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FEBRUARY 10, 1923.

Hunterian LectureON THE

RELATION OF

DISEASE OF THE GALL-BLADDERTO THE SECRETORY FUNCTION OF THE

STOMACH AND PANCREAS.Delivered at the Royal College of Surgeons of England

on Feb. 5th, 1923,BY H. ERNEST GRIFFITHS, M.S.LOND.,

F.R.C.S. ENG.,HUNTERIAN PROFESSOR, ROYAL COLLEGE OF SURGEONS OFENGLAND ; DEMONSTRATOR OF ANATOMY, ST. BAR-THOLOMEW’S HOSPITAL MEDICAL SCHOOL ; SURGEON

TO THE ALBERT DOCK HOSPITAL ; REGISTRARTO THE ALL SAINTS HOSPITAL.

INTRODUCTION.DISEASE of the gall-bladder has long been recognised

as a cause of digestive disturbance. It will be myendeavour first to trace the anatomical and physio-logical relations of the gall-bladder to the stomach and Ipancreas, paying particular attention to the controlexercised by the sympathetic filaments derived fromthe ninth thoracic segment of the cord and the vagus ;then to analyse some symptoms and signs of gall-bladder disease, showing how many of them are

dependent on disturbance of gastric and pancreaticfunctions ; finally to enumerate a few tests which maybe used to determine error in the secretion of thestomach and pancreas.ANATOMICAL RELATIONSHIP OF GALL-BLADDER.The close anatomical relationship of the pylorus,

the first part of the duodenum, and the head of thepancreas with the gall-bladder need not be emphasisedhere. There are, however, a few points concerningtheir peritoneal connexion, nerve-supply, and lymphdrainage which must be carefully considered. Thefundus of the gall-bladder is surrounded by parietalperitoneum. The body, however, is only covered onits sides and inferior surface, its upper surface beingbare and approximated to the right lobe of the liver.Passing from the neck of the gall-bladder downwardsto the first part of the duodenum, and sometimescrossing this to reach the transverse colon, is found acrescentic fold of the peritoneum with a free anterioredge. This has been variously called the cysto-colic,hepato-colic, and cysto-duodenal ligament. Addisonfound it present in 33 per cent. of cases. In 100 con-secutive cases which I have examined at operation,in the post-mortem room or dissecting room, the foldwas present in 52, absent in 24, and in the remaining24 there were so many adhesions around the gall-bladder that it was impossible to say whether the foldwere originally present or not. The cysto-duodenalfold is a remnant of the anterior part of the ventralmesogastrium. Contraction of this fold, due toinflammatory changes in the gall-bladder, tends tocause constriction of the duodenum and may be oneof the factors concerned in the causation of theregurgitation test-meals commonly found in gall-stone cases. Bricon wrote that the cysto-duodenalfold functioned as a safety-valve in gall-stones bycontracting during inflammation and approximatingthe gall-bladder to the anterior surface of the duo-denum, so that the stones might ulcerate through thewalls of the viscus into the gut and a spontaneouscure result. In one case I have seen completeobstruction to the duodenum by the cysto-colic fold.The case was diagnosed as carcinoma of the pylorus,and the true condition was found at operation.

LYMPHATICS.The efferent lymphatic vessels of the gall-bladder

pass in the main to a lymphatic gland situated at thejunction of the cystic duct with the neck of the gall-bladder, and from there downwards in the gastro-hepatic omentum in relation to the common bile-duct ;several lymph-nodes which occasionally attain the .

size of glands interrupt their course. The relationshipto the common bile-duct is maintained as that struc-ture passes behind the first part of the duodenum tobecome embedded in the posterior surface of the head "of the pancreas. Here they inosculate freely with thelymph vessels of the pancreas and duodenum, andshare with them the retro-pancreatic lymph glands.Although the flow of lymph from the gall-bladder innormal conditions passes directly to the reoeptaculumchyli via the retro-pancreatic and coeliac groups oflymph glands, in inflammatory conditions, wheresome of the channels become occluded, this lymphfinds its way into the pancreatic plexus and infectionis thus communicated directly to the pancreas.

Nerve-supply.The nerve-supply of the gall-bladder is derived from

the hepatic plexus, the filaments being conducted totheir destination along the cystic artery and itsbranches. The hepatic plexus is an offshoot from thecoeliac plexus, which is derived from the fifth to thetenth thoracic nerves via the great and small splanchnicsand the right vagus. In the small omentum thehepatic plexus is joined by the branches from the leftvagus and also from the diaphragmatic ganglionwhich marks the junction of the diaphragmatic plexuswith the right phrenic nerve. Thus, from a purelyanatomical study it might be assumed that the gall-bladder received its nerve-supply from the fifth tothe tenth thoracic nerves, both vagi, and the rightphrenic. The vagi are undoubtedly the motornerves to the viscus. There is considerable differenceof opinion as to whether the liver, gall-bladder, andbiliary passages are endowed with sensory nerve

filaments. At one time it was almost universallyaccepted that the right phrenic nerve supplied theliver and the gall-bladder with sensation, but manyanatomists now consider that all sensation of the gall-bladder is due to interference with its peritonealcovering. According to K. G. Lennander, the parietalperitoneum is intensely sensitive to pain, but not topressure, heat and cold, and this sensibility is increasedby inflammation. He states that the visceralperitoneum and abdominal organs are entirely devoidof any sense of pain when inflamed, and that all painarising from disturbances within the abdominalcavity is caused by irritation through the spread ofinflammation to the abdominal walls or pressureexerted upon those parts inervated by the cerebro-spinal system, and that those parts supplied by thevagus and sympathetic nerves only have no afferentfibres for the transmission of painful impulses.

In operations performed on the upper abdomenunder local anaesthesia stimulation of the gall-bladderdoes not produce pain, but this in itself is not a proofof the absence of sensory fibres. Kast and Meltzer,of the Rockefeller Institute, showed that cocaine actscentrally as well as peripherally. When an animal isoperated upon under local anaesthesia the abdominalviscera appear to be insensitive to painful stimuli.If, however, the abdomen is opened without anaesthetic,stimulation of any organ causes pain which maybe abolished by the injection of cocaine into the limbof the animal. Sensation is similarly lost after exposureof the viscera to the atmosphere. This accounts forthe well-known surgical phenomenon that a colostomymay be opened without anaesthetic after the initialoperation. All surgeons know that a colostomy is notinvariably insensitive. Kast and Meltzer summed uptheir work by stating that " all experiments lead upto the one unmistakable result which can be statedin a few words : the normal gastro-intestinal canalpossesses a sensation of pain." In support of the viewthat the phrenic nerve supplies sensory fibres to thegall-bladder, cases of gall-stones are quoted in whichpain was referred along the phrenic nerve to otherbranches of the cervical plexus supplying the skinin the region of the point of the shoulder and theaxilla. In the series of cases which I have examinedthis referred pain has been a rare symptom, alwaysassociated with spread of inflammation to the parietalperitoneum in relation to the diaphragm, thus directly

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affecting the twigs of the phrenic nerve which piercethat muscle. Working purely on an anatomicalbasis, Ramstrom was unable to demonstrate anyfilaments of the phrenic or intercostal nerves enteringthe liver.

In inflammatory conditions of the gall-bladderthere is frequently an area of hypersesthesia whichfollows closely the distribution of the ninth rightintercostal nerve. In two cases I have seen an attackof herpes zoster affecting the area of skin supplied bythis nerve following an attack of acute cholecystitis.Frequently a zone of hyperaesthesia is found belowthe angle of the right scapula over an area of skinwhich is supplied by the posterior branch of the ninthintercostal nerve. To sum up : The vagus is themotor and secretory nerve to the gall-bladder and bilepassage, and is inhibitory to the sphincter of the

ampulla of Vater. The sympathetic deriving itsfibres from the ninth right intercostal segment is thesensory nerve to the gall-bladder ; it is inhibitoryto the muscular wall, but supplies the motor filamentsto Oddi’s sphincter. Thus stimulation of the vaguscauses emptying of the gall-bladder through a relaxedsphincter, and stimulation of the sympathetic causesclosure of the sphincter and filling of the lax-walledgall-bladder with bile. The vagus in the stomach is,again, the motor and secretory nerve and is inhibitoryto the pyloric sphincter. The sympathetic derivedfrom the fifth, sixth, seventh, eighth, and ninththoracic segments is inhibitory to the muscle ingeneral, but motor to the pyloric sphincter. Theninth intercostal segment is mainly responsible forthe contraction of the pylorus. The pancreas derivesits nerve-supply from both sympathetic and vagus.Stimulation of the vagus causes profuse, thinsecretion from the pancreas, whereas stimulationof the sympathetic is followed by a small but thicksecretion. My investigations upon the nerve-supplyof the pancreas are not yet complete, but so far theyseem to point to the fact that the sympatheticfilaments are mainly derived from the ninth thoracicsegment.

PHYSIOLOGICAL RELATIONSHIPS OF THE

GALL-BLADDER.

It is now necessary briefly to review the normalphysiological relationship between the stomach,pancreas, and gall-bladder. Appetite and the ingestionof food into the stomach are the signals for the secre-tion of acid gastric juice; the pyloric canal is firmlyclosed, and the peristaltic waves of the stomachchurn up the food and impel it against the barrierof the pyloric sphincter. As the food gets brokenup the stomach contents become more acid, thesphincter relaxes, and a little chyme is squirted intothe duodenum, where its acidity causes immediatereflex closure of the pylorus. This process is repeateduntil the stomach is emptied. While this process isgoing on secretin is produced, which stimulates thepancreas. and liver to the increased production oftheir digestive ferments. Rhythmical contractionsof the gall-bladder also occur, and its store of con-centrated bile is added to that produced by the liver.The presence of the alkaline juices in the duodenumrapidly neutralise acid chyme escaping from thestomach, and themselves tend to produce a reflexrelaxation of the pyloric sphincter. In the later stagesof gastric digestion the movements of the stomachbecome less violent, and the pressure within is con-siderably diminished. At the same time the alkalinityof the duodenum rises, with resultant reflex inhibitionof the sphincter, and thus a small amoun of regurgi-tation occurs periodically from the duodenum to thestomach.The liver and the pancreas are both stimulated by

the same hormone secretin, and their outflowings passto the duodenum through a common opening. It isevident, therefore, that there must be a close relation-ship between the bile and pancreatic juice. Chemicalinvestigations have proved that the digestive activityof pancreatic juice is increased twofold by an adequatequantity of bile. One phase of my work has been

to study the effect on digestion of the elimination ofthe gall-bladder by disease. In all diseased conditionsof the gall-bladder its function as a reservoir of bileis temporarily or permanently abolished. Themajority of cases which I have studied have beeninflammatory, generally complicated by the presenceof gall-stones. It has long been known that in suchcases the little muscular tissue of the gall-bladder isgradually replaced by fibrous tissue/and its elasticityis lost. On this pathological fact Courvoisier basedthe interpretation of his law. Studying these casesfrom the physiological point of view, and for themoment ignoring the pathological aspect, a conditionis produced equal to extirpation of the gall-bladderfrom the biliary circulation. Considering this froma purely theoretical point of view, it would beexpected that the bile from the liver would pass in asteady stream into the duodenum with no reservecollection for use when most needed for digestion.The bile entering the duodenum when the stomachis at rest would produce a relative increased alkalinityon the distal side of the pylorus resulting ininhibition of the sphincter and consequent regurgita-tion into the stomach. Small doses of alkali injectedinto the stomach would stimulate the secretion andproduce a condition of hyper-acidity, which, however,would tend to be neutralised by the alkaline causativeagent. The effect of this constant stimulation of thestomach with neutralisation of its contents producesa condition of atonia of the walls of the viscus, butalso hypertrophy of the pyloric sphincter from itsconstant exercise. In the normal process of digestionbile does not start to flow freely into the duodenumuntil the acid chyme has entered. Where bile ispassing constantly into the duodenum in the earlystages of digestion, however, it still tends to regurgitateinto the stomach, neutralising the gastric juice andinterfering with the process of gastric digestion.

So much bile having been wasted between meals,there is an insufficient store forthcoming for theprocess of digestion. This defect makes itself mostfelt in its effect on the pancreatic juice, the activityof whose ferments is very much diminished by theabsence of bile. The fat-splitting ferments in particularare affected, and it would, therefore, be expected thatin patients suffering from this condition there would beinability to digest fatty foods. The effect is also

marked on the protein-splitting ferments, and theincomplete digestion of protein leads to increase inintestinal decomposition and toxaemia, with resultingindicanurea. It must be remembered that naturegenerally attempts to make some compensation forloss sustained to the body. When the normal gall-bladder is removed, the common bile-duct endeavoursto take its place as a reservoir by dilation. The amountof the bile held in this way is inconsiderable, unlessthere is some pathological obstruction to its outflow,and its composition remains the same as when it wassecreted by the liver.

INFLAMMATION.

Inflammatory lesions of the gall-bladder may pro-duce disturbances in the neighbouring organs in fourways : (1) By destroying its physiological function,as already described ; (2) by reflex action ; (3) bydirect spread of infection ; (4) by toxic effect. Inflam-mation of the gall-bladder is, in the majority of cases,produced by infection with the Bacillus coli communis.In a few cases other organisms of the coliform groupare found, and more rarely streptococci. It is beyondthe scope of this lecture to discuss in detail the routeby which the gall-bladder becomes infected ; in myopinion, however, it is generally infected by organismsin process of elimination from the portal system bythe liver.

Infection may be carried from the gall-bladder tothe pancreas by four routes : (1) By the commonbile-duct to the ampulla of Vater, then by regurgita-tion along the main pancreatic duct; (2) by thelymphatic stream already described ; (3) by the blood-stream ; (4) by direct infection in those cases wherethe gall-bladder becomes adherent to the duodenum

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and lies in close proximity to the head of the pancreas.The two latter routes are of great rarity and will notnow be discussed.

Bile in the common bile-duct normally flows at apressure equal to that of the juice in the pancreaticduct, about 40 mm. of water, so that there is notendency for regurgitation of bile from the ampullaof Vater along the pancreatic duct. If the pressuretends to rise in the common bile-duct, the gall-bladder,dilating, acts as a safety-valve and reduces the tension.When, however, the gall-bladder contracts in theprocess of digestion, there is inhibition of Oddi’ssphincter, and a free flow of bile into the duodenumresults. In certain conditions obstruction to the out-flow of bile occurs at the duodenal orifice of thecommon bile-duct. In these cases there is a tendencyfor regurgitation of bile towards the pancreas. Onecause of obstruction is a gall-stone impacted in theampulla of Vater. In many cases the impacted stonenot only prevents bile in any quantity in passinginto the duodenum, but is so situated as to preventits entrance into the pancreatic duct.Another common cause of obstruction is car-

cinoma of the head of the pancreas, which involvesnot only the terminal part of the common bile-ductbut also the pancreatic duct.

Sclerosing pancreatitis also has the effect ofinhibiting the flow of bile into the duodenum, but itnearly always does so by pressure on the commonbile-duct proximal to the ampulla ; at this stage ofthe disease, therefore, regurgitation of bile is unlikelyto take place, although its previous occurrence

may have been one of the causes of the sclerosingpancreatitis.

Finally we must consider Oddi’s sphincter itself.The occurrence of spasm of this muscle may cause atransient flow of bile into the pancreas in cases wherethe gall-bladder is already diseased, and cannot actas a safety-valve. The bile may penetrate only ashort way along the pancreatic duct and then, withthe relaxation of Oddi’s sphincter, be washed backinto the duodenum by the pancreatic juice; but itsstay in the pancreas has been long enough to occasioninfection without producing such serious changesas would have occurred had the obstruction in theampulla of Vater been permanent.

Catarrhal jaundice should be mentioned here as apossible cause of regurgitation of bile, but in themajority of cases the swelling of the mucous

membrane of the bile-duct extends above the ampullaof Vater and causes obstruction at a higher level.

Changes in the Pancreas due to Infection from theGall-Bladder.

Such changes are :-(1) Catarrhal pancreatitis due to direct inoculation

of the mucous membrane of the pancreatic duct withinfected bile, generally occurring as the result of aspasm of Oddi’s sphincter. The temporary arrest of i

the secretion of pancreatic juice into the intestinal ’,tract produces considerable disturbance in the processof digestion, particularly of fats, and results in oneof those well-known attacks of diarrhoea which areoccasional features in some cases of gall-stones.Vomiting may be a serious symptom in these cases,and is proportionate to the degree of infection of thepancreas.

(2) Chronic parenchymatous pancreatitis, whichcan be detected macroscopically or microscopicallyin all eases of long-standing infection of the gall-bladder. It is due to infection by organisms carriedfrom the gall-bladder to the pancreas in the lymphaticstream. In the majority of cases it produces few grosssymptoms, because the islands of Langerhans are

only slightly involved, and because the alveoli ofthe major part of the body and the tail of the glandgenerally escape. In a few cases, however, sclerosisof the head of the pancreas is sufficient to cause

obstruction to the pancreatic and common bile-ducts.The condition may then easily be mistaken for car-cinoma of the’ head of the pancreas. In the largergroup of cases careful pathological examination will

generally reveal evidence of disturbance of both theinternal and external secretions of the pancreas. Thissubject will be referred to later.

(3) Acute pancreatitis of the haemorrhagic, suppura-tive, and gangrenous varieties is, in my opinion,almost always due to infection from the gall-bladder.It may be impossible to determine the route of infec-tion at operation or autopsy, owing to the extensivedestruction of pancreatic tissue. In some cases thereis very definite evidence of regurgitation, in othercases there is none, and it must be presumed that theinfection spreads via the lymphatics.The Common Bile-Duct and the Sphincter of the Ampulla

of Vater.I should like to consider for a few moments the

changes that may occur in the common bile-ductand the sphincter of the ampulla of Vater (Oddi’s)in so far as they are concerned with the conditionalready described. I have already referred to catarrhalchanges in the mucous membrane, and shall now dealonly with the fibrous and muscular coats. The passageof irritant fluid, such as infected bile, always tends toproduce increased muscular activity in an endeavourto expel it. The walls of the common bile-ductcontain very little muscular tissue, but what is therecontracts in peristaltic waves and, at the same time,reflexly, causes inhibition of Oddi’s sphincter. Attimes it appears that the peristaltic action loses itsrhythm, and the most marked result is a temporaryspasm of the ampulla of Vater. The muscle in thisregion is so much greater than that in the commonbile-duct that where the latter is diseased it becomesa law unto itself, and if for any reason there occurscontraction of the sphincter, independent of the muscleimpulses passing down the bile-passages, the spasmproduced is sufficiently strong to ignore the naturalstimuli. It is found that spasm of the sphincter ofthe pylorus is associated with spasm of Oddi’s muscle,and if a relationship can be found between pyloricspasm and disease of the gall-bladder, another verydefinite reason may be deduced for the temporaryobstruction to the flow of bile into the duodenumand its temporary regurgitation along the pancreaticduct. The infected bile entering the duodenum setsup a mild duodenitis which in itself is one of the mostfrequent sources of pyloro-spasm.

THE REFLEX NERVOUS ARC.

Irritation of the mucous membrane of the gall-bladder causes a reflex irritability of the vagus whichis most marked by its action in the stomach, wherean increase in the amount and acidity of the gastricjuice is produced, associated with relaxation of thepylorus and regurgitation from the duodenum.Whereas in the majority of cases the vagus reflex isthe more marked, in others the sympathetic reflexis more evident. In this type of case the inflammationis generally less chronic. As would be expected, itis shown by increased action of that portion of thesympathetic derived from the ninth thoracic nerve. °There is spasm of the ampulla of Vater and relaxationof the gall-bladder walls with consequent dilationof the viscus ; in the stomach there is spasm of thepylorus, but as the ninth thoracic segment suppliesonly the pylorus there is no sympathetic effect on theremainder of the stomach, and the vagus reflexremains unchecked, causing hyperchlorhydria andcontraction of the organ. The first and second partsof the duodenum are dilated and the pancreaticsecretion is concentrated but small. This conditionis clinically known as pyloro-spasm, and althoughin the majority of cases the irritating focus is in thegall-bladder it may occur anywhere in that portionof the digestive tract where the terminal filamentsof the sympathetic derived from the ninth thoracicsegment are found-namely, gall-bladder, bile-ducts,pylorus, the first and second parts of the duodenum,and the pancreas.

I wish now to dwell for some time on the evidenceof gastric and pancreatic disturbance which may bededuced from the history and clinical examination

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of patients suffering from gall-bladder disease. HereI shall take as a type cases of cholelithiasis associatedwith cholecystitis. From the patient’s point of view,the most important symptom of the gall-stones ispain, which may be of three types : (1) biliary colic,(2) biliary ache, and (3) biliary dyspepsia.

Biliary CoKc.—This is an agonising pain, startingin the right side of the abdomen. Usually, when itcan be accurately located, at a point one-third of theway from the tip of the ninth right costal cartilageto the umbilicus, but the point of maximum intensityof the pain varies slightly in position, and may befound immediately below the xyphoid cartilage ordeep behind the eighth or ninth right costal cartilage.The pain is seldom limited to this one spot ; it isgenerally described as shooting through the rightshoulder." On careful questioning of the patient,the right shoulder is found to refer to the right inferiorscapular region. Instead of passing to this regionby the direct route, the pain is often stated to shootround the chest on the right side, following the courseof the ninth intercostal nerve. Less commonly painis referred to the inferior angle of the left scapula ;in these cases it appears to shoot through the thoraxand never round the left side. Again, the pain maybe felt behind the inferior angles of both scapulae.The pain frequently radiates down the abdomen asfar as the umbilicus and sometimes into the rightloin. The distribution of referred pain on which moststress has been laid by the majority of authors is oneradiating upwards from the right hypochondrium tothe point of the shoulder and the axilla on the rightside. When present this symptom is pathognomonicof a severe inflammatory lesion of the hepatic, biliary,or right diaphragmatic regions. This pain neveroccurs in gall-stone colic uncomplicated by acute orsubacute cholecystitis. The onset of the colic issudden, and its intensity rapidly increases to reach amaximum in a few minutes. The attack may lastfor half an hour or be prolonged for several hours,with short respites from the more severe pain. Thecolic ceases as abruptly as it commenced, but is alwaysfollowed by a feeling of soreness underneath the rightcostal margin and in the region immediately below it.Usually the pain starts half an hour or more after afull meal, sometimes when the patient is in bed, andsometimes after he has been shaken by riding ormotoring. Although in this lecture I do not proposeto deal with the effect of stomach and pancreaticfunctions on the disease of the gall-bladder, it maybe noted again that the digestion of food in the stomachand duodenum, through the production of secretin,stimulates the muscle of the gall-bladder, and thenormal inhibition and contraction of the pyloricsphincter reflexly find their counterpart in the move-ments of the sphincter of the ampulla of Vater andthe neck of the gall-bladder. In this way it willseem that the passage of a stone from the gall-bladdertowards the duodenum is more likely to occur withinthe first two hours after a meal than at any othertime. In long-standing cases, where the muscle ofthe gall-bladder has been replaced by fibrous tissue,there is no response to the stimuli of the stomach,and biliary colic becomes a rare symptom.

Biliary Ache.-Gall-stone pain is frequently of adull, aching character, interspersed with periods ofacute exacerbation. It is referred to the right subcostalregion and the right lumbar region, the pain appearingto travel through the abdomen between these twoareas. A constant and steady pain in the rightlumbar region, which may extend to the left side ofthe spine, is often present. It seldom becomes acute,and is not, therefore, usually a primary source ofcomplaint on the part of the patient, but a leadingquestion will nearly always establish its presence.It generally becomes most evident as the more severeanterior abdominal pain is subsiding. The onset ofbiliary colic has been already described as dramaticallysudden ; the pain now under review has a moreinsidious beginning. There is a vague feeling ofabdominal discomfort, gradually increasing until painbecomes definite and localised. The severity of the

pain varies considerably ; it may cause little incon-venience, or the patient may be prostrated. In thisacute condition the pain differs from biliary colic inseveral essentials ; it is not of a griping nature, butis rather burning and stabbing, whilst referred painalong the superficial cervical plexus is the rule ratherthan the exception. The pain is sustained, and whenremission occurs it is gradual. Shivering almostinvariably heralds an attack, and always occurs

before the rise of temperature. Constitutionaldisturbance is marked in severe cases, the tem-perature rising to 103° F. or higher, and thepulse-rate increases to 120-140. Furred tongue,constipation, scanty urine, and vomiting testify tothe degree of toxaemia. It is evident that biliaryache is due to infection of part or all of the extrahepatic biliary apparatus, and that the pain is theresult of inflammation. It may be caused by irritationof the nerve endings of the mucous membrane byproducing a catarrhal condition of the bile-ductsresulting in increased resistance to the flow of bileand consequent increased tension in the liver andgall-bladder. The referred pain to the neck andacromial region only occurs when the inflammatorychanges have spread to the serous coverings of thegall-bladder and the peritoneum on the under surfaceof the diaphragm, thus involving terminal sensoryfilaments from the right phrenic nerve. The achein the lumbar region is due to the spread of infectionto the head of the pancreas, resulting in congestionof that organ. It might be expected that there shouldbe some anterior pain felt just above the umbilicusto demonstrate the involvement of the pancreas, butclinically it is impossible to differentiate between thispain and that due to the involvement of the bilepassages and the neighbouring peritoneum. -

Biliary Dyspepsia.-The third type of pain, usuallydescribed by the patient as " indigestion," appearsto have a definite relation to meals. There is a feelingof weight and fullness in the epigastrium, accompaniedoften by a dull aching in the left scapular region.Flatulence is constantly associated with these sym-ptoms, and belching or vomiting gives considerablerelief. This condition is usually most acute abouthalf an hour after taking food, and lasts about twohours. Almost every patient who has biliary dyspepsiadiscovers, sooner or later, that the old householdremedy of a glass of hot water will give relief. It hasbeen claimed that the drinking of a glass of hot waterbefore meals is a panacea for all. digestive ills. Itmay now be stated, with a greater degree of certainty,that the drinking of a glass of hot water after mealsin women is diagnostic of one of the most severe ofdigestive ills-gall-stones.

VOMITING.

Vomiting is one of the commonest symptoms ofgall-stones, and occurs in 81 per cent. of my cases.It occurs in a variety of different forms ; in biliary colicwith impaction of the stone, generally in the cysticduct, the patient experiences an extreme degree ofnausea associated with a feeling of goose-flesh, whichis rapidly succeeded by cold, clammy sweating andsevere vomiting. The patient is quite prostrated, and,according to Moynihan, with the general loss ofmuscular tone the stone, which is at the mouth of thecystic duct, falls back into the gall-bladder, and reliefof symptoms is obtained. He describes one case inwhich on two occasions he was able to detect thegradual enlargement of the gall-bladder accompanyingtwo severe attacks of biliary colic with nausea andvomiting. In this patient the obstruction of thecystic duct was due to kinking and not to a stone.I have met two such cases ; in one the obstructionwas due to a solitary gall-stone, and in the other to ashrapnel ball. The latter-was a case of a young officerwho was wounded in the right side of the chest, themissile passing through the pleural cavity, thediaphragm. the right lobe of the liver, and penetratinginto the gall-bladder. X ray localisation suggestedthat the position of the foreign body was in the right= lobe of the liver, but succeeding attacks of biliary colic.

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accompanied by deadly nausea and vomiting, withcoincident enlargement of the gall-bladder, succeededby prostration with abatement of the symptoms,indicated the presence of the foreign body in the gall-bladder. The diagnosis was confirmed at operation,the shrapnel ball was removed, and as there was noevidence of inflammatory change in the walls of thegall-bladder it was closed. The patient made anuninterrupted recovery.The vomiting associated with biliary colic is in the

main reflex. In the first stage contraction of the wallsof the gall-bladder is associated with regurgitationof duodenal contents through the pylorus, and thepatient experiences nausea, rapidly succeeded by areflex spasm of the pylorus in response to the spasmof the sphincter of the neck of the gall-bladder or theampulla of Vater ; peristaltic waves of the stomachwall increase and violent vomiting results.

Biliary dyspepsia is accompanied by vomiting of adifferent kind, occurring after a full meal, and not, asa rule, accompanied by much nausea. It is generallysmall in quantity and of a watery regurgitant type.Occasionally it is copious, resulting in completeevacuation of the stomach, and affording the patientcomplete relief from pain without producing thatdegree of prostration which is a feature of vomitingassociated with biliary colic. Vomiting in these casesis due to direct irritation of the mucous membrane,the stomach having been rendered hypersensitive byinflammatory changes consequent upon the regurgi-tation of duodenal contents and the increased acidityof gastric juice.A third type of vomiting occurs in patients who

have been jaundiced. Nausea is again a distinctivefeature, but the amount of material expelled from thestomach is often small. - This vomiting may occurafter every meal or, as is more frequent, attacks ofshort duration occur at regular intervals coincidentwith the rise and fall of the pigmentary curve. Twofactors operate in producing this condition : first,the gastric irritability already described in biliarydyspepsia, and secondly, the toxic effect of thecirculating bile on the vomiting centre in the medulla,shown by the increase in vomiting found with theincrease in jaundice. A fourth type of vomiting whichoccurs in gall-stone patients is periodio. It does notappear to be associated with any gross disturbanceof the gall-bladder or bile passages, although it mayfollow an attack of cholecystitis. It is not associatedwith that degree of nausea found in the first and thirdtypes, but is always accompanied by mild diarrhoea,the stools being fatty and undigested, resemblingsomewhat those found in coeliac disease. The attackgenerally lasts for several days, in more severe casesextending into weeks. Wasting is a very markedfeature in cases of long duration. The characterof the stool, with the marked increase in undigestedfat, is symptomatic of pancreatic insufficiency.Other evidence of pancreatic insufficiency, such asincreased diastase content of the urine, indicanurea,positive Loewe’s mydriasis test, and sometimestransient glycosuria, all tend to add weight to the Idiagnosis. It may safely be assumed that this typeof vomiting is due to a type of pancreatitis whichinvolves both the internal and external secretion. Ihave not had the opportunity of making a post mortemon such a case, but hazard the. opinion that the con-dition, is due to catarrhal pancreatitis, the result ofperiodic invasion of the gland by micro-organismsderived from the gall-bladder.The next class of case with which I propose to deal

is that arising from ulceration of gall-stones throughthe wall of the gall-bladder into the alimentary tractand causing intestinal obstruction. It is difficult tospeak of the vomiting in this condition as a definitefifth type, because as the disease progresses thecauses and character of the vomiting alter. In thetypical case the gall-bladder becomes adherent to theduodenum. At the commencement of the ulcerativeprocess severe nausea and vomiting set in, similar tothose experienced with the impaction of a gall-stoneiti the -cystic duct. As the stone emerges into the

duodenum the vomiting becomes more persistentand regurgitant in character, and may be foundto contain a small amount of blood. When the stonehas left the gall-bladder and commenced its journeydown the small intestine, there is a temporary abate-ment of symptoms until the stone becomes impactedin some part of the bowel. As a rule impaction occursfor a short interval at several points before the calculusis brought finally to rest about 18 inches proximalto the ileo-caecal valve. During the temporarystoppages there is considerable intestinal colic, whichmay be accompanied by reflex vomiting withoutnausea. When finally the intestinal obstruction hasbecome established, vomiting once more becomespersistent, at first consisting of unaltered stomachand duodenal contents, but later becoming faeculent.In rare cases where obstruction occurs after ulcerationof the stone into the transverse colon, the initialvomiting is less severe and no blood is found in thevomit. On the other hand, streaks of bright bloodmay be found in contents of the lower bowel evacuatedbefore the obstruction occurs.

Jaundice.-Jaundice, although one of the classicalsymptoms of gall-stones, only occurs in about 17per cent. of all cases. The percentage of hospitalcases who suffer from jaundice is much greater because, Ias a general rule, only those come up for treatmentwho have suffered from biliary colic, which itselfoccurs in only a minority of cases. Jaundice, asso-ciated with disease of the gall-bladder, is essentiallyof the obstructive type. Clinically, it may be inter-mittent, remittent, or progressive. The onset ofintermittent jaundice is generally preceded by anattack of biliary colic a few hours before. In a typicalcase the patient complained that she had an attackof pain in the evening and the next morning her friendsnoticed her eyes were yellow. Early jaundice isdifficult to recognise in artificial light, which probablyaccounts for the fact that the condition is nearlyalways first recognised in the morning. This type ofjaundice lasts for only two or three days, and maycause the patient little inconvenience ; in the majorityof cases it is-due to the temporary arrest of a gall-stonein the common bile-duct, and subsequent inflammationand swelling of the mucous membrane. The degreeof infection is reflected by the rise in the eveningtemperature to 101°F., which nearly always accom-panies the case of transient jaundice. In the remittenttype of jaundice the onset is similar to the one alreadydescribed, but may persist for weeks and even months,and is never of the same intensity during the wholeof that period. As a rule the degree of jaundice variesfairly regularly every three to five days, gettinggradually deeper and lighter but never disappearing.A simple test for determining slight variations in thedegree of jaundice may be made by collecting a littleblood in a capillary tube, allowing it to stand, andcomparing the pigmented serum with that taken atsome other time. The jaundice in this type of caseis due to a stone in the ampulla of Vater, causingincomplete obstruction. The morning and eveningvariation is due to the greater amount of bile secretedby the liver during the day.The onset of progressive jaundice is insidious, and

seldom associated with biliary colic as in the twoprevious types. The degree of pigmentation increasesfrom day to day, and although in the early stages ofthe disease, before obstruction to the outflow of bileis complete, there may be slight variation betweenmorning and evening, this soon disappears. Thetemperature generally remains normal, the obstructionmay be due to the stone in the cystic duct causinglateral pressure on the common bile-duct, adhesions, or,more commonly, changes in the pancreas. Sclerosingpancreatitis, already described, causes increasedpressure on the buried portion of the common bile-duct. Other evidence of the disease of the pancreasis forthcoming in periodic attacks of vomiting, withmarked wasting and the undigested fatty stools towhich I have already alluded. I have not endeavouredto describe all the methods by which jaundice mayoccur in cases of disease of the- gall-bladder, but

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only to emphasise the type in which it is definitelyassociated with the kind of pancreatic complicationwhich is dependent upon cholecystitis.

CLINICAL EXAMINATION OF THE PATIENT.

On inspection of the abdomen it is unusual toobserve anything, apart from occasional jaundice,indicative of gall-bladder disease or associated dis-turbance of its neighbouring organs. In the majorityof cases the patient is well covered; rarely, a visiblefullness to the left of the mid-line may indicatedistension of the stomach. Rapid loss of weight,with attacks of diarrhoea and vomiting, is shown bythe looseness of the skin. When in such cases the skinis dry and parchment-like, or even scaly, furtherexamination always reveals definite pancreaticinvolvement.

Findings on Palpation.-In acute, and often insubacute, cholecystitis definite areas of superficialhyperaesthesia can be made out. This hyperaesthesiamost commonly follows the course of the ninthintercostal nerve on the right side ; it is also foundin the distribution of the branches of the right cervicalplexus. On two occasions I have observed super-ficial hyperaesthesia over the seventh and eighthintercostal nerves on the left side. In each thesymptoms appeared after the acute stage of chole-cystitis had subsided and gastric disturbance hadbecome a prominent feature. On deep palpation themost constant sign of gall-bladder disease is tender-ness below the tip of the ninth right costal cartilage.In chronic cases which are associated with biliarydyspepsia there is generally tenderness below theensiform cartilage, which is more or less constant inall inflammatory lesions of the stomach. Sometimesafter an attack of cholecystitis, when the gall-bladdertenderness is no longer diffused over the upperabdomen but is limited to Murphy’s sign, pain may beelicited by pressure above the umbilicus. Whenpresent, this points to subacute inflammation of theproximal portion of the head of the pancreas. Boasfirst described an area of tenderness on deep pressureextending for 3! inches to the right of the spinalcolumn on the level of the eleventh thoracic to thefirst lumbar spines. His explanation was that thetenderness was in relation to the posterior surfaceof the liver. The cases that I have examined in whichthere is tenderness in the loin fall definitely into twoclasses-those where a point of maximum tendernessis situated over the eleventh rib, about 3 inches fromthe mid-line, and those where the tenderness issituated lower down to the right, and often extendingto the left of the second lumbar vertebra. Thetenderness over the eleventh rib has been found inall cases of cholecystitis that I have examined ; Ibelieve it to be due to the spread of inflammationfirst to the parietal peritoneum, and then, via theextra-peritoneal lymphatics, to this point, which isthe most dependent when the patient is lying down.The lower area of tenderness occurs in its maximumintensity in cases of acute pancreatitis. It occursonly in a minority of cases of gall-bladder disease,but is always associated with other definite signs ofpancreatic disturbance. In my opinion it is due to aninflammatory lesion of the pancreas.

Other areas of deep tenderness to which attentionhas been drawn by various authors are over thespines of the fifth, sixth, seventh, and eighth thoracicvertebrae, and over the inferior angle of the left scapula.Tenderness in these regions is by no means as markedas that which occurs over the eleventh right rib, andis present in the more severe forms of biliary dyspepsiaand is most marked after an attack of vomiting.Tenderness in these two places can be found in allcases of gastric ulcer, which occur proximal to thepylorus. It seems, therefore that it is due to aninflammatory lesion of the stomach. Finally, deeptenderness may be found over the distribution of theright superficial cervical plexus.On percussion and auscultation valuable informa-

tion may be obtained of gastric disturbance. In all

cases of biliary dyspepsia, and practically ail cases ofgall-stones, the stomach is found to be enlarged.X Ray MMKs.—X ray examination of the

stomach, after introduction of a barium meal, showsdilation of the stomach and evidence of pylorospasm.When examined on the screen regurgitation throughthe pylorus is seen to be much more marked, and tooccur much earlier than in the case in normal digestion.

CHEMICAL PATHOLOGY.

The clinical evidence already deduced of stomachand pancreatic disturbance lead to deductions whichwould have to be regarded as theoretical unlesschemical pathology demonstrated their truth. Inthis branch of the research I have worked withDr. Mackenzie Wallis, who has conducted all thelaboratory investigations and with whom I hopeshortly to publish a complete account of our work.

Test-Meal.-The examination of a large number ofsimple test-meals extracted after one hour’s digestionin the stomach has shown that in over 90 per cent.of all cases of gall-stones there is definite hyper-chlorhydria associated with regurgitation. In onlytwo cases have we found true hypochlorhydria.Occasionally it was found that there was definitehyperchlorhydria without any evidence of regurgita-tion. In these cases there was clinical evidence ofpylorospasm. We have not found the fractional test-meal of value in the investigation of gall-bladderdisease, owing to the difficulty in determining theamount of regurgitation.

Tests of Pancreatic Sufficiency.-The estimation ofthe amount of diastase in the urine has proved themost delicate test of pancreatic error that we possess.In the normal person the amount of diastase variesbetween 10 and 30 units, with an average of about22-5. In our series of cases we have found that in28 per cent. of cases the diastase has risen to between50 and 100 units, being always high in cases associatedwith acute inflammatory lesions of the gall-bladder,and in cases where diarrhcea is a symptom. Theamount of diastase in the urine of an individualpatient varies from time to time, and is an indicationof the varying degree of pancreatic inflammation.

Glycosuria is rare, and has only been found insome of those cases where there has been extensivedestruction of the pancreas as a result of sclerosingpancreatitis or acute haemorrhagic pancreatitis.Indicanuria in varying degree is present in all casesof old-standing gall-bladder disease. It may bestated that bacterial decomposition taking place inthe digestive tract and giving rise to the indicanuriais the cause of the diseased gall-bladder. The prob-ability is that a vicious circle is established, andwhichever is primary at the onset, in the later stagesthe interference with pancreatic digestion from themaladmixture of bile predisposes towards intestinalputrefaction, and organisms carried away by theportal stream and eliminated by the liver are a

constant source of reinfection to the gall-bladder.Steatorrhcea is found in all cases of obstructivejaundice, and in cases of advanced sclerosing pan-creatitis, and in that form of catarrhal pancreatitiswhose presence is indicated clinically by diarrhoea.Steatorrhcea is due to lack of pancreatic lipase or itsincomplete activation owing to the lack of bile.Loewe’s mydriasis test has been positive in only aminority of cases, but in these there has always beenother definite evidence of pancreatic insufficiency.

CONCLUSIONS.

I have endeavoured to show that the gall-bladderis only a unit in a definite digestive complex embracingthe liver, gall-bladder, pancreas, and stomach, andthat any disease affecting one unit is bound to bereflected in the whole system. A careful analysis ofthe history and clinical examination of a patientsuffering from disease of the gall-bladder will revealmany points indicative of involvement of the stomachand the pancreas, but which none the less point to the

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original trouble. Infection of the gall-bladder actingreflexly through the vagus nerve tends to cause

hyperchlorhydria and regurgitation. In some cases,where the sensory stimulus is greater, pylorospasmis the result of a sympathetic reflex through theninth thoracic segment. Regurgitation from theduodenum may also be attributed to the unregulatedflow of bile in cases where a gall-bladder is no longercapable of acting as a reservoir.The pancreas is peculiarly prone to infection from

the gall-bladder. In the majority of cases infectionoccurs through the lymphatics, in others by theregurgitation of bile along the main duct consequentupon obstruction at the ampulla of Vater. Thisobstruction is frequently due to spasm of Oddi’ssphincter and occurs with pylorospasm. The secretionof the pancreas into the duodenum is seldom markedlydiminished, the exception being in cases of catarrhalpancreatitis, but through lack of adequate admixtureof bile the digestive function of the pancreatic juicemay be seriously diminished.The internal secretion of the pancreas, except in

very rare cases-e.g., pancreatic necrosis-is- not verymuch upset, although the increased amount of diastasein the urine and occasional positive Loewe’s reactionare indications of some slight alteration.

It will be seen that in some obscure cases of gall-bladder disease, where the cause cannot be found bythe ordinary clinical methods, exhaustive examina-tion of the functions of the stomach and the pancreasmay lead to a correct diagnosis.

An Address[ABRIDGED]

ON

PROGRESS AND PROBLEMS INEPIDEMIOLOGY.

The Presidential Address delivered before the Section ofEpidemiology and State Medicine of the Royal

Society of Medicine on Feb. 2nd, 1923,

BY RICHARD J. REECE, C.B., M.D.,M.R.C.P., D.P.H.

MY first duty is to thank the Section of Epi-demiology and State Medicine of the Royal Societyof Medicine for the very great honour conferred onme by the members in electing me to the importantposition of President, and my second is to offer myapologies to the section for the delay that has occurredin the delivery of the customary Presidential address. ITo what extent and with what success this Societyhas contributed to the science of epidemiology andto medical literature can be realised by reference tothe index of the papers that have been read at itsmeetings and to the reports of its various committeeswhich have been. formed from time to time for thepurpose of studying special branches of epidemiology,but there is yet much to be learnt and many problemsremain to be solved.While the Society’s transactions bear witness to the

wide range of subjects considered at its meetings andto the merit of the contributions furnished by itsmembers to the study of epidemiology, they alsotestify that many of the most important papers havebeen written by medical officers of the Royal Navy,the Army, and the Colonial services, and by medicalmen who have not served in any of the State medicalservices, but without in any way detracting from thevalue or minimising the high esteem that is due, anddeservedly due, to the work of these men, it can besaid that the elucidation of epidemiological problemshas been closely associated with the public healthdepartment of the Civil Service.

THE FOUNDATION OF THE SOCIETY.

The birth of our Society in 1850 took place at atime when John Simon had commenced to write,and the medical staff of the Privy Council came intoexistence. To this staff belonged Netten Radcliffe,George Buchanan, and others, the value of whoseepidemiological work cannot be overrated. Whenthe State Medical Department was transferred to thenewly constituted Local Government Board in 1871,other men joined the service, and the study ofepidemiology was continued by Power, Thorne-Thorne, Ballard, Barry, Parsons, T. W. Thompson,Theodore Thomson, Bulstrode, and many more

whose names are household words in this Society.Only last year one of our members, who joinedthe Society in 1887, departed from us, my oldcolleague, Robert Bruce Low, who by his industry,skill, and perseverance materially assisted theadvancement of our knowledge in regard to theprevalence and distribution of disease throughout theworld.When our Society was first instituted it advocated

adequate endowment for medical research. Wecannot claim that such a proposition emanated solelyfrom our Society ; it has been advanced by others, butwe can congratulate ourselves that with the adventof the Medical Research Council, one of its primaryobjects has been fulfilled. The science of epidemiologyis not limited to one country, it embraces the wholeworld ; it is not confined to one race of man, nor,indeed, to mankind alone, it extends to the animaland vegetable kingdoms. It is closely associated withgeography and history, with the work of the physi-ologist, pathologist, bacteriologist, and chemist, withthe science of statistics, and with clinical medicine.Its interests are far-reaching and our Society, foundedfor its study, can look forward with satisfactionto the progress our branch of medicine is boundto make as a result of the comprehensive workcarried out under the auspices of the MedicalResearch Council.

SIR PATRICK MANSON’S VIEWS ON FUTURELINES OF RESEARCH.

In his Presidential Address to this Society inNovember, 1900, Sir Patrick Manson set forth whathe thought should be the future lines of research inthe elucidation of the many epidemiological problemsbrought prominently before the world by having toinclude the protozoa and nematodes among theimportant pathogenetic organisms affecting man, andby the knowledge that many diseases are spread in avariety of ways by blood-sucking arthropods. Heconsidered that each problem, after thoughtfulformulation, should be carefully worked out by aspecial investigation. He expressed the opinion thatthis was the only way to advance, as it was the onlyway to economise the somewhat limited supply ofpathological and epidemiological energy in the market,and that as each investigation would probably extendover a considerable period, probably one or two years,in order to secure continuity of work and to minimiserisk of interruption by ill-health or other contingencies,it would be better to have two investigators for eachsubject. During the 22 years that have elapsed sinceManson delivered the address there has been con-siderable stimulus in the study of pathology andbacteriology, sciences that directly improve our

knowledge of epidemic disease though not of theepidemicity of disease. Many workers have enteredthese fields of study, but it cannot be said that therehas been any comparable influx of workers in thedomains of epidemiology. There are few men whohave the time and opportunity to devote to thisscience, and however rich the reward that may fall tothe successful worker from the fact that he hasmaterially assisted in advancing knowledge and inaffording relief to suffering humanity, it is neverthelessa sad truism that, judged on the sordid basis offinance. there are other branches of medicine that aremore remunerative.