Further observations on the pathogenesis of peptic ulcer

Acta Medica Scandinavica. Vol. CIII, fasc. 111-V, 1940.

From the Medical Clinic (Direct,or: Professor Sven Ingvar) of the Royal University a t Lund (Sweden).

Further observations on the pathogenesis of peptic ulcer.

BY

ERIK ASK-UPMARK, M. D.

(Submitted for publication November 3rd 1939).

In a previous paper of mine evidence has been presented support- ing the neurogenic conception of the pathogenesis of peptic ulcer (Ask-Upmark, 1939). The opinion was maintained tha t the neurogenic factor t o be assumed was, reasonably, closely connected with a metabolic disorder. In the sequence of events inherent t o this disorder a central position was occupied by the liver. The present study will attempt an analysis of the pathophysiological participa- tion of the metabolic factor in the development of peptic ulcer with special regard to the behaviour of the liver.

Earlier investigations.

The evidence hitherto available on the involvement of the liver in the pathogenesis of peptic ulcer refers to three series of observations, derived from the experimental physiology, from the human pathology and from the clinical medicine.

1. Erperimental observations.

The evidence to be obtained from animal experiments about the r61e of the liver in ulcer genesis is fairly abundant. Crandall

F U R T H E R O B S E R V A T I O N S O N T H E PATHOGENESIS O F PEPTIC ULCER. 281

and Ivy (1938) have recently summarized the matter thus: ,It is striking that so many types of liver injury (Eck fistula, ligation of common duct, bile fistula, hepatotoxin) are followed in many instances by ulcerations of the duodenum which are chronic and have many of the characteristics of human ))peptic)) ulcer. Corre- spondingly, most of the methods employed to produce experimental peptic ulcer seem to depend upon interference with hepatic function.)) The various observations pertain to the following methods: Eck fistula, impairment of bile drainage, ligation of arteria hepa- tica, cinchophen intoxicalion.

a) The Eck fistula was used in dogs by Crandall and Ivy (1937), who noticed the development of ulcus in some 10 yo of all experiments. Already previously La Barre (1931) observed a considerably increased motility and secretion of the stomach in Eck-fistul- ated dogs. Gerez and Weiss (1937), in dogs correspondingly prepared, likewise registred the gastric secretion to be increased with regard to amount, to hydrochloric acid and to duration; they concluded that substances interfering with gastric secretion be present in the porta-system and ordinarily managed by the liver (retention, destruction); if the liver be injured or eliminated disturbances of the upper alimentary tract might be liable to result from the substances presumed. In this connection I should want to call attention to the fact that a man with pronounced liver cirrhosis as a matter of fact is to be looked upon as having an Eck-fistula (derivation of the portal blood through the anastomoses established with the cava system, the liver hence being partially evaded). As for the hypothesis of Gerez and Weiss i t may be said that a by far more likely explanation of the increased gastrointestinal activity in the Eck dogs seems to be furnished by the hypoglycemia induced by the intervention as observed already by La Barre; to this matter will be returned.

b) Impairment of the bile drainage may be established by means of ligation of the common bile duct (Berg and Jobling 1930, Fiess- inger and Palmer 1935, Hebert 1938: peptic ulcers obtained in dogs in a high percentage, usually of duodenal localization), by arranging an external biliary fistula after section of the common bile duct (Hawkins and Whipple 1935: purpura, osteoporosis, cholelithiasis, ulcus duodeni; Hanke 1937: peptic ulcers in 7 dogs out of 7) and by divertion of the bile from the upper alimentary canal (stomach and 1 9 - dcta med. scandinao. Vol . C I I I .

282 fi R I Ii A S Ii- U P M A It h

jejunum), for example by transplantation of the common bile duct to the terminal part of ileum (De Bakey 1937, production of ulccr in 50-100 %). In this series of experiments the peptic factor is obviously of outstanding importance, the ulcers and erosions bcing liable to develop within areas of duodenal mucosa exposed to tlie onrush of acid gastric juice and insufficiently buffered on account of the absence of bile. Whether still other mechanisms should be presumed to be a t work seems uncertain (cfr Hebert). These observations in animals may be paralleled by the clinical record, described by Holzweisser of a woman aged 58, who had an obstruction of her Vaterian ampulla and eventually developed eight erosions and ulcers below the duodenojejunal flexure.

c) Ligation of the hepatic artery was, among otlier methods, used by Muto (1934) in dogs. The gastric secretion was found to be interfered with and the conclusion was drawn that an undisturbed liver function was essential to normal gastric secretion.

d) Experimental intoxications of the liver have been performed witli various substances (chloroform, avertin, phosphor, cinchophen; see for example Muto). By far the most important results have been achieved by tlic use of cinchophen, regardless of the method of administration. Originally introduced by Van Wagoner and Churchill this method has since been applied in various studies performed by Bollnian, Stalker and Mann (1937-38) as well as by Simonds (1938). If dogs are given cinchoplien a peptic ulcer, in all essentials similar to the spontaneous ulcer in m m , mill develop in almost 100 %. The ulcer is usually single, tlie location thc minor curvature or the pyloric region (less often duodenal), gross haemorrhages and perforations are complications frequently occurring; the ulcer is preceded by acute gastritis, mainly involving fundus ventriculi; large doses of cinchophen and coarse food reduce the time necessary for the development of the ulcer. I t is obvious that gastric secretion and acidity represent an important factor since no ulcer was obtained if milk and alkaline powders wcre included in tlie diet. The acidity level is not impaired but hypersecretion is constantly present and the gastric content remains acid longer than normal. I t is well known that, in man, cinchophen belongs to the deadly liver poisons: personal observations 011 this topic will be referred to later on (p. 286). As for the gastritis to be noted in the cinchophen dogs i t is tempting to explain i t along the lines indicated

F U R T H E R O B S E R V A T I O N S O N T H E P A T H O G E N E S I S O F PEPTIC ULCER. 283

by Wichels and Brinck (1933, department of Katsch, cfr p. 284), since the method of administration of the drug was of no importance.

2. Observations pertaining fo human pathology.

'The evidence along this line has hitherto been fairly scanty. Maluschew (1931) described two instances of liver echinococcus

in connection with peptic ulcer, maintaining that gastric disturbances Iw much more common in this disorder than generally assumed.

Schnitker and Hass (1934) made a histological study of the liver in 100 patients affected with peptic ulcer as compared with 100 controls. Among the ulcer group histological alterations of the liver were encountered in 50 instances, among the control-group in 36 cases. The difference may not seem very striking but if conditions otherwise liable to affect the liver were ruled out the figures became 24 versus 14. Additional evidence was obtained from 72 instances of liver cirrhosis, in 14 of whom (i. e. about 20 yo) peptic ulcer was to be noted. The authors conclude that a connection is probable between peptic ulcer and affection of the liver.

Elton (1937), discussing the clinical pathology of the liver, briefly remarks that liver cirrhosis of the Laennec-type frequently s associated with duodenal ulcer. To this matter will be returned.

3. Clinical obserualions. ,

Clinical evidence has been accumulating during recent years indicating involvement of the liver in peptic ulcer. The observations hitherto assembled may be briefly summarized.

Kalk (1931) has emphasized the frequent involvement of the biliary system in duodenal ulcer. In some 33 "/o of all duodenal ulcers Kalk noticed various symptoms from the liver and the biliary tract: colicnl pains, tenderness, enlargement and increased density of the liver, jaundice or (mostly) subicterus, appearance of urobilinogen in thc urine, positive (i. e. pathological) bilirubin tolerance test ad moduni v. Bergmann. As a matter of fact anybody with some experience of peptic ulcer will be able to testify the possibility of encountering jaundice, especially perhaps when duodenal ulcers are concerned.

284 E R1 K ASR-U P M A R K . Scharpff (1926) examined 15 patients suffering from gastro-

duodenal ulcer, using the levulose test. 80 gram levulose, dissolved in 300 cm3 fluid produced an increase of thc blood sugar levcl exceeding that to be observed under the same conditions in normal individuals. No sugar was encountered in the urine. The conclusion was derived that the liver be functionally impaired in peptic ulcer and the interesting remark was added that a similar levulose test was liable to be positive in vasoneurotic individuals.

Sjostrom (1 936, 1937), investigating the citric acid metabolism in health and disease, produced convincing evidence indicating the presence of liypercilriceniia in parenchymatous disorders of the liver. As a matter of fact this test should undoubtedly be looked upon as one of our most reliable tests of liver function. I t was observed, however, that also in certain other disorders hyper- citricemia was to be recorded, one of the most outstanding affections of this kind being represented by peptic ulcer: in no less than 2/3 of 56 determinations in peptic ulcer the level of the citric acid was elevated, probably on acrount or a liver involvement.

Wichels and Brinck (1933, department of Katsch) have furnished clinical and experimental evidence suggesting the participa- tion of disturbances of the liver function in the pathogenesis of gastritis. The gastric secretion was studied in disorders of the biliary tract, in dcterus simplex)), after administration of liver poisons and in affections of the organs drained by the portal system. As a rule hyperacidity was to be registered in acute stages, depressed gastric secretion in the subsequent course, the underlying cause being a gastritis, supposed to be brought about by the liver disorder to be presumed (toxic factors of the porta properly managed by the normal liver should pass the liver functionally impaired and cause various disturbances, such as gastritis).

Quaglia (19:)6) made a somewhat similar investigation, studying gastric secretion in various affections of the biliary and hepatic system. His material did amount to 386 cases, 60 of which were represented by hepatocellular jaundice, whereas 31 instances of cirrhosis were examined. He arrived a t the conclusion that the secretion of the gastric juice was liable to be interfered with by the affections mentioned.

Marino and Saladino (1937) noticed thc appearance of certain polypeptids in the scruin of 15 instances of gastroduodvnal ulcer,

FURTHER O B ~ E R V A T I O N S O N THE PATHOGENESIS OF PEPTIC ULCER. 285

ascribing the increased levels registered to functional disturbances of liver and kidney.

Loning (1930) in an interesting although mainly theoretical study, calls attention to the spastic activities frequently associated with hypoglycemic conditions whereas on the other hand the administration of glucose may favourably influence various neurospastic conditions. If, for example, the stomach was examined under X-rays, the increased motoric activities brought about by injection of insulin rapidly quieted down if glucose was administered intravenously. The author concludes that peptic ulcer ought to be liable to benefit from a sufficient storage of carbohydrates in the liver, and that, accordingly, functional correlations also in this regard may exist between liver and stomach.

Bruhl (1938) has recently studied the stimulation of the gastric secretion brought about by insulin. In accordance with earlier observations of Kalk and Meyer he found a considerable retarda- tion of the insulin effect with regard to the gastric juice if the individual examined was affected with a severe disorder of the liver, such as cirrhosis. The conclusion was derived that the liver was functionally connected with thc mechanism by means of which insulin did increase gastric secretion. To this important conclusion will be returned.

Personal material and observations.

My own investigations on the subject in question are represented by three series of observations concerning

1. The occurrence of peptic ulcer in connection with cirrhosis of the liver.

2. The functional analysis of the liver in peptic ulcer with special regard to the galactose test.

3. The performance of the galactose tolerance test in healthy individuals under standard conditions as compared with the introduction of galactose in the same individuals by means of duodenal tube.

1. The occurrence of peptic ulcer in liver cirrhosis.

This was an anatomical study, based upon the material of autopsies, performed in our department of pathology during the

286 E R I K A S K - U P M k R K .

last 10 years. For the permission to use this material I am indebted to the kindness of professor Einar Sjovall.

My personal interest in the subject dates back to a case of pronounced liver cirrhosis in connection with osteomalacia, described elsewhere (Ask-Upmark, 1939: 2); in this case a duodenal ulcer was going strong clinically as well as pathologically.

During the last decade (up to and including 1938) necropsy has been performed in 38 instances of cirrhosis hepatis, the very majority tieing of the Laennec type. In 22 of these cases details have been taken to the records about the anatomy of the gastrointestinal tract. I t was found that in no less than 9 out of these 22 observations a peptic utcer was to be registered either in the stomach (7 cases) or in the duodenal bulb (2 cases). In a t least 7 instances the ulcus was in active stage, whereas i t seemed to be morc or less healed in the remaining two cases. The frequency of peptic ulcer in the upper alimentary tract is thus striking in cirrhosis of the liver and it seems safe to say that in a t lcast one case out of three such an ulcer may be encountered. ‘This observation seems remarkable and it is in perfect accordance with the impressions of Elton and of Schnitker and Hass (p. 283), although the localization of the ulcer in my own material was the stomach more often than the duodenum. I t was moreover noted, when looking over the records of the autopsies, that an ulcer of peptic type was strikingly often to be registered also in other affections of the liver, such as amyloidosis, venous stasis (in heart failure) and metastatic deposits; no figures wcw however collected on this suljject. In one case of hepatitis gravis, due to cinchophen poisoning in a woman aged 30, the stomach was filled with blood, the gastric mucosa presenting numerous minute haemorrhages although no ulcer was to be registered; in another fatal case of cinchophen poisoning, likewise treated in our department by myself no autopsy was to be securcd in spite of efforts to this effect, hut in the light of the experimental evidence available on the ability of cinchophen to cause ulcer i t seems urgently indicated that the attention in the future be focussed also on the gastrointcs- Cinal tract when necropsies of such cases are being performed.

F U R T H E R O B S E R V A T I O N S ON T H E PATHOGENESIS O F PEPTIC U L C E R . 287

2 . The liver function in peptic ulcer.

A. M a t e r i a l a n d m e t h o d s .

The material was represented by 26 cases, specified as follows. Gastric ulcer 8 cases. Duodenal ulcer 12 cases. Pseudo-ulcer 3 cases. Peptic ulcer, previously operated upon, 5 cases.

‘ihe diagnosis was established along the usual lines, positive radiogram (including niche) being required for the diagnosis gastric or duodenal ulcer. The diagnosis ))pseudo-ulcer)) should be considered as corresponding to the German ))Reizmagen)) and char- acterized by a history similar to the ulcer type occurring as a rule in a young person, by a negative radiogram (i. e. no niche), by a gastric hypersecretion, frequently with climbing acidity, and by an essentially normal appearance of the gastric mucosa when examined by gastroscopy. All radiograms have been performed in our department of roentgenology under the experienced supervision of Dr Hellmer. The gastric acidity was as a rule examined by fractional test meal, which method of course is superior to the old Ewald method but on the other hand inferior to the recently described method with continuous suction through a specially divised rubber tube (Lagerlof- &ren method; for references see Ihre, 1938). Gastroscopy was performed in several instances, as a rule by myself. The condition of the liver was examined by the following four methods: the galactose tolerance test, the citric acid determination ad modum Sjiistrom, the Takata-Ara method as described by Hafstrom (1935) and the lipasc determination ad modum Rona. The galactose test was as a rule carried out along the original lines indicated by Bauer 1908: administration per 0s of 40 gram galactose on a fasting stomach and determination of the amount secreted in the urine for the following hours. Amounts exceeding 3 gram are always to be considered as pathological, amounts between 2 and 3 gram as rather suspicious, probably often pathological. The sources of error inherent to this method will be considered later on. In some instances the galactose test ad modum Malmros-Silver-Swaetichin was

I . c. 3 cases examined only after the operation + 2 cases observed before as ivcll as after the operation.

288 I: It 1 K AS K- U P M A R I<.

performed: administration per 0s on a fasting stoniach of $'i gram galactose/kgm body-weight and determination of the blood sugar curve, which in normal instances does not rise above 0.18; the es- cretion has been determined also in these cases although the figures obtained for obvious reasons are not quite compatible with those registered by the Bauer method. For particulars about the citric acid method may be referred to the important monograph of Sjo- strom (1937); it is based on an enzymatic reaction devised by Thunberg; the normal level is 17-27 micrograms. Details about the Takata-Ara method will he found in the paper of Hafstrom (1935). The Rona method is indicated in the textbooks; in the present study i t was considered conclusive only if the difference in number of drops did exceed 10. There are various reasons why a determination of the functional abilities of the liver may prove difficult in the individual case; in order t o get as good appreciation of the matter as possible it has been attempted in the present study on the one hand to use different methods, on the other hand to repeat the various tests.

B. 0 b s e r v a t i o n s.

The total number of galactose tolerance tests carried out in thc. present material of 26 cases was 62 ad modum Bauer and 7 ad modum Malmros-Silver-Swactichin (MSS).

The individual observations as far as the Bauer tests are concerned may be briefly summarized in the following diagram, where each vertical column represents one case and each point represents one determination (fig. 1).

The amount of galactose eliminated in the urine under the given conditions may be indicated as follows (only unoperated cases tabled).

Elimination of galactose (gram).

Gastric ulcer Duodenal ulcer Pseudo-ulcer

Maximum .................... 11 G.6 10.3 Minimum .................... 0.3 0.3 0.9 Average, all determ. .......... 3 2.1 3.4 Average, top determ. ........ 3.5 2.5 5.5 ~~ - ~

Average of all 52 determinations: 2.7 gram Average of all 22 top determinations: 3.3 gram.

F U R T H E R O B S t R V A T I O N S O N T H E P A T H O G E N E S I S OF P E P T I C U L C E R . 289

As a matter of fact i t seems entirely reasonable in this connection to use the top determinations. If such is the case the average elimination will be seen to exceed the pathological level of 3 gram. If on the other hand the average of all determinations is considered i t must without doubt be considered as strikingly high. If, until further, only the unoperated cases are considered i t will be seen that the various determinations divide themselves as follows.

Elimination of galactose (determinations).

Gram galac- 8 Gastric 12 Duode- 3 Pseudo In tosclurine ulcers nal ulcers ulcer

1 3 4 4 4 12 < 3 2 2 8 8 _ - 16 < 2 1 1 3 4 5 12

( 1 3 2 12 n

In all 18 23 11 52 determinations

I t will be seen that a pathological amount of galactose in the urine is to be encountered quite frequently. If the individual cases are concerned it will be noted from fig. (1) that no less than 8 out of 22 thus investigated unoperated instances did present an elimination exceeding 3 gram. Yet this figure should be considered as a minimum which most probably might be exceeded since on the one hand a positive MSS test may be present in spite of a normal Bauer test (vide infra) and on the other hand an analysis of the determinations as reproduced in fig. (1) will show that a definitely positive (i. c. pathological) Bauer test was to be registered in 7 out of 8 instances where.3 or more than 3 determinations were performed, whilst a similar response was to be elicited only in 1 out of 14 instances where less than 3 analyses were made; since i t moreover may be discussed whether not a t least some of the determinations ranging between 2 and 3 gram might be considered pathological i t may bc concluded that the galactose test ad modum Bauer is liable to present a positive (i. e. abnormal) response in quite a number of the instances here concerned.

I 9 3 9 S 6 7 8 9 1 0 1 1 1 4 / 3 1 4 15- 1 6 17 lk i f P O t i X f 4 3 t f ?5-

?'JJvneEh O F C R I C

1. Diagram .on the"eliminat1on of galactose when tested ad inodum Bauer. Each vertical column represents one case, Figures exceedintr Cnch point or cross represents one determination (point means unoperated, cross operated instances).

3 gram pathological, figures between 2 and 3 gram suspicious (shaded area). Case 1- 8 Gastric ulcers.

Case 9-19 Duodenal ulcers. Case 20-22 Pseudo-ulcers.

Case 23-25 (partially also rase 8 and 1 1 ) : Ulcers operated upon.

F U R T H E R O B S E R V A T I O N S O N T H E P A T H O G E N E S I S O F P E P T I C U L C E R . 291

The galactose test ad modum MSS. with determination of the blood sugar curve was performed in 7 instances:

Ulcer

1. Gastric 2. * 3. 0

4. u 5. I)uotlenal 6. ))

r I . ')

Gram administered

45.6 45 46 57.1 53 53 ''

Blood sugar max. 0.17 0.19 0.22 0.21 0.16 0.19 0.1 (i

Gram eliminated

1.94 2.4 8.9 4.68 0.29 2.78 1.2

I t will be observed that a pathological level of the blood sugar is attained in 4 cases out of 7 and it is instructive to note that in a t least 2 out of these 4 positive instances the galactose test .ad modum Bauer was normal. With due reservation for the limited size of the material the conclusion may hence be derived that the galactose test of MSS represents the superior sensitivity when compared with the Bauer method.

As to thc other tests applied in the present investigation the citric acid was determined in all instances but one; in 7 cases out of 22 a pathological (i. e. increased) level was attained. The Takata test was likewise performed in 22 (unoperated) patients and was negative throughout, a result entirely in accordance with previous investigators (e. g. Hafstrom, Ihre). The Rona test was examined only in 9 instances; as could be expected i t was negative except of in one case where i t was pronounced (in this case a certain ethylism seems to have been present). In two cases, examined in this regard on account of a slight jaundice, the bilirubin level a. mod. Hijman v. d. Bergh was slightly increased. The result of the various laboratory determinations in the individual cases may be reproduced in the following diagram (fig. 2).

As could be expected cases were thus to be registered where oiie of the tests was suggestive of a functional impairment whereas another was essentially normal. If regard is taken only to the galactose tests a pathological condition was to be noted in 11 cases out of 23. If the result of all tests is considered positive evidence of liver involvement was to be obtained in 19 cases out of 23.

With regard, finally, to the 5 cases operated upon for peptic ulcer two instances had been registered previous to the operation

292 E l i 1 6 A S K - U P M A R K .

(Billroth I) as well, whereas three were observed in Lhe clinic several years after the operation (one G. E. 26 years ago, one G. E. + E. A. 14 years ago, one Billroth I1 5 years ago). The galactose tests in these instances are reproduced in fig. 1. The citric arid test was determined after the operation in 3 instances, in one of which it was markedly positive. As to this group of cases i t should be stressed firstly that a positive galactose test previous to the operation (Billroth I) might be positive after the operation as well,

A A D A A A A A

OASTRIO ULCER wEi~ini

'PSNDO*ULCES" mum - - - Pig. 2. Diagram on the liver function tests in the unoperated cases (8 gastric ulcers, 12 duodenal ulcers, 3 pseudo ulcers). Each vertical group of symbols represents one case. Black symbol means positive test, white symbol negative, striated symbol borderline caws (elimination of more than 2 but not 3 grain galactosc in the Bauer test). Large vertical rectangle means galactose test Bauer, small horizontal rectangle galactose test Malmros-Silver-Swaetichin, triangles citric acid tests, B bilirnbin increased, R Rona positive. All Takata-Ara

reactions negative (horizontal lines).

secondly that the evacuation of the stomach did not seein to fle

very hurried (no sSturzentlecrungo) in the (3) cases thereupon examined, as far a t least as could be judged from the X-ray examination and the fractional test meal.

C. P r c 1 i ni i n a r y c o n c 1 u s i o n s.

Briefly summarized the observations here reported seem to warrant the following general conclusions.

1. A positive galactose test is frequently to be encountered in peptic ulcer, particularly so if repeated determinations are performed and the hehaviour of the blood sugar level is considered as well.

F L , R T H E B O B S E R V A T I O N S O N T H E P A T H O G E N E S I S O F P E P T I C U L C E R . 293

2. The average amount of galactose, eliminated in the urine, did in the prcsent material exceed the pathological level (3 gram) if the top determinations of each case are considered and closely approach this level if the average of all determinations is about.

3. If the individual case is considered a striking fact was often the variability of the amount of galactose eliminated in the urine on different occasions. Examples:

one gastric ulcer: 4.8-1.9-5.1-2.6 gram one duodenal ulcer: 3.3-0.8-1.3-3.5-2.1 gram one pseudo ulcer: 10.3--1.7-7.8-1.9-5 gram one operated ulcer (G. E.): 23.2-2.9-3.2 gram

4. A functional impairment of the liver in peptic ulcer seems to be indicated also by other tests. With special regard to the citric acid determinations the present investigation, although confined to a considerably smaller material, seems to confirm the observations previously reported by Sjostrom, who in a large number of peptic ulcers noticed a hypercitricaemia interpreted as due to a disturbed citric acid metabolism in the liver; it was also emphasized by Sjostrom that spatients with an anamnesis that pointed to gastric or duodenal ulcer but with normal X-ray findings exhibited elevated citric acid values in several cases)); i t seems likely tha t the last mentioned patients may correspond to my pseudo-ulcer group. The Takata-Am was negative in all instances, the Rona test negative in all but one. An increased bilirubin content of the serum was registered twice (not looked for in the other instances).

3. T h e introduction of galactose in normal individuals fhrough a duodenal tube.

In order to determine whether an abrupt introduction of galactose from the stomach into the bowels might facilitate the appearance of a positive galactose test the following Cxperiment was carried out.

9 healthy male medical students, for the kind cooperation of whom I am indebted, were submitted to the galactose test along the usual lines. In 7 instances the Bauer method was used, in 2 instances the MSS method was selected. The elimination in the urine averaged 1 gram, the minimum figure being 0.37 and the maximum

294 C R l K A S K - U P N A R K .

2.4 gram; the blood sugar curves were entirely normal (maxinirun attained 0.15).

After some days (as a rule one week) the test was performed again in the same students but with the modification that the galactose was introduced not in the stomach but directly into the duodenum by means of a duodenal tube, the correct position of

i l a c t o s e liminated ram

4

2

1

Galactoee t e a t i n 9 hmalthy medical students

a) adminlatsrsd i n the ueual way i n t o the etomach

b) adminiatered d i r e c t l y into duodenm by meana of a duodenal tube

.when the galactoee

3 0

0

0 8

0

0

0

8 . 0 0

0 8 0

8 0

2 3 4 5 6 7 8 9

Fig. 3. Diagram on the elimination of galactose in 9 healthy medical students. Each vertical column means one case, each white point the elimination of galactose in the urine in the usual Bauer test, each black point the elimination in the urine of galactose administered through a duodenal tube directly into the duodenum.

which had been determined in the usual way (X-ray rxamination etc.). The average elimination of galactose in the urine was also under these circumstances 1 gram, the minimum figure 0.3 gram, the maximum figure 2.4 gram. The blood sugar curve (determined in onc case) did attain a maximum of 0.14.

The results may be hriefly summarized in the following diagram (fig. 3).

I t may hence be justified to conclude that the introduction of galactose in normal individuals by means of a duodenal tube will not be able to induce a positive galactose test.

FL'IITIIER O B S E R V A T I O N S olri T H E P A T H O G E N E S I S O F PEPTIC U L C E R . 295

General comment and discussion.

Whilst no attempt will be made to discuss the numerous theories and hypotheses on the pathogenesis of peptic ulcer it is the purpose of this paper to report the observations already described and to point out certain features and facts which may throw some light on the pathophysiology of the enigmatic disorder here in question.

1. Interpretation of the galactose tests of the present investigation.

The galactose test is based on the ability of the normal liver to convert galactose into glycogene; if the liver is disabled galactose will pass through and become excreted in the urine. If the amount excreted does exceed a certain quantity it may be concluded that the function of the liver is impaired. With regard to the observations of the present investigation there are however certain sources of error to be considered:

a) The alimentary factor? If glucose has been administered during the days previous to the galactose test conclusions about the amount registered in the urine are liable to be erroneous. Since glucose is commonly used in the treatment of peptic ulcer care was taken to avoid this source of error, which of coursemaybe present as well if the galactose test be repeated within a too limited time. As for the diet i t was found that a positive galactose test might be present a t the end of the dietic series as well as in the start of it. 'I'he alimentary factor will hence have to be considered as negligible. All tests were of course performed on a fasting stomach.

No essential difference was to be noted in the occurrence of a positive galactose test between eases with high and cases with low acidity viz. secretion. As a rule hypersecretion was present in the duodenal ulcers and the pseudoulcers, absent in the gastric ulcers, whilst a positive galactose test was to be encountered in all three instances.

c) The gastrointestinal motility? The increased irritability of the stomach in peptic ulcer might bring about a more rapid evacuation into the bowels, the possibility hence having to be considered that the burden thus suddenly thrown on the liver might overcome its ordinary abilities; a certain evidence in this direction might be obtained from the extraordinary amount of galactose eli-

b) The gastric secretion?

296 E R I K A S K - U P M A R K .

minated in one gastroen terosloniy case (fig. 1). That this factor might be of contributory importance should by no means be denied but valid objections may be raised against its being the only point concerned. Firstly, the abrupt introduction of galactose through a duodenal tube did not bring about any pathological response (vide supra p. 294). Secondly, in the gastroenterostomy instances no uSturzentleerung)) was to be observed and the galactose test was moreover variable on differcnt occasions in the same individual. Thirdly, several ins tanccs were recorded where no acceleration of the ventricular evacuation was to he noted as judged from thc X-ray examination and yet the galactose test was positively ah- normal.

d) The condition of the gastrointestinal wall? The possibility should be considered that the resorption of galactose might l ~ e speeded through the wall of the stomach. Under standard conditions the monosacharides are absorbed from the small intestine whilst the resorption from the stomach is negligible (Best and Taylor; a somewhat different opinion maintained hy Christlieb and also by Shay et al.). As to absorption through the ulcer this possibility is no doubt t o be discarded (positive tests in pseudo-ulcer; positive tests as well before as after Billroth I). I t should on the other hand he admitted that the common occurrence of a gastritis with hypercmia and edema of the gastric mucosa might be liable to alter the permeability and farilit ate the absorption (cfr Ihre, 1938). There are however two 1e:itiires which make this mechanism unlikely, a t least in the observations here concerned. On the one hand a markedly positive galactose test may be observed in instances, devoid of any gastritis as judged by the gastroscopy (for ex. one case of pseudo-ulcer with a n elimination of 10.8 gram galactose). On the other hand the variability with regard to the amount of galactose eliminated in the individual case on different occasions (cfr p. 293) strongly suggests a functional mechanism not connected with any anatomical condition, such as gastritis. I t was hence deemed reasonable to consider the factor of altered ventricular absorption as of only contributory, if any, importance.

e ) The Eck fistula mechanism? In cirrhosis and chronic hepatitis a considerable amount of galactose may be excreted in the urine without necessarily indicating a more severe injury to the liver function. This depends upon the possibility inherent to such

F V H T H E R O B S E R V A T I O N S ON T H E P A T H O G E N E S I S OF P E P T I C ULCER. 297

instances that the galactose resorbed may avoid the liver, passing into the general circulation by using the venous anastomoses established between the system of porta and the system of cava. This factor of error is reasonably to be ruled out in the present material; only one case was open to the suspicion of having a liver cirrhosis in connection with the ulcer but in this case the galactose did not attain the pathological amount although other liver tests were positive (citric acid; Rona).

It will thus appear as if the positive galactose tests of the present material cannot he explained by the local conditions of the upper alimentary tract. 11 seems on the other hand reasonable to ascribe the galactose observations to a functional involvement of the liver. This apprehension seems to be strongly supported by the occurrence in peptic ulcer of other symptoms of liver involvement: the bilirubin studies of Kalk, the citric acid investigations of SjostrBm, the levulose tests of Scharpf and the study also of other tests than the galactose in the present investigation may thus be mentioned as clinical evidence in this direction.

The close connection between peptic ulcer and liver involvement is thus clinically well established. The same may he said about the evidence to be derived from experimental medicine: on the one hand the various animal experiments already quoted (Eck fistula, cinchophen intoxication etc.), on the other hand the importance of the liver for a due regulation of the gastric secretion, so commonly affected in peptic ulcer, along the lines indicated by Bruhl. Finally, the common occurrence of peptic ulcer in instances of liver cirrhosis as demonstrated by the present investigation may be called upon as evidence from the pathology on the correlations t o be presumed between liver disorder and ulcer disease.

2. Interpretation of the liver involvement in peptic ulcer.

Clinical, pathological and experimental evidence has been presented converging towards the impairment of the liver in peptic ulcer. With regard to the character of the relationships here concerned the first problem to be settled is to decide whether the ulcer should bc considered responsible for the liver involvement or whether the liver disorder may in some way or another favour the development of ulcer, or, finally, whether the liver disorder 20 - .icta med. scandinav. Val. C I I I .

298 I' I1IK A S K - U P M A 11 K .

and the ulcer sliould be looked upon as more or less parallel phenomena occurring in the same sequence of events and clue to the samc underlying mechanism.

In this regard the evidence to be derived from pathology favours the conception of the liver involvement as primary to the gastroduodenal ulcer. On the one hand i t has thus been demonstrated in the present study tha t peptic ulcers are commonly to he cncountered in connection with liver cirrhosis, on the other hand thc converse is not true, since cirrhosis hepatis only accidentally is to be registered in peptic ulcer; as to the histologic alterations of the liver in patients affected with ulcer, described hy Schnitkcr and Hass, they were present to a considerable extent also in thc controls (cfr p. 283). The. evidence to he obtained from the experimental physiology likewise points in the general direction t h a t the evolution of the ulcer in some way or another seems to bc facilitated or even caused 1)y the liver injury, c. g. the cinchophen ulcers or the ulcers in connection with an Eck fistula, viz. I)y the sequence of events hrouglit about by the established disorder of the liver. With regard, finally, to tlie clinical experiences they arc somewhat more difficult to evaluate, since obviously the ulccr :is representing a lesion a t the wells of the porta system might I)(> d ) l c unfavourahly to influence the liver. On the other hand the occurrence of positive signs of functional impairment of the liver in thc instances licre termed pseudo-ulcers (German: ~liyperrrgischcr Heizmageno) makes it likely that the causal conditions may Iw complicated enough. I t should also he remembered tha t the great variability in the response of tlie galactose test, as elicited in thc present niaterial, hardly seeins very compatible with tlie damage to the liver parcwchyma to be presumed from any more or less continuous drainage of toxic products from the gastrointestinal tract b y means of t h e porta system, let alone the fact that the existence and character of such products in peptic ulcer remains to he estn- hlished.

'I'he discussion so far conducted seems to warrant the conclusioris tha t the conception of the ulcer as the primary condition, causing liver disturbances (for example by means of an altered absorption, cfr the gastritis) seems unlikely and tha t on the other hand evidence is available suggesting the liver disorder to range 1)efore the ulcer in the sequence of events concerned, This being assumed until

F C R T I I I R O B S l I l V A T I O h S O N T H E P A T H O G E N E S I S O F P E P T I C U L C E R . 299

further as a I\ orking hypothesis the following possibilities will have to be considcred:

1. lnsufficiency of detoxicating power of the liver with resulting gastritis along tlie lines indicated by Wichels and Brinck and eventually ulcer development ad moduni Konjetzny. This explanation seems about as difficult to prove as t o deny; i t cannot be es- cludcd t h a t this factor may participate. In this connection it niay be mentioned tha t 1)anielopolu e t al. have produced experimental evidence t o the effect t h a t a damagc to the liver is liable seriously to interfere \\it11 its ability to influcncc the regulation of the levels in the I,lood of substances such as adrenalin and cholin.

2. Insufficiency of bile production with resulting deficient neutralization of t he duodenal content. 'I'his interpretation, although compatible with the results of the hilt divertion cxpc'- riments, seems entirely unlikely, since no acholia is t o be observed in peptic ulcer.

3 . Venous stasis in the porta system was assumed to favour developinent of peptic ulcer by Axel Key almost 170 years ago. Without entering more closely upon this hypothesis i t may be said that no evidence of portal obstruction is t o be produced in peptic ulcer except of in cases with liver cirrhosis.

1. lnfluence of liver injury on gastric secretion. l'he eiperinic.n- tal observations already quoted (La Rarre; Gerez and Weiss; Bollmann and Stalker and Mann) are decidely in favour of this conception. From clinical point of view attention may be called to the observations of Kalk and Mcyer and of Bruhl t ha t the liver be involvcd in the sequence of events inherent t o the effect of insulin 011 gastric secretion. Since on the one hand the peptic activities of the gastric juice are of importancc in the evolution of ulcer (vide infra p. 300) and on the other hand, according t o the investigations just quoted, the liver may he able to influence the gastric secrc- tion it seems by noineans unreasonable t o presume t h a t a functional inipairnient of the liver may be of importance in the development of ulcer by involving tlie peptic factor.

3. Aletabolic correlations in peptic ulcer.

Definite relationships have been established between the occurrence of ulcer of the upper alimentary tract and the peptic activities

300 E R I K A S K - U P M A R H .

of the gastric juice. The topographical position of the lesion within areas of mucosa exposed to the acid gastric juice without producing it themselves, the abnormalities frequently inherent to the gastric secretion in peptic ulcers and the therapeutical results to be achieved in peptic ulcer by means of alkalies as well as the benefit obtained by exclusion of coarse and acid stimulating courses from the diet, represent the outstanding evidences available. As to the gastric juice in peptic ulcers is not only hypersecretion a common feature hut the hyperpepsinia frequently encountered should be particularly emphasized, since on the one hand the pepsin production has been found to he fairly constant over months and on the other hand i t lias been felt that the pepsin concentration may be a measure of the vagal tonus of an individual, i t being influenced only by means of vagal stimulation (e. g. insulin) and not by purely humoral impulses (such as histamine, Ihre, 1938). This conception seems to be important since i t represents additional evidence for the correlations 1)etween the alimentary tract and the nervous system briefly to be referred to later on in this paper.

The effect of insulin on the gastric activities represents a most important series of observations pertaining to the ma tter here discussed. Detailed refercnces are to be had in the papers of Livie- rato and Tsclio (1936), Welin anti Frisk (1936), Ihre (1938) and Hruhl (1938). I t is generally agreed that injections of insulin are liahle to increase the motor and secretory activitics of the stomach, that this result will be obtained only if a certain degree of hypoglycemia is obtained, that this hypoglycemia will exert its action on the stomach hy means of the vagus centre, the impulses using the vagi to reach the alimentary tract, that , accordingly, no gastric effects will he achieved on administration of insulin if atropin is previously given or if both vagi have been eliminated. The gastric juice obtained by insulin hypoglycemia is induced by vagal stimulation, which accelerates the pepsin production, whilst the effect of histamine is purely humoral and does not ljring about any increase of vagal tonus, thus being of no effect on pepsin production (Ihre). Attention has already been called to the importance of the liver for the due performance of the effect of insulin on the stomach (Kalk and Meyer; Briihl). Since i t has been demonstrated by the present investigation that a functional impairment of the liver is commonly to be registcred in peptic ulcer i t is tempting to con-

F U R T H E R O B S E R \ A T I O N S o h T H E P A T H O G E N E S I S O F PEPTIC U L C E R . 301

sider on thc one hand the relations between liver function and blood sugar regulation, on the other hand the behaviour of the blootl sugar in peptic ulcer.

l h e liver has a central position in the carbohydrate metabolism, as demonstrated already by Claude Bernard 90 years ago and con- firmed by numcrous later investigations. I t represents a most important depot for glycogen, which is subject to hormonal and nervous regulations, and also to a periodic rhythm in its functional performan- ces (Forsgren, 1935). If we remember that the total amount of sugar in the circulating blood does not exceed 5 gram and that this quantity is liable to 1)c entirely consumed in 5 minutes (covering only 20 out of 3,000 calories as needed in 24 hours) the paramount importance of t h c hepatic regulation of the carbohydrate metabolism becomes apparent. I t will hencc be understandable that hypoglycemia may be noted clinically in disorders of the liver (references with Coller and Jackson, 1939). Hypoglyceniia is, further, a regular feature in connection with the Eck fistula experiments in dogs (La Barre); the frequent occurrence of peptic ulcer in such dogs has already been stressed and as a matter of fact the voracious appetite of tliesc animals observed already by the Pavlov school may reasonably hc related to the induced hypoglycemia. I t should also be remembered that spontaneous hypoglycemia in man, irrespective of its caust., may present symptoms most similar to a peptic ulcer such as attacks of hunger pains, night pains, vomiting and sometimes also gastric haemorrhages (references with . J . Wilder 1936 and Peskin 1937). Considering the importance of the hypoglycemia in the gastric activities, the r81c of the peptic factor in the ulcer genesis and thc central position of the liver in carbohydrate metabolism it is im- possible not to he impressed with the evidence hence available on the correlations between the mechanisms concerned. I t may also I x mentioned that the occurrence of peptic ulcer in persons afflicted with diabetes rnellitus generally is considered as strikingly rare (liosenberg and Kallner 1927, Leser 1935; cfr Kathery and Ferroir 1937). l’he general impression of Loning (cfr p 285) that peptic ulcers seem liable t o benefit from a sufficient storage of carbohydrates in the liver may be quoted as a convergent matter and every clinician is familiar with the favourable results t o be obtained in the ulcer disease by the repeated administration of sugar. The striking effect of a sweat orange, a cake or a piece of sugar on the

302 I Hlh 4 b h - 1 P I l h R h .

nigh 1 pains should like\+ is, h remembered (vide infra). ‘l’hc oltl clinical experience tha t the pains of R peptic ulcer arc liable to disappear in connection with :I big haciiiorrliage may he rcilated to lhtj incrcase of blood sugar following any consit1cral)lc bleeding (aAclt.rl:i~sungsliyperamiew of Hang; cfr I h i n g ) . I t is perfectly obvious lhat in as much as an nlteration of thc carl~oliydrate nieta- l~olisni is t o be assumed in peptic ulcer the functional impairrncnt o l Lhe liver, as clemonstratrtl 1 ) ~ the present investigation, hecomes :I

salienl fealurc in thc patliogcncsis. J’i’ith partjedar regard to thr night pains the 24 hours rliythni of the liver function as demonstrattd hy Forsgrcn assuincs incrcnsctl importancc, particularly as far :I\

Lhe management of carbohytlrates is conccrncd; it may hc :icltlccl that night pains of ulcer type may 1)c obscrvccl also in instance4 of liver cirrhosis (personal observations; t he most severc night pains I liavc ever witnessed appeared in a man having cirrhosis of the liver

The hcliaviour of thc 1)lootl sugar i n pcptic ulcer lias I K Y I I studied by several authors by means of the glucose tolerance test. Earlier observations yielded soniewhat divergent results (rcfcrcncc+ with Christlieb 1938) but it may now he said that the blood sugar curve Ilius ohtained is not infrcqucntly abnormal, rising too high in the liypc~glyccniic phase a i d dropping too low in the hypoglycc- mic period. The former point was strcsscd already I)y Hijmans v. d. Rcrgli and I-Ienkelom (1925) who maintained tha t the risc in hlood sugar on peroral adniinistration of glucose might approach t hc level at taincd in diabetes. ‘l’he sccontl point, the pronounced hypo- glyccinic phase, has r i u ~ n t l y I w n slressctl hy Christlieh (1938), being particularly markctl in duodcnal ulcers antl ))hypercrgischc Heizmagenr. Christlieb maintains t h a t a corrcsponclance be present 1)etwcen thc drop in blood sugar and the pains antl Castellani ( t 935) arrived a t a similar conclusion. Considering the ovidence already quoted about the importance of hypoglycemia for tlic gastric activities this point of view seems t o deserve consideration, although marc research will be needed.

iln interesting series of observations does concern hypoglycts- nria occurring in individuals who have gone through a ventric- iilar operation (gastroenterostomy, Billroth 11, Billroth I). Such instances have been observed by Lapp and Dibold (1931, 1932), Rcckcrniann (1935), Koranyi (1936), W6hrle (1936), Christlieb

t duodcnal ulcer).

1 U R T H E R O B S E I l V A T I O N S O N T H E P A T H O G E N E S I S O F P E P T I C U L C E R . 303

(1938), Ask-Upmark (1939). I t is generally indicated that the base line of the hlood sugar is fairly normal and tha t the hypoglycemia is to be induced only by a meal, rich in carbohydrates or after peroral glucosc tolerance test; in m y own case, however, the blood sugar was a l o ~ v as 0.015 before meals. The hypoglycemia thus 01)- tained may be severe and cause alarming symptoms but more often i t is clinically rather silent. l'he phenomenon seems by no means to he uncommon; i t was registered by Beckermann in 12 o u t of 30 operated instances and by Koranyi in 21 cases out of 72 (hypoglycemia was in these instances considered t o be present if thc blood sugar droppcd 1)elow 0.07). As for the cxplanation i t has offerctl considcrahle difficulties. 1 t is possible tha t the more rapid evacuation 01 the stomach may bc of some importance but for reasons tlcveloprtl hy Wiihrlc i t seems unlikely tha t this factor alone should I)c 1)lainetl and thc same goes for the secretory conditions of the operated stomachs. Uisturbances of the secretin-mechanism havc. been proposed, being about as difficult to deny as t o prove. 'I'liat an irritation of the pancreas may be caused by the operation should hc. conccived but why a remaining irritability of the insular apparatus (~Hcizpancrcas))) should result is difficult to see. Most authors dealing \vith thc question have arrived to the theory of tlisturbonccs of the vegetative reflexes in the local region concerned by the operation. This assumption seems to he supported to a wrtain degwc hy the observation reported by Cozzutti (1935) that thc Incrch introduction of a duodenal tube may cause hypoglycemia, pro1):iI)ly I)y means of some duodeno-insular reflex, which may be prcsumctl to he interfered with by a surgical intervention. In this connection attention should be called to t h e important investigation of Shay et al. (1938) on the effect of duodenal stimulation in man on alimentary hyperglycemia. Already in 1906 Bayliss and Starling found tha t injection of acid extracts of intestinal mucosa into animals decreased blood sugar. Shay and coworkers noted the absence of alimentary liyperglycemia after ingestion of glucose into the stomach and simultaneous duodenal instillation of 0.47 pct hydrochloric acid (or 5 pct sodium chloride, olive oil, 7 pct sodium bicarbonate, hypertonic glucose); if the pancreas was damaged duodenal stimulation failed to prevent the alimentary hyperglycemia, the conclusion being derived that the mechanism concerned

This case will receive separate publication.

30 1 E R I K A S K - U P M A H H .

was due to islet stimulation I)y an agent originating in the duotlr- num. On the other hand no change in fasting blood sugar follon.etl the duodenal instillation ~nentioned and neither was the hypcr- glycemia t o be induced I)y adrenaline prevented by duodenal stimulation. Koranyi maintains that only individuals operated upon in local anesthesia should present the alimentary hypoglyce- rnia hcrc in question, injurics to the retropcritoneal ganglia being likely to havci I)ccn causcd hy lhe anesthesia; in 3 out of 5 dogs, where alcohol had 1wen injectctl into ganglion coeliacurn a glucosc test brought out hypoglycemia. I t may htwce be concluded that although apparently no cmtirely convincing explanation of tlic liypoglycernia after operations of the stoniach has been furnished so far, i t seems possihle tha t Lhe carhohydrate metabolism be interfered with by means of a disintegration of the local reflex activities. Another possibility to the best of my knowledge not mentioned in the literature is t ha t the hypoglycemic reaction may have existed already 1)eforc the operation, i . e. being inherent to the ulcer (clr p. 302) and not t o the surgical intervention; in those instanccs, howcvcr, where clinical nianiirstations of thc hypoglycemia do occur after the operation hut not hefore this explanation seeiris in- sufficient. 'Hit matter has I)ccn discussed here to some cxtent sincc it illustrates another rrlat ion hetween stomach and blood sugar, the ohscurc character of which is rather significant for the difficulties to I)c encountered when dealing with t tic, mechanisms hcrc roncernctl.

Briefly suniniarizing the discussion herc conducted on t lit, carbohydratc metabolism in peptic ulcer i t may I)(> said that tlic peptic activities of the gastric juice are of irnportancc in the ulcer pathogenesis, t ha t insulin [nay bring ahout peptic activities by means of thc hypoglycemia induced, t h a t this peptic effect of insulin has to do M ith the nervous system as well as wit11 the l iwr, t h a t the I iwr has a central position in the carhohydrate metabolism, tha t various clinical and rxperimcntal disorders of the liver may present hypoglycemia, t h a t hypoglycemia thus obtained may present symptoms suggestivr of the ulcer symptoms, t ha t the carbohydrate metaholism in peptic ulcer frequently seeins t o he impaired, and t h a t rather obscure instances of hypoglycemia may he observed in connection with surgical interventions for ulcer.

F U R T I I E R O H S E R \ ‘ A T I O K S O N T H E P A T H O G E N E S I S O F P E P T I C G L C E R . 305

4. Involvemeni of nervous system.

The neurogenic conception of the pathogenesis of peptic ulcer, marshalled by Hokitansky 1842 and revived and evidenced by Cushing 1931, was reviewed in a previous paper of mine, where refe- rcnccs arc to be had (Ask-Upmark 1939). Vonderahe has since published a study on related subjects (1939) to whicli paper also may be referred for further particulars. Briefly summarizing the evidence in favour of a neurogenic conception of the ulcer genesis i t may he said tha t the general medicine, the clinical pathology and tlir experimental physiology have yielded numerous observations, converging towards the presence of a hypothalamic parasympathetic centre in the tuber region. I t is connected on the one hand with cortex cerebri, enabling the influence of mental factors along the lines indicated by Pavlov and by the general clinical experience ahout the r61e of mental strain, on the other hand by means of a longitudinal pathway in the brain-stem with the vagal centre of thc I)ulb, from which impulscs are discharged through the vagi, provoking in the stomacli parasympathetic effecls on secretion and motility, hencc inviting to the development of ulccr in accortlanrr with our knowlcdge about the importance of the peptic factor. ‘l’hc cornpalibility between the neurogenic and the peptic conception of ulcer pathogenesis 11 as thus established and the embarrassing cleft overbridged Iiithcrto chisting hetween thescx two series of fundamental observations.

In the present study evidence has hecn presented suggesting the involvement of the liver in the chain of events connected with the development of peptic ulcer. I t has heen maintained t h a t this liver involvemcknt as a rule be of functional character and tha t i t may I)e connected uitli the central position inherent to t h e liver in the carbohydrate metabolism, particular attention being called to the effect of insulin on the gastrointestinal activities. This insulin reaction is closely related to the nervous system (cfr p. 300). With regard to the liver it may likewise be stated tha t numerous correlations art’ present between this organ and the central nervous apparatus. Not only are both systems involved in the Wilson syndrom hut hepatic activities are liable to exert an influence upon the nervous system as illustrated pathologically by the yellow staining of glohus pallidus in jaundice of infants and clinically by

306 I R I K 4 s i \ - ~ r i \ i in i \ .

tlw ccrt~l)rnl s y ~ i ~ p t o m s , so oftcn prevailing in wvcre 1ivc.r disorders (hepnlargia, sornctimcs liypoglyccniic symptoms). On tlir other liand tlie nervous system may induce functional involvcmcnt of tlic liver, experimental evidcnre to this effect lwing represented by tlie piyure of C:laudt~ Bernard (bringing about the convertion of liver glycogcn if available into glucose) \I herens clinical cvitlencc is furnished by thc so-called cniotioiial jaundirc hy the occurrenct’ of glycosuria a n d liypcrglycenii:~ in connchction with Iicatl-injuries and by the appearance of functional liver disturl)ances in ronnec- tion with various organic. affections of the brain, such as a slight jaundice in scvcral instanccs of Parkinson’s syntlrorti a~i t l of b u l l m paralysis and intcrfcrencv with the mctabolic activities of thc 1iL.c.r in conncction ni th cnccphalitis. l‘hus, the possibility of emcounter- ing an :tl)normal citric acid test in enccplialilis was stressed as nc.11 by Sjostriiiii (1937) as by .\sk-tTpiiiark (1937). IYith regard to the galactosc test, as studied in the present pap’r, thc following two ohsc~rvations s w n to dcscrvc consider a t’ ion.

1 j .IJrdirtrl ( ‘ I i t i i i 2 9 3 4 .Ilrrrt u g i d 1Iivcti i t i j t i t ! y I I ( 115 tc1111 I -

( I L ~ L Zni~rjerenc.e ri11th L L ~ Y I ] u n ( / i o t t ~ ‘1‘1114 ( *iztl \\<is t l e sc r i l~d in rl

I)revion\ pq)er already (1 93:)) :ind slroultl only Jw l ) r i t ~ f l > rew)llec~tetl. Tht, Inan, previously enjoying ‘1 pcrfrct health, had a Iic~atl injury m d t n o days .rftcmards Inc4acnci. He wdb .tdinittctl to thc clinir \viLIi a p ~ o i i o u n c ~ d .trieinia arid troatcd ,morciingl! For oil(’ 1 CRP no , i l ) t l o r i i i i i d discomfort \\lratsoever (dietary p c a u t ion& ohswwr l ) . T t i r i i I )din\ a p ~ ~ ~ w ~ ~ d localiectl lo the epigastriurn a n d p:irtic~ril,irJ~ SPVIW I\ tien norking or ,iftc’r fat ,ind #atrongo food. I~ventually t h c w \\:is a ntw ~iic~laeri~i :rnd l i t , M A S reatlmittetl Uov. 17th with a moderate mt’mia ( I l b ( ~ 1 , r w l count = 3 46 inill.). Radio- graphy hov. 18th: almoncl-sii.etl iirclic a t t l ic ininor curvature, no r e k m lion after ‘1 liours, ]Ice. 12th conGderably rcduccd size of nicl~e. Fractionat- i.ti test meal: no increased ‘ic’idity but prolonged scrretion. Liver: Gal- x t o s e test Nov. 23d (4ti grnrri galactose) =- dirnination of 8.9 gram, blood sugar t’iirve reaching 0.22; J k . 1st (40 grmii - 1 1 gram eliminated; Dee, 7 t h ( 4 0 gram) = 2.3 grain (4niinattd. Citric, x i t t tes i Xov. 22d = 2 1 ‘I’akata repeatedly negative. 20 iinpro\ cmcnt being obtained by ronwr- vative therapy, opcration w u advised and carried out nets. 17 th (by Doc Iiedberg) ad niodum Billroth I with no complications. On readmittance to the metlical clinic J a n . 21st galnrtose test (40 grain) -= X I eliminated, hilirubin normal.

This condition although previously deiiicd has nowadays enjoyed a rehabi- litation although opinions may differ as to the mechanism involved, whether spasm in the sphincter Oddi (cfr the provocation of biliary stone-attacks by emotional factors) or influence on the activity of the liver parenchyma (cfr the importance of emotions with regard to several other kinds of glandular activity: lacrimal glands, adrenals, thyroid).

F U I ~ T H E I ! O U S E R \ A T I O H S O N T H E P A T H O G E N E S I S O F PEPTIC U L C E R . 307

I n this casc it is tempting to consider the head injury at least contributory and possibly responsible to the development of the gastric ulcer. The galactose test was repeatedly positive and although the possibility of a mere coincidence might not be entirely refused, it scems in view of the evidence on the subject presented i n this pa pi^ reasonable to connect this positive reaction with the ulccr and lirncc also t o look upon the response to the galactose test as induced from tlie central nervous system. It is interesting to note that the surgical removal of the ulcer did not imply the disappear- NICC of the a1)normal galactose test.

2 ) Medical C:linic 6 4 5 / 1 9 3 9 : M a n , aged 1 7 . Encephalitis 4- Interference with lhe liver function 4- Interference with the cardiovascular appnratus. Observed in thc hospital Fehr. 7th-March 17tli, Apr. 17th--.Zpr. 2 4 t h , Map 24th---Mny 27 th.

a) Matters ncurological. Previously healtlry, the boy was rather siiddcdy takcln ill Febr. 6th with headaches, vomiting, rigidity of the neck, sornnolenco and mental deterioration. On admittance next clay pyrexia (39.6" C; irregular with remissions for some 8 days, afterwards subsiding), JJltlSf2 70, blood pressure 150/80. Complete mental confusion, crying loudly, giving no answer, wrestling about in bed. Rigidity of neck, 1,askgue f ISo, Ihbinski {- left foot. Some 8 days later mentally improyed, cooperative, answers questions adequately, lieadaches on decrease, Laskgue -+- 40'. In the subsequmt course gradual improvement. Babinski variable for one irionth, afterwards negative. Transitory paresis of right abducens, transit - ory slight choking of optic. discs, remaining destruction of cochlear and ymtibular abilities of left ear (no local affection of the ear). Lumbar puncture on admittance bloody tap, pressure exceeding 400; Febr. 28t t i

iiiicoloured, waterlike fluid, pressure 205 mm, Nonne +-, Pandy $-, I3is- quard + 1 : 40, Lymfocytes 12.5/mm3, Leucocytes 0.6/mm3. Subsequent punctures on various occasions showed improvement but not until May 25th normal condition (Bisgaard yct 1: 20). Radiography of skull: normal conditions.

b) Matters liepatic etc.: blood sugar Febr. 17th 0.08, Febr. 18th 0.13. Citric acid test Febr. 21st = 32.5, March 10th = 33.9, Xpr. 20th = 37.2. Galactose test (Bauer) Febr. 20th = 6.43 gram eliminated, Febr. 21st = 2.6 gram, Apr. 20th = 0.46 gram. Takata repeatedly negative. Rona bor- der values. Fractionated test meal: Febr. 20th low acidity, Apr. 20th: no hydrochloric acid except by histamine.

c) Matters cardiovascular: Blood pressure on admittance 150/80, sub- sequently rather low, as a rule 105/75, minimum 90/65 (Febr. 27th). Brady- cardia (about 50) present most of the time in hospital. Venous pressure Febr. 28th = 16 cm, March 3d = 15 em, March 6th = 13 cm, March 11th =

8 cm. Vital capacity Febr. 28th = 2700 (length 177 cm). Electrocardio- gram pathological: Febr. 28th: T I slightly positive, T I1 absent, T 111

:m E R I K A s h - L P h l A R h .

negativc. otheruise normal. March 13th: sinus arythrriia, T variable, S‘l? depression when negative 1’. Apr. 20th: bradycardia, all T:s positiw. Radiography of heart: normal configuration.

In this case, which apparently may have represented an encephalitis, evitlcnce of disturbed liver function was noted repeatedly (citric acid test, galactose test). The interpretation of this liver involvement as secondary t o tlie intracranial affection seems reason- ahk. I t is instructive t o register in the same case various symptoms of cardiovascular disturbanccs; since their general character was transitory, since an acute enccphalitis was ahout and since it has heen demonstrated tha t cardiovascular cffects may he expcri- mentally induced by stimulation of the hypothalamic region (cfr Uealtic 1932, 1938) i t seems cntirely possible that thcy might have bccn caused by thc inlervention of iicrvous mechanisms. Against these interpretalions thr ok)j ections may, of course, Iw raised tha t the condition of liver and cardiovascular systein hefor(%, the cnccxplialitic accident was unknown and tha t the possiibility also has to be considered whether not the functional disorders in clues- lion might have been due to an involvement of liver antl heart 1)). the same agent t ha t caused cnccphalitis. Although the validity ol‘ these objections should riot be denied it was nevertheless f e l t that thc rvitlcncc otherwisc :~v:iilal)lc~ on llie corrclations 1)ctwcc.n liver and Ibrain justified an rsplanation of tlie prcsent case along I lie lines prclviously indic.atctl.

‘l’lic analysis so far conducted has illustrated thc intini:\tt, connections pr-csent betwcen the central nervous systcm and thc liver. Considering on tlic olher hand the closc corrclations already referred t o between the nervous apparatus ant1 the tlcvclopmcnt or ulcer antl, finally, the coinnion occurrence ol‘ functional liver involvement in peptic ulcer as rlescri1)etl in this paper, i t will appear a s if the pathogenesis of tlie ulcer discasc might I)c cncircled Iw- tween two mutually coIinectetl functional units, the leading of which seems to bc represented by the n iwous mechanism. ‘lhis general aspect seems to bca supported by a consideration of the rela- tionship present betwcen the nervous system and tlie carbohydratc metaibolisiii. ‘Hiree series of observations are awiilahlc in this regard.

1) l‘he anatomy of diahetc~s mellitus. ’lhc wcll known absenci~ of pathologic changes in the pancreas in several instances of diabetes

W R T I I E R O B S ~ R V A T I O ~ S O N T I I E P A T H O G E N E S I S O F P E P T I C U L C E R . 309

has received substantiation by the investigations of Warren (1930), who in 69 out of 229 diabetic autopsies failed to register any histologic alteration in the islands of Langerhans. On examination of the hypophyses of 27 diabetic patients, in whom no symptoms of pituitary disorder had been registered, Warren (1930) likewise met with essentially normal conditions. Since i t on the other hand is obvious, as judged from clinical and experimental observations, tha t the pituitary gland is functionally involved in the carbohydrate metabolism, i t seems reasonable to ask whether affections may be cncountered in the hypothalamic area connected with the gland. Morgan, Vondcrahe and Malone (1937) studied the hypothalami of 15 patients with diabetes mellitus as compared with 5 non-diabetic controls and registered a constant loss of cells, ranging from 30 to 05 per cent, in the nucleus paraventricularis in all the patients with diabetes, in connection with marked retrograde changes in the rcmaining cells of this nucleus. This important study seems to confirm certain earlier observations since Urechia and Elekes (1924) observed changes in the same nucleus in a case of diabetic coma and Urechia and Vitescu (1925) maintained that the nucleus undergoes degeneration after pancreatectomy in dogs; i t is of particular interest to note that the same authors did encounter degenerations in the paraventricular nucleus following puncture of the dorsal vagal nucleus. In the post mortem of a case of terminal hyperglycemia in an alcoholic Ncgress, Vonderahe 1937 registered recent hemorrhages in the anterior part of hypothalamus, implicating nucleus paraventricularis.

2) Experimental observations pertaining to this subject have been amply reviewed by Fulton (1938), to whom may be referred for particulars. Among more important recent contributions may be mentioned the study of Barris and Ingram (1936) who found that small lesions anywhere in the hypothalamus of cats were liable to produce a transient glycosuria; in 10 of the animals the postopera- tive hyperglycemia was followed by a remaining and persistent hypoglycemia, the lesion in these instances being found in the anterior hypothalamus, in the majority of the cases in the paraventricular nucleus; the insulin sensitivity was increased in these animals, but unaffected if the lesion was placed elsewhere in the hypothalamus. Davis, Cleveland and Ingram (1935) maintain that bilateral lesions in the hypothalamus a t the level of the tuber

310 I ILlh A S K - L P M A I l h

nuclei (damaging the, vcntrometlial Iiypolhalainic nuclci) \\ill protect tlie animals from diaheies if pancreatectomy is performeil later, thus acting in the same way as does hypopliysectomy (Houss;iy and Ijiasctti 1931); incidentally, lesions of the same nuclei will prevmt the liyperglycemia and glycosuria to I)c induced i n a normal cat ljy stimulating t h e superior cervical sympathetic ganglion (prcsuma1)ly I)y liberating the diabetogcbnic hormone from tlir hypophysis). .I related ohscrvation hy Hill and Iiokas is rcferrctl to by Heattic (1938): irritativc Icsions of thc vcntromedial nuclci of the hypothalamus protlucccl marked glycosuria and hyperglycv- mia.

3) Clinical evitlencc~ is al)undant. a) G1ycosuri:i and hypcrglyccmia arc fcaturcs coninionl>

c~nrounterccl in acroniclgaly as well :is in pituitary hasofilism (Cushing); since the basophil adenonias as a rule arc only micro- scopical and tlic cosinophil atlcnomns as :I rulc do not attain thc size of t h o chromopliol~r pituitary tumours (where the sugar tolerancc on the contrary is increased) i t may be concluded that thc cffcct 1)c tluc t o pituit:iry activities rather. th:ui to any iniplica- tion of hypothalaniic s truc lures. ‘lhc n cll kilo\\ n glycosuriu I)roughl about I)y emotions may 1)c due to impulses dischargctl from l hc syriipathetic ccritrc of poslcrior hypotlia1:imus t o thc adrc- nals. ‘I‘hc glycosuria (with or without hyperglycemia) to he ol)servetl in connection with liead injurics and ccrc1)ral 1irmorrh:igc.s should f i n :i 11 y 1,c rein em t )ercd.

I ) ) 1 Iypoglycemia on 1 tic ollier hand may he observed in various intracranial disorders, such as head injuries, enceplialitis ant1 tumours. I’aticnls afflictcd ith clia1)ctcs insipidus and dystropliia ndiposogcnitalis are 1ial)lr to present hypoglycemia, increased sensitivity t o insulin and increased toltmnce t o carbohydrates. ’ 1 1 1 ~ saiiie goes for scvcr:il instances of Simnionds syndrom, wlierc the anlcrior 101)~ of the pituitary gland is destroyed (references with .J. \l.’ildcr 1936, Bernhard t 1937); an clxpcrirncn tal correlation is reprcscmtcd by the observation of Malioncy and others that mi- inals in which the hypophysis has been removed tend t o succumb in hypoglycemic coma and may be saved hy administration of glucose. Niclscri (yuoted hy Wilder) studied functional disorders of tlie vegetative nervous system and noted in 15 out of 17 instances of wagotoniao a liability to hypoglycemia (42- 80 mg O/O). The ob-

F I R T I I L R O U S E ~ L V I T I O N S oli T H E P A T H O G E N E S I S O F P E P T I C U L C E R . 31 1

scrvations pertaining to hypoglycemia in encephalitis and (occa- sionally) lieati injuries have been reviewed by M'ilder. As for intracranial tumours one of the first observations of human hypoglycemia ever made was recorded by Cushing (1910) in connection with tlic removal of a pituitary tuniour. Gibbs (1932) analysetl the general syiiiptomatology of the ])rain tumour material ol Cushing; among other symptoms the curious plienomcnon of craving for s~ eets was registered in tumours neigli1)ouring the third ventricle and I have in a prcvioiis paper called attention to the likelihood of the presence, in tlicsc instances, of liypoglycciiiia (Ask-Upmark 1939).

'I'lic relationships thus established bctM cen the nervous systmi and thr carboliydrate metabolism may be summarized thus: 'Hit. normal 1)lood sugar level is l~alanced between the insular systcm of pancreas and tlie hormonal impulses of the pituitary gland. Eli- mination of lhc insular organ on the one side, hyperactivity (c. g. acromegaly) of the pituitary system on the other tend to increase tlie level wliert~as pituitary deficiency on the one side, insular hyperactivity (1 he insulomas) on the other will bring ahout hypo- glyccniia. ?'lie liypothalnniic mechanism will under normal conditions act as a huffer: if the 1)lood sugar is too Iiigli impulses mill be cliscliargetl along the dorsal longitudinal I)untlle, in the vagal nuclri of tlic hull) and the vagi to the pancreas wherc insulin is being liberatcd. If' on the other hand the blood sugar level should I)c too low its riy,ulation will he performed not only hy the discharge of hypothalamic impulses via the sympathetic system t o the pituitary gland liberating the odiahetogenic hormoneo (whicli may or may not act I)y stirnulation of the adrenals)l but also by stiinulat- ing the parasympathetic mechanism, impulses being discharged along lhc dorsal longitudinal bundle with the vagus system to the upper alimentary tract where the resulting activitics are liable to further the preparation and resorption of the food and thus ultimately to increase the amount of carbohydrates available. This aspect may appear teleological but i t is in accordance with the experimental and clinical observations on the subject and it may

1)ivergent opinions are preseut 011 this poiut (cfr. Ueattie 1938, Jores 1939). Besides of this stimulation, which should be established from ventromedial hypothalamic nuclei, sympathetic impulses may, in emergency instances, be discharged from the posterior hypothalamic nuclei via the splanchnic nerve to the adrrnals (the piqfire is believed to act this way).

3 12 E I\ 11, A S K - L PIM A n li.

anyway servc as a working l~ypothesis .~ Considering 1) the importancc' to be attributed to the nervous system in the pathogenesis of peptic ulcer, 2) the functional involvement of the liver in ulcer as drnionstrated by the present investigation, 3) the relationships existing between the nervous system and the liver not least S O with regard to the carbohydrate meta1)olism and 4) the connections present hetween peptic ulcer and carbohydrate metabolism (glucose tolerance test, gastric responsc on insulin etc.) i t will appear as if the aspect just marshalled on lhe hypothalamic functions might serve a useful purpose in the syntlicsis. I t will, moreover, facilitate our understanding of several matters hitherto rather obscurc. Thus, hypophyscctomy has been found to induce hypoglycemia (Gage1 and Mahoney, 1933) hut the same intervention may also bring about gastric hemorrhages (Nlalioney, quoted by Fulton 1938). 'I'he ohmvation of Kellrr and d'Amour (1936) that tuber lesions in dogs will result in ulcers with crater formation if the animals are prc,viously sympathectomizcd may he explained by the prevailing in such instances of the parasymphathetic system. With regard to clinical mattcrs it has already been emphasized tha t disorders of and interventions on the hypothalamic region may be accompanied as well by peptic ulcers of the upper alimentary tract as by hypoglycemia. As particularly instructive in this regard may be quoted a case recently describcd by Foley, Snell and Craig (1939) concerning a man aged 28 who presented an anterior pituitary tumour (chromophobe adenoma) in connection with cachexia, duodenal ulcer and hypoglycemia (30---78 mg yo). In this case the hypoglycemia did not manifest itself clinically and it may well be tha t in other similar instances tho level of the hlood sugar will pass un- observed.

Although thc hypothalatitic ccntrc coticerned may be multiple (paravcntricular nuc lcu~, ventroniedial ~iuclcus, tuber ~iuclcus) their close relation- ship is obvious. I t may also be emphasized t h a t an important link in this mechanism is represcntcd by the pnraventricular nucleus and tha t this nucleus deserves special considcration: i t is (together with the supraoptic nucleus) the oldest structurc of the hypothalamiis from phylogenetical point of view (a good reason tor its importance), and the density of its capillary bed (Finley, 1938) isexceed- cd by no other structure in thc central nervous system and paralleled only b y tha t of the supraoptic nuclei (water mctabolisml) and t ha t of locus coeruleus (respiratory centre suspectiblc t o carbon dioxide!), the cells accordingly being particularly exposed t o the humoral coiiditioris of thc blood (blood sugar level?) (cfr. Vonderahe 1939).

F U R T H E R O B S E R V A T I O N S O N T H E P A T H O G E N E S I S O F PEPTIC U L C E R . 313

5. Final remarks.

Whilst the evidence hence assembled on the patho-physiological correlations between nervous system, liver and peptic ulcer seems abundant i t should not be forgotten that the problem on the ulcer genesis is complicated and that i t is entirely possible that still other factors are involved.

The objections may thus be raised against the analysis so far conducted that ulcers may occur where no increased activities of the gastric secretion are to be registered, that hypoglycemia may exist without ulcer and that outstanding abnormalities with regard to the fasting blood sugar level in ulcer apparently are unusual (cfr Stenstrom, 1936). The gastric secretion registered does not, however, inform us about the condition originally existing (Kalk: no ulcer will develop in anacidity), let alone the objections often to be raised against the method of determination. Hypoglycemia may present various clinical manifestations and it may be surmised that consti- tutional factors are of importance in this regard. With regard to the behaviour of the blood sugar in peptic ulcer it may be sufficient to recall the investigations of Christlieb and others already quoted (p. 302).

As to the involvement of other mechanisms attention should be called to the enigmatic frequency of ulcer of the upper alimentary tract in Addison's disease, an observation mentioned in numerous textbooks and apparently substantiated also by animal experiments (ulcers after adrenalectomy: see for ex. Chahovitch et al. 1934 and Freud et al. 1935). The interpretation of this phenomenon should consider the following topics:

1. In Addison's disease the carbohydrate metabolism is impaired (hypoglycemia, enhanced sensitivity to insulin, increased tolerance to glucose) but since the gastric secretion nevertheless as a rule is inhibited, the peptic factor otherwise to be furthered by the liability towards hypoglycemia is negligible; whether the severe abdominal pains so frequently observed in this disorder be due to increased motor activities of the digestive tract remains to be established (similar pains may be noted in Simmonds syndrom, where gastrointestinal atonia is prevailing).

2. Scattered evidence is available suggesting the importance of the suprarenal cortex for a due transmission of adrenergic nerve 21 - A d a med. scandinav. Vol. C I I I .

314 E R I K A S K - U P M A R K .

impulses (references with Dale, 1939). In this connection the gastric activities induced by acetylbetametylkolin may be remembered (Necheles, Banting) as may the observation of Keller and d’hmour already quoted on the evolution of ulcers with crater formations on tuber stimulation in sympathcctomized dogs.

3. The close relationships present between the adrenals and the pituitary system should be remembered. As already mentioned various interferences with the pituitary and hypothalamic region may bring about ulcers of the upper alimentary tract and the question may be justified whether the mechanism involved has anything to do with the adrenals.

4. The main importance of the adrenal cortical hormone seems to be represented by phosphorylation (Verzar, quoted by Jores). If this process is deficient, as may be presumed in Addisons disease, the intestinal resorption of glucose and fat will become impaired and the intermediary carbohydrate metabolism will be seriously interfered with in the general direction of block. Since deficiencies in this regard may be able to bring about lesions of the central nervous system (vide infra), neurogenic mechanisms might possibly be brought into action, favouring the development of ulcer.

I t should he observed that not only may the central nervous system be of importance for the condition of the upper alimentary tract but the converse may be true as well. Thus Vonderalie (1939) noticed the Occurrence of hemorrhagic extravasations in vagus nucleus and anterior hypothalamus in connection with peptic ulcer, the interpretation being given that the irritative afferent impulses from the ulcer be causing vasomotor alterations a t the point of their arrival in the nervous system (cfr the observation of Cobb and Talbott on increased capillarity in the olfactory lobe of a rabbit exposed to olfactory stimulation just before death). I t should also be remembered that a patient with peptic ulcer may be subjected to dietary restrictions, which if unwisely managed may invite to deficiency syndroms such as avitaminoses. In this connection the observations on the hemorrhagic polioencephalitis of Wernicke

Histologic alterations of the visceromotor vagus nucleus in connection with gastroduodenal ulcer were observed already by Docq (1935; destructive affections of the nucleus in 9 cases out of 10) and referred to also by Laruelle (1939, 111 d international congress of neurology). The occurrence of degeneration in the paravcntricular nucleus of hypothalamus in conneclion with injuries to the dorsal vagal ~lucleus has already been described (p. 309).

F U R T H E R O B S E R V A T I O N S O N T H E P A T H O G E N E S I S O F PEPTIC U L C E R . 315

seem to be instructive: Neubiirger (1937) observed this condition in connection with gastritis (no ethylism present), and Alexander (1939) has described the same condition as a complication in beri- beri pigeons, occurring if the B,-defiency of the diet was combined with disproportionately ample supplies of other vitamins (A, B,, C, D). On the whole the vitamin B, is closely related to the carbohydrate metabolism, to the nervous system, to the liver and to the upper alimentary tract and considering not least the discussion conducted in this paper i t is entirely possible that a deficiency in this regard under circumstances may be involved in the chain of events resulting in a peptic ulcer (cfr Seyderhelm, 1938)., In Addison’s disease the resorption from the digestive tract is seriously impaired in several regards and i t seems not out of the way t o remember also this factor when attempting to explain the occurrence of ulcer in this disorder. The possibility has, therefore, to be taken into consideration that a vicious circle may become established between the nervous system and the digestive tract in much the same way as has been presumed in the remarkable condition known as pseudotabes acromegalica (Ask-Upmark, 1939). The importance of adequate dietary habits in peptic ulcer seems hence to receive substantiation.

I t may, finally, be added that the aspect here maintained on the ulcer as a ncurometabolic disorder will enable an understanding of several topics hitherto more or less obscure. The night pains in ulcer may thus be connected with the rhythmic abilities of the liver as asserted by Forsgren which so closely parallels the rhythm of sleep (cfr the physiological sleepiness after dinner, the winter sleep etc.). The enigmatic occurrence of duodenal ulcers in burns will he explainable, if we remember the hypoglycemia induced by these accidents and its importance for the gastric secretion (the liberation of histamine, which has been suggested, is by no means equivalent in this regard since i t leaves the secretion of pepsin unaffected). The rare occurrence of peptic ulcer in diabetes, the comparatively common occurrence of peptic ulcer in Addison’s disease may be more easily understood. The curious connection of polycytemia on the one hand with narcolepsy, on the other hand

1 I t may be mentioned in this connection that a deficiency of vitamin B, is liable to cause bradycardia, which a t least in certain experimental animals is due to increased vagal tone (Best and Taylor); the enigmatic occurrence of bradycardia in peptic ulcer vill be remembered.

31 6 E R I K A S K - U P M A R K .

with peptic ulcer appears less enigmatic if we remember the diencephalic centre of hematopoesis. The bradycardia in peptic ulcer is entirely compatible with the parasympathetic hyperactivity which is inherent to the ulcer syndrom according to the neurogenic conception: i t is possible that afferent impulses from the ulcer to the vagal nuclei may be of contributory importance (cfr Vonderahe and p. 314).

With regard, finally, to the ulcer therapy, several conclusions may be derived. The surgical intervention in a subtil metabolic mechanism may present results (e. g. Graves disease) but i t should never be forgotten that as far as peptic ulcer is concerned any abdominal operation is to be considered palliative from the pathophysiological point of view here maintained. The medical treatment with atropin empirically established long ago, receives substantiation (inhibition of parasympathetic hyperactivity). The alkaline therapy should not be neglected (cfr the observations in the cinchophen dogs, p. 282). As for other remedies I am under the impression that barbituric preparations are of outstanding importance, an observation likewise elucidated by considering the diencephalic mechanisms involved. With regard to the diet the present analysis seems to confirm the empirically established experience that starvation is dangerous, that meals have to be frequent and small, that an ample amount of carbohydrates has to be supp- lied, that sugar in any form is suitable in between meals and by night, that the vitamin content of the food must be sufficient. That a person with few and irregular meals will be liable to develop ulcer, is easily understood from the points of view here maintained. The importance of mental strain becomes obvious and the old experience that cooling the feet may provoke a gastric hemorrhage becomes a matter feasible for biological understanding.

Briefly summarizing the analysis hence conducted evidence has been marshalled suggesting disturbances in the normal correlations between the nervous system, the liver and the upper alimentary canal as the prevailing factors in the pathogenesis of peptic ulcer. Nervous impulses, metabolic factors and local conditions in the digestive tract converge towards a desintegration of the functional relationships established long ago in the evolution between the nervous system and the gastrointestinal tract. I t has sometimes

1 Further clinical implications will be found p. 301.

F U R T H E R OBSERVATIONS O N T H E P A T H O G E N E S I S O F PEPTIC ULCER. 317

been maintained that the pituitary and hypothalamic region should represent the rostra1 end of the body and the multitude of important abilities inherent t o this region, the total weight of which is estimat- ed to some 4 gram, seems as a matter of fact to be entirely compatible with this commanding position, One of its most important functions for the preservation of individual life does concern the intake of food and i t seems reasonable ultimately to consider the peptic ulcer as an impairment of this function.

Summary and conclusions.

1. The present study will attempt an analysis of the pathogenesis of peptic ulcer with special regard to the involvement of the liver. Earlier observations pertaining to this subject are quoted, being derived from experimental physiology, human pathology and clinical medicine.

2. The material was represented by the necropsies of liver cirrhosis performed during the last decade in the department of pathology, by the clinical study of 26 instances of peptic ulcer with special regard to the functional analysis of the liver, particularly by means of the galactose tolerance test and by the investigation of the behaviour of the galactose test in normal individuals when the galactose be introduced by means of duodenal tube.

3. Among 22 instances of liver cirrhosis in whom necropsy was performed and the condition of the upper alimentary tract was registered, a peptic ulcer was encountered in 9 instances. An ulcer of peptic type may be noted also in connection with certain other affections of the liver. Attention is called to the importance of examining the stomach in cases of cinchophen poisoning and one such observation is briefly described.

4. The clinical investigation was mainly concerned with the functional behaviour of the liver in peptic ulcer, viz. pseudo-ulcer (definition p. 287). Galactose tolerance test was performed ad modum Bauer (62 analyses) and (or) ad modum Malmros-Silver- Swaetichin (7 analyses). Other tests employed were the citric acid test of Sjostrom, the Takata-Ara test, the Rona test and (occa- sionally) bilirubin determinations. The conclusions were derived that

318 ERIK A S K - U P M A R K .

a) a positive galactose test is frequently to be observed in peptic ulcer, especially if repeated determinations are performed and the behaviour of thc blood sugar curve is considered as well;

b) the average amount of galactose, eliminated in the urine did in the present material exceed the pathological level (3 gram) if thc top determinations of each case are considered and closely approach this level if the average of all determinations is about;

c) if the individual case is considered a striking fact was often tlie variability of the amount of galactose eliminated in the urine on different occasions (examples see p. 293);

d) a functional impairment of the liver in peptic ulcer seems to be indicated also by other tests, particularly so the citric acid test. If regard is taken only to the galactose test a pathological condition was to be noted in 11 casrs out of 23. If the result of all tests is considered positive liver involvement was noted in 19 cases out of 23.

5. In 9 healthy medical students the introduction of galactose directly into the duodenum (by means of duodenal tube) failed t o induce a positive, i. e. pathological galactose test (diagram p. 294).

6. The interpretation of the galactose test in the present material is discussed, the conclusion being warranted that the positive tests should be asrribcd to a functional involvenient of the liver.

7. The liver involvement in peptic ulcer lience demonstrated is discussed. The conception is maintained that the liver disorder ranges before the ulcer in the sequence of events concerned; under circumstances the liver disorder and the ulcer may be considcred as more or less parallel phenomena but no evidence is available suggesting the ulcer to be responsible for the liver involvement.

8. The character of the liver involvement is discussed. The importance of the liver for the due performance of the effccts of insulin on tlie upper alimentary tract, the central position of the liver in the carbohydrate metabolism, and the impairment of this metabolism in peptic ulcer are topics to l x stressed. The occurrence of hypoglycemia in connection with ventricular operations is briefly mentioned.

9. The implication of the nervous system in the ulcer pathogenesis is reviewed. The correlations between the liver and the central nervous system arc recollected and exemplified by clinical

F U R T H E R OBSERVATIONS O N THE PATHOGENESIS O F PEPTIC ULCER. 319

observations. The relationships existing between the nervous system and the carbohydrate metabolism are briefly outlined. The attempt is made to cover the various observations available by a working hypothesis, which gives to the hypothalamus a central position in the sequence of events, connected with the intake of food, the behaviour of the metabolic activities and ultimately the development of peptic ulcer.

10. The correlations hence established are discussed and certain conclusions derived pertaining t o the prevention and therapy of peptic ulcer.

Bibliography.

Alexander, L.: 1939, I11 Internationale Neurolog. Kongress, Kobenhavn. Ask-Upniark, E.: 1937, Med. Forens Tidskr. p. 173. 1939, Acta Med. Scand. 99: 204. 1939, Acta Chir. Scand. 82: 336.1939, Svenska Lakartidn. 1939, Un- published observations. Barris, R. W. and Ingram, W. R.: 1936, Am. J . Phy- siol. 1 2 0 : 225. Beattie, J . et al., 1938, The hypothalamus, Oliver and Boyd, London. Beckermann, F.: 1935, Dtsch. Med. Wochschr. I: 18. Berg, B. N. and Jobling, J. W.: 1930, Arch. Surg. 20: 997. Bernhardt, H., 1937, in Adam: Steuerung im menschl. Organismus, Fischer, Jena. Best, C. H. and Taylor, N. B.: 1937, Physiological basis of medical practice, Baillikre, London. Bollmann, J., Stalker, L. and Mann, F.: 1938, Arch. Int. Med. 61: 119. Briihl, W.: 1938, Zschr. Klin. Med. 135: 1. Castellani, E.: 1935, Osp. magg. 23: 5. Chahovitch et al: 1934, J . Physiol. et Path. g6n. 32: 7 4 . Coller, F. and Jackson, H. C.: 1939, J. Am. Med. Ass. 112: 128. Cozzutti, G.: 1935, Rif. med. p. 244. Crandall, L. A. and Ivy, A. C.: 1937, Surgery, 3: 815. Christlieh, W.: 1938, Dtsch. Arch. klin. Med. 181: 394. Cushing, H.: 1912, The pituitary body and its disorders, Lippincott, Philadelphia. 1932, Pituitary body, hypothalamus, and parasympathetic Nervous system, Thomas, Springfield. Dale, H.: 1939, I11 d internat. congr. Neurology, Copenhagen. Danielopolu, Proca, Bramer: 1930, Wien. klin. Wochschr. p. 1437. Davis, L., Cleveland, I. and Ingram, W. R.: 1935, Arch. Nrurol. Psych. 33: 592. De Bakey, M. E.: 1937, Arch. Surg. 34: 230. Docq, P.: 1935, Arch. Med. Appar. digest. 25: 1057. Elton, N. W.: 1937, Congrks Internat. L’Insuff. Hbpatique, Vichy. Fiessinger, N. and Palmer, R . G.: 1935, Bull. SOC. Med. HBp. Paris, 111: 51, 814. Finley, K.: 1939, in Symposion on the circulation of the brain and spinal cord, Williams and Wilkins Co, Baltimore. Foley, M., Snell, A., Craig, W. McK.: 1939, Am. J. Med. Sci. 198: 1. Freud, J. et al: 1935, Brit. M. J . 3884 , 1216. Fulton, J.: 1938, Physiology of Nervous System, Oxf. rned. Publ. Gagel, 0. and Mahoney, W.: 1933, Z. ges. Neurol. u. Psych. 148: 272. Gerez, L. and Weiss, A,: 1937, Z. exper. Med. 100: 281. Gibbs, F., 1932, Arch. Neurol. Psych. 28: 969. Hanke, H.: 1937, Arch. Klin. Chir., 187: 675. Hawkins, W. B. and Whipple, G. H.: 1935, J. Exp. Med. 62: 599.

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Hebert: 1938. Hijmans v. d. Bergh, A. and v. Henkelom, A. S.: 1925, Dtsch. med. Wochschr. p. 645. Hill and Kokas, quoted by Beattie, 1938. Houssay, B. A. and Biasotti, A.: 1931, Endocrinology 15: 511. Ihre, €3.: 1938, Acta Med. Scand. Suppl. 95. Jores, A.: 1939, Klinische Endokrinolo- gie, Springer, Berlin. Kalk, H.: 1931, Das Geschwiir des Magens etc., Urban etc., Berlin. Kalk, H. and Meyer, P. F.: Zschr. klin. Med. 120: 692. Keller, A. D. and d’dmour, M.: 1936, Arch. Path. 21: 185. Koranyi: 1936, Dtsch. Arch. klin. Med. 178: 353. La Barre, J.: 1931, C. r. Soc. Biol. Paris 107: 906,907. Lapp, P. W. and Dibold, H.: 1931, Klin. Wochschr. 10: 1221. 1932, Dtsch. Arch. Klin. Med. 1 7 3 : 550. Leser, A. J.: 1935, Arch. klin. Chir. 182: 143. Levieratos, S. G. and Tselios, P. A.: 1936, Arch. Verdauungs- krh. 59: 313. Loning, F.: 1930, Klin. Wochschr. 9 : 541. Maluschew, D.: 1931, Dtsch. Ztschr. f . Chir. 2 3 2 : 684. Mann, F. C.: 1937, Minnesota Med. 20: 755. Marino, S. and Saladino, A.: 1937, Arch. Farm. sper. 63: 161. Morgan, C. O., Vonderahe, ,4. R., Malone, E. F.: 1937, J. nerv. ment. Dis. 85: 125. Muto, M.: 1934, Naunyn-Schmiedebergs Archiv 1 7 6 : 431, 446. Neubiirger, K.: 1937, Ztschr. ges. Neur. Psych. 160: 208. Quaglia, F.: 1936, Arch. Sci. med. 62: 457. Rathery, F. and Ferroir, J.: 1937, Dtsch. med. Wochschr. p. 183. Rosenberg, M. and Kallner, A.: 1927, Dtsch. med. Wochschr. p. 183. Scharpff, W.: 1926, Klin. Wochschr. 6: 138. Scherk, G.: 1926, Klin. Wochschr. p. 1459. Schnitker, M. A. and Hass, G. M.: 1934, Am. J. Digest. Dis. a. Nutrit. 1: 537. Schur, M. and Taubenhaus, M.: 1935, Z. klin. Med. 128: 292. Seyderhelm, R.: 1938, Die Hypovitaminosen, Barth, Leipzig. Simonds, J. P.: 1938, Arch. Pathol. 26: 44. Sjostrom, P. M.: 1936, Acta Chir. Scand. 7 7 : 505. 1937, Acta Chir. Scand. Suppl. 49. Stalker, C. K. and Bollman, J. L.: Proc. Staff. Meet. Mayo Clin. 12: 38. Stalker, C. K., Bollman, J. L., Mann, F.: 1937, Am. J. Digest. Dis. a. Nutrit. 3: 827. Stenstrom, T.: 1936, Nord. Med. Tidskr. 12: 1905. Urechia, C. I. and Elekes, N.: 1924, Encbphale 21: 352. Urechia, C. I . and Nitescu, 1.: 1925, Bull. Acad. MBd., Paris 93-94: 188. Vonderahe, R.: 1937, Arch. Int. Med. 60: 694. 1939, Arch. Neurol. Psychiat. 41: 871. Warren, H.: 1938, Surgery 3 : 370. Welin, G. and Frisk, R.: 1936, Acta Med. Scand. 90: 543. Wichels and Brinck: 1933, Zschr. f. klin. Med. 1 2 3 : 303. Wilder, J.: 1936, Zucker- mangelkrankheit, Weidman, Wien. Wohrle, M.: 1936, Dtsch. Arch. klin. Med. 1 7 9 : 412.

Further observations on the pathogenesis of peptic ulcer

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