acid taken with their meals may produce relief but in our experience most patients claim they receive no benefit or are made worse, they usually prefer alkaline powder Certain foods may aggravate the pain particularly fat pine apple cabbage and condiments although there is great variation from patient to patient There are exacerbations and remissions in the symptoms the exacerbations being brought on by an associated illness undue mental or physical stress or over in dulgence in alcohol Lack of appetite is common and may lead to loss of strength and weight this in turn may create a fear of cancer in the mind of the patient and indeed in the mind of the physician Adding to this fear may be the finding of hypochromic anaemia and occult blood in the stools resulting from gastric ercsions Occasionally especially in alcoholic gastritis haematemesis or melaena is encountered and thus gastritis must be considered a ·34 CHRONIC GASTRITIS Fig 18 Types of mucus secretong cell in chronic gastritis from same biopsy as figs On the upper left hand side the normal mucigenic theca of the super ficial gastric epithelium is sisible On the upper right hand side the goblet cells in areas of intestinal metaplasia stain heavily In the base of the mucosa pseudopyloric mucus secreting cells are increased in amount replacing parietal and chief cells (mucicarmine x 150) Fig 19 Chronic atrophe gast 1815 Intestinal et splasi A crypt containing dark intestinal type tall columnar epithelium and some got let cells Dark granules are sus ble in the Paneth cells (trichrome stain * 600) ·CHRONIC GASTRITIS 35 For 20 Chron cal plic gastr t Intestinal o etapla 1a Argentafyn cells are ssible * the base of the columnas cells wedged in herneen them (assons sites impregnation x 600) Fig 21 Ci on atrope gast afts Intest nal metoplo io Gastric b opsy with a focus of int samal metaplassa sth superfic al ep thel um There 1$ abrupt chang from the normal regulat tall columnar gastr c epsthem on the right hand so to the deeper sta ni ng cafuma cells # th the dark border and godt t Ils on the left hand sid ( os and haematontin x 600) ·34 CHRONIC GASTRITIS .. Fig 18 Types of mucus secretin cell in chronic gastritis from same biopsy as fig 5 On the upper left hand side the normal mucigeni, theca of the super ficial gastric epithelium is wa ible On the upper right hand sıde the goblet cells in areas of intestinal metaplasia stain heavily In the base of the mucosa pseudopy loric mucus secreting cells are increased in amount replac ng parietal and chief cells (mucicarmine x 150) Fig 19 Chronic atropli gastritis Intests al m tapi zsia Acrypt contain ng dark intestinal type tall columnar epithelium and some goblet cell granules are visible in the I aneth cells (trt hrome st x 600) ·CHROVIC GASTRITIS 37 aged She is intelligent but may wear a worried expression There may be crachs at the angle of the mouth and atrophy of the tongue The finger nails are brittle with longitudinal furrows rarely hoilonychia There is diffuse epigastric tenderness but no mass or rigidity The liver and spleen are not palpable except when pronounced malnutrition is present usually due to chronic alcoholism Examination of the nervous system reveals no abnor mality except perhaps some diminution of the knee and ankle jerks Although the above description does represent a proportion of cases many reveal io abnormal findings on physical examination except perhaps slight epigastric tenderness during an exacerbation in the disease Aetiology of chronic atrophic gastritis Chronic atrophic gastritis is a more advanced stage than super ficial gastritis and results from some damaging processes either intermittent or continuous the nature of which is often obscure Once the gastric mucosa has reached the chronic atrophic stage usually there are few signs of recovery of the mucosa as revealed by improvement in the test meal or the gastric dropsy Factors which may play a part in the production of chronic atrophıc gastritis are sex advancing age perhaps due to increas ing atherosclerosis with depleted blood supply of the gastric mucosa chronic debilitating diseases chronic alcoholism associated with malnutrition and the drinking of other gastric irritants prolonged psychic stress and finally irradiation of the stomach especially ray irradiation either in the treatment of abdominal malignancy or in the purposeful production of achlorhydria in the treatment of duodenal ulcer It is of interest to consider some of these factors in greater detail Sex distribution in chronic gastritus dra, nosed bi gastric bropsy There was a preponderance of females especially amongst the cases of superficial gastritis (Doig and liood 1992) TABLE I Vales Fernales • Females 12 7, Superficial gastritis Atrophic gastritis Total 36 36 28 56 10 64 ·36 CHRONIC GASTRITIS cause of overt upper gastrointestinal bleeding However it is most unusual for the bleeding to be of sufficient severity to warrant a laparotomy Severe and persistent bleeding favours the diag nosis of a peptic ulcer cancer or bleeding oesophageal varices Che bowels function normally or there may be intermittent constipation Although hypochlorhydria or achlorhydria is the rule, attacks of diarrhoea are rare The age of onset of the pain is of interest Doig and Wood (1952) found that whereas the pain of duodenal ulcer usually began in the mid thirties the pain of gastric ulcer superficial gastritis and atrophic gastritis usually began in the mid forties When the age of first examination in hospital was studied it was found that patients with superficial gastritis were younger than those with atrophic gastritis Doig and Wood concluded that gastric ulcer is more closely related to gastritis than to duodenal ulcer and that atrophic gastritis is a more advanced stage of superficial gastritis In a survey of 623 patients in the Royal Melbourne Hospital mostly gathered from our unit which was primarily interested in gastroenterology Joske Tinckh and Wood (1955) found 221 cases with pronounced atrophic gastritis In 40 per cent of these there were gastro intestinal symptoms considered to be entirely or in part due to the gastritis whereas 23 per cent had gastro intestinal symptoms due to other causes and 37 per cent had no gastro intestinal symptoms In 50 patients the symptoms were considered to be entirely due to the gastritis It is our firm belief based on extensive experience with proien cases of chronic atrophic gastritis that these subjects may suffer pain and flatulence due to the inflammatory reaction in the gastric mucosa and to deny this cause of dyspepsia is a grave error of medical judgement It is obvious from the above survey that chronic atrophic gastritis may be present without symptoms but of course this in no way invalidates the belief that pain may occur in other subjects and that occasionally it may be moderately It should be recalled that gall stones chronic pancreatitis and even pronounced peptic ulceration may be present without symptoms and it could never be claimed that these diseases rarely or never produce discomfort or pain Physical examination Although chronic atrophic gastritis occurs in both sexes and even in the third decade it is typically seen in an elderly female with grey hair and perhaps prematurely sei ere ·CHIRONIC CASTRITIS 39 gastritis These may be explained partly on the basis of malnutn tron partly big circulating tarins damaging the mucosa Sjogrens disease where there is atrophy of the lacrymal and salsary glands unh depleted secretion and recurring inflammation in the eyes and mouth gastric biopsy may reveal gastritis with sarying degrees of atrophy (fig zz) Joske et al 1995) It is of interest that in haemochromatosis there is deposition of sron in the deeper layers of the gland cells (Althausen Doig et al 1951) but as a rule there are few degenerate changes (fig 23) In 15 gastric biopsies Joske et al (1935) found iron deposits in all yet 9 were otherwise within normal limits and 6 showed only superficial gastritis This is in contrast to the changes in the Iner and pancreas in this disease Chronic gastritis due to chronic alcoholism and malnutrition Chronic alcoholism is quite frequently associated with varving degrees of gastritis although some indriduals can tolerate exces Skve intake of alcohol without des eloping persistent changes It is probable that after an alcoholic bout the mucosa shows the signs of acute gastritis but it heals uithout residual change Thus E Palmer (1954) selected 34 young men who were physically fit and not alcoholics and examined them by gastroscopy and gastric bropsy within 6 hours of an alcoholic bout Thirty showed acute exogenous gastritis to gastroscopy and all 34 had ab normal biopsy findings mostly superficial gastritis and resembling the acute changes seen in acute staphylococcal food poisoning (E Palmer 1951) Cleren of the 34 were submitted to a second bropsy after an intersal of 7-20 days during which time they took no alcohol Nine of the biopsies were now within normal isttssts Palmer (1994) also studied the history of alcoholism amongst 200 patients selected at 525dom whose gastric bropsy was then within normal limits and found that during the previous 12 months 112 admitted being drunk at least once 81 at least 12 times and 18 at least once a neek Palmer wisely accepted their statements with caution Howeser it would seem that excess consumption of alcohol does not always cause chronic gastritis This of course does not indicate that st may not da so in certain susceptible in dnviduals especially when malnutrition is a pronounced feature Palmer does not relate whether there were other features of chronic alcoholism in these subjects such as disease of the brais penipheral ner es or liter However he concludes by favouring ·38 gastritis for CHRONIC GASTRITIS Ser Sex appears to play a role in the aetiology of females are more commonly affected than males even though alcoholism favours the male incidence 71 per cent of the alcoholics in our unit being males Doig and Wood (1992) reported that amongst cases of superficial and atrophic gastritis 6.4 per cent were females (Table 1) This increased incidence amongst females suggests an endocrine factor or perhaps malnutrition as Australian housewives are prone to fas our a diet high in carbohydrate and deficient in protein and vitamins (Epstein et al 1990) However Fairley Joske and Turner (19,5) could not find convincing evidence that malnutrition played a leading role Ageing and the gastric mucosa The age of onset of the symptoms of gastritis varies greatly the average being 44 years (Doig and Wood 1992) Our experience indicates that atrophic gastritis results from a progression from superficial gastritis and that once the stage of atrophic gastritis is reached the condition rarely re verses with healing It is therefore to be expected that gastritis becomes more frequent with advancing age That it is by no means invariably present in elderly subjects has been revealed by I Palmer (1954) who carried out gastric biopsy in subjects over the age of 60 who were not suffering any dyspepsia and found 30 with normal gastric mucosa Moreover Joshe and his colleagues (1955) performed gastric biopsy on 214 patients over the age of 60 and found 18 per cent had normal gastric mucosa Many of the patients in this series were examined because chronic gastritis was suspected so there was a bias towards an abnormal gastric biopsy finding It is of interest that in the same series 218 subjects aged betsteen 20 and 40 years were examined by gastric biopsy and 10, (47 per cent) had normal gastric mucosa Although most of the subjects in this group were suffering from dyspepsia the group included cases of duodenal ulcer where the biopsy is usually normal and also normal subjects without dyspepsia who acted as controls so there was less bias towards an abnormal mucosa When achlorhydria is found in an elderly individual it is probably due to chronic gastritis and it should not be considered to be a normal finding any more than chronic nephritis or chronic bronchitis is considered to be normal in the aged Chronic debilitating diseases Diseases such vi chronic infec tions ulcerative colitis rheumatoid arthritis chronic nuphritis and long standing malignancy may be associated with chronic atrophic ·CHRONIC GASTRITIS ism the idea that although acute alcoholism may cause acute gastritis chronic gastritis rarely if ever is a direct result of chronic alcohol We disagree most emphatically with his opinion Indeed Doig and Wood (1932A) surveyed 312 cases of gastritis and found 19 vere chronic alcoholics This series was later extended by Joske Finckh and Wood (1955) who reported that of 95 biopsies on alcoholic subjects 39 showed superficial gastritis 11 atrophıc gastritis and 1 gastric atrophy wathout overt pernicious anaemia Our experience with serial biopsies over many months indicates that whereas superficial gastritis amongst alcoholics may resolve should the patient quit his alcoholic indulgences a sare happening it more often progresses to severe atrophıc gastritis with continuing alcoholic bouts Moreover the severe atrophic gastritis suffered by a chronic alcoholic rarely resolves with re generation of the chief and parietal secreting cells even though the intake of alcohol be reduced or even withheld for a year or more the chronic gastritis has passed the point of no return Whether alcohol acts directly on the gastric mucosa either by bathing and irritating its surface or by way of the blood stream is a matter of debate and it may well be that it acts by both these means Moreover chronic alcoholism is frequently associated with chrome malnutrition deficencies in protein and vitamins of the B group being most commonly encountered These de ficiencses probably play a part in the atrophuc changes in the gastrıc mucosa just as may be clearly seen in the tongue In this regard it is of interest to note that Farley et al (1955) carried out a dietetic survey on 30 cases of chronic atrophic gastritis followed for a period of 5 years or more Although they could not determine a clear relationship between chronic atrophic gastritis and malnutrition they found that 5 patients had taken a consistently poor diet and 9 a poor diet for ses eral months It is anticipated that studies on a greater number of cases will provide further evidence that malnutrition may lead to atrophic gastritis and that even though a suitable diet With added vitamins is Inststuted the change in the gastric mucosa may be irreversible Hot tea and gastritts Edwards and Edwards (1956) hay e studied tea drinking amongst 155 subjects with dyspepssa in whom gastrıc biopsy had recently been performed and they produced evidence that the drinking of excessnely hot tea fanoured the deselopment of gastritis On the other hand it may be that the sufferer from chronic gastritis is soothed by hot be erages so that chronic

·40
CHRONIC GASTRITIS
Fig 22 Itropl ic gastritis in 5 grens disease Gastric biopsy from female
patient aged bo vears th classical Sjogren s disease including conjunctritis
dry mouth arthritis and achlorhydria There is intense inflammatory infiltra
tion of the lami a propria disappearance of glands and some foci of intestinal
metaplasia in the elongated pits (trichrome stain x 150)
F1R 23
Tacmocl romatosis Gastric biopsy from a female p tient bdfos
1 th pigmentation hepatornegaly and deb lits
Is er b opss sho Jrhosis
and gross accumulation of iron The Alandular epithel um I th
contains iron granules (prussian blue stain x boo)
stoma h

·CHRONIC CASTRITIS ug 27 Rod at ngasi 11s a male patient aged 34 sears ith a chronk duodenal ul er ** gnen deep ray therapy to the stomach Alastrichsopay taxen 66 day afte th rapy shows acs ve gassists with atrophy the superficial epithelium is flattened and it ular and shonap limorphonuc ar pener atron 'Th pts ar clongated and di ind and the hands contain many non spec te of my w seting cells Tht ka hea inflation f the leap ia by polmo phs plasma cells and lymph stes At thy stag hs tarmari cest seal sho dhia hur Du in th next 2 to 3 13 bronsils and histamin test meat revealed a refun to normal { ce sa 253 (on and haemators 1 x 150) 1 R$ 23 Rud of u gasitif (a trcbope { m satnc patient as fil 24 taken Gyrad at an of the stomach when ch h scamse rest meal had re mal let 1 17 muco a is almost ith n norm i imits ( osis and hartiatorylın x 150) ·42 CHRONIC GASTRITIS gistritis favours the drinking of hot tea rather than the contrary There is no es idence that tea per se is a direct cause of gastritis Psychic stress It has been shown by Wolf and his colleagues (1948) that psychic stress may cause congestion of the gastric mucosa and also the colonic mucosa and that if the stimulus is severe and prolonged erosions and bleeding may occur Moreover Gray et al (1993) found that stress increased the peptic activity of gastric juice It is possible therefore that long continued stress may lead to chronic atrophic gastritis Psychic stress certainly aggravates the symptoms in an established case of gastritis Gastritis due to I ray irradiation The use of \ ray irradtation to reduce the secretion of acid and pepsin in the treatment of duodenal ulcer was first advocated by Bassler in the United States of America in 1909 and later was reported Holman and Lewis (1941) in Tasmania and Ricketts and his colleagues (1948) in Chicago In 1997 the Chicago group (Levin et al 1997) published a follow up of 723 patients and claimed an improvement in the relapse rate compared with the control series However there were 6 deaths from cancer in the test series 2-13 vears after the irradiation (z.de infra) In 1948 these workers studied the changes in the gastric mucosa in their duodenal ulcer series following ray irradiation by taking sections at operation or post mortem In 19,1 serial biopsies with the flexible tube were carried out in similar cases in our unit and the morphological changes following ray irradiation were correlated with the secretion of acid and pepsın (Doug I under and Weiden 1991) One patient with chronic duodenal ulcer had bropsies taken 21 38 66 136 374 and 465 days following a gastric tissue dose of 1500 r given over a period of 3 weeks (figs 24 and 25) The morphological picture of the gastric mucosa changed from normal to one of atrophic gastritis of moderate severity with corresponding depletion of the acid and pepsin secretion the maximum changes being observed during the first 3 months There was then a slow return towards normal of the histological changes and secretion with almost complete restoration to normal at the end of a year However the secretions returned to normal les els rather than the high levels which preceded treatment This case is representative of the majority treated by us and is in keeping with the findings of the Chicago group However there is a considerable indivdual variation some patients proving sery susceptible and later showing little or no mucosal regeneration or ·CHRONIC GASTRITIS 45 when she was nothing in the ray department for a period of 8 months During this time she frequently assisted in prolonged screening examinations to test draphragmatic moement in everely paralısed parents There was histamiae fast achlorhidea and gastric biopst revealed serere atrophı gastritis Her duties were changed and her simptoms gradually improved over the next 3 tears but the achlorks dna and atrophic gastritis persisted We have had no experience with the radiation hazards other than rays but it may be that with the coming of the atomic age Tadiation will play an increasing part as a cause of ga intis Relationship of chronic gastritis 10 peptic ulcer Doig and flood (1992) studied the relationship betueen the age of onset of gastric ulcer superficial gastritis and atrophic gastritis and found the 3serage age to be simulas being 325d $6 sears respecta ely whereas the average age of onset of duodenal ulcer was significantly less being 36 years It may be that gastritis in its superficial and atrophic forms may be related to gastric ulcer but not to duodenal ulcer which may have a different acuology If gastritis in its initial stages » patchy and limned in extent et may lead to some superficial ulcerations The remaining normal mucosa may then secrete sufficienth concentrated gast ac juice to cause further breakdown of tissue with extension of the ulcer in size and depth Honeter should the gastritis in the first place be widespread 11 reduces acid and pepsin secretion and thus mins mises the tendency to chronic ulceration A gastric ulcer with its zonal gastritis (fig 27) forms an area of impaired gastric secretion and this tends to limit gasess secretion Thus in gastric ulcer there is reduced secretion of acid and pepsin compared with duodenal ulcer where the mucosa of the body of the stomach is normal or near normal (Perry et al 19,6) In an testigation of g cases of duodena) ulcer Doig and lood (1992C) found bo per cent sith normal gastric mucosa and 30 per cent with superficial gasinitis sithout atroph Cox (1932) studred the secreting bulk of gastne mulosa in patients with duodenal ulcer and found it to be an excess of normal This has not been apparent in our biopsy studies Vagnus (193-) found the mucosa of the body of the stomach to be normal in most cases of duodenal ulcer but that a slight to moderate deg et of antral gasiratis might occuir ·44 CHRONIC GASTRITIS return of secretions others showing only a minor reaction with rapid return to normal of both structure and secretions With increasing dosage of rays the changes became more pronounced and more prolonged (Levin et al 1957 Brown and Wood 1955) It is of interest that most patients subjected to radiation gastritis suffer little or no discomfort true pain rarely being reported may be that the pain nense endings in the stomach wall have been rendered insensitive by the \ ray irradiation Other studies were made in our unit of cases of duodenal ulcer treated by antroduodenectomy followed by \ ray irradiation In antroduodenectomy the antrum and most of the first part of the duodenum including the ulcer were removed followed by end to end anastomosts the irradiation served to reduce the high acid secretion which persisted after the operation (Brown et al 1992 Brown and Wood 1955 and 1996) Fig 26 shows that there was pronounced lowering of the acıd 3 months after the irradiation as compared with the pre irradiation levels Case Distr bution Maxim m free acid after Histamine >100- 81 100 61 80+ 41 604 21 40 1 20- Xray irradiation All 0 Beto a Irradi tion 12 18 24 Months after Irradiation Fig 26 The effect of Pray irradiation on gast ic secretion 2000 r gastric tissue doses were gi en over a period of 3 weeks to lower the gastric secretion in cases of duodenal ulcer p es sously treated by antroduodenectomy with resection of the ulcer It will be noted that after an initial depression some cases showed a return of acıd secretion One year after the irradiation and later higher levels were reached in many of the cases while a fex remained achlorhydric Serial gastric biopsies on a limited number of cases showed there was a corresponding change in the histology of the gastric mucosa (Brown G et al 1952 Brown G and llood I J 1995) The following case history illustrates the possibility of gastritis being caused by ray irradiation A nurse aged 26 years de veloped considerable flatulent dyspepsia and occasional vomiting ·CHRONIC GASTRITIS 47 and most probably has preceded the cancer (fig 28) However it may well be that the cancer came first and this caused an extensive zonal gastritis Possibly this was made worse by the malnutrition which results from the anorexia and dyspepsia of cancer Joske et al (1955) found normal mucosa in only 4 of 20 cases of cancer of the stomach examined by random biopsy Fg 28 Epithel al metaplasia in chron gastritis Gastri biopsy from a male patient aged 61 years known to have chronic atrophic gastritis for 10 yea $ There is an unusual type of metaplasia of the epithelium with the down growth of ur egular tubules lined by tall hyperplastic or atrophic epithelium There is a local inflammatory infiltr ton The patient 1 being closely observed for development of carcinoma (eos n and haer atoxyl n x 150) Fairley et al (1955) surveyed 32 patients who for 5 years or more had been shown by gastric biopsy and other examinations to have uncomplicated chronic gastritis During the period of follow up serial tests were made including test meal gastric biopsy and barium meal The gastric biopsies showed little overall change during the period of observation the pronounced atrophic gastritis persisting with some fluctuation in the cellular infiltration There was a corresponding persistence in the depletion of acid secretion -4 of 32 showing either a fall or no change in free acıd concentra tion and the remaining 8 a minor rise No patient in this group showed evidence of gastric cancer either during the period of ·46 CHRONIC GASTRITIS It is most improbable that duodenal ulcer would occur in the presence of an extensive gastritis owing to the lowered acid and pepsin secretion which results from the gastritis However on rare occasions gastritis may develop long after a duodenal ulcer has entered the chronic irreversible stage with penetration into the pancreas The anomalous position may then be found where a duodenal ulcer is associated with achlorhy dna Probably most duodenal ulcers heal spontaneously after the development of extensive gastritis A similar set of circumstances is provided artificially when gastritis is produced by ray irradiation of the stomach (zrde supra) This may lead to healing of the duodenal ulcer FS 27 Zonal gast this The edge of a fast ic ulcer showing zonal gastritis The lymph follicies are inc eased in number and size and the plands ha e almo t completely disappeared There is dense submucosal fibrosis Ulceration is evident (lower right) (eosin and haematorylin X 40) Relationship of chronic gastritis to carcinoma It has been debated oser the years whether chronic gastritis favours the development of cancer It is known that cancer of the stomach especially when situated in the body of the stomach is usually accompanied by hypochlorhydria often achlorhydria It could therefore be concluded that extensive gastritis is present ·CHRONIC GASTRITIS 49 reduction in the secretion of intrinsic factor the most significant results being obtained by studying the absorption of Scobalt labelled stamın Bs, the addition of intrinsic factor returning the absorption to normal Using our gastric biopsy tube they found atrophic gastritis in 41 of 50 patients with iron deficiency anaemja 2 further cases having gastric atrophy Davidson and Markson (1955) had similar results Witts (1956) concluded that gastritis and achlorhydria are the direct result of iron deficiency Joshe et al (1955) carried out gastric biopsy in patients with hypochromic microcytic anaemia who were not showing asert bleeding and 6 showed atrophic gastritis 3 superficial gastritis and the remaining 2 were within normal limits They concluded the achlorhydria so frequently seen in this type of anaemsa results from inflammatory gastritis Absorption of son from alimentarz canal Using foods contain ing radioactne iron Moore (1995) showed that absorption of iron was normal en patients suffering from iron deficiency anaemia and achlorhydria It is most probable that the majority of his subjects had atrophic gastritis Moreozer he demonstrated that the addı tion of bberal volumes of dilute hydrochlonc acid did not increase the absorption TABLE 2 Absorptrore of cron Cases of frypochromic anaemia (probably assacsated with chronic atrophic gastritis and anaemia) can absorb hberal amounts of iron given by mouth Hoveier cases showing the malabsorption syndrome wsth steator boca show grossly impaired absorption Authority Disease state Test dose of ferrous iron ghen by mouth Iron absorbed Dubach et al (1948) Img/kslo body weight -+71 10 mg Badenoch and Callender (1954) Vormai subjects Hypochromic anzemia Hypochromic anaemia Steatorrhoea and hypo chromic anaema 0-3 ·48 CHRONIC GASTRITIS observation or at the final assessment In addition there were 9 cases of atrophic gastritis who died before the 5 year period had passed and none had gastric cancer Although the number of patients in this study is limited it does not support the opinion that chronic gastritis strongly favours the development of cancer If atrophic gastritis is not a precursor of cancer it would suggest that the causal factor of gastritis is not carcinogenic However in this regard one would not readily care to discard the thought that rays could act as a carcinogen (Brown and Wood 1956) In deed Levin and his colleagues (1957) in a follow up of 723 patients treated by irradiation for duodenal ulcer reported 6 to have died from carcinoma of the stomach duodenum or pancreas 2-13 years after irradiation They considered that the significance of this is yet to be determined Witts (1996) who had studied cases of achlorhydria atrophic gastritis and hypochromic anaemia for many years could find no reliable data on the liability of women with iron deficiency and achlorhydria to develop carcinoma of the stomach in later life He concluded we know that they are abnormally prone to de. velop carcinoma of the mouth and hypopharynx and we should keep an open mind about the labılıty to carcinoma of the stomach Tig 28 is of interest in this regard Relationship of chronic gastritis to anaemia When anaemia does occur in cases of chronic atrophic gastritis it is usually of the iron deficiency type being hypochromic and microcytic Several factors contribute to this anorexia leads to a depleted intake of food and the food taken is often low in iron and protein content secondly it has been claimed that there may be impaired absorption of iron due to greatly reduced secretion of acid by the stomach thirdly there may be repeated gastric haemorrhages due to excessive shedding of gastric epithelium the haemorrhage usually being minimal but oft repeated and lastly with increasing atrophy of the gastric mucosa the supply of in trinsic factor may be reduced causing impaired absorption of vitamin B, and ultimately pernicious anaemia (see Chapter 5) litts Witts (1996) found that the incidence of achlorhydria is increased at all ages amongst cases of iron de ficiency anaemia—under 50 years it was 4 times as common as in a control group Ile and his colleagues at Oxford also found a anaemia ·(ITRONIC GASTRITIS 51 medical treatment (fig 29) However the blood loss in gastritis is usually occult although it may lead to pronounced anaemia Treatment Since most patients with chronic gastritis suffer minor bouts of discomfort they only require simple treatment during the attacks We found that alkaline powders provided the greatest relief odd though this may seem in the light of the achlorhydria It is of course rational to administer dilute hydrochloric acid with meals, but few claim benefit from this and actually mo t are made mort uncomfortable However there were exceptions to this experience for a few patients obtained considerable benefit from the acid Should the relapse be moderately severe and prolonged oral penicillin may be given with benefit~-100 000 units 4 hourly for 10 days There is evidence that penicillin is absorbed through Tormal gastric mucosa (Hurley and Bazeley 1997) but it is not kroun whether this pertains then chronic gastritis is present When overt haemorrhage occurs with melaena or haematemesis the patient should be given rest in hed and placed on a haematemesis regime However rapid and severe blood loss requiring a liberal blood transfusion or gastrectomy rarely occurs Should anaemia be present it is usually of the iron deficiencv tvpe and responds to iron given by mouth 1 errous sulphate is a satisfactory salt but should this cause added dyspepsia the other salts such as ferrous lactate or iron and ammonium citrate may be satisfactory Some patients are intolerant to all oral medication or the anaemia is not relieved owing to intestinal malabsorption (Table 2) In these an intramuscular preparation such as Imferon* - mi twice a weeh) is of value Hagedorn (1957) has described a short high dosage course of this preparation If the anaemia is not reheved by iron then further search should be made for blood loss or other causes of inaemia such as chronic nephritis (Joske et al 1996) or carcinoma of the colon It should be remembered that the atrophic gastritis may eventually cause progressively increasing vitamin B, deficiency from d minishing secretion of intrinsic factor - macrocytic anaemia will then appear This onset of pernicious anaemia will respond to injections of B, When chronic flatulent dyspepsia lack of appetite loss of Weight and anaemia occur in an elderly patient as a result of * Benger Laboratories I td Cheshire England ·CHRONIC GASTRITIS 50 It will be noted in Table 2 that the absorption of iron from the alimentary canal is increased in iron deficiency anaemia unless this deficiency is associated with steatorrhoea when absorption is reduced In steatorrhoea it is the intestinal barrier which is at fault for iron is readily absorbed and utilised when injected parenterally (Dubach et al 1948 Badenoch and Callender 1994) It would appear probable that the most common causes of hypochromic anaemia associated with gastritis are deficiency of iron in the diet and loss of iron from chronic bleeding from the gastric mucosa (fig 29) Moreover it is considered that the iron deficiency follows the gastritis rather than causing it as has been claimed by Witts Indeed the gastritis is one of the causes of the iron deficiency Ci ont FI 29 of opluc ga tritt url haci Tan A male patient aged 38 ars had periodi ep gast paino a pe od of sSear Admitted ith haematemes s and melaena ra e aled n ulcer or an ir Ih Aastric bu pss p of med u days after admiss on sho s haemor bane innftrati nofth Imant propra The red c IJs stan da kls (t hr me stain x 150) Orert bleeding In a study of 112 ca es of gastritis diagnosed by gastric biopsy Doig and Wood (1992) described 4 cases of super ficial gastritis and 3 of atrophic gastritis s ho had been admitted to hospital with haematemesis or melaena No other cause for the bleeding such as ulcer or cancer was found and all recovered with ·CHAPTER 4 DIFTUSF GIANT HYPCRTROPHIC GASTRITIS Since the earliest description of diffuse giant hypertrophic gastritis by Venetrier (1888) perusal of the literature shous that personal experience of this disease by any one author is restricted to only a few cases and we have encountered only one case to be described later Nevertheless Fieber (1955) has recorded an excellent analysis of 50 cases reported in the literature The lesion is traditionally regarded as inflammatory in origin but the aetiology is unknown It may be that the pathological changes seen in this disease are basically neoplastic an anatomical variant gastri adenomatosis and that the inflammatory reaction is a secondary occurrence This views 15 favoured by the very prom nent folis the profuse epithelial proliferation and the occasional detelopment of true carcinoma ("latzner et al 1951 Palumbo et al 1931 Texter et al 1973) The lesion may diffusely involve the whole gastric mucosa or it may be more localised in distribution particularly in the antrum The gastric mucosal folds are swollen tortuous nodular and even polypod ranging from 5 to 3 5 cm in height The surface of the folds may be congested with a mammillary or cobblestone pattern superficial haemorrhages and erosions The mucosa is soft and usually mobile but may become mote turgid and rela trely fixed due to infammatory induration or malignant change There may be a tendency for the redundant mucosa to prolapse through the pylorus The microscopic appearance is basically that of benign hyperplasia of the surface epithelium resulting in extensa e elongation, branching and tortuosity of the pits Cistic changes may become Pronounced presumably the result of obstruction and infiamma tion in these pits There 13 infiltration of the interstitium by infiammatory cells Normal glands may be visible in the depth of the mucosa 53 ·52 CHRONIC GASTRITIS chronic gastritis malignancy may well be suspected by both patient and physician Indeed it is essential first to exclude the presence of cancer in such a patient But once this has been done, the patient will profit greatly by having the disease entity chronic gastritis explained to him (or more frequently her ) He should be reassured that his symptoms are typical of this malady and that there is no evidence of cancer Moreover, he will be comforted by the knowledge that although he may suffer a minor relapse from time to time he will enjoy good health and regain his weight with improved dret and medicinal treatment He should be seen from time to time to maintain treatment and to ensure accuracy of diagnosis It is our opinion that the acceptance by physicians and surgeons of chronic gastritis a real disease entity with specific symptoms and signs is essential to the efficient practice of medicine ·DIFFUSE GIANT HYPERTROPHIC GASTRITIS > F1g 30 Diffuse gant hypertrophic gast this Operati e specim n of stomach There is pronounced thickening tortuosits and mamm I tion of the rugae of the body of the stomach The antrum (left) i normal The patient was a male aged 47 scars ith ep gastric pain and recurrent haematemesis for 2 years 1 pre operative diagnosis of carcinoma of the stomach as made in error (approxi nately half natural size) FR 31 Dffuse gant li pert ophi ga tas V croscop c appearance of the gast c mucosa (see Fig 30) There is gro s prolif ration and stic ch nge in the Pits Th interstit al tssue is heavily infiltrated wth infl mmaton cells teosin and ha matorslin X 45) ·54 DIFFUSE GIANT HYPERTROPHIC GASTRITIS Fieber (1935) found that diffuse giant hypertrophic gastritis occurred in adults of all ages but particularly in the fourth to sixth decades of life Males outnumbered females by 3 I The average duration of symptoms was 2 years and these included in order of frequency diffuse post prandial epigastric pain and tenderness sometimes relieved by food and alkalıs weight loss vomiting and bleeding Test meal findings were not characteristic The large rugae were detected by gastroscopy and barium meal examination The differential diagnosis at this stage is from (1) malignant neoplasms of the stomach notably carcinoma (most frequent misdiagnosis) sarcoma and reticulosis (2) benign neoplasms of the stomach (3) large gastric rugae especially in the deflated stomach (Ricketts et al 1947) (4) granulomata of the stomach () extrinsic tumours invading the stomach Biopsy through the gastroscope cytological studies and blind biopsy with the flexible gastric biopsy tube may be of value in differentiating between these conditions but a reliable diagnosis of diffuse giant hypertrophic gastritis can only be made by the pathologist with access to the full thickness of the stomach wall at any area he may wish to examine Cases in which there is any suspicion of a resectable malignancy should be submitted to laparotomy Stiegmann et al (1957) consider the following fea ures suggest that the large rugae are benign a long history response to medical treatment absence of a palpable mass normal or near normal test meal a smooth outline of the filling defect elasticity of the under lying gastric wall smoothness and continuity of the rugae and decrease in the size of the lesion during observation Such a case they suggest may undergo conservative treatment and observa tion but generally the resemblance of diffuse giant hypertrophic gastritis to carcinoma leads to laparotomy Fieber (1995) states that the response to medical regimes or deep ray therapy is not good Where there is suspicion of malignancy and the lesion is diffuse total gastrectomy is necessary but if the lesion is proven to be benign at operation subtotal gastrectomy suffices even though the lesion is diffuse Case history We are indebted to Dr 1 Ching for the follow A male patient aged 42 vears was admitted to hospital with a history of indigestion for 10 years and during the past year a haematemesis followed by tiredness malaise and epigastric pain barium meal examination showed an extensive ing cise record ·CHAPTER 5 GASTRIC ATROPHY, PERNICIOUS ANAEMIA AND SUBACUTE COMBINED DEGENERATION ON THE CORD Structural changes of gastric atrophy and pernicious anaemia In 1849 Thomas Addison presented his classical description of the anaemia which for many years bore his name It was in 1860 however, that Flint drew attention to the gross reduction of gastric secretion in Addisonian anaemia and Cohn and son Mering (1866) noted the absence of hydrochloric acid from the gastric juice The gastric atrophy accompanying this condition was first noted by Samuel Fenwick (1870) who subsequently confirmed this finding in 3 other cases (Fenwich 7880) Faber (1935) con sidered the changes in the stomach were inflammatory in origin and that gastric atrophy was the end result of this process but Mignus and Ungley (1938) described a non inflammatory atrophy of the body of the stomach in 8 patients with pernicious anaemia Sumlar observations were also made by Meulengracht (1939) and Cox (1943) The macroscopic appearances described by these authors are characteristic of gastric atrophy The mucosa of the body of the stomach is reduced in thickness and the atrophy also includes the muscle coats By contrast the pyloric mucosa and muscle coat are normal in appearance the demarcation between the two areas being quite sharp (fig 32) The histological changes in the mucosa of the body of the stomach as recorded by these authors resemble the gastric atrophy described in the gastric biopsies by Motteram (1991) of our unit These changes are the virtual disappearance of the parietal and chief cells of the glands with partial replacement by areas showing intestinal metaplasia and non specific secreting cells while in fiammatory changes are minimal or absent (fig 6) In 90 per cent of cases all the specific cells of the glands have disappeared while 57 ·56 DIFFUSE GIANT HYPERTROPHIC GASTRITIS filling defect suggestive of carcinoma of the stomach At gastro scopy thickened folds suggestive of carcinoma were seen project ing into the stomach Total gastrectomy was performed by Nr JO Smith The post operative recovery was slow and he con tinued to suffer from dyspepsia The pathologist Dr J D Hicks reported that the stomach measured 23 cm along the lesser curvature the mucosa was pink hypertrophied and heaped up into numbers of large papillary folds the whole of the mucosa having a gross mammillary appearance (fig 30) On microscopic examination the epithelium of the mucosal folds was in many places normally differentiated but contained numerous plasma cells in the outer portion of the mucosa and many lymphocytes in the basal portion (fig 31). Also there were cystic glands in the lower portion of the mucosa and in some areas these were well differentiated Some dilated glands extended into the submucosa and were lined by regular mucus secreting cell ·Votteram 1991 GASTRIC ATROPHY 4VD PERNICIOUS ANAEMIA 59 Miotteram 19,0 Doig Motteram Robertson and Wood 1950 Wood 1991 Finchh and Wood 1993 Badenoch and Richards 1993 Doig 1954 Badenoch 1954) In practice a continuous range of histology is encountered from atrophic gas tritis to gastric atrophy so that it is possible that many cases of gastric atrophy are in fact the inactive end result of a severe atrophic gastritis Conversely cases of gastrie atrophy from time to time may develop superimposed inflammatory changes For the purposes of classifying and analysing our biopsy results we have used the criteria set out in Table 3 TABLE 3 The histological changes in atrophic gastritis and gastric atrophy Biop y examination Atrophic gastritis Gastric atrophy Disappearance of Usually incomplete Usually com gland cells plete Intestinal metaplasia Uncommon and is patchy and Usually present often confined to the pits and tends to be diffuse Inflammatory Epithelial irregularity cellular | Usually mild or changes infiltration including poly absent with morphs increase in lamina only super propria thickened and splin ficial changes tered muscularis mucosae all pronounced Of sooo gastric biopsies reviewed in 1955 by Joshe Finckh and Wood 100 were obtained from patients with either pernicious anaemia or subacute combined degeneration of the cord or both Gastric atrophy was present in 40 and in the remaining 60 there were varying degrees of chronic gastritis with severe atrophy All of the 100 patients had histamine fast achlorhydria These authors also found gastric atrophy in 16 biopsies from patients without overt pernicious anaemia or subacute combined de generation of the cord One of these subsequently developed macrocytic anaema and subacute combined degeneration of the cord which responded to treatment with vitamin B12 (Robertson Wood and Joske 1955) (lide infra) Three of the other biopsies were obtained from patients who at other times showed atrophic gastritis illustrating both the relationship between these conditions ·58 GASTRIC ATROPHY AND PERNICIOUS ANAEMIA an occasional chief cell may be found in the others Parietal cells are rarely seen Intestinal metaplasia is usually present and diffusely distributed in the mucosa the superficial epithelium consisting of columnar cells with a dark border goblet cells and argentaffin cells while Paneth cells are present in the bases of the crypts Gastric type epithelium when present stains intensely for mucin The superficial epithelium is regular and the muscu laris mucosae is thin The lamina propria is slightly increased and often contains a few plasma cells and lymphocytes the latter occasionally aggregated into small follicles at the base of the The average width of the processed mucosa in this condition is 0 42 mm the average normal being o 54 mm (Joshe et al 1957) mucosa Fig 32 Gastric at oph Am le ag d 58 scars with se ere pernici us anaemia died immediatels after admission to hop tal from an emia bronchopneumonia and cardiac failure There is gross at ophy of the mucosa of the body of the stomach The antruon and plorus (I ft) appear normal (approximately half n tural 2) It cannot be stated however that the morphological changes in the stomach found in cases of pernicious anaemia and subacute combined degeneration of the cord are uniform except in so far as most authors nou agree that atrophy with or without inflamma tion of the mucosa of the body of the stomach is invariable and usually severe (Dorg 1949 Doig and Hood 1950 Doig and ·GASTRIC ATROTHY AND PERNICIOUS 4 VAEVIA 61 gastric biopsies and maximum stimulus histamine test meals over a period of 8 years (fig 33) With treatment he made the usual complete clinical recovery and then remained well on maintenance treatment first with liver extract and then liberal doses of vitamin B12 but gastnc atrophy and achlorhydria persisted throughout (Finckh and Wood 1953) Symptomatology of gastric atrophy and pernicious anaemia Mluch depends on the sequence of events which leads to gastric atrophy If gastric atrophy is a slox primary atrophy of the mucosa probably genetically determined and unaccompanied by an inflammatory reaction (gastritis) then the gastric symptoms will usually be minimal or absent and the clinical picture will he dominated by varying degrees of vitamin B2 deficiency with anaemia and subacute combined degeneration of the cord If however the advent of vitamin B, deficiency is preceded by severe chronic gastritis slowly progressing from the stage of superficial gastritis to atrophic gastritis and perhaps thence to gastric atrophy then it might be expected that there would be a long history of intermittent fiatulent dyspepsia typical of gastritis Analysis of the symptoms before the appearance of overt pernicious anaemia is therefore of considerable interest Most cases of pernicious anaemia enjoy excellent health without dyspepti symptoms once adequate vitamin B,g therapy has been established Thus the gastric atrophy per se produces fes symp On the other hand some patients first presenting with the pernicious anaemia picture complain of sore tongue poor appetite mild to moderate flatulent dyspepsia general malarse and perhaps bouts of diarrhoea Most of this can be attributed to Sitamin B 2 deficiency and not to gastric atrophy and the resulting achlorhydria The male patient aged 6 years previously reported by Robert son Wood and Joske (1955) is of considerable interest in this regard When seen in February 1949 he stated that he had suffered from flatulent dyspepsia since the age of 1, came on soon after taking food and was relieved by belching or taking alkaline powders His appetite was poor and he had lost Weight He was referred to the hospital with the provisional diagnosis of gastric carcinoma but this was excluded by Y ray and gastroscopy Investigation showed that he had achlorhydria gastric atrophy (repeated biopsiest normal bone marrow and toms The pain ·60 GASTRIC ATROPHY AND PERNICIOUS ANAEMIA and the difficulty of completely separating them on histological grounds Following the administration of vitamin B12 to cases of perni cious anaemia there is no change in the appearance of the gastric biopsy (Doig and Wood 1950 Tinchh and Wood 1953) We have not been able to observe a change in the size of the epithelial cells which would be in accord with the findings of Graham and Rheault (1954) who reported large gastric epithelial cells in gastric washings comparable to the megaloblasts in the bone marrow and which returned to normal size with vitamin Big therapy Also Massey and Rubin (199+) and Gamble et al (1957) noted no significant change in the size of the epithelial cells in gastric washings following vitamin Btherapy Fig 33 Castric air phy A maie aged 47 years with pernict us anaemia treated with laver extract and then t min B for 8 ) ars The gastric biops: shows d ffuse intestinal metaplasia and omplete atrophs of the gland There ! sl ght infiltration of the lamina p up a with plasma c lls and lymphocytes Serial gastric biopsies taken before and during tre tment have sho n no change in th histological app arance (mu icarmine * 150) In our experience the gastric atrophy and the resulting achlor hydria remain unchanged even after many years of tull parental vitamin Biz therapy One such patient a male chocolate maker aged 47 years suffering from pernicious anaemia and subacute combined degeneration of the cord has been studied by serial ·GASTRIC ATROPHY AND PERNICIOUS ANAENTI 4 63 cord in the absence of any abnormality in the peripheral blood or bone marron mas present a considerable problem in diagnosis (Victor and Lear, 1956) (figs 34 35) It is odd that vitamin B, deficiency causes such a variable clinical picture varying from severe anaemia with no osert subacute combined degeneration of the cord to severe combined cord degeneration and no anaemia In our present state of knowledge we can but helieve that there is a different degree of system vulnerability varying from patient to patient Ilowever histamine fast achlorhydria is always present and gastric biopsy reveals a sei ere degree of atrophy of the gastric mucosa (Doig et al 19,04) F. 34 Sezore acti < chroic al opi i gast tis A male pat nt aged 64 ears was admitted with eahness in the legs and idence of poster or and late al column degeneratron in th spinal ord. Th rei as a histamin fast achlorhy dra but per pheral blood and b) marros ir normal The gast i biopsy shov s stregulanty and shedding of the superficial thelum ps udopyloric meraplasta and complete loss of parietal and chief ells of the glands The lan snap op a s inbitrated nath infiammatory ells and the m set lar s mu o ac 15 th ckened and splintered Ther as a good re ponse to itamin B, therapy (eosin and haematorslin x 150) *Cobalt labelled vitamin B,, has been used to detect impaired Vitamin B, absorption in this syndrome (NicIntyre et al 1956) Lnversedge et al (1997) found radioactive vitamin B12 of con siderable help in confirming doubtful cases of subacute combined ·62 GASTRIC ATROPHY AND PERNICIOUS ANAEMIA peripheral blood and only very minor signs suggestive of subacute combined degeneration of the cord The technique for estimating serum Bı, levels was not then avarlable He was not gn en vitamin Biz treatment as he was enjoying quite good health and he im proved with reassurance and a more satisfactory diet However he was kept under close observation and in September 1954 he developed overt pernicious anaemia with pronounced subacute combined degeneration of the cord and a low level of serum vita min B l'here was a full response to liberal vitamin B, and he was well controlled by continuing therapy When last seen nearly 4 years later he was enjoying excellent health but still suffered from some flatulent dyspepsia Examination of his blood and nervous system were satisfactory there was achlorhydria to maximum histamine stimulation covered by antihistamine (hay 1953) and gastric biopsy showed the same picture of gastric atrophy A similar delay in the development of overt pernicious anaemia after depleted vitamin B, absorption from intrinsic factor lack may be observed in patients subjected to total gastrectomy Here the onset of symptoms may be delayed for periods up to 3 years or more after the gastrectomy the patient meanwhile subsisting on the body stores of vitamin B 2 (Welbourn et al 1956 Harvey 1956) Recently Holmes (1996) has stressed the mental changes which accompany pernicious anaemia and which he attributes not only to cerebral anoxia but also to the effect of vitamin B, deficiency on the brain for the symptoms may be present before anaemia and subacute combined degeneration of the cord appear Nore over they are relieved by vitamin B, therapy Wilkinson (1948) reported flatulence or dyspepsia in 59 per cent of cases of pernicious anaemia and the symptoms often ante dated the anaemia by many years Davidson (1997) noted that poor appetite and vague abdominal discomfort were frequent in pernicious anaemia but diarrhoea only occurred in 9 per cent of 250 cases which he reviewed in Ldinburgh during 1944-36 He contrasted this finding with Cabot s series of 1200 cases seen before the discovery of Inver therapy where the incidence of diarrhoea was 51 per cent It may sell be that vitamin B12 deficiency directly impairs gastric and intestinal function and this is remedied by vitamin B12 therapy The development of subacute combined degeneration of the ·GASTRIC ATROPHY AND PERNSCIOUS ANAEMIA 65 setere atrophy of the gastric mucosa so the cause of this atrophy must be sought when determining the cause of pernicious anaemia Since gastric biopsy examinations were first made in our unit in 1948 we have made a number of studies of pernicious anaemia In 1950 Doig and Wood examined by gastric biopsy 45 cases of established pernicious anaemia or subacute combined degeneration of the cord and more recently Joske Finckh and Wood (1955) have extended the series to 100 cases All had severe gastric changes with atrophy 40 were classified as gastric atrophy no signs of in flammation being present and 60 had varying degrees of chronic gastritis with severe atrophy All had histamine fast achlorhydria In Scotland Ilarkson and Davidson (1936) carried out gastric biopsy tn 16 cases of pernscious anaemia and found gastric atrophy in 14 and atrophic gastritis in 2 It is rational to conclude that sesere atrophic gastritis may lead to gastric atrophy with subsidence of the infiammatory reaction and that the causes of pernicious anaemia thus anulude the causes of superficial gastritts which then progresses to atrophic gastritis (see Chapter 4) This progression probably takes a number of years and so far our 8 year study of gastritis has not produced an example of the complete progression through the 3 phases We have seen some cases of superficial gastritis progressing to atrophic gastritis and some cases of severe atrophic gastritis progressing to gastric atrophy but without the des elopment of overt pernicious anaemia or subacute combined degeneration of the cord These may appear later with depletion of the vitamin B12 Stores There is also evidence that gastric atrophy may occur as a primary process a simple abrotrophy of the gastric mucora without a preceding inflammatory gastritis (Alagnus and Unglev 1938 Motteram 1991) It may well be that there is a genetic influence in this primary degeneration It is therefore of importance that the occurrence of pernicious anaemia in families has been reported by a number of writers Wilkinson (1949) investigated 1600 cases of pernicious anaemia and found a history of pernicious anaemia in at least one other member of the family in 19 per cent Mosbeck (1953) investigated 132 patients with pernicious anaemia in whom a relathely complete family history could be obtained There were 1958 relatives with si (23 per cent) cases of pernicious anaemia this was 20 times that found in a control series More Bier 30 per cent of the families had one or more cases additional to the index case ·64 GASTRIC ATROPHY AND PERNICIOUS ANAEMIA degeneration of the cord either when there was no accompanying anaemia or when vitamin B12 had been given before the blood state had been adequately examined Fig 35 Subacute combined degeneration of the cord A female patient aged 64 years developed urinary retention and progressive weakness of the legs over 2 weeks She had a smooth tongue wasting of the leg muscles with absent deep reflexes extensor plantar responses and loss of sensation to light touch pinprick and vibration over both legs Gastric biopsy sho ed gastric atrophy She died of urinary sepsis 6 weeks later despite injections of liver extract and antibiotics A section of the lumbar portion of the spinal cord shows extensive demyelina ton of the posterior and lateral columns (l ergert stain x 20) Aetiology of gastric atrophy and pernicious anaemia It is of considerable importance to speculate as to the cause of pernicious anaemia As will be discussed later it must be accepted that pernicious anaemia is due to impaired vitamin B, absorption which in turn is due to deficiency of Castle s intrinsic factor This intrinsic factor is present in the mucoprotein fraction of gastric juice Some patients may also secrete intrinsic factor in the duo denum and perhaps the upper sleum but in relatiely minimal amounts (Castle et al 1929 Grasbeck 19,6) in pernicious anaemia the cause of the deficiency of Castle s intrinsic factor 18 ·GASTRIC ATROPHY AND PERVICIOUS AVAEVIA 67 of 18 patients with severe atrophy of the mucosa had a loss total Solume of secretion achlorhydria and lou or absent pepsin while all of 36 patients with normal or nearly normal mucosa had normal or intermediate type secretions (blood et al 1949B) Similarly the total mucus secretion was reduced in chronic gastritis and more so in gastric atrophs even though the mucus was more concentrated (Il eiden 1949) In a later sunez Joshe et al (19)) recorded 784 gastric biopsies in patients who had also been examined by histamine test meal (see fig 1 Chapter 1) The test meal velded a concentration of Over 20 units of free acıd in 76 per cent of 27, biopsies which were within normal limits in only 1, per cent of 172 showing pronounced atrophic gastritis and in none of 41 showing gastric atrophy In 19-9 Castle and his co workers demonstrated that an in trinsic factor present in normal human gastric juice combined with the food to produce a haemopoietic response when given orally to patients with pernicious anaemia 'I he localisation of the intrinsi factor in the pylorus and duo denum of the pig was achiesed by Veulengracht (1939) but For and Castle (1942) demonstrated that in man this factor was present mainly in the body of the human stomach so that the gastric lesion could be correlated with the absence of intrinsic factor Goldhamer (1937) had shown that the gastric juice of patients with pernicious anaemia contained minute amounts of intrinsic factor but because of the achy lia he suggested that the defect was mainly quantitatne Intrinsic factor has since been identified as a mucopolypeptide (Williams et al 1994) present in the mucoprotein of gastric juice (Latner et al 193+) It now seems Itkely that intrinsic factor combines with extrinsic factor (vitamin B, or cyanocobalamın isolated by Smith 1948 and Riches et al 1948) and facilitates its absorption in the small intestine (Ross 19 ) It is stored in the liver combined to a beta globulin (Pitney et al 1995) and then combined to an alpha globulin (Pitney et al 199+) it is transported in the plasma to the sites of utilisation In conjunction with folic acid vitamin B, is thought to play a major role in the synthesis of nucleoprotein particularly at the sites of rapid cell proliferation such as the bone marrow Vitamin B, deficiency occurring as a result of deficiency of intrasic factor is followed by a decrease in the rate of cellular proliferation The cells instead of dividing ·66 GASTRIC ATROPHY AND PERNICIOUS ANAEMII 4 It is also of interest that Videbaeh and Mosbech (199+) found gastric carcinoma to be 4 times higher in the relaties of patients with gastric carcinoma than in a control series and that in their series the incidence of pernicious anaemia was about 3 times higher than the normal in the relatives of patients with gastric carcinoma a finding which accords with the treble incidence of gastric carcinoma in patients with pernicious anaemia Thes con cluded changes in the gastric wall-which presumably may bethe result of exogenous as well as hereditary factors—therefore appear to predispose to both gastric carcinoma and pernicious anaemia Doig et al (1950B) carried out histamine test meals on 134 healthy medical students and found only one with histamine fast achlorhydria This student a male aged 2, had no signs of per nicious anaemia and the barium meal \ ray was negative Gastric biopsy in 1949 showed an unusual type of atrophy of the acid and pepsin secreting cells and an absence of inflammation His maternal grandmother had died at the age of 70 from pernicious His mother at the age of 44 suffered from flatulent dyspepsia and weakness and a gruel meal showed hypochlorhydria and excess mucus In 1955 histamine fast achlorhydria sas still present and in 1957 when last seen he was well and had required no treatment In conclusion it can be stated that there is evidence that a pro portion of the cases of pernicious anaemia result from a primary atrophy of the gastric mucosa which may begin early in life and be determined by a genetic factor The extent of the atrophy may not be sufficient to produce uttamin B, deficiency and per nicious anaemia till middle age or later Secondly the remaining cases of pernicious anaemia probably result from superficial gastritis progressing to severe atrophic gastritis with resulting depletion of Castle s intrinsic factor which in turn leads de pleted vitamin B12 absorption and vitamin B, deficiency Thus atrophic gastritis may become quie cent with disappearance of the inflammatory reaction in the gastric mucosa and so the gastric biopsy finding is that of gastric atrophy anaemia The relationship of the gastric changes to pernicious anaemia subacute combined degeneration of the cord and other megaloblastic anaemias In a correlation of the gastric secretions obtained by histamine test meal with the findings on gastric biopsy it was found that all ·CASTRIC ATROPHY AND PERNICIOUS ANAEMIA 67 of 18 patients with severe atrophs of the mucosa had a low total volume of secretion achlorhydria and low or absent pepsin while all of 36 patients with normal or nearly normal mucosa had normal or intermediate type secretions (Wood et al 1949B) Similarly the total mucus secretion was reduced in chronic gastritis and more so in gastric atrophy even though the mucus was more concentrated (Heiden 1949) In a later suney Joske et al (1993) recorded 784 gastric biopsies in patients who had also been examined by histamine test meal (see fig : Chapter 1) The test meal yielded a concentration of over 20 units of free acid in 76 per cent of 275 biopsies which were within normal limits in only 1, per cent of 172 showing pronounced atrophic ga tntis and in none of 41 showing gastric atrophy In 1929 Castle and his co workers demonstrated that an in trinsic factor present in normal human gastric juice combined with the food to produce a haemopoietic response when given orally to patients with pernicious anaemia The localisation of the intrinsic factor in the pulorus and duodenum of the pig was achieved by Veulengracht (1939) but Fox and Castle (1942) demonstrated that in man this factor was present mainly in the body of the human stomach so that the gastric lesion could be correlated with the absence of intrinsic factor Coldhamer (1937) had shown that the gastric juice of patients with pernicious anaemia contained minute amounts of intrinsic factor but because of the achy lia he suggested that the defect was mainly quantitative Intrinsic factor has since been identified as a mucopolypeptide (Williams et al 199+) present in the mucoprotein of gastric juice (I atner et al 199+) It now seems likely that intrinsic factor combines with extrinsic factor (vitamin B, or cyanocobalamin isolated by Smith 1948 and Rickes et al 1948) and facilitates its absorption in the small intestine (Ross 19,0) It is stored in the liser combined to a beta globulin (Pitney et al 19,) and then combined to an alpha globulin (Pitney et al 199+) it is transported in the plasma to the sites of utilisation In conjunction with folic acid vitamin B, is thought to play a major role in the synthesis of nucleoprotein particularls at the sites of rapid cell proliferation such as the bone marrow Vitamin B22 deficiency occurring as a result of deficiency of intrinsic factor is followed by a decrease in the rate of cellular proliferation The cells instead of dividing ·68 GASTRIC ATROPHY AND PERNICIOUS ANAEMIA and maturing become larger and remain immature, giving rise to megaloblasts Vitamin B12 is stored in the liver in liberal amounts and its utilisation is slow Thus when the absorption from the alimentary canal is retarded or ceases completely there is a delay in the de velopment of overt pernicious anaemia or subacute combined degeneration of the cord As stated previously this is demon strated after total gastrectomy when it may take several years for megaloblastic anaemia to develop The relationship of vitamin B, deficiency to the demyelinating peripheral neuritis and subacute combined degeneration of the cord is obscure The lesions have been attributed to defective ribose nucleic acid synthesis affecting especially the long axones of nerve cells in the spinal cord (Nieweg et al 1954) Can pernicious anaemia be diagnosed in the presence of normal acıd secretion and normal appearance of the gastric biopsy Mollin et al (199) presented a case of pernicious anaemia without gastric atrophy This case was initially diagnosed at the age of 13 months The father of this patient subsequently de veloped an early pernicious anaemia which was associated with gastric atrophy The mother had a brother who died of carcinoma of the stomach when aged 30 years Moreover it is of considerable interest that the mother and father were cousins as consanguinity greatly enhances genetic influences It was suggested that the early development of pernicious anaemia in the propositor was genetically determined the patient being homozygous with respect to the faulty gene It was also suggested that the early treatment of the case presented the development of gastric atrophy and that gastric atrophy was in fact secondary to prolonged vitamin B, deficiency which might be clinically silent for a long period Similarly Harris Jones et al (1997) reported pernicious anaemia without gastric atrophy in a gırl of 16 years Pernicious anaemia is very rare in children but Reisner et al (1951) found , cases in the literature in which hydrochloric acıd was found in the gastric juice and they described 3 further cases in which there was hydrochloric acid in the gastric juice at some stage 1 his suggests that in the pernicious anaemia of ·GASTRIC ATROPHY AND PERVICIOUS ANAEMIA 69 childhood achiorhydria is not so constant and that presumably the gastric atrophy is either absent or incomplete This finding is consistent with the concept of Mollin and his colleagues but it must be emphasized that such cases are at most rarely found -in classical pernicious anaemia the atrophic changes in the gastric mucosa are severe and achlorhydria is present Indeed we have not seen a case of pernicious anaemia without gross atrophy of the gastric mucosa and achlorhydria Like Witts (1996) we wish to resene judgment on the cases in this group lle do not consider the should be diagnosed as suffering from pernicious anaemia Definition of" pernicious anaemia' It is of interest that Davis and Brown (1993) defined pernicious anaemia as a megaloblastic anaemia with sreversible degeneration of the gastric mucosa Witts (1996) stated the final argument for the prionty of gastric atrophy in the development of pernicious anaernia is the complete failure to reverse the atrophy and achylia by vitamin B, or any other therapeutic agent In our present state of knowledge we agree with Watts Treatment of gastric atrophy, pernicious anaemia and subacute combined degeneration of the cord Once the diagnosis of pernicious anaemia or subacute combined degeneration of the cord is established intramuscular injections of vitamin B12 should be given Before overt macrocytic anaemia or subacute combined degeneration of the cord appear there is a gradual depletion of the vitamin B, stores especially in the hver so that when treatment is begun these stores should be rapidly and fully replenished It is wise to gie 1000 micrograms of vitamin B12 every second day for the first week and then weekly for 2 months Sron also may be required to restore the normal blood picture After 2 months liberal treatinent with vitamin B12 smaller doses of 100 micrograms can be gnen every 3-4 weeks to maintain adequately the erythrocyte count and haemoglobin level A few patients appear to require 200 micrograms or more but once vitamin B, fails to control the anaemia other causes should be sought especially cancer of the stomach or bowel or chronic renal disease ·GASTRIC ATROPHY AND PERNICIOUS ANAEMIA 70 Should the initial anaemia be profound and the patient s life threatened and especially if there be an accompanying infection such as pneumonia then a blood transfusion can be life saving The blood should be carefully matched and cross typed for trans fusion reactions are frequently encountered in these patients The use of packed cells to avoid overloading of the circulation with plasma should be considered However most cases can be restored to health with liberal doses of vitamin B, and appro priate antibiotics without resorting to transfusion Throughout the present studies full doses of parental vitamin B, have been employed Preparations for oral administration containing both B12 and intrinsic factor in the form of animal (heterologous) mucosal extract have been disappointing in that their potency may wane after the passage of months or years Schwartz and Meulengracht (1997) have attributed this fall in potency to the development of antibodies to heterologous extract They demonstrated human (autologous) gastric mucosal extract to be still efficient when the animal extract was farling The treatment of patients with severe subacute combined de generation of the cord with or without accompanying pernicious anaemia requires the same initial liberal dosage of vitamin B, It has been claimed that with continued high dosage good results are obtained All patients show improvement but in severe cases the recovery is incomplete Moreover should the residual weak ness be pronounced it may increase with advancing years probably due to failing blood supply from progressive atherosclerosis It has already been emphasised that the gastric lesion in classical pernicious anaemia and subacute combined degeneration of the cord is irreversible despite long continued therapy with Inner preparations (Doig and Blood 1930 Ilkinson 1919) and with vitamin B, (Finchh and Slood 1993) Thus gastric biopsy is of value in reviewing the diagnosis in patients who have recen ed some previous treatment with lover or vitamin Biz It is also of value in the diagnosis of pernicious anaemia as opposed to other types of megaloblastic anaemia in which selere gastritis or gastril atrophy may not occur namely those due to dietetic deficiency intestinal malabsorption liver disease and drugs such as I panu (Badenoch 199+) Delay in the diagnosis and treatment of subacute combined degeneration of the cord may result either from fatlure to recognise Epanutin (sodium pheni toin) latke Das is tin ·GASTRIC ATROPHY AND PERVICIOUS ANAEMIA 71 the significance of the peripheral dysaesthesiae which may precede other manifestations by many months or from a reluctance to diagnose this condition in the absence of the characteristic haematological abnormalities Here gastric biopsy has been a most valuable and in making an early diagnosis (Doig Alotteram Robertson and Wood 19,04) The serum vitamin B, estima tions and radioactive vitamin B, absorption tests are also proving to be of considerable value Alcoholic peripheral neuritis associated with chronic atrophic gastritis and histamine fast achlorhydria may simulate early subacute combined degeneration of the cord ·EPILOGUE And what of the future In the light of experience in our unit and elsew here will gastritis become a widely accepted malady sympathetically managed by the attending physician? Will the atomic age with increasing exposure to radiation produce more sufferers from chronic atrophic gastritis) Will this in turn lead to more cases of pernicious anaemia? And more cases of gastric cancer And fewer cases of duodenal ulcer? What will be the future of alcoholism-will it be successfully controlled by social reform? And what will be the final assessment of the effect on the gastric mucosa of the stress reactions of Selye and of Wolf and Wolff? 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A textbook of histolog) II B Saunders Co Philadelphia and London MEULENGRACHT C (1939) Histologic investigation of pyloric gland organ in pernicious anaemia Amer med Sct 197 -01 MOLLIN D L BAKER S G and DovrACu G (1955) Addisonian pernicious anaemia without gastric atrophs in a young man Brit ſ Haematology 1, 278 MOORE CI (1955) The importance of nutritional factors in the pathogenesis of iron deficiency anaemia Amer ſclin Vutrition 3 3 MOSBECH J (1953) Heredity in pernicious anaemia Copenhagen MOTTERAM R (1951) A biopsy study of chronic gastritis and gastric atrophy ſ Path Bact 63 389 VIEWEC HO FABER J G DE RIES J A and ROESE FS (1954) The relationship of vitamin B,2 and folic acid in megalo blastic anaemias ſ Lab clin Med 44 118 NYFELDT A and VIMTRUP B (1932) Gastritis acuta bei diphtheria faucium Acta med scand 78 447 PALMER C D (1950) Gastric mucosal biopsy findings correlated with gastroscopic diagnoses Preliminary report based on fifty patients Imer med Sa 219 648 -(1951) The morphologic consequences of acute exogenous (staphylococcic) gastroenteritis on the gastric mucosa Gastro enterology 19 46 (1954) Gastritis—A revaluation lledicine 33 199 (1954) State of the gastric mucosa of elderly persons without upper gastrointestinal symptoms 9 Amer Geriatrics Soc 2 171 PALMER E D and Sun M (1953) Submucosal gastric hema Complication of vacuum tube biopsy technic Recres of Gastroenterology 20 330 toma ·REFERENCFS 81 WILLIAMS WL ELLENBOCEX L and ESPOSITO R G (1954) Pre paration of highly purified intrinsic factor Proc Sac exper Brol 87 400 \ITTS L ) (1976) Anaemia and the alimentary tract The relation ship between changes in the alimentary tract and deficiencies of iron folic acid and vitamin B, Royal Coll Phys Fd Publica trons 10 7 37 ITOLF S and VIOLFF HG (1943) Human gastric funchon in experimental study of a man and his stomach Oxford University Press I ondon WOLFF H G KOLF S GARE ) HOLMES T F STEVEX3OV I STRAUB L GOODELT, H and SETON P (1948) Changes in form and function of mucous membranes occurring as part of presentare reaction parterns in man during periods of life stress and emotional conflict Transactions Ass Amer Phys 61, 313 Wood II (1991) Value of gastric biopsy in the study of chronic gastritis and pernicious anaemia Bnt med f 2, 8-3 Wood I J Doic Rh MOTTERAV R and HUCHES A (1949A) Castric biopsy Report on fifty five biopsies using a new flexible gastric bropsy tube Iance 119 Hoop I J Doig RI MOTTERAY R WEIDEN S and MOORE A (19498) "The relationship between the secretions of the gastric mucosa and its morphology as shown by biopsy specimens Gastroenterology 12 949 ·Lancet 1, 757 80 REFERF\CES SCHINDLER R NFCFIELFS II and Gold R (1939) Surgical gastritis A study on the genesis of gastritis found in resected stomachs with particular reference to the so called Antral Gastritis associated with ulcer Surg Ginec Obstet 69 281 SCHINDLER R and ORTWAYFR M (1942) Histopathology of chronic gastritis am y dig Dis 9 411 SCHWARTZ MI LOUS P and MEULENCRACIT [ (1957) Reduced effect of heterologous intrinsic factor after prolonged oral treat ment in pernicious anaemia Suunner M and DONJACH I (1937) A study of ray negatre dys pepsia with reference to histologic changes in the gastric mucosa Gastroenterolog) 32 313 SMITH EL (1948) Purification of anti permicious anaemia factors from liver Nature 161 638 STEIGMANN F HYMAN S and h 4144PELL (1957) Large gastric rugae Benign or malignant Gastroenterology 32, 7- SWALM " A JACKSON C L and Morriso L (1936) Correlation of clinical and gastroscopic findings in chronic gastritis Rec Gastroenterol 3 219 TFXTER E C (Jnr ) LEGERTON CU Reeve RJ SWTH A G and RUFFIN J M (1993) Coexistent carcinoma of the stomach and hypertrophic gastritis Gastroenterologi 24 579 Trousen F (1925) Études sur lachylie neurogene et cellulaire ! 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·80 RETIRFVCTS SCIUNDLFR R ECHELDS H and GOLD R (1939) Surgical gastritis A study on the genesis of gastritis found in resected stomachs with particular reference to the so called Antral Gastritis associated with ulcer Surg Ginec Obstet 69 281 Schindre R and ORTWAYER M (1942) Ilistopathology of chronic gastritis Am dig Dis 9 411 SCHEN ARTZ M Lous P and MIEL LE\CRACHT F (1997) Reduced effect of heterologous intrinsic factor after prolonged oral treat ment in pernicious anaem13 Lancet 1, 751 SHIINER MI and Dovich I (1997) A study of ray negative dis pepsta with reference to histologic changes in the gastric mucosa Gastroenterology 32 313 Switu E L (1948) Purification of anti pernicious anaemua factors from liver Nature 161, 638 STEIGMINA F HYMAN S and HANSAPEL " L (1957) Large gastric rugae Benign or malignant Gastroenterolog) 32 7- SWALV WA JACKSON C L and MORRI ON I (1936) Correlation Rer of clinical and gastroscopic findings in chronic gastritis Gastroenterol 3 219 TEXTER C C (Jnr ) LECERTON CU REEVE RJ SMITH A G and RUTFIN J M (1993) Coexistent carcinoma of the stomach and hypertrophic gastritis Gastroenterologi 24, 579 THOMSEN E (1925) Etudes sur lachyle neurogene et cellulaire 1 Acta med scand 61 377 TOMENIUS J (1952) A new instrument for gastric biopsies under visual control Gastroenterologi 21 5++ VICTOR M1 and LEAR A (1956) Subacute combined degeneration of the spinal cord Current concepts of the disease process Value of serum B, determinations in clarifying some of the problems mer y lled 20 896 \ IDEB AEK A and MOSBECH I (1954) The aetiology of gastric car cinoma elucidated by a study of 302 pedigrees Acta med Scand 149 137 IMTRUP B (1929) Two lectures on gastritis Bibliotck / Laeger 212 119 WEIDEN S (1919) Some observations on the secretion of the stomach with special reference to mucus lled y Aust 2 81 11 ELBOURN RB NELSON M G and 2 ACI ARIAS FJ (1956) Alega loblastic anaemia following gastric resection Brit Sur 43 unaz WILKINSON J F (1949) Megalocytic anaemias Lancet 1 +9 Brut WILLIAMS A " (1950) The stomach of the recently deceased med i (1956) Effects of alcohol on gastric mucosa Brit med II -56 I02 ·INDEY 83 Gastric atrophy-ontd Gastric mucosa microscopic appearance 57 58 effect of age on 38 preceding pemicious anaemia 61 effect of alcohol 2 relation to pernicious anaemja argentaffine cells in 14 57 64 6, 66 67 68 artefacts 14 without pemicious anaemia 41 changes after death and surgery as a primary process 57 65 1 symptomatology 6t early fixation 1 18 treattnent of 69 goblet cells in 13 lack of response to vitamin B1, mitoses in 14 1, 60 70 normal appearance in biopsy 13 Gastne biopss secreting bulk 45 in achlorhydna 15 Castnc secretion see also Achior in alcoholism 22 39 41 hydria artefacts 17 effect of age 38 complications 16 relation to gastric biopsy 66 67 contraindications 15 in chronic gastritis 46 47 48 efficiency of flexible tube 10 mucus content in chronic gastritis structure of flexible tube 79 and gastnc atrophy 67 in gastric atrophy 57 58 59 60 normal in possible case of per relation to gastric secretion 66 Nicious anacmia 68 69 67 in peptic ulcer 45 45 in acute gastritis 19 - 21 22 following ray irradiation 42 39 in chronic gastntis 24 Gastritis acute serial in chronic gastntis 47 in alcoholism 22 39 in diffuse giant hypertrophic - causes 18 21 22 23 gastritis 5+ gastric biopsy in 19 in radiation gastritis 42 ++ 22 32 relation to gastroscops 5 - gastroscopic appearances 21 history 6 22 indications la - gastroscopy in > in megaloblastie anaemia 1, 63 history 18 701 macroscopic appearance 18 normal appearance 13 14 MICROSCOpic appearance 12 correlation with pepsin secretion 1 - perforation in 20 in pemicsous anaemia 59 63 6, - regeneration in 20 68 due to staphylococcal enteroin duznosis of pernicious anaemia toxin 21 23 and subacute combined de - staphylococcal gastroenteritis generation of the cord 71 21 23 39 preparation of specimen 11 12 - symptomatology 29 2! 23 - treatment 23 sampling erTOS II Gastritis chronic scamong of specimen it --achl shs dna in 3 technique using facsible tube 7 scutt exacerbatom in 27 9 10 zety Iryny 37 technique umz Penedict operat -- 2?e of met 36 inz gastronope 7 incidence with a ¢ 37 3% oortelaion xrbo cal 34 ~ aicium and 22 37 39 41 Its value ! - relatxanhp tr cancer 34 gr mitts bopaxt x mame 47 +2 -- Avctz* yn with chronic de Carc Estul in Ist tating Crear y 34 3) 0 21 20 ·INDEL Cancer of the stomach-contd resembling chronic gastritis 5 zonal gastritis in relation 10 47 relationship to pernicious anaemia 66 rays as possible cause of 48 Carcinoma of colon causing anaemia 51 Clinical history 2 Cytology of gastric washings 17 in pemicious anaemia bo Achlorhydria age and 38 associated with alcoholism 71 in cancer 46 familial incidence of 66 in gastric atrophy 59 66 value of gastric biopsy in 15 in chronic gastritis 36 in healthy subjects 66 iron deficiency in 48 and peripheral neuritis 71 in pernicious anaemia and sub acute combined degeneration of the cord 59 63 67 69 Acute gastritis see Gastritis acute Alcohol effect on diet - 37 39 41 effect on gastric mucosa 22 39 +1 and acute gastritis 2.39 and chronic gastritis 2. 37 39 41 and hepatomegaly 2 peripheral neuritis caused by 71 Anaemja see also Pernicious anaemia carcinoma of colon causing 31 chronic nephritis causing 51 macrocytic 51 Witts hypochromic 48 gastritis in 48 49 50 51 -- gastric biopsy in 49 as precursor of cancer 48 -vitamin B1, absorption in Atrophic gastritis see Gastritis chronic Atrophy see Gastric atrophy Diarrhoea in chronic gastritos 36 Diet in alcoholism 37 39 41 in cancer 47 in chronic gastritis 33 37 38 in clinical history Diphtheria acute gastritis in -3 Dyspepsia age of onset in gastritis 36 in cancer 47 caused by gastritis I in chronic gastritis 33 36 SI in radiation gastritis 44 in gastrie atrophy 61 6. in pernicious anaem).2 61 0 treatment with hydrochloric acid 33 2 Flexible gastric biopsy tube see Gastric biopsy 48 49 Biopsy see Gastric biops Cancer of the stomach 2 3 achlorhydria in 46 dyspepsia in 47 familial incidence 65 66 relationship to gastritis 36 46 Gastrectomy cause of vitamin B12 deficiency 6. 68 Gastric atrophy 57 see also Per nicious anaemia achlorhydra in 59 aetiology of 64 65 66 dyspepsia in 61 6.. relation to chronic gastritis -5 33 59 61 65 66 genetic influence in 65 66 68 history 57 macroscopic appearance 57 47 48 8 ·83 1 INDEX Gastric atrophiconid Gastnc mucosa microscopic appearance 57 58 effect of age on 38 preceding pernicious anaemia bi effect of alcohol 2 relation to pernicious anaemia argentaffine cells in 14 57 64 65 66 67 68 artefacts 14 without pernicious ansemia 41 changes after death and surger as a primary process $76, symptomatolog) 61 early fixation 1 18 treatment of 69 goblet cells in 13 lack of response to vitamin B1 mitoses in 14 15 60 70 normal appearance in biopsy 13 Gastric biopsy secreting bulk 45 in achlorhidria 15 Gastric secretion see also Achior in alcoholism 2. 3) +1 hydria artefacts 14 effect of age 39 complications 16 relation to gastric biopsy 66 67 contraindications 15 in chronic gastritis 46 47 48 efficiency of flexible tube 10 mucus content in chronic gastritis structure of flexible tube 79 and gastric atrophy 67 in gastric atrophy 57 58 59 60 normal in possible case of per relation to gastric secretion 66 Nicious anaemia 68 69 67 in peptic ulcer 45 in acute gastritis 19 o 21 -2 following ray irradiation 4. 39 in chronic gastritis 24 Gastritis acute serial in chronic gastritis 47 -- in alcoholism 2. 39 in diffuse giant hypertrophic causes 18 21 22 23 gastritis 54 - gastric biopsy in 1921 in radiation gastritis - 44 -- 39 relation to gastroscopy 5 gastroscopic appearances I history 6 7 indications 15 -- gastroscopy in 5 in megaloblasti anaemia 15 63 history 28 70 71 macroscopic appearance 16 nommal appearance 13 14 - Microscopic appearance 19 correlation with pepsın secretion perforation in 20 in pernicious andemia 59 63 65 regeneration in 20 08 due to staphylococcal entero in diagnosis of pernicious anaemia toxint -1 -3 and subacute combined de -- Staphylococcal gastroenteritis generation of the cord 71 21 23 39 preparation of specimen 11 - symptomatology - I 13 - treatment -3 sampling error 11 Gastritis chronic statning of specimen II achlorhydria in 36 Technique using flexible tube 7 - acute exacerbationis in 27 9 IO aetiology 37 technique using Benedict operat age of onset 36 in gastroscope 7 incidence with age 37 38 correlation with test meal 34 alcoholism and -- 37 3) 41 its Talue i relationship to cancer 36 46 in Witt hypochromic anaemja 47 48 49 -association with chronic de Gastric fistula is bilitating disease 37 38 39 0 I ·to 84 INDEX Gastritis chronic classification -5 Gastritis diffuse giant hyper - diarrhoea in 36 trophic relation to chronic diet in 33 37 38 gastritis 24 25 53 distribution of 25 - gastroscopy in 54 dyspepsia in 33 36 SI macroscopic appear gastric atrophy and 25 33 59 ance 53 61 65 66 - microscopic appear -senal gastric bropsy in 47 ance 53 gastric biopsy in 24 47 --relation to neoplasm 53 atrophic gastritis 25 29 33 treatment of 54 36 41 42 45 47 48 Gastritis zonal 47 - relation to diffuse giant hyper Gastroscopy 5 trophic gastritis 24 25 53 in acute gastritis 21 2. - superficial gastritis 25 27 36 in alcoholism 39 38 39 41 45 complications 5 - gastroscopy in 5 relation to gastric biopsy s association with haemochro findings in acute gastritis 5 matosis 39 findings in chronic gastritis 5 - haemorrhage in 33 36 50 findings in diffuse giant hyper - history 24 trophic gastritis 54 intestinal metaplasta in 29 findings in pernicious anaemia 5 - resemblance to malignancy technique 5 52 instrument Benedict 7 macroscopic appearance 25 instrument Cameron 5 microscopic appearance 27 instrument llermon Taylor relationship pernicious 5 7 anaemia 65 66 -- instrument Schindler 5 7 - physical examination in 36 Giant hypertrophic gastritis see 37 Gastritis diffuse giant hyper - psychic stress and 4- trophic gastric secretion in 46 47 48 sex incidence 33 38 - association with Sjogren s Haematemesis disease 39 after gastric biopsy 16 17 -- structural changes in 24 in acute gastritis 20 symptomatology 33 Haemochromatosis 39 tea drinking and 41 Haemorrhage - atrophy of tongue in 37 after gastric btopsv 16 17 treatment with acid 33 in chronic gastritis 33 36 50 treatment with alkalı 51 in diffuse giant hypertrophic treatment with iron si gastritis 54 treatment with penicillin 51 Hepatomegaly and alcoholism 2 relationship to peptic ulcer 45 Hypertrophic gastritis Witts anaemia and 48 Gastritis diffuse giant hyper - causing vitamin B, defi trophic ciency 51 - vitamin deficiency in 38 -ray irradiation 37 4. 44 Influenza acute gastritis in 23 45 Intestinal mnetaplasia Gastritis diffuse giant hyper in gastric atrophy 57 trophic 25 53 in chronic gastritis 29 barium meal in 54 Intrinsic factor of Castle 64 66 biopsy in 54 67 differential diagnosis in gastric mucoprotein 67 Iron absorption 49 50 54 see also ·INDES 85 Iron deficiency relation to achlorhs dna 48 in Witts anaemia 48 49 50 Irradiation see ray srradiation Malnutriton see Diet Megaloblastic anaema caused by Epanutın 70 gastric biopsy 185 63 70 71 gastric changes in 66 67 68 Mental changes in starris Bar deficiency 6. Perniicious anaema-contd subacute combined degeneration of the cord in the absence of 6. 63 sytreptomatology 6, tongues 61 trans{usion in 70 treatment of 69 70 Physical examination 2 3 in chronic gastritu$ 36 37 Pneumonia acute gastritis in 23 Psychic stress cause of gastritis 47 cord 71 Ocsophagus perforation after Radiation see also I ray irradiation biopsy 17 and Gastritis chronic bleeding from vances 36 Radtologs in diffuse giant hyper trophic gastritis 4 54 Pain in gastritis see Dispepsia radiology in chronic gastritis + Pancreatitis - Rugae effect of distension 25 Pepstrogen in chronic gastritis 25 plasma + in diffuse giant hypertrophic urinary 4 gastritis Pepsın secretion see olso Gastrıc pronounced 4 secretion correlation with gastric bsopsy 15 Salmonella infections 20 in peptic ulcer 45 Sjogren s disease 39 Pesspheral neuritas 75 Staining of gastric bropsy section alcohohc simulating subacute 13 combined degeneration of the Staphylococca food poisoning 21 23 39 Pescious anaemia see also Vita gastroenteritis 21 39 min 2 Subacute combined degeneration aeriology of 64 65 66 of the cord 57 59 asesbiotics i 70 achlorhydria in 59 relation to cancer 66 gastric biopsy indicated in 15 in childhood 68 69 diagnosis with Jastric bropsy definition of 69 71 dyspepsia in 65 6 relation to gastric changes 66 familial incidence of 65 66 68 acroscopic appearance of the 69 stomach m 57 58 gastric cytology in 60 croscopic appearance of the gastroscopy in 5 stomach in 59 preceded by gastric atrophy 6: peripheral neuntis 3 normal gastric biopsy in 68 development without pemicious and gastric changes 57 59 66 anaemia 6. 63 history 57 symptomatology 65 intrinsic factor in 67 treatment of 69 70 macroscopic appearance of the cobalt labelled vitamin stomach in 57 absorption test 19 63 microscopie appearance of the relation to stami B deficiency stomach in 37 38 69 oral administration of vitamin Superficial gastritis see Gastntrs B: 70 chronic ·86 IDEX Tea cause of gastritis 41 l'est meal correlation with gastric biopsy 3 4 histamine § 66 insulin 4 maximum secretory response + ovemight 4 tubeless 4 Tongue atrophy in chronic gastritis 37 in pernicious anaemia 61 Trichrome stain for gastric biopsy II, 12 Vitamin B contd non reversibility of gastne atrophy to 15 60 70 deficiency due to chronickastritis 51 relation to intrinsic factor of Castle 67 68 storage in her 68 mental changes in 62 oral administration of 70 in pumicious anaemia 15 serum estimations 71 relation to subacute combined degeneration of the cord 68 transport in serum 67 in treatment of pernicious anaemia 69 70 in treatment of subacute com bined degeneration of the cord 69 70 absorption in Witts anaemia 45 49 Vitamin deficiency In alcoholism 41 causing cardiac enlargement 3 in chronic gastritis 38 causing peripheral neuritis 2 causing tachycardia 3 Ulcer 2 3 age of onset 36 bleeding from 36 duodenal 42 44 45 46 gastric secretion in 45 46 relationship of chronic gastritis to 45 zonal gastritis in relation to 45 47 Witts anaemia see Anaemia Vitamin B1, see also pernicious anaemia mode of action 67 68 56cobalt labelled in absorption test 15 63 71 deficiency following total has trectomy 62 68 deficiency manifestations of 61 62 63 in gastric atrophy 61 ray irradiation 42 44 as a carcinogen 49 effect on gastric secretion 42 44 cause of gastritis 37 42 44 45

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