53
CLINICAL AND EXPERIMENTAL STUDY OF DISORDERS OF THE PANCREAS
SHINGO AOYAMA 2nd Department of Internal .Medicine, Nagoya University School of Medicine (Director: Prof. Shingo Aoyama)
For the past several years various experimental and clinical observations have been made on disorders of the pancreas in this department by the writer and his co-researchers (Motoaki Kishikawa et a!.). The items of content listed below are the selective results of those observations, which the writer presented as a special report before the joint meeting of the 51st General Assembly of the Japanese Society of Internal Medicine and the 41st Assembly of the Gastro-enterological Society of Japan, held in April, 1954. A summary of this report constitutes the body of this paper, arranged in the same order as the original. Due to the limited space most of the data on the indi vidual experiments have been omitted, and, as a whole, only their summarized results are recorded herein.
CONTENTS
I. Some fundamental items 1. Pancreatitis due to Candida albicans i. Method of the administration of Candida ii. Histopathological changes in the pancreas iii. Effects of killed Candida on the pancreas iv. Instilling of Candida into the gall bladder, the biliary tract, the portal vein and the liver parenchyma v. Emigrated enzymes in the blood vi. Blood sugar and its regulation vii. Changes in various body organs viii. Attitude of Candida on pancreatic juice, bile and emulsion of the pancreas ix. Effects of some drugs on the growth of Candida x. Therapeutic effects of some drugs on pancreatitis due to Candida 2. Viral pancreatitis i. Coxsackie-virus ( Connecticut-5 strain) a. Histopathological changes in the pancreas b. Emigrated enzymes in the blood c. Changes in the blood sugar ii. Influenza virus iii. Mumps virus 3. Allergic pancreatitis i. Antigen and the method for its administration ii. Histopathological changes in the pancreas iii. Emigrated enzymes in the blood iv. Blood sugar and its regulation v. Changes in various body organs
Received for publication March 2, 1955. 54 S. AOYAMA
vi. Clinical cases 4. Transplantation of chick sarcoma into the pancreas i. Histopathological changes in the pancreas ii. Emigrated enzymes in the blood iii. Changes in the blood sugar iv. Comparison of cases where transplants are made into various parts of the pancreas 5. Pancreatic impairment due to bacterial exotoxin 6. Pancreatic impairment due to ethionine 7. Oxygenase system in the normal and impaired pancreas i. Succinic acid dehydrogenase system in the pancreas, the liver and the kideys ii. Cytochrome oxygenase system in the pancreas, the liver and the kidneys iii. Malic acid dehydrogenase system in the pancreas, the liver and the kidneys 8. Acid soluble phosphorus, lipoid phosphorus and nucleic acid phosphorus in the tissues of the normal and impaired pancreas 9. Water soluble vitamines in the pancreas and pancreatic juice i. Thiamine and riboflavin in various viscera a. Normal dog, liver-impaired dog and pancreas-impaired dog b. Changes after loading ii. Ascorbic acid in viscera a. Normal dog, liver impaired dog and pancreas impaired dog b. Changes after loading iii. Thiamine and riboflavin in pancreatic juice a. Normal condition b. Effects of loading and drugs stimulating pancreatic secretion c. Action of transforming the thiochrome reaction negative of pancreatic juice iv. Ascorbic acid in pancreatic juice a. Under normal conditions b. Effects of loading and of agents stimulating pancreatic secretion II. Diagnosis of pancreatic disorders and its basis 1. Emigration of enzymes into the blood i. Blood diastase a. Fundamental items 1) Comparison of the method of estimation 2) Blood diastase, visceral diastase, and Vagostigmin test in various experimental pancreatic impairments, and histopathological changes 3) Pancreatic secretion stimulant and blood diastase 4) Blood diastase and visceral diastase after complete pancreatec· to my 5) Relation of internal pressure of pancreatic duct to blood diastase 6) Blood diastase and Vagostigmin test in relation to histopathologi cal changes 7) Effect of the intravenous injection of fresh pancreatic juice on blood diastase 8) Process of emergence of pancreatic diastase in the blood 9) Diastase of the blood passing in and out of various abdominal organs under normal and affected conditions 10) Kidney impairment and blood diastase DISORDERS OF THE PANCREAS 55
11) Liver impairment and blood diastase 12) Reticuloendothelial system and blood diastase 13) Salivary glands and blood diastase 14) Vagus nerve and blood diastase 15) Various drugs and blood diastase b. Clinical items 1) Blood diastase and Vagostigmin test in healthy human body 2) Blood diastase and Vagostigmin test in various pancreatic diseases 3) Relation of blood diastase after Vagostigmin injection to diastase in duodenal fluid in various pancreatic diseases 4) Blood diastase and V agostigmin test in diabetes 5) Blood diastase and Vagostigmin test in diseases of the alimentary tract 6) Blood diastase and Vagostigmin test in renal diseases c. Summary ii. Blood esterase a. Fundamental investigations 11 Consideration of the method of estimation 2) Esterase of the various organs of a normal dog, and its nature 3) Esterase in pancreatic juice and bile, and its nature 4) Blood esterase of a normal dog 5) Blood esterase after intravenous injection of pancreatic juice 6) Blood esterase during fatty necrosis in peritoneal cavity 7) Blood and visceral esterase during the pancreatic impairment 8) Blood and visceral esterase after complete pancreatectomy 9) Rlood and visceral esterase during the liver impairment 10) Salivary glands and blood esterase 11) Histochemical investigations of visceral esterase b. Clinical items 1) Esterase in human pancreatic juice 2) Visceral esterase in the human liver and pancreas 3) Blood esterase of healthy human body 4) Blood esterase of patients with pancreatitis. pancreatic tumour, after complete or partial pancreatectomy 5) Blood esterase in patients with diseases of the liver, the gall bladder and the biliary tract 6) Blood esterase in diseases of the stomach and the duodenum c. Summary iii. Blood protease a. Method of estimation b. Protease in blood during experimental pancreatitis c. Protease in blood during complete pancreatectomy d. Protease in blood during the liver impairment e. Significance and value of protease in the blood in the diagnosis of the pancreatic impairment 2. Blood catalase 3. Blood sugar and its regulation i. Fundamental items a. Consideration of the Staub effect b. Comparative studies of methods to test the sugar regulation c. Salivary glands and sugar metabolism 56 S. AOYAMA
ii. Clinical items iii. Summary 4. Investigations on the duodenal contents i. Estimation of enzymes a. Experimental pancreatic impairment b. Pancreatic disease c. Comparison between natural secretion and secretion after stimulation d. Diagnostic value ii. Microscopic examination 5. Stool examinations i. Method of examination ii. The three enzymes in the stools of patients with chronic pancreatic disease iii. Digestion of animal nucleo-proteins in pancreatic disease iv. Digestion of animal proteins in tuberculous disease v. The three enzymes in the stools of anemic patients 6. X-ray diagnosis i. Method of examination ii. Findings on pancreatic tumour iii. Findings on acute pancreatic disease iv. Findings on subacute pancreatic disease v. Findings on chronic pancreatic disease 7. Summary III. Changes during pancreatic impairment 1. Pancreatic impairment and cardiac disorders i. ECG in experimentally induced pancreatic impairment ii. ECG in complete pancreatectomy iii. ECG in various pancreatic diseases iv. Secretin, insulin, Kallikrein and cardiac function 2. Pancreas and hypotensive substances i. On Kallikrein, insulin and secretin ii. On the pancreas, the salivary glands and the anterior pituitary iii. On hypotensive substances in urine 3. Pancreatic impairment and sweat 4. Pancreatic impairment and changes in the blood i. The blood in experimentally induced pancreatic impairment ii. Pancreatic impairment and antithrombin iii. Pancreatic impairment and electrolytes iv. Pancreatic impairment and pictures of the blood and the bone marrow a. Experimentally induced pancreatic impairment b. Pancreatic disease v. Bleeding time, coagulation time and resistance of erythrocytes in pan creatic disease 5. Pancreatic impairment and gastric function i. Gastric secretroy function in experimentally induced pancreatic impair- ment ii. Gastric motor function in experimentally induced pancreatic impairment iii. Gastric secretory function in pancreatic disease iv. Gastric motor function in pancreatic disease 6. Pancreatic impairment and sugar metabolism i. Sugar regulation in experimentally induced pancreatic impairment DISORDERS OF THE PANCREAS 57
ii. Insulin sensitivity in complete pancreatectomized dogs iii. Changes in blood sugar after intravenous injection of fresh pancreatic juice iv. Effects of pancreas stimulating agents on blood sugar v. Vagus nerve and sugar regulatory function vi. Blockage of the reticuloendothelial system and blood sugar vii. Functions and histopathological changes of the anterior pituitary and the adrenals in complete pancreatectomy viii. a cell impairment and sugar metabolism 7. Pancreatic impairment and blood proteins i. Plasma proteins in experimentally induced pancreatic impairment ii. Plasma proteins in pancreatic disease iii. Salivary glands and plasma proteins 8. Digestion and absorption of proteins during pancreatic impairment i. Digestion and absorption of proteins in experimentally induced pancreatic impairment ii. Digestion and absorption of proteins in pancreatic disease 9. Pancreatic impairment and fat metabolism i. Changes in plasma lipids ii. Lipids in the blood of the portal vein, the hepatic vein, the right ventri cle and in the lymph of the thoracic duct in completely pancreatectomized dogs iii. Digestion and absorption of fatty substances a. Digestion and absorption of lipids in experimentally induced pancreatic impairment b. Digestion and absorption of lipids and vitamine A, when the pancreatic duct is ligated, or in complete pancreatectomy c. Digestion and absorption of lipids in pancreatic disease 10. Pancreatic disorder and hepatic impairment i. Fundamental items a. Hepatic function and changes in histopathological findings in experi mentally induced pancreatic impairment b. Appearance of fats in the liver, and the effects of some drugs and pancreatic juice on them ii. Clinical items iii. Summary IV. Changes in the pancreas during impairment of various organs 1. In cardiac disorders 2. In abnormalities of blood pressure 3. External secretion and histopathological changes of the pancreas in pulmo- nary tuberculosis 4. Fever and external secretion of the pancreas 5. Anemia and external secretion of the pancreas 6. Disorders of the liver, the biliary tract and the gall bladder in relation to pancreatic external secretion 7. Changes in the pancreas in partial hepatectomy and in hepatic impairment after the administration of carbon tetrachloride and phosphorus 8. External secretion and histopathological changes of the pancreas after the administration of bacteria into the liver 9. Blood diastase and histopathological changes in the pancreas during the trans plantation of chick sarcoma into the liver 58 S. AOYAMA
10. Blood diastase, blood sugar and its regulation and histopathological changes in the pancreas in experimentally induced cirrhosis of the liver 11. Gastric disease and external secretion of the pancreas 12. The autonomic nervous system and the pancreas 13. Blood diastase, esterase, sugar metabolism and blood picture after splenectomy V. Clinical cases 1. Chronic pancreatitis a. Clinical observations Incidence, past history, family history, sex, age, tastes, state of food consumption, nature of onset, symptoms, abdominal signs, emigrated enzymes, Vagostigmin test, sugar disposal func- tion, peripheral blood picture, picture of the marrow, resistance of the erythrocytes, diameter of the erythrocytes, bleeding time, coagulation time, antithrombin, prothrombin, blood sedimentation test, composition of sweat, plasma proteins, hepatic function, findings in gastric juice, findings in duodenal juice, stool findings, urine findings, X-ray findings and others, histopathological findings, considerations on the causation of pancreatitis b. Clinical cases 2. Tumour of the pancreas a. Clinical observations On icterus, on pain, on metastasis, changes in the liver, the biliary tract and gall bladder, emigrated enzymes in the blood, Vagostigmin test, sugar disposal function, pancreatic secretory function etc. b. Clinical cases VI. Therapy 1. Treatment of shock 2. Treatment of pain 3. Effects of various drugs on the external secretion of the pancreas 4. Therapeutic effects of various drugs on pancreatitis 5. On diet 6. Others 7. On surgical treatment 8. Summary
I. Some Fundamental Items
1. PANCREATITIS DUE TO CANDIDA ALBICANS In the literature on moniliasis, there are none that particularly make note of pathological changes in the pancreas. However, the writer's experiments, in which Candida albicans were introduced into the pancreatic duct of the test dog, revealed marked inflammatory changes throughout the pancreas thus affected. The changes can, in general, be divided into the following 4 stages, namely: First stage (Moniliasis apostematosa): accompanied by necrosis and hemor rhage in the pancreatic tissue. Abundant blastospores were found in the abscess. The basic pathological change consisted of the serofibrinous purulent inflam mation. Second stage (Moniliasis apostematosa et nodularis): there was found the DISORDERS OF THE PANCREAS 59 formation of the granulation tissue and nodules in the pancreatic tissue. In the necrosed portion there were seen numerous blastospores and hyphae. The funda mental change was purulent nodular inflammation (Fig. 1). Third stage (Moniliasis nodularis): where there was the formation of nodules, the pancreatic tissue was entirely rotten (Fig. II), and the organisms within the tissue were seen in abundance in the secondary layer of the nodules. The funda mental change consisted of the formation of the nodules and the proliferation of the connective tissue (Fig. III). Fourth stage (Moniliasis fibrosa): there was the proliferation of the inter lobular connective tissues, leading to the healing stage, in a state of inflammatory fibrosis of the pancreas. The organisms were not seen in the tissue, and cultural tests also indicated the negative. The fundamental pathological change took the form of pancreatic fibrosis. Throughout the entire stages described above, no marked changes in the ducts and islets were observed. In the case where the living Candida were introduced into the vein of a dog's paw, or into its pancreatic artery, there were seen no changes in the pan creas. However, in the rabbit, when they were introduced into the ear vein, changes were produced in the islets of Langerhans and numerous collections of the Candida could be recongnized (Fig. IV), although no changes were seen in the parenchyma. Further in dogs, when the heat-killed Candida were introduced into the duct, the pancreas was intact. In the case where the living Candida introduced into the liver of a dog via the gall bladder or bile duct or via the portal vein, there was seen only slight degeneration and formation of small nodules in the liver; and when equal quantities of Candida were introduced into the parenchyma of the pancreas and the liver of the same dog simultane ously, the changes in the liver were extremely slight while those in the pancreas extremely marked. As has been described above, Candida albicans, introduced into the pancreas of the dog via the pancreatic duct, produced an extensive inflammation which took about 4 weeks to cure. In the human body also, if Candida enter the pancreatic duct, the possibility is great that fulminating pancreatitis will result. It is necessary that sufficient clinical attention be paid in the future to the possible presence of pancreatitis due to this microorganism. Further, as this pancreatitis is characterized by a marked inflammation within a short space of time, it affords a suitable material for researches on pancreatitis. Descriptions of the blood diastase, the blood sugar, changes in other organs, and the effects of pancreatic juice, bile and emulsions of the pancreas on the growth of Candida albicans are not described here.
2. VIRAL PANCREATITIS Since 1948 numerous investigations have been undertaken on the Coxsackie virus, but the results have not always agreed with one another. In the author's experiments, where the Connecticut-5 strain was induced into the peritoneal cavity of the mice, marked changes were found in the pancreas. About 12 hours after 60 S. AOYAMA
the injection, there were seen many white spots in the pancreas, which 30 hours from the time of the injection, spread throughout the entire pancreas. On the 5th day, the pancreas presented a menbranous appearance, the parenchyma de creased in volume, and the colour changed into greyish yellow. After the lOth day the colour turned grey again, and the parenchyma began to increase. Histologically, a slight degeneration started to appear at about the 12th hour, at the 24th hour there was seen the infiltration mainly of mononuclears, and the destraction of glandular cells began to be noticed. Marked necrosis was observed after 30 hours, and the vacuolization of the gland cells in the lobules, accom· panied by necrosis. The changes generally reached a maximum after 48 hours; and a high grade of necrosis was seen in the parenchyma of the pancreas, but the infiltration of the interstitia was slight, and the cells partaking were mainly mononuclear cells. (Fig. V). At about the 66th hour, there began the regeneration of the glandular tissues and the proliferation of the connective tissues. No signs of necrosis were seen at the end of 2 weeks. No marked changes were noted in the islets of Langerhans and in the pancreatic duct. In other words, the pan creas showed a serous inflammation, followed by a degeneration and necrosis of the parenchyma and an increase in fats, indicating the typical appearance of a viral inflammation. During the inflammatory stage the blood diastase generally increased, and returned to normal during the recovery stage. The blood sugar was in most cases rather decreased, but in some increased, reflecting an instability in the function of the islets. Cellular infiltration, derangement of the cells, necrosis and vacuolization took place in the liver. Pancreatitis could not be induced by the mump and influenza virus, and together with other viruses, further investigations are being made.
3. ALLERGIC PANCREATITIS Schweizer, Rogers and In have investigated hyperergic changes as a factor in pancreatitis, and basic researches have been made by Horster, Ono, Sunada and others on the relationship of the formation of pancreatitis to the Schwartzman reaction. Reports on clinical cases of pancreatic allergy are scarce, and there are only the reports by William, Linder and Louis, Morsen, Sunada et al., on 4 cases of acute necrosis of the pancreas complicated by urticaria, and those by Schaffer on 3 cases of acute pancreatitis apparently due to dietary allergy. The present author and his colleagues investigated the establishment of allergic pan creatitis in animals, and attempted to find a connection between the obtained results and clinical cases. Normal dogs or dogs with alloxan glycosuria were sensitized with an emul sion of the pancreas from a normal dog, horse serum, an emulsion of the pan creas from alloxan glycosuric dogs and an emulsion of the horse pituitary or ACTH, and the same antigen was reinjected later into the pancreatic artery, the pancreatic duct and the pancreatic tissue, or the same procedure taken after the pancreatic duct was ligated, though there were differences in grade, in the pancreas there resulted an Arthus' phenomenon in the tissue, unlike the usual inflammation seen in the controls. DISORDERS OF THE PANCREAS 61
In other words, with the lapse of time, there were seen edema, hemorrhage, a fibrinous exsudative inflammation, a degeneration of the pancreatic parenchyma, necrosis, and a proliferation of the connective tissues. These changes were seen mostly around the blood vessels when the antigen was reinjected into the pan creatic artery or the pancreatic parenchyma, and the infiltrating cells consisted mainly of acidophilic cells, sometimes intermingled with giant cells. Also, in some parts were seen the thrombus in the lumen of the blood vessels (Fig. VI IX). When the antigen was reinjected into the pancreatic duct, basically similar changes appeared, but in this case, the changes were less marked, and the point to be noted is that the changes appeared almost around the pancreatic duct (Fig. X). When the external or internal portion of the pancreas was blocked beforehand, the above changes were seen in a much more marked degree. The islets of Langerhans showed some changes, such as frequent occur rences of irregularity in the arrangement of the islets cells, nuclear degeneration, vacuolization of 11-cells, hemorrhage within the islets, hyalinization, necrosis and scar formation. As the islets in the Teleostot exist independent as Brockman's bodies, an emulsion of these bodies was prepared from the Bonito, and with this antigen, experiments similar to the above were made, in which were observed marked changes in the islets, an atrophy or degeneration of the parenchyma, exsudative or fibrinoid changes in the interstitia, an infiltration by acidophils, mononuclears and other cells, and granulation (Fig. XI). Thus, in this case, though there was some selective action to the islets, there could not be seen a specific inflammatory changes limited merely to the islets. From the above experiments it was found that 1) an allergic inflammation was produced through the blood stream or the pancreatic duct, and 2) when there was an impairment in the external secretory portion, the islets also showed some change, though this was slight in the internal secretory part. In contrast, when the islets were involved, the picture of degenerative necrosis in the external secretory portion was enhanced, 3) when an antigen was made to act through the pancreatic duct the inflammation was slight, and the changes in the pan creatic duct itself were almost unnoticf;able-the pancreatic duct appeard to have a high degree of resistance-, and 4) the degenerative changes were produced in the ganglion cells of the sympathetic, but the significance of this still remains to be seen. Further, when chronic suppurative foci were produced under the skin or in the joint cavity by the injection of Streptococci viridans or hemolyticus into normal dogs or into dogs sensitized by the horse serum, and were treated further by the injection into the pancreas of dead bacillary suspension, bacterial filtrate or horse serum, the histological picture of Arthus' phenomenon in the pancreas became extremely marked. This helped to show that the presence of the primary foci promoted the establishment of allergic pancreatits. After the reinjection, changes indicative of rheumatoid nodosities were observed in the pancreatic interstitia during the early stage and in the pancreatic lobules during the later stage. With the lapse of time these were transformed into the granulation tissue, as may be the case with the human body. Also in some cases, around the fatty tissue were seen cellular infiltration by numerous acidophils, mono- 62 S. AOYAMA cytes and others, which all showed changes in the nuclei; indicating a high degree of fatty necrosis (Fig. XII, XIII). In other words, in allergic pancreatitis there are seen two types, one in which the course is acute or chronic and in which there are seen formations of rheumatoid nodosities composed of the specific granulation tissue, and the other a fluminating severe form characterized by widespread fatty necrosis attacking the fatty tissue. Changes in the blood diastase, blood sugar, and in viscera other than the pancreas, as well as human cases, will be described later.
4. TRANSPLANTATION OF CHICK SARCOMA INTO THE PANCREAS When the Chiba type of chicken sarcoma was transplanted into the pan creas, at the junction of the sarcomatous tissue and the parenchyma, spindle shaped cells were seen infiltrating the intercellular spaces of the gland cells, and the pancreatic gland cells intersected by the sarcomatous tissue were detected as in a state of forming numerous isolated areas within the sarcoma tissue. 1) The parenchyma of the remaining pancreas formed small glandular duct cavities, with the cells flattened and the mitochondria and zymogen granules decreased or lost. The interstitial connective tissue was in a state of proliferation. Changes of this sort were termed B type (glandular duct type). 2) The remaining paren chyma showed atrophy of the gland acini, and some derangement with slight degeneration, but the zymogen granules remained. This type of change was called A type. The B type appeared later than the A, and represented a change not seen in the other viscera. With the growth of the sarcoma, the blood diastase rised markedly. The group with the transplants in the pancreatic head rose higher than those in the tail or body of the pancreas, those with the transplants in the tail rising lowest. The B type showed a higher rise than the A. The changes in the blood sugar were not very conspicuous, but in the tail transplant group there was a slight tendency to increase, and the body transplant group showed a slight tendency to decrease. No changes were noted in the head transplants. The growth of the tumour was strongest in the head and weakest in the tail.
5. PANCREATIC IMPAIRMENT DUE TO BACTERIAL EXOTOXIN In the case where there is an overall infection, the pancreas seemes to be impaired by the bacterial soma or toxin. As an example of it, an experiment on the disturbance resulting from the diphtherial toxin, which is an exotoxin, is described in the following paragraphs. When the purified diphtherial toxin was introduced into the pancreatic artery of a dog, the blood diastase began to increase on the next day, started to de crease from about the 5th day, and on about the lOth day returned to the normal value. The blood esterase also generally showed a similar change. The changes in the blood diastase due to Vagostigmin (m-oxyphenyltrimethylammonium methylsulfatdimethylcarbaminester) were abnormal even on the 20th day. In the early stage of the experiment the parenchyma became coarsely granu- DISORDERS OF THE PANCREAS 63 lar, and in the lobules were seen some round cell infiltrations. The islet cells were scattered, a small amount of hyaline substance appeared in the islets, and the cell infiltration was clearly seen in the covering membrane. Later, the inflam mation of the interstitia around the pancreatic duct was noted. The gland cells became small in shape and compact. On about the lOth day this inflam mation spread throughout the entire organ, and part of the parenchyma became necrosed and showed a degeneration of the gland cells. In the islets were seen edema and a low degree of degeneration. These changes practically were over on about the 30th day.
6. PANCREATIC IMPAIRMENT DUE TO DL·ETHIONINE When 250 mg of dl-ethionine was injected intraperitoneally into adult guinea pigs daily, the pancreatic interstitia showed some hyperemia after a few days, while the arrangement of the baciliform mitochondria of the hepatic cells became deranged and showed some fatty infiltration in the liver. A week later the pancreas turned yellow and somewhat hypertrophied, the interstitia showed round cell infiltration, hemorrhage, and irregular arrangment of the gland cells with hypertrophy of the islets. The liver showed, in places, hemorrhage and necrosis, and the liver cells underwent fatty infiltration. These changes became much more marked at about the lOth day (Fig. XIV). The above findings coincide with those reported by Farber, Goldberg, Popper and Chaikoff, but there are many others that do not. All of the findings ob tained have led the writer to feel that ethionine affects both the pancreas and the liver simultaneously. To clarify the impairment of the pancreas due to the substances whose chemical structures are known, is important in investigating the causative factors in pancreatitis.
7. OXYGENASE SYSTEM IN THE NORMAL AND IMPAIRED PANCREAS This experiment is a part of the investigations that have been made on TCA cycle. When pancreatitis due to Candida albicans, pancreatic necrosis due to the introduction of olive oil into the pancreatic duct, alloxan glycosuria, and an a cell impairment produced by cobalt chloride, were examined, the activity of succinic acid dehydrogenase in the pancreas decreased in the case of the first three and increased in the case of the a cell impairment. In the liver there was seen an increase in the case of pancreatic necrosis, and a slight decrease in the others. In the kidneys there was seen a marked decrease in the case of the a cell impairment, and a clear increase in the others. The activity for cytochrome oxidase showed in the pancreas a marked increase in the case of the a cell impairment, and a decrease in the others. In the liver all produced a decrease. Thus, in these cases, cell oxidation received marked changes in the pancreas. The degree of activity of succinic dehydrogenase was examined in conjunc tion with the changes of cytochrome oxidases in the case of an allergic inflam mation of the pancreas. The manner of the organic acid oxidation in the tissue 64 S. AOYAMA was revealed as follows (Fig. 1): 1) The activity of succinic oxidase "n in the homogenate of the inflamed Nor-mal Dog pancreas decreased remarkably sn E ~p,_,r;rnen!al Allergic compared with the normal case. f'cli•o..r~'clliti~; in Do9 2) No disturbance was noted in 70 cytochrome oxidase. 3) When the cytochrome system was saturated, GO the oxidation of succinate was not accelerated. 4) These showed that the apo-enzyme of the succinic dehydrogenase was disturbed. 5) In such a case the succinic de 30 hydrogenase system in the liver and kidneys showed an increase 20 in its activity. In other words, the enzyme system was not directly 10 disturbed, but the inflammatory substance acted on this enzyme secondarily. 6) It may be thus in· 10 30 40 so 60 ferred that in pancreatitis the for· FIG. 1. Succinic dehydrogenase as mation of important organic en- say ( 37° C). oxygen uptake per 22 mg of zymes, such as succinic dehydroge- the fresh tissue pancreas (left branch). nase, is impaired. In this case the lowering in energy metabolism of the pancreas is compensated by the other viscera, especially by the liver.
8. ACID SOLUBLE PHOSPHORUS, LIPOID PHOSPHORUS, AND NUCLEIC ACID PHOSPHORUS IN THE TISSUES OF THE NORMAL AND IMP AIRED PANCREAS
From the results of the investigations made on acid soluble lipoid phosphorus and nucleic acid phosphorus (RNA, DNA, protein phosphorus) existing in the tissue of the pancreas, the liver and the kidneys of normal and experimentally induced allergic pancreatitis, it was found that the normal pancreas cytochemically showed no marked differences when compared with the other important viscera. Further, during the acme of the allergic inflammation of the pancreas, these phosphorus showed no marked changes from the normal. In pancreatitis due to the Candida, and in pancreatic impairment due to alloxan, no changes from the normal state were observed in acid soluble lipoid phosphorus, but the .d 7 P, which has the most intimate relation to the metabolic function of tissues, was found to show a marked fluctuation, and, DNA and RNA showed an increase in the values of the standard deviation, indicating instability in the metabolic function of the pancreas. Further, in such cases, changes in RNA of the liver and kidneys became noticeable (Table 1). DISORDERS OF THE PANCREAS 65
TABLE 1. Phosphorous contents in the fresh tissues of the pancreas, the liver and the kidney in dogs ( mg/100 ms) Experimental I - -- - d" : --~- Monili~l - -- Normal dogs I all~r~ic_ pancre- Alloxdo ~abetlc pancreatitis in aht1s m dogs ___ g______dogs __ _ 1. Pancreas-head Acid soluble-P 98-126 (109.7) I 96-137 (109.1) I 89-124 (102.6) ~2-115 (106.3l Lipoid-P 102-141(117.7) 1103-141(117.7) 99-126 (120.3) 96-146 (120.Q) PNA-P, Protein-P 118-138 (130.0) : 106-141 (126.7) 99-129 (112.1) 86-114 ( 99.3) DNA-P 53- 63 ( 58.2) i 51- 67 ( 56.5) 5~- 79 ( 62.0) 51- 80( 68.1) I 2. Pancreas-body I 1 Acid soluble-P 92-136 (108.0) 94--131 1107.5) I 82-133 (106.1) 91-125 (108.5) Lipoid-P 112-138 (120.8) 101-145 (120.2) I 93-149 (115.8) 100-1:'15 <117.0) RNA-P, Protein-P 1118-142 (129.5) 128-142 (132.3> i 100-156 (127.7) 91-131 (1C6.5) DNA-P I 52- 66 ( 58.5) ' 45- 66 ( 59.8) I 52- 78 ( 62.3) 48- 58 ( 55.1)
3. Liver Acid soluble-P I 99-125(1125) 112-125(112.5> lno-141(120~-:[ 98-131(114.~ Lipoid-P 128-151 (141.5) 130-147 (138.0) 105-132 (120.9) I 96-145 (115.0) PNA-P, Protein-P 55- 70 ( 64.4) 69- 75 ( 73.2) 1 48- 89 ( 68.1) 27- 49 ( 38.1) DNA-P 23- 39 ( 29.2) 20- 27 ( 23.2) i 29- 45 ( 37.3 ) 28- 40 ( 34.4)
4. Renalc~rtex I I Acid soluble-P 1 89-102 ( 93.0) 1 81-110 ( 95.0) 70- 89 ( 78.3) 75-105 ( 91.6) Lipoid-P 1103-111 (107.6) 1 105-113 ( 99.0) 95-112 (105.5) 98-122 (108.C) 16- 42 ( 25.8 ) --~A-I'_'_!'rot~in-P __ 47______j_~~~-~7.0) 15- 44 ( 28.1)
9. WATER SOLUBLE VITAMINS IN THE PANCREAS AND PANCREATIC JUICE i. Thiamine and riboflavin in various viscera The vitamine contents of the pancreas of normal dogs consisted of 200 r% of thiamine (free form about 15%), and 600 rJ~ of riboflavin (free form about 3% ). When the free form of thiamine was administered in normal dogs (Fig. 2), first the free form and later the ester form showed an increase, markedly in the liver, and somewhat less so in the pancreas. The increases in the ester form were lower, and the time required to reach a maximum was greater with the pancreas than with the liver. When administered with the ester form of ribo flavin (Fig. 3), the increase of the ester form in the pancreas was more marked than in the case with thiamine. In the hepatic impairment, the contents of thiamine in the liver were lowered clearly, but in the pancreas there was practically no changes, the free form only showing a slight increase. The riboflavin content in the liver showed a marked decrease, running parallel generally with the impairment seen after the brom sulphalein test, but the decrease in the pancreas was slight. The changes after thiamine and riboflavin administration were, in general, similar to that in normal dogs (Fig. 4, 5). In pancreatitis, the vitamin content of the pancreas showed some decrease (Table 2), and the other viscera indicated no changes. In alloxan glycosuria, the administration of the thiamine resulted in an extremely rapid excretion from the liver, and the thiamine during the maximum excretion was practically in the 66 S. AOYAMA
Yo/o --Total VB 14()0 ---Free VB,
~\ 1000 I ' 5000 II ' \ I \ I I I I I I I I I I I I I I 1 \ liver 500 I 1 I I I \ 1 ~~'liver ( ...... Pancreo6 1000 100 I _,/ ---- Pancrea& 500 Pancreas / 0 L-....L--'---'--'---"-'Biood 0 30 60 90 120 0 30 60 90 120 Minutes Minutes FIG. 2. Thiamine contents in FIG. 3. Riboflavin contents in the liver and the pancreas after 20 the liver, the pancreas and the mg of thiamine-HCI was adminis· blood after 20 mg of riboflavin was tered. administered.
Y% 1500 --Total 8, ----Free B,
Y% 1000 5000
.3000
300
1000 liver 100 _...,------_Pancreas
0 L-..J:.~-'---.:==="'-Biood 0 .30 60 90 120 0;306090120 Minuies Minutes FIG. 4. Thiamine contents in FIG. 5. Riboflavin contents in the liver and the pancreas after 20 the liver, the pancreas and the mg of thiamine-HC!was adminis blood after 20 mg of riboflavin was tered to a liver damaged dog. administered to a liver damaged dog. DISORDERS OF THE PANCREAS 67 free form. In this case, the pancreas showed a marked increase in the content of the free form, and compared with normal dogs, it began to decrease earlier, while despite the great increase at the start, the concentration in the pancreatic juice did not run parallel. Riboflavin decreased markedly in the liver, and in general ran parallel with the degree of hyperglycemia, but in the pancreas there was seen only a slight decrease. The changes after its administration resembled the case of thiamine.
TABLE 2. Riboflavin contents in various organs of pancreas impaired dog by olive oil injection ( y %) 30 minutes after intra No treatment administered venous injection of riboflavin ( 20 mg) -bays after the operation 2~~~~y 3rd day 6th day 7th day Pancreas 539 264 344 431 Liver 2560 3 003 2406 4519 Submaxillar gland 365 384 507 522 Parotic gland 473 277 599 Blood (before injection) 25 27 29 37 Blood (after injection) 154
Hence, it is to be considered that the pancreas can scarcely esterify the vitamines. Rather, those esterified by other viscera, such as the liver, seem to be utilized by the pancreas. In the slight pancreatic impairment, the vitamine content in the pancreas shows a tendency to remain comparatively constant.
ii. Ascorbic acid in viscera In normal dogs the content of ascorbic acid in the pancreas was about 12 mg%, and did not differ much with the site of the pancreas examined. After loading with ascorbic acid in normal and alloxan glycosuric dogs, the liver and the pancreas showed increased contents of it, but in the latter the increase was delayed, while in the case of liver impairment, there was an in crease, though less than under normal condition, and the decrease appeared later in the pancreas than in the liver (Table 3).
TABLE 3. Total ascorbic acid ( mg5',;') in pancreatic tissue in dogs before and after intravenous administration of ascorbic acid (200 mg)
After administration Experiment Before No. administration 30' 60' 120' I Normal dog 1 9.64 13.36 i~~~--~- 16.84 2 13.88 I 16.41 20.94
Liver 1 11.44 18.55 16.64 --:------116.55~ impaired dog 2 11.10 I 15.01 14.50 18.45 1 17.86 22.32 Alloxanized dog I 2 1 - t~:~-~ __ [ __i~:§r 13.63 I 16.21 ---- 68 S. AOYAMA
iii. Thiamine and riboflavin in pancreatic juice The average thiamine and riboflavin contents in the pancreatic juice of a normal dog under the fasting condition were 6.60 r% and 6.0 r% respectively and variations during a day were slight. After the administration of thiamine or riboflavin (Table 4), there was an increase, and the degree was very slight, and irrespective of the type of thiamine administered, the thiamine in the pancreatic juice was almost in the free form. Through substances stimulating the secretion of pancreatic juice were adminis tered, it only resulted in a very slight increase in the total thiamine content of the pancreatic juice. When thiamine was administered at the same time as the secretory stimulant was administered, the concentration of thiamine that excreted showed only a slight increase. Such an attitude differed from that pre sented by the liver.
TABLE 4 (a). Thiamine contents in pancreatic fluid by a normal dog after 20 mg of thiamine-HCI was administered
v 1 f fl 'd j Thiamine contents I Thiamine contents Time 0 0 I ume m 1 in 1 ml : in excreted fluid (minutes) 1 (mil I ( Y) 1 ( Y ) Before 30 I - ~:g----~-- g:g~~ ----~------g:~~g--- - After 30 II 60 2.3 I 0.111 0.256 II 90 1.6 0.140 0.224 II 120 2.0 0.093 0.186
Secretion Before 30 2.0 0.034 0.068 injection After 30 12.5 0.016 0.200 II 60 3.0 0.031 0.093
TABLE 4 (b). Riboflavin contents in pancreatic fluid of a normal dog after 20 mg of riboflavin was administered
-----~~·---- Time v 1 f fl -d [Riboflavin contents I Riboflavin contents '[. 0 ume 0 UJ in 1 mg in excreted fluid (minutes) (mil I (y) (y) Before 30 After 30 -~~i II 60 - II -fl_1 ____ - 90 II 120 II 150 ------~----~ Before 30 12.5 0.042 0.525 After 30 8.7 0.088 0.765 Imidalin II 60 31.5 0.036 1.134 injection II 90 47.5 0.025 1.187 II 120 44.5 0.025 1.112 II 150 36.0 0.026 0.936
When thiamine hydrochloride was mixed with the fresh pancreatic juice of the dog, the thiamine content showed a definite decrease (Table 5). Within a certain range the rate of decrease was speeded with a rise in temperature and the maximum decrease was seen at pH of 9.0. This phenomenon was not ob- DISORDERS OF THE PANCREAS 69 served a remarkable degree when the thiamine solution was mixed with heated pancreatic juice. From these results, it is considered that the pancreatic juice can act to transform the thiochrome reaction negative, and this action is not due to a simple oxidation process but to the effect of both the pH of pancreatic juice and pancreatic juice itself.
TABLE 5. Thiamine hydrochloride influenced by pancreatic juice
E--~_~x~=pe=r=im~~e~n-=t=------~=- pH 1 ~:~~- Time I ~:f~~~~o~e~~- ~N~~~i~ve
No. Specimen analized Con- 1 Speci- ! (°C) (minute)] trast men i <%) Pancreatic fluid 1 ml with I 7:01--4-0 - -60 ------T-6s- - thiamine 2 Y 1 Protein-free pancreatic fluid II I II II 67.5 I 1 ml with thiamine 2 Y ~0 -TPancreaticfluld.-Tm1 wit1lT74-~ 50 60 ' thiamine 2 y · • 33 2 0 lj Protein-free pancreatic fluid j' 11 II 33 1 ml with thiamine 2 Y 1 " ------Tr~~~~~~ _ ~~- -- 3 gu;-ccTmlwit11 ___ 6 8 60 60 41 ! ~0 Protein-free pancreatic fluid~- 11 11 1 II 42 i 1 ml with thiamine 2 y I ----~-Pancreatic fluid 1 ml with I ---1 60 60 thiamine 2 y 7.4 i 34.5 I 4 ' 30.3 Water 1 ml with thiamine 11 j' II 2 y II 49.5 I I - --Pi!ncreatictfliid 2 ill! with---~ 60 thiamine 0.5 y 7.4 60 5 Water 2 ml with thiamine 11 11 -l"l~8.4 0.5 y II -Pancreatic fluid 2 ml-wid1i-- 60 60 58.5 thiamine 2 Y 7·2 6 Pancreatic fluid (100° C, 10 21.5 minutes) 2 ml with thia- 11 11 11 74.5 mine 2 y ·------
iv. Ascorbic acid in pancreatic juice The average of ascorbic acid content of a normal dog's pancreatic juice was 0.43 mg%'. The changes resulting from the administration of ascorbic acid or from that of secretory stimulants closely resembled that of thiamine and ribo flavin (Table 6). Further remarks to be made on the above are: 1) in spite of the markedly low content of thiamine compared with that of riboflavin in the normal dog pancreas, the concentrations of the two in the pancreatic juice are almost equal. Thiamine plays a more active role than riboflavin in metabolic activity, while riboflavin seems to be more connected with the structual constituents of the pancreatic cells. 2) In spite of the fact that most of the thiamine in the pan creas consist of the ester form, the thiamine in pancreatic juice consists mainly of the free form. It is probably due to the presence of certain hydrolytic en zyme for the ester form in the pancreas, or to the presence of some mechanism whereby the free form is selectively filtered. A definite conclusion cannot be drawn on this at present. However, the writer has proved the hydrolysation of thiamine ester by pancreatic homogenate. Also, the thiamine of the pancreatic 70 S. AOYAMA
TABLE 6. Total ascorbic acid in pancreatic juice in dog before and after intravenous administration of ascorbic acid 200 mg
-~==== c_-_-_--___--______
's~foe;l Afterf 60' ]I 90' -~120' 115~' 1180' ,II , 3o' 3o· I _J~:J __ -·"·· ~----- Quantity of-flu 2.2 2.5 1.4 I 2.2 i bJJ id (cc) I I 0 [ I 1.9 I I "d 1 Concentration o f ascor- I 0.30 0.48 0.60 o.36 I 0.30 bic acid (mg "(,) i I ro ... I a I .... Quantity of flu id (cc) 2.3 I 5.7 3.0 1.8 I 0.8 I 0 I 2 I ! z Concentration o f ascor- ! 0.421 0.60 0.54 0.481 0.30! bic acid (mg 0.~) I 1 -~--- Qua~~ity -cl-ftuicl-(~~) ' 1 1.8 1 o.6 1.7 ! 1.2 1 o.7 B.S.P. 155'.;' ·8 1 ,Concentration of ascor-] 1 o. bJJ : bic acid ( mg9{,) ' 0.30 1 0.54 0.48 1 0.30 1 .§ .g ------· Quantity of fluid (cc) 4.5 11.01 0.4 I 5.6 9.0 2 Concentration of ascor- : bic acid 1 mg9{,') 0 36 0·38 ! 0.48 ____ _
.g !Quanti~;:-;;;-fl-~id (c~)- 8.0 2.5 2.0 0.8 0.7 ] I Blood sugar ""' 1 :c: oncentratwn. of ascor- 225 mg?t;' ~ bic acid (mg%'l 0.31 0.58 0.47 0.42 0.38 i 1 1 --:-[~:::::~,:c:~~~-~~~,1 ::o I::,! ::,I ::, i :::, ~---l "JrO'.::~,-, ~ bic acid ( mg._9-"-(,._) ----c- ---'---.c_---"---
1)~ ~~ Quantity of fluid(cc) I 1.4 ! 25 I 6.2 I 77 1100 I 82 I 8.4 [ ~:::!""' 1 Concentration of ascor- . . . ] . I -!;;..§]: bic acid (mg?(,) 0.39 0.58 0.81 1.16 1.93 1.04 0.58
:~ ~ gJ ! Quantity of fluid ( cc) -0.5 I 2 5 ~-4.0--~ 6:ol-1.3!i:7 ---;:~- 2 1 ""' ..c:: c: ' 1 Concentration of as cor- , ~ -~ ·-! bic acid (mg 9(,) 0.36 1 0.72 0.96 1.08 1 1.68 j 0.78 0.48 ______juice seems to be reabsorbed in the intestinal tract, and utilized. 3) A comparison of the thiamine, riboflavin and ascorbic acid contents in the pancreas and in pancreatic juice before and after the administration, and the attitudes of the pancreas and the liver during the impairment indicate that the fixative and secretory functions for thiamine, riboflavin and ascorbic acid of the pancreas are independent, and the former function seems to be impaired more easily than the latter secretory one. 4) From the attitude of the pancreatic tissue to the free and ester form thiamine, it can be said that the pancreas is able to hydro lyze the ester form, but the phosphorisation action is extremely weak. 5) When the pancreas is administered with thiamine, riboflavin or ascorbic acid, their con tents in the tissue increase, but they are not especially voided by pancreatic juice. When the pancreatic secretion is stimulated, there is seen an increased flow following the increase in volume of the pancreatic fluid secreted, but there are no indications beyond this of an increased secretory activity. In other words, it can be said that the pancreas is not the secretory organ for either of thiamine, riboflavin and ascorbic acid. DISORDERS OF THE PANCREAS 71
II. Diagnosis of Pancreatic Disorders and Its Basis
1. EMIGRATION OF ENZYMES INTO THE BLOOD
t. Blood diastase a. Fundamental items The significance of the blood diastase in pancreatic diagnosis has long been recognized. The Wohlgemuth method of blood diastase estimation is not suitable for cases other than those where there is a high increase. Therefore, Somogyi's, Ottenstein-Baltzer's or Tamai-Kobayashi's method were employed in the follow ing experiment. The blood diastase exhibited a marked variation when there was an impair ment in the pancreas. For example, in pancreatitis due to the Candida, high values were found during the suppuration and suppurative-nodose stages, then decreased gradually during the nodose stage, to return to the normal during the fibrous stage. In order to evaluate Knight's Prostigmin method, various pancreatic stimu lants were examined, and it was found that when the pancreas is healthy, pilocarpine, acetycholine, Dehychol (dehydrocholic acid) and Imidalin (benthy limidazolin) slightly increase the blood diastase content, but histamin, secretin, (based on Friedman and Thomas' new method) and Vagostigmin (Prostigmin) have no effects on it. At the height of inflammation, the increase in the blood diastase resulting from these stimulants was further greatly enhanced. However, when the blood diastase showed an extremely high value during the earliest stage of the onset of inflammation, loading with drugs sometimes did not bring about an increase. When the fasting blood diastase returned to the normal, the above drugs even during the disease could increase the blood diastase content. However, when the disease began to settle down, the effect of histamin was lost compara tively early. On the basis of these experiments and other clinical experiences, it may be said that the Vagostigmin or secretin tests are the best (Fig. 6). The Vagostigmin reaction value in a normal human being was below 30 mg"il'. In vestigations made on normal persons and patients affected by pancreatic disease revealed that fluctuations of over 50 mg9 5th ,iay ,:.~~~t'9f1CXI RO\J(l 7000 rAJ()( I \Oth day Xl'lth day IC(,l[l pL______.J_ __ _ r' yo (JO 90 120 M1nui..e FIG. 6. Vagostigmin test in experimental monilial pancreatitis. 72 S. AOYAMA The reaction curves obtained after injection can be classified into the follow ing 5 types, (Fig. 7). Type I: the curve takes a downward course after injection, and despite some fluctuations, remains at a level lower than the pre-injection value. Type II : the curve takes an upward course after injection, and though 1 'vo< m 19C.JSU: ~ 21 Time:,..' l6Cuses\l't' Times~ 4 100! IX] I 0[ ______oL-----~--~--- OV____ ~ 0 6U 120 6·'J )0 80 o oo go '20 0 .30 CO 9C 1~0 I""~ ,., M:.,..,t~, 400) Typr;, fV lype V ;oof ~Cases( 5 Tirnesl ooo=·cosesi6Timesl 200~ 200 ·oo I 100 ! OL------~--- 0 . 0 YJ 60 90 120 0 30 60 90 120 FIG. 7. Classification of curve in the vagostigmin test in chronic pancreatitis. l'lljk!~mi(""' '00 ,,... I ! I suo ,XXX) I I /00 2000 100 1000 ' .... o------o--- --·)------() ~:~,--o-pe-,-,t-ive-----~,0------~~------~9-0------~,Q~O Time .n o"llnJtes FIG. 8. Relationship between blood diastase and duodenal flu;d diastase. DISORDERS OF THE PANCREAS 73 there are some fluctuation, remains higher than the pre-injection leveL Type III : the curve turns upwards after injection for some time, after which there is seen a tendency to falL Type IV : the curve falls after injection, but later shows a tendency to rise. Type V : the curve takes a horizontal course, showing practically no fluctuation. The relationship of these types to the histological changes in the pancreas was minutely examined, but except for the Type V in the case of the hardening of the pancreas or the atrophy of the parenchyma, no special connection cound be demostrated. Between the blood diastase value after the injection of V agostigmin and the duodenal fluid diastase value, no parallellism was found, except in a small num ber of cases (Fig. 8). When the pressure within the pancreatic duct was examined experimentally for its relationship to the blood diastase, (Fig. 9), it was found that when the lumen of the duct was closed, the blood diastase increased and the Vagostigmin curve rose. However, when the internal pressure was lowered, the blood diastase did not fall immediately, but showed a still higher rise by the injection of Vagostigmin. The former findings support the views of Knight and Malinowski, but the latter findings do not. " I ~ I Hlood [),o',to,,e f I ;I F'oncrcotir.. Duct Pt-essure ~I iii E I E ~0 !- ?(X)()0 I I() r I C1 I '' I " 1'7: 17 1r, I 10 I I~ i I 'J 14 14 13 13 12 I? II I II !00 l 10000 I 9 r- 0 I s 1- s 7 l ' I 10 !- 1000 o L o """" ----L~---~ ------______~---'----~- ~----L--l. () 20 t>il 1()0 120 FIG. 9. Relationship between pancreatic duct pressure and blood diastase. "' Blood diastase curve in pancreatic duct occulsion and opening. ( tJ, Vago stigmin injection.) x Vagostigmin test during the messuring of pancreatic duct pressure. © Blood diastase during the messuring of pancreatic duct pressure. 74 S. AOYAMA TABLE 7. The comparison of mean blood diastase values in arterial and venous blood of the pancreas, the liver, the spleen and the kidney 'L· f f t" Olive oil injected into Difference between Normal dogs ', Iga wn °. pancrea IC. ligated pancreatic the two vessels I duct m dogs i duct in dogs ---·-··-··----·-- ·------Pancreatic vein -pancreatic artery 568.5 2 510.5 4192.5 Pancreatic vein 590 2 577.5 - peripheral vein 4 275 Hepatic vein - hepatic artery 121.6 56 686 Hepatic vein - peripheral vein 157 15.5 682.5 Portal vein -79.5 276.5 278.5 - hepatic vein Splenic vein -41.5 - splenic artery 36.1 404 Splenic vein 72.8 - 9 522 - peripheral vein Portal vein 292 961 - peripheral vein 140.6 Renal vein -725.5 -peripheral vein -483.9 627 ------~------ fT)%£ / 2200() / / / / / ~ = ~-- i&cOC I I I I 16000 I I I 140UO I I I I I 1~()()J I I I I woou I I I 8000 I I I I 6000 I / I - -- lhorocjc Duel Lymph I / 4000 I -- Pancreotic Venous elood I / I / =Y 0 1;---~~------;-- 12 15 18 21 24 Pre-op .. rat,vt: Hours FIG. 10. Diastase in the thoracic duct lymph, pancreatic vein and periphery blood after ligation of the pancreatic duct. DISORDERS OF THE PANCREAS 75 20000 16000 12000 ------~ . -- _, ------8000 -- Peripheral BicJOr:l DOa~+ose 4ooo --- Thoracic Lymph Dlasta~E: 0~.------~------L-----~------~------~----~ Pre -oparative I 0 20 30 40 50 60 Time in Minutes FIG. 11. Diastase curve of the lymph and peripheral blood, after artificial fistula of the thoracic duct following ligation of the pancreatic duct. The estimation of the diastase contents of various viscera and the blood, the diastase in the blood flowing in and out of the various viscera, also the di astase in the lymph of the thoracic duct of normal dogs, of dogs with pancreas impaired or completely removed, and dogs with hepatic impairment, (Table 7, Fig. 10, 11), produced the results showing that the blood diastase orginated mainly in the pancreas, that in normal conditions the liver threw out its diastase into the blood, and that when there was a large escape of diastase from the pan creas, the liver captured some of it. Also, the experimental results showed the importance of the route whereby the enzyme that escapes from the pancreas passes into the circulation from the lymph spaces via the thoracic duct. b. Clinical Items-To be described later. c. Summary It will be clear from what has been stated above that the blood diastase should be considered as a valuable aid in the diagnosis of pancreatic disorders. However, an abnormality of this cannot be taken immediately as an indication of pancreatic impairment, nor can any variation of this be necessarily taken to represent the character of changes in the pancreas. Even in the case where a marked abnormality is found, as in acute pancreatic necrosis, this test should be conducted at an appropriate time. In a chronic inflammation of the pancreas, accurate estimations should be made repeatedly, or the Vagostigmin test should be made in conjunction. Further in chronic pancreatitis, it is not unusual for the changes to indicate only slight deviations from the normal, or to be entirely normal. Hence, the absence of abnormality in the blood diastase cannot be taken as a sign of normality in the pancreas. However, in general, an abnormally high value indicates the presence of inflammatory necrotic changes in the pan creas, and an abnormally low value represents pancreatic hardening or an atro phy of the glandular cells, but it must be remembered that this does not al ways hold true for all cases. Clinically, besides the panceas, special attention should be paid to diseases of the liver, the gall bladder, and the kidney, when there is abnormality in the blood diastase (Table 8). 76 S. AOYAMA TABLE 8. Value of fasting blood diastase and Vagostigmin test in various diseases Abnormal ele-! Classification of values of vataion of 1 Positive V agostigmin test fasting blood 1 reaction ___ di Case i ()'£) 1 Case 1 (96') (mg/dl) 99i 199; 299 999 1000 o 1 6 , ------r -~ ---- Normal 6 0 0 0 Acute pancreatitis 4 2 . 50 4 1oo I ' 4 Chronic pancreatitis 49 14 I 28 39 2 Pancreatic tumor 9 5 55 7 ~~ . 1: 12~ ~ i 6 1 Pancreatic atrophy 2 0 0 Biliary disease 32 5 15 10 31 2 2 2 3 1 Gastric cancer 37 8 22 17 44 20 6 5 4 2 1 Gastric ulcer ' 24 4 17 9 37 15 6 2 1 1 Duodenal ulcer ' 18 1 6 4 22 14 3 1 Chronic gastritis 45 2 4 7 16 38 6 1 Acute g astrtis 4 0 0 4 Other gastric disorders 2 0 0 2 Ascariasis 6 0 1 17 5 Hepatitis 18 1 6 3 15 15 Cirrhosis of the liver 4 2 50 2 50 2 Heinsen has adovocated repeated tests of the fasting blood diastase in place of the Vagostigmin test, but, when there is a suspicion of pancreatic disorder, it is believed from the above results, that the Vagostigmin test should be con ducted, though there be no abnormality in the fasting value. ii. Blood esterase The blood esterase in pancreatic disorders has been studied with renewed emphasis in recent years, and in some quarter its significance is made much of. The writer's research on it has produced the following results. Kayashima's method was mainly employed for its estimation, at times with a slight modification, depending on the nature of the specimen to be examined. Here, T stands for tributyrin decomposing power, A for decomposition power for tributyrin in the presence of atoxyl, C for tributyrin in the presence of quinine and M for methylbutyrate decomposition powers. a. Fundamental investigations By the method of Seligman et al., the various visceral esterases in normal dogs, not considering their bone-marrow, were found in the following organs, the ratio of abundance corresponding to the order mentioned; the liver, the pancreas, the gastric mucosa, the lung, the renal cortex, when P'-naphthyl acetate was the substrate; the pancreas, the liver, the gastric mucosa, the spleen, the renal cortex, the intestinal mucosa when laurate; the pancreas, the liver, the spleen, the gastric mucosa, the renal cortex when sodium taurocholate was added to laurate; and the pancreas, the gastric mucosa, the liver, the spleen when stearate was the substrate. Thus, the decomposition with short chain fatty acid esters is more marked in the liver than in the pancreas, and the decomposing power of the lung is high compared with those for other substrates. With middle chain fatty acid esters the pancreas is overwhelmingly powerful, and the decomposing DISORDERS OF THE PANCREAS 77 power of the spleen is high compared with other substrates. When sodium taurocholate is added, the power of the pancreas becomes marked and enhanced, but in all the other organs there is seen an inhibition. The decomposing power for long chain fatty acid ester is outstanding in the pancreas, and in most cases in the gastric mucosa it is higher than in the liver. By Kayashima's method examined, the visceral esterase of the pancreas showed the properties of lipase, and possessed somewhat high atoxyl-fast decom position power for tributyrin. The esterase of the liver and the kidneys ex hibited the properties of esterase, and that of the liver esterase showed accele ration by quinine, and the esterase of the kidneys possessed quinine resistance (Table 9). TABLE 9. Esterase activity in normal dog's organs I Experi- I * T c M I M/T ! ment No. I A A/T ICjT I ~~~ ------~- -· ~--- I 1 3.42 2.84 1.86 1.23 0.83 I 0.54 0.65 0.31 2 3.75 3.35 2.02 1.36 0.89 0.54 0.60 0.36 I 3 2.97 2.10 1.45 1.30 0.86 0.59 0.69 0.53 Pancreas 4 2 ·90 2.47 1.80 1.50 0.85 0.63 0.73 0.52 5 2.80 2.24 1.86 1.65 0.80 0.66 0.82 0.49 1.78 I 1.48 0.88 i 0.5!1 0.63 0.46 I 3.85 1.42 0.85 0.61 0.73 0.30 I 2.38 I 1.22 0.84 I 0.63 0.74 0.32 ~--~~-- __!_ H8 H~ I - I ----;- , Mean value 3.32 2.75 I 2.07 1.40 o.85 1 o.59 _o~J 0.41 ------1- ~-Ill 0.82 0.44 I 1.26 1.32 0.53 1.50 3.49 1.60 2 1.58 0.73 1.80 2.15 0.46 l.ll 2.46 1.14 3 i 0.87 0.45 0.88 1.69 0.52 1.01 1.98 1.94 Liver 4 I 1.52 o.68 1.72 2.21 0.45 1.14 2.53 1.46 5 ' 1.26 0.44 1.50 2.16 0.35 1.19 3.40 1.71 6 I 1.38 0.68 1.65 1.94 0.49 1.19 2.42 1.40 i 7 I 1.91 0.12 2.04 2.56 0.38 ! 1.07 2.83 I 1.35 8 0.90 0.56 1.62 1.88 0.62 I 1.80 2.79 2.09 I ------o.4sll.25- Mean value I 1.25 I 0.59 I 1.59 1.99 2.74 I 1.59 ' 1 -o~79- oA7·------c--~ --1 0.69 0.57 0.59 0.87 1.47 0.72 2 0.48 0.34 0.33 0.44 0.77 0.69 0.98 0.92 3 0.33 0.11 0.32 0.31 0.33 0.99 2.91 0.94 Kidney 4 0.38 0.15 0.36 0.35 0.39 0.95 2.40 0.92 5 0.31 0.18 0.34 0.43 0.58 1.10 1.89 1.39 I 6 0.24 0.18 0.24 0.33 0.75 1.00 1.33 I 1.37 7 1.10 0.49 1.13 1.10 0.45 1.03 2.30 1.00 8 0.22 0.10 0.18 0.33 0.45 0.81 1.80 1.45 ------Mean value 1 0.48 0.25 * T: Substrate "Tributyrin," A: Substrate "Tributyrin with atoxyl," C: Substrate "Tributyrin with quinine," M: Substrate '' Methylbutyrate." Hence, in the case of blood esterase too, a large A IT and small C 1A and MIT seem to indicate an extremely close relationship to the pancreas, while a small AIT, and large CIT, CIA and MIT indicate an intimate relation to the liver and the kidneys, especially the former. 78 S. AOYAMA The AfT of pancreatic juice esterase was small, C /T rather high, and C j A extremely large, while MjT was rather small (Table 10). In other words the nature of the atoxyl-fast and quinine-fast decomposing powers for tributyrin of pancreatic juice esterase rather closely resembles the visceral esterase of the liver, while the decomposition power for methylbutyrate resembles the visceral esterase of the pancreas. TABLE 10. Esterase activity of pancreatic juice in dogs. ( 1:100 dilution) Experiment No. T A c M AJT CJT C/A MjT 1 0.69 0.27 0.57 0.19 0.39 0.83 2.11 ' 0.28 2 1.44 0.36 1.30 0.42 0.34 0.90 2.30 0.29 3 2.14 0.90 1.98 0.40 0.41 0.93 2.22 0.19 4 1.53 0.70 1.32 0.47 0.46 0.87 1.90 0.30 5 2.15 1.05 1.96 0.53 0.49 0.92 1.96 0.25 ---M~~~ value - ~o.7o Tl.59 1.43 o.4o 1 0.42 1 o.89 1 2.09 0.30 ~-- When fresh pancreatic juice was injected intravenously, or the pancreatic duct opened and the pancreatic juice allowed to flow into the peritoneal cavity, the ferment in the blood exhibited the properties of normal blood esterase to which had been added pancreatic juice esterase. In the case of the pancreatic enzyme that had escaped into the circulation because of a pancreatic impairment, (Table 11, 12), the blood esterase increased, and presented the properties resembling pancreatic juice esterase rather than pancreatic visceral esterase. Hence, when there is an increase in blood esterase, and when there results an especial increase in the values of C j T and C j A and a decrease in Mj T, it may be considered that a pancreatic disorder exists. TABLE 11. Blood plasma esterase activity after ligation of all pancreatic ducts in dogs A c M ______L T I AJT ! C/7' I CJA I MJT Pre-operative 1.18 0.89 0.77 0.63 o.75 o.65- o.87_[_ o.53 __ _ Post-operative I 1st day 1.42 1.22 1.18 0.70 0.86 0.83 0.96 0.49 2nd day 1.22 1.08 0.99 0.63 0.88 0.81 0.92 0.51 3rd day 1.10 0.85 0.85 0.55 0.77 0.77 1.00 0.50 5th day 0.96 0.71 0.71 0.49 0.74 0.75 1.01 0.51 7th day 0.99 0.71 0.74 0.56 0.72 ' 0.75 1.04 0.56 lOth day 1.02 0.71 0.75 0.53 0.70 0.73 1.04 0.52 15th day 0.94 0.69 0.68 0.54 0.73 0.72 0.96 0.57 20th day 0.88 0.68 0.60 0.47 0.77 0.68 0.88 0.53 25th day 0.76 0.56 0.49 0.38 0.74 0.64 0.86 0.50 30th day 0.84 0.59 0.55 0.39 0.70 0.66 0.94 0.45 35th day 0.92 0.72 0.62 0.44 0.78 0.67 0.86 0.48 40th day 1.09 I 0.86 0.75 0.48 0.79 0.69 0.88 0.44 - DISORDERS OF THE PANCRJ:!AS 79 TABLE 12. Blood plasma esterase activity in experimental monilial pancreatitis in dogs MjT Pre-operative 0.58 Post-operative 1st day 1.94 1.51 1.62 0.78 0.84 1.07 0.57 3rd day 2.18 1.64 1.76 0.76 0.81 1.06 0.55 5th day 2.10 1.68 1.53 0.80 0.73 0.91 0.55 9th day 1.70 1.34 1.20 0.73 0.71 0.97 0.61 12th day 1.82 1.51 1.23 1.04 0.83 0.68 0.82 0.57 17th day 1.79 1.40 1.18 1.20 0.78 0.66 0.84 0.68 23rd day 1.48 1.26 0.98 1.02 0.85 0.66 0.78 0.69 30th day 1.41 1.15 0.95 0.90 0.82 0.63 0.82 0.64 35th day 1.44 1.26 1.03 0.90 i 0.87 0.71 0.82 0.62 42nd day 1.36 1.18 0.90 0.75 0.87 0.66 0.77 0.55 ------ In the case of experimental pancreatic necrosis, the blood esterase increased markedly shortly after the onset but decreased with comparative speed. In this case most of the blood esterase originated from the pancreas, especially from the pancreatic juice, and also partly from the liver impaired by pancreatic necrosis. In this case, the visceral esterase of the pancreas became low during the acme of necrosis, while those of the liver and the kidneys showed almost no change (Table 13). In experimentally induced hepatic obstruction, the increase in the blood es terase was due mainly to a lowering in A/T and a rise in CjT, C/A and MjT (Table 14 ). In other words it was due mainly to the escape of the liver ester ase. In this case there were no changes in the visceral esterase of the pan creas and the kidneys, but a marked decrease in that of the liver was noted. Hence, when there is an increase in the blood esterase which is due to a marked rise in T, C and M, resulting in the lowering of A/T, and the rising of CjT, CjA and MjT, a hepatic disorder can be considered to exist. Animals with complete pancreatectomy were divided into three groups ; untreated, insulin-administered, and lipotropic-substances-administered; and their blood esterases were examined (Table 13, 15). The following three types of reaction were observed ; 1) after a temporary rise, there was a fall to below the pre-treatment level, followed later by a tendency to increase, 2) immediately after the treatment there was a fall followed by a tendency to rise, and 3) there was no change (Fig. 12). The T, A, C, M and the visceral esterase of the liver were examined in these three types, and the relationship of each group to these types was studied. Histopathological examinations were also conducted, and considering further the results of a liver impairment after complete pancre atectomy, a summary became available that the increase of the blood esterase during the early stages of removal was due to the liberation of esterase from the liver, and the decrease that followed was due to the absence of the pan creatic esterase and the decrease in the liver esterase resulting from the lowering in hepatic function. The increase that followed later seems to have been due to the compensation by the other viscera. 80 S. AOYAMA TABLE 13. Blood esterase in experimental Stages T A C I M I Initial increased slight I slight --~~-s'lccig-h,--;-t---~ Ligation of the __s_t_a~g~e ______,_ __increased __i_n_c_r_e_a_se_d--;- __in_c_r_e_a_s_e_d-'---u_n_c_h_a_nged large pancreatic duct Recovery stage recovered I recovered I recovered I recovered Initial incresed shght I increased increased increased stage I I I I increased Decreased Ligation of the all slight intermediate decreased pancreatic duct I decreased I decreased deer eased stage I I I Recovery stage I recovered recovered I recovered decrea sed I I I Initial increased I markedly 1 slight I increased increased ~ta_ge I I increased· incr eased Pancreatic necrosis -~ ------I Recovery stage recovered recovered recovered recove red I I I I lmt1al mcreased I increased increased markedly I slight Abdominal fatty s_t_a-=g_e ____-i------increased increased necrosis ---~----~--- ___IR~covery stage recovered recovered recovered I recovered ----- Initial increased increased slight I increased stage [ increased increased I Decreased inter- I decreased I decreased I decreased I slight-- mediate_s_t 'I decreased I I lnit-i~~creasedstage Tdecr:~~ed un~~:~~:d un~ha~ged Decreased inter slight mediate stage decreased decreased I decreased I decreased Recovery stage recovered recovere-~J recovered I decreased ln!i~aie unchanged] unchanged I unchanged unchanged I sli~~~eased -U~~~:rn~=~=~e--,~-~nchanged -~.___u_n_c_h_a_n_g_e_d---'-_u_n_c_h-anged -~-=~mge~ stage -;:c~::~-:~~~ ~-~:::~=---~-recovered recovered I decreased -u-~-~--.-~~~-C-a-se_s_o_f~~~I~n'i~tl~-ai stage 1 exceedingly v after hepatic exceeding! yl increased [markedly I increased 1 increased increased I , slight · ~ ill c~:::e:;e.l rnl~~:~~rif~ic unchanged I increased Jl unchang:d I I increased[ .§ ro unchange impairment 1 I Initial stage I inconstant inconstant inconstant I inconstant ------;- Partial pancreatectomy In!~~~eedi:: __ _l inco:~:~~:c_o_nstan~- --i~~ons-ta_n_t__.,d~ecreased slight Recovery stage I recovered recovered recovered decreased ------· -~-- DISORDERS OF THE PANCREAS 81 pancreatic impairment in dogs (Summary) AfT _I C/T C/ A j M/ T Remarks unchanged unchanged unchanged 1 sli_ght Slight increase of pancreatic esterase mcreased--~ recovered recovered recovered-~--1~------~--1 recovere I D ___ e_c_r_easeesterase and recovery of pancreatic --~---.-c--.;------c-----;-- .::_:::__c:______------slight I slight I shght i slidght dj Increase of pancreatic esterase increased increased decreased' ecrease 1 ~------~--~-~--~~-ht-- ' i Presumably decrease of pancreatic 1 unchanged uncha_ nge_ d _s ~ _ d' unch_ anged I _esterase and increase of hepatic I mcrease i esterase ~~~~~~~d~- recov~r~d-~-;~c-o~~d-rde~r~~~d~pn~~~~~:~e 0df h~~~~fc e~~~~a~~es and silj~Iit___ d~- i~creased i increased i slldght dl Increase of pancreatic·-;;terase mcrease 1 1 ecrease recov;;~d-~ recover-~d-~-;~o~;;e·d-~~~~~red I D~~~~~~~e and recovery ofPai:icreatrc ' sli~~~easedl increas~l increased - ~-sf~ehc~e~::lM~-lncrease in pancreatic esterase ;e~~~dT~~~-;~~~~d 1--;.~~-o~~~ reco~~;~d- : D~~~~~~~e and recoveryat- pancreatiC Marked decrease of pancreatic es- , unchanged I increased I increased I increased I terase and increase of hepatic es- 1 terase d h Decrease of pancreatic and hepatic I_ un~:nged I_\l_nc~~f;"~~ I anged I inconstant I esterase I d I I d I decreased -~-fu-;;;.~-~~--of esterase by other organs , recovere 1 recovered recovere and decrease of hepatic esterase 1-----'---- , j 1· ht I 1- ht I Marked decrease of pancreatic es- 1 unchanged . s fncreasedl increased s ~~creased terase and slight increase of hepatic 11 1 esterase unchanged ! unchanged ~-~~h~~;~dpliJe~~~:sedl D~~~~~~~e of-pancreatic and hepatic ---~d--·-· s d I Increase of esterase by other--~;;;s- recovered I recovered I recovered I ecrea e and decrease of hepatic esterase -~~--- I 1. ht 1 Marked decrease of pancreatic es- unchanged unchanged I unchanged s 1fncreasedl terase and slight increase of hepatic esterase 1 -u-n~han~e~- 1 ~n~hange~l!,i--=-~~anged I, unch:~: rDe~;~ase- -;;-f-pancreatic esterase and 1 j slight decrease of hepatic esterase --:ecover~~-:~~-~~;:;~-~ecovered I decreased I Increase of esterase by other organs and decrease of hepatic esterase ~r ~edly I mark ed!y ~~e~x~c~e~e~rl~i~n~g~lY-+-1-m_a_I. nr-kc-re-ed-al-sy~e~d-i-1-M_a_r k-ed_i_n_c~r-e_a_s_e_o_f_h_e_p_a_t_ic_e_s_t_e_r_a-se- decreased increased increased unchanged I increased I increased I mf~~:~l;'edl Slight increase of hepatic esterase unchanged I inconstant I inconstant unchanged I In~~~as~epaa~~ ~~~~~=~: of pancreat!C Increase and___ decrease of pancreatic unchanged I unchanged ~-i~co~s;~~t I decreased / esterase and decrease of hepatic ~~~----~_e_s_t_erase I slight j recovered j recovered j recovered 1 decreased Decrease of hepatic esterase 82 S. AOYAMA TABLE 14. Blood plasma esterase in Stages . --r,~---_1._1-_-----_A_····===-+-~---_--_····-oc~·--·~ M Initial increased I markedly I . d I exceedingly;!. exceedingly Heptic impairment stage increased mcrease increased increased caused by CC1 4 Re~:~~~~ge -r~~;~G~~vered ~-recovered I recovered Initial increased !-markedly I . d .I. e-xceedingly[ exceed!nglv Ligation of biliary stage I increased! mcrease increasedj increased tract Recovery stage I. recovered [ recovered 1 recovered j recovered Initial increasecr-~---·· d I' slight I markedly 1 markedly stage mcrease increased increased, increased Pa~~~a~tectomy In~~~~e~~~~estage! decreased ~-~~~~~e~[decreased I md~~:~!~ed .. ···---·----~=c~very stage _I recovered Jrecovered j recovered I recovered TABLE 15. Blood plasma esterase activity in depancreatized dogs I T A c M I A(T I C(T I C/A M/T I -·-~~-----~ Pre-operative 1.21 1.07 0.69 0.60 I 0.88 0.57 0.64 0.50 Post-operalive 1st day 1.10 0.88 0.67 0 .61 0.80 0.61 0.76 5.55 4th day 0.70 0.54 0.44 0.37 0.76 0.62 0.81 0.52 6th day 0.80 0.64 0.45 0.39 0.80 0.56 0.67 0.49 8th day 1.00 0.81 0.53 0.54 0.53 0.66 0.54 I 0.80 lOth day 1.04 0.91 0.57 0 .50 0.87 0.55 0.63 0.48 12th day 1.04 0.93 0.47 0 .33 0.89 0.45 0.51 0.32 16th day 1.07 0.95 0.73 0 .50 0.89 0.63 0.77 0.47 21st day 1.04 0.91 0.71 0 .61 0.87 0.68 0.78 0.59 24th day 1.15 0.97 0.86 0 .41 0.84 0.75 0.89 0.36 2~th day 1.05 0.86 0.74 0.36 0.82 0.74 0.71 0.34 27th day 0.95 0.78 0.67 I 0.33 0.82 0.70 0.86 I 0.35 I --~----·--- .. -·------~-- ~·------ ...___..Type I Cr---0-----u Type ll ~TyfJciD j 5 ? 9 I! IL~ I~ 17 19 21 23 25 27 29 -31 3..:~ Days FIG. 12. Plasma esterase activity in depancreatized dogs (three model-types). DISORDERS OF THE PANCREAS 83 hepatic impairment in dogs (Summary) CjT C/A MjT Remarks I AjT I , decreased I m~~~:~~~edl mf~~:~~~ed~-~~;-~ased Increase of hepatic esterase ~--~----~--- I I I Decrease and recovery of hepatic recovered recovered recovered recovered esterase decreased -m recovered recovered I recovered 1re~;ve;~d 1 In~~~:::se and recovery oC hepatic-- , sl~ehc~easedl increased I m~~~:~~~eiincre~~~I~~;ea~e- of- hepatic esterase ! - I ------~--~------.. -Marked decrease of hepa--ct~ic-e-st:-e_r_a-se- i increased unchanged I decreased decreased 1 and co~pensatory increase of 1 , I , pancreatic esterase ,_'_r_e_c_ov--ered I d I' d 1-r_-~c--o-ve-red--fi::\ecsrteearsaes'_e_and recovery-oChepatic ___ ~~~~~covere 1 recover~ To summarize these results, the blood esterase under normal conditions originates from the pancreas, the liver and other organs, in the order of im portance. The abnormal blood esterase during the disease is dependent on the attitude of the three organs mentioned above (Fig. 13-17). Further, on investigating the blood esterase of the blood vessels related to the principal viscera, it was found that part of the blood esterase enters the circulation mainly via the pancreatic and hepatic veins and another part of it via the intestinal vein, and in a pancreatic impairment the volume of the flow in the pancreatic vein becomes greater, and some could be considered to enter the circulation 11ia the thoracic duct. Blood Plasma Esterase Blood Plasma Esterase Pancreatic Estera~e in Blood Plasma Pancreatic Est-erase in Blood Plasma Hepatic Esteras{_ in Blood Plasma t~epatic Esterase in Blood Pla~ma Other f sterases in Blood P/a5mQ Other E.ster-ases in Blood Pla::.ma Days FIG. 13 (left). Blood plasma es terase at the time pancreatic esterase appears in the blood (imaginary model graph for explanation). Days FIG. 14 (right). Blood plasma es terase at the time pancreatic esterase disappears in the blood (imaginary model graph for explanation). 84 S. AOYAMA Blood Plasma Esterase Blood Plasma Es+era5e Pancr-eotic Esterase in Blood Plasma Pancreatic E!>+erase in Blood Plasma HepcrlicEs+erase in Blood Plasma Hepatic Esterase in Blood Plasma Other Esterases in Blood Pla::,ma Other Esterases in Blood Pla~ma (\ I \ I \ j_ ____ \. __ ------.------.--- 1 \ I \ Doys \ ...... ______ Blood Plasma Esterase ------Pancreatic Esterase in Blood Plasma Days Hepatic Esierase in Blood P!asmLJ Other Esteroses in Blood Plasma FIG. 15 I left). Blood plasma es terase at the time hepatic esterase ap pears in the blood (imaginary model graph for explanation). FIG. 16 (upper right). Blood plasma esterase at the time hepatic esterase ,/·'·· .. , ____ -...... -- .. -.--.... -- .. disappears in the blood (imaginary model graph for explanation). .-..._ / FIG. 17 ( l wer right). Blood plasma "'------·-- esterase at the time both pancreatic and hepatic esterase appears in the blood (imaginary model graph for explana tion). Dcrys b. Clinical Items By a special pancreatic catheter designed by the writer, pure pancreatic juice was obtained from the human body and the esterase contained in it was investigated. The value of M was extremely low and MIT very small. Also as in the case of dogs, the visceral esterases of the pancreas and the liver of the human body showed a small M for the pancreas, and hence a small MIT, while, compared with the pancreas, the CIT, CIA, and MIT of the liver were large (Table 16). The blood esterase of healthy persons showed a maximum of 1.59 and a minimum of 1.15 for T, and there were no special differences between the two sexes (Table 17). TABLE 161 a). Esterase activity in human pancreatic juice ( 1 : 100 dilution) I T A c M A/T CjT C/A MjT :~~~-"--~~---:- Pancreatic juice I 1.54 1.34 0.86 0.27 0.87 0.56 0.64 0.18 DISORDERS OF THE PANCREAS 85 TABLE 16 (b). Esterase activity in human organs ( 1 : 250 dilution) I T I A c M AfT CJT CJA M/T 1.03 0.76 Pancreas 3.15 I 4.20 I 0.55 I 0.57 Liver 1 3.31 1 3.72 o.54 0.99 1.83 1.11 TABLE 17. Blood esterase activity in normal human subject Case T A c M AjT I C,IT I C/A I MjT 00 1 ].34 0.18 ].14 1.01 0.13 0.85 6.33 0.75 2 1.25 0.15 1.00 0.90 0.12 0.80 6.60 0.72 3 1.35 0.22 1.10 0.78 0.16 0.85 5.00 0.58 4 1.38 0.19 1.27 0.93 0.14 0.92 6.99 0.69 5 1.15 0.13 0.88 0.79 0.11 0.72 6.89 0.68 6 1.40 0.20 1.24 0.96 0.14 0.88 6.20 0.68 I 7 1.34 0.17 0.93 0.93 0.13 0.69 5.47 0.69 I 8 1.43 0.20 I 1.21 0.90 0'14 0.89 6.05 0.63 9 1.52 0.27 1.44 0.99 0.17 0.94 5.33 0.65 10 1.38 0.28 1.02 0.90 0.20 0.74 3.64 0.65 : Male 0.68 11 I 140 I 0.16 1.32 0.96 0.11 0.94 8.25 12 1.57 0.23 1.45 0.86 0.14 0.92 6.39 0.58 13 1.54 I 0.29 1.45 0.93 0.18 0.94 5.00 0.60 I 14 I 1.51 0.21 1.42 0.96 0.14 0.94 6.76 0.68 15 I 1.54 0.19 1.30 1.17 0.12 0.84 6.83 0.76 I 16 1.52 I 0.21 I 1.30 0.97 0.13 0.86 6.19 0.63 17 1.54 I 0.21 1.42 0.58 0.14 0.92 6.78 0.55 18 I 1.54 0.23 1.30 0.95 0.14 0.70 5.60 0.6] I 0.12 0.80 6.50 0.76 19 1.28 i 0.16 1.04 0.95 20 1.23 0.16 1.09 0.76 0.13 0.88 6.81 0.51 i I I I I jMean value/ 1.41 ! 0.21 1 1.21 0.91 I 0.14 I 0.85 I 6.14 I 0.65 -·---.------·· ----"T------.--- 1 1.34 I 0.19 J.l4 1.04 0.14 0.85 6.00 0.55 2 1.26 0.16 1.07 0.83 0.13 0.85 6.69 0.66 3 1.29 0.17 1.10 0.66 0.13 0.85 6.48 0 51 4 1.24 0.19 1.02 0.77 0.15 0.82 5.36 0.64 5 1.24 0.22 1.08 0.68 0.18 0.87 4.91 0.54 6 1.59 0.25 1.40 1.08 0.16 0.88 5.60 0.68 7 1.56 0.28 1.44 I 1.10 0.18 0.92 5.72 0.69 8 1.44 0.36 1.38 1.04 0.25 096 3.83 0.72 9 1.34 0.13 1.08 0.94 0.09 0.80 8.32 0.70 10 1.34 0.18 1.20 0.57 0.13 0.98 6.66 0.42 1.43 0.24 1.28 0.17 0.89 5.34 0.51 1.42 0.21 1.20 0.15 0.85 5.71 0.59 1.36 0.20 1.19 0.14 0.87 5.95 0.73 1.39 0.19 1.28 0.14 0.92 6.70 0.54 1.42 0.20 1.29 0.15 0.97 6.45 0.71 6.25 0.51 9.08 0.71 4.34 0.48 8.80 0.42 7.50 0.58 6.30 86 S. AOYAMA In pancreatitis the great majority showed high values in the blood esterase, exhibited by an increase in AIT and a decrease inC I A, while MIT was indefinite. In tumours of the pancreas, there were cases with high or low values, and there was a tendency for AIT to be great, and MIT to be somewhat small. In complete pancreatectomy or partial resection of the pancreas, there was a marked decrease, and the values of CIT and CIA were lowered, accompanied by a marked decrease in MIT. In complete pancreatectomy there was also seen a marked increase in AIT (Table 18). TABLE 18. Blood esterase activity in patients with pancreatic diseases T ~··A c M I A/T-1 C/T C/A M/T I 1 l.SO : 0.35 1.35 0.90 0.24 0.91 3.81 0. 60 2 1.50 0.27 1.12 I 1.94 0.18 0.75 4.15 0. 69 I 3 1.30 0.22 1.24 I 0.90 0.17 0.95 5.63 0. 69 4 1.85 0.35 1.55 1.13 0.19 0.84 4.45 0. 61 5 1.66 0.35 1.50 1.30 0.21 0.90 4.28 o. 78 I 6 1.24 0.13 1.03 0.96 0.10 0.83 7.90 o. 77 5.61 Pancre- 7 1.30 0.21 1.18 0.47 0.16 0.91 0. 36 atitis 8 2.14 0.91 2.00 0.83 0.43 0.94 2.20 0. 39 9 1.94 0.64 1.78 0.58 0.33 0.92 2.78 0. 30 1.59 4.64 0. 40 10 0.30 1.39 0.63 0.19 0.87 11 I 1.60 0.29 1.42 0.49 0.18 0.89 4.90 0. 31 I 12 1.57 I 0.31 1.40 0.91 0.18 0.89 4.51 0. 58 13 1.79 0.39 1.43 1.04 0.22 0.80 3.66 0. 58 14 1.87 I 0.41 1.68 1.18 0.22 0.90 4.10 o. 68 15 2.40 1.06 2.35 1.92 0.44 0.98 2.22 o. 77 I I I I ! l 1 1.80 0.40 1.66 1.01 0.22 0.92 I 4.15 0. 56 Pancre- 2 1.28 0.27 1.16 0.92 0.21 0.90 4.30 0. 71 a tic 3 1.29 0.17 1.00 0.89 0.14 0.77 5.88 0. 68 tumour 4 1.19 0.15 1.89 0.68 0.12 I 0.74 5.88 0. 59 5 1.82 0.39 1.60 1.00 0.21 0.88 4.10 0. 55 I I I Total and] partial 1 0.99 0.12 0.68 0.24 0.12 0.68 5.68 0. 24 resection 2 0.83 0.12 0.64 0.24 0.14 0.77 5.33 0. 29 of 3 0.31 0.14 0.25 0.12 0.45 I 0.80 1.78 0. 39 pancreas I I In liver diseases, the great majority showed low esterase values, with AIT and CIT inconstant, CIA low in many cases, and MIT indefinite. In diseases of the biliary tract, fairly high values were obtained, the proportional relationship being inconstant. c. Summary Based on what has been stated regarding the blood esterase, when we con sider its significance in the diagnosis of pancreatic disorders, this enzyme clearly indicates changes in pancreatic disorders, and hence, may be considered to have diagnostic value. However, the fluctuations generally run parallel with that for diastase, and in general are less marked. Further, the continued rise seen after recovery from an acute inflammation is not more marked than in the case of di- DISORDERS OF THE PANCREAS 87 astase, as has been pointed out by some workers. Regarding its origin too, compared with diastase, it is more influenced by other organs, especially by the liver. The methods of estimation are not at all simple. Hence, there seems no reason why this should be especiaily selected as a diagnostic procedure for pan creatic disease. Also regarding the atoxyl- and quinine-fast character of the pancreatic and hepatic sources, too much attention should not be paid to the source as it generally has been; rather, it should be paid more to the substrate. The results by the present researchers also showed that the combined use of methylbutyrate and tributyrin is important. iii. Blood protease The protein decomposing ferments of the blood in case of high degrees of pancreatic disorder and hepatic disturbance were examined by Rathnoff's method employing the photoelectrometer to measure the degree of casein digestion (Fig. 18). It was found that in the blood there was a fair amount of protein decom posing ferments, but no definite corelationship could be found between it and pancreatic disorders, and in case of a hepatic disturbance a more marked vari ation was seen than in a pancreatic impairment. Thus, the estimation of this ferment is not significant in the diagnosis of pancreatic disorders. mg / ~ 1.0 ~~ ------...... ______....------~, 08 ,~, ' 04 0.2 0 R--(' -operati~ 2 4 6 8 17 23 44 Days FIG. 18. Blood proteolytic enzyme in experimental monilial pancreatitis. 2. BLOOD CATALASE The visceral catalase of the pancreas tended to decrease with the lapse of days in alloxan glycosuria, while in pancreatitis due to the Candida a fall was seen on the 7th day. In the necrosis of the pancreas, there was a rise for a few days after the onset, but later there resulted a fall. A rise was seen in a cell impairment. Liver catalase showed no marked change throughout. In alloxan glycosuria blood catalase showed a rise up to the 5th to the 8th days, followed by a tendency to fall. In pancreatic necrosis there was a rise for 24 hours after the operation, followed by a fall. In a cell impairment there was a rise up to the 3rd day, followed by a slightly raised state. 88 S. AOYAMA Thus, the blood and visceral catalase show a lowering of activity when there are marked changes seen in the pancreatic cells, and in comparatively mild cases there seems to be a transient rise followed by a fall later, thus differ ing from the attitude taken by the blood diastase, the findings seem to have some significance in the diagnosis of pancreatic diseases. 3. BLOOD SUGAR AND ITS REGULATION i. Fundamental items Investigations on the blood sugar curve by double loading tests have been carried out from long ago and the so-called Staub effect has been upheld as a method of investigating the pancreatic function. However, various criticisms have recently been made, which can be found in the reports of Kosaka, Kuzuya, Herring, Rausch, W ohlen, Okamoto and Tsutsui of this department. There the Staub effect in relation to histological findings concerning the pancreas in case of chronic pancreatitis and other pancreatic diseases was ex amined, and among cases with the negative Staub effect, there were almost equal numbers of cases of those showing and those not showing changes in the islets. Also in those with the positive Staub effect, there were similarly equal numbers of cases where changes in the islets could be demonstrated and those where they could not. Investigations had previously been made by the writer and his colleagues on the sugar metabolism of healthy people and those with hepatic disease and diabetes, and it was then reported that in double sugar administration tests, though the second loading was made in a fixed time, the Staub effect did not necessarily produce the same result. When the conditions for the time of the second loading were examined, it was found that 90 minutes was most suitable. Further, in judging the Staub effect it was necessary to weigh carefully the conditions for sugar loading or the state of the hyperglycemia curve, while it was further found that in the mechanism of its appearance special attention has to be paid to the important role played by the liver. Three tests were made, namely: 1) double loading with glucose 30 grams given orally (interval 90 mins., judged by the Staub effect); 2) double loading with glucose solution, 505'6', 20 ml, given intravenously (interval 30 mins., judged by Shoji's effective amount); 3) single loading with glucose solution, 505'6', 20 ml, given intravenously (judged by the time required to return to the previous level). Comparative studies were made on the same patients with pancreatic disease, and it was found that in the great majority the results coincided, and especially in the double loading per os, when the effective amount was taken as the decisive standard, the coincidence became closer. Thus, irrespective of the method employed, there was found no difference, and hence clinically, it may be considered that from the view point of time and manipulation, the intra venous single loading test is most convenient ii. Clinical items-To be described later. iii. Summary It is not the writer's intention to deal here m a great measure with his DISORDERS OF THE PANCREAS 89 present study of the physiology and pathology of sugar metabolism, but, generally in case of pancreatic diseases, it may be particularly pointed out that in pathologi cal conditions of the external secretory systems, there is frequently seen an impairment of the regulation of blood sugar and that most frequently such is not satisfactorily demonstrated by tests made with the fasting blood sugar only. Hence, an investigation of sugar disposal function by means of the sugar loading test, though it may not be satisfactory from the essential nature of sugar metabolism and insulin incretion, can nevertheless offer a powerful clue in the diagnosis of pancreatic disturbances. In such cases, attention should also be paid especially to the possibility of the existence of diseases of the liver and biliary tract. Also, in pancreatic impairments, there may be an abnormal increase, as well as a decrease of the sugar content. That there may be a decrease of blood sugar should be well considered in case of not only insuloma, but pancreatic cancer and pancreatitis. 4. INVESTIGATIONS ON THE DUODENAL CONTENTS Examinations of the duodenal juice are made mainly for estimations of pan creatic ferments and bicarbonates. However, the existing methods have many defects, and more satisfactory ones are required. One such method to be con sidered is to find the secretory state when the secretion is stimulated. By injecting Vagostigmin into 15 pancreatic patients and the resulting se cretions were examined for 3 hours, and were compared with those obtained under natural secretory conditions of the same patients. The results did not indicate which method was the better (Table 19). When an impairment of the pancreas existed, a fall in secretion was noted in many cases. For example, in allergic pancreatitis, (Table 20), during the m- TABLE 19. External pancreatic secretion in patients with chronic pancreatic diseases (Findings of duodenal fluid 1 Case I - I . I . I V_ago~l . I . I -- No. D1astaseiTrypsm L1pase I· s~1gn;m D1astase Trypsm Lipase m]ectwn I 1 1 ---:.;-7 307 67- r --+ 55 3591 -43 2 81 1584 278 ..... 50 659 110 3 109 858 97 55 466 76 4 133 362 5 97 , 345 34 Chronic 5 157 2 326 197 ..... 346 ' 2 641 293 pancreatitis 1 6 159 1 472 242 120 693 133 7 173 1159 197 ..... 61 377 59 8 231 1 797 289 __,. 152 11 700 312 6 16 ___ j~~ - ~ ~~~--- 2~~ ______:_ ·--- i~~-- ~~~ i~~ Chronic pancreatitis 11 145 I 7 44 I 139 --+ I 80 -~ 450 66 ~;!~ch~~~~~~~~~-J.~-J~~ _ 3~~~ i i~i . : I~~ 2~~! ~~~ Pancr_e:tic canc_~j!_l __ :~~ -~~- i~~ 1 __1~~ ]~--=--~-~i~_J i g~~-~ 3~~ _ 90 S. AOYAMA TABLE 20. External pancreatic secretion in experimental allergic pancreatitis in dogs with duodenal fistula (Secretin test) - .::::-_--:-==:::~'-"-'-·_c--- - Pre-operation Post-operation ------Toi:al units in every------Time Total units in every Fluid 30 minutes Fluid 30 minutes volume 1------,------c--- ~~- volume 1 ( cern) Trypsin I Diastase , Lip a se (cern) Trypsin I Diastase I Lipase 30' 10 32 000 34 470 157.6 8.6 27 520 32 482.2 : 44.376 1c 0.6 1920 2 171.8 7.0 92 4 12 800 I 14915 69.04 1 °30' 9 98800 31815 118. 26 8 25600 30824 62.88 20 0.8 1280 2 775.2 11. 552 9 28800 29115 129.6 2°30' 0.8 1280 2 757.6 11.552 0.6 1920 1 668.6 4.716 so 15 48 000 55 830 197.1 1 3200 3143 31.5 3°30' 0.6 960 2175.6 7.192 5 16000 18145 59.1 40 0.6 960 2 068.2 7.884 3.8 6080 11046.6 49.932 4°30' 14 44 800 49 798 202.16 0.6 !160 1762.8 8.64 so 0.7 1120 2 368.8 9.198 1.6 5120 6 491.2 25.216 5'30' 0.5 800 1 734.5 5.91 6.4 20 480 25 964.8 100.864 60 9 28 800 32 850 129.96 8 25 600 27 464 115.2 I Total 61.6 190 720 220 814.7 ! 866.8 56.6 174 080 665.064 ~ 1 203 023.2 1 flammatory stage both the natural and the reactory secretions resulting from injection of secretin, showed a fall, and with the end of the inflammation both recovered. When 8/10 of the pancreas was excised, both secretions showed a transitory fall, which generally recovered with the lapse of time. Clinical cases will be described later. The results obtained on Katsch's ether test and cell constituents in the duodenal juice, especially examinations for cancer cells, are ommitted here. 5. STOOL EXAMINATIONS Regarding the stool, chemical and morphological studies of the constituents of the food residue, and estimations for ferments have so far been conducted. However, the ferments in the stool may originate from viscera other than the pancreas, on the other hand there may be the effects of the intestinal flora, and the latter have gradually come to receive greater attention, so that estimations of fecal ferments have even been considered by some to be entirely without significance. After previous emptying of the intestinal contents, milk was given as a test meal followed later by the administration of Mg. sulphate and Na. bicarbonate solution. The entire feces obtained had its pH adjusted by Sorensen's buffer solution, and taking into consideration the method of enzyme estimation and the conditions of the test, it was expected that a general picture of pancreatic se cretion would be obtained after due consideration of the fecal protein contents and bacteria (Table 21). However, when no pretreatment or a test meal was given, and examinations were made on usual feces, it was extremely difficult to judge the secretory power of the pancreas in individual cases. In 43 cases of chronic pancreatic disease thus examined, the three ferments DISORDERS OF THE PANCREAS 91 in the stool generally showed values lower than normal, and though there were some cases with abnormally high values, they mostly corresponded to the subacute stage of illness. Tests on digestion of animal proteins and others are ommitted here. TABLE 21. Pancreatic enzymes in feces of chronic pancreatic patients ------Trypsin Amylase Lip a se (N/20 KOH) I ...., 6. X-RAY DIAGNOSIS In the X-ray diagnosis of pancreatic disease, the simple abdominal observa tions of the path, morphology, peristalsis and state of mucosa of the gastroin testinal tract by the use of opaque substances, and observations of the pancre atic head and gall bladder are employed. In addition, increase or decrease of the diameters of the soft tissues of the posterior gastric region have significance as pathological findings of the pancreas. The body positions employed for ex amination are face down, supine, unilateral and erect, while the direction for the roentgenography are ventro-dorsal, dorso-ventral, side-to-side and oblique, and these have to be employed, as the need arises, in combination. In case of a tumour in the head of the pancreas, attention had to be paid to the pressed indentures or a wide C loop of the duodenum, the saw-edged indentures, the so-called reversed 3 configuration, and abnormal morphology, dilatation, decrease in the intensity or impossibility of opaque roentgenography of the gall bladder. Also the closure of the lower part of the ductus choledochus, and decrease or loss of peristalsis had to be considered. Further, in case of a large tumour, there was sometimes seen a change in the position of the greater curvature of the stomach upwards and to the left, or sometimes the stomach was shifted somewhat forwards, and the pressure on the pylorus might cause delay of emptying. Tumours of the body and tail were intimately related to the stomach, but depending on the physique of the patient, position and size of the tumour, there resulted indentures in the lesser or greater curvatures, or there might be produced change in shape or site of the stomach, or there might be seen the so-called phantom indenture. In acute pancreatitis, there was seen functional abnormality of the stomach, the duodenum and the transverse portion of the colon, and a picture of edema in the intestinal mucosa. When the pancreatic head was large, there might be seen an increase in size of the duodenal ring or this might be displaced to the right, depressed inwards, and pressed upon the transverse colon. With further progress in condition of the disease, adynamic ileus resulted. In some cases the diaphragm was slightly elevated, its movements became limited. These phenomena associated with the diaphragm were seen to a greater degree and earlier in the left side and recovery was also delayed. In subacute pancreatitis, there might be seen ileus of the duodenum, the je junum and the central portion of the transversum, and a limitation in the move ment of the diaphragm. There was also seen some limitation in gastric motility. In the diagnosis of chronic pancreatitis, points that need attention were calcium deposits, tumour formation, decrease in the diameter of the posterior soft tissues of the stomach, an adhesion of the stomach with the pancreas, an abnormal movement of the duodenum and the small intestine, changes in the villi of them, an enlargement of the biliary ducts, and the change or the loss of peristalsis of the ductus choledochus. 7. SUMMARY For the diagnosis of pancreatic disturbances, there are many methods besides the above, and there are cases where a particular method has an almost con- DISORDERS OF THE PANCREAS 93 elusive significance under particular conditions, but in general, what have been described above are the more important ones, and of these the blood diastase and the blood sugar regulation are not only essential but most sensitive. III. Changes during Pancreatic Impairment 1. PANCREATIC IMPAIRMENT AND CARDIAC DISORDERS In experimentally induced allergic pancreatitis there was frequently seen a picture of a myocardial impairment by ECG. There was not necessarily seen a special relationship between the degree of pathological change in pancreas and the state of ECG changes. When the pancreas was merely mechanically impaired there was seen a picture of myocardial disturbance in the ECG. When the pan creas was completely excised, frequent myocardial disturbances were recognized, but in such cases the lowering in general condition could not be neglected as a factor. When various pancreatic patients were examined with the limb and unipolar chest leads, a change was noted in the S-T in 17 out of 22 cases of acute and chronic pancreatitis, and the great majority suggested impairment in the anterior wall of the right ventricle. In 3 out of 4 patients of allergic pancreatitis, there were noted changes in S and T, as also a shortening of P-Q, and a tendency to prolongation of Q-T. In cancer of the pancreas there were frequently seen signs of myocardial impairment, but in this case the effects of generalized dis turbance have to be considered. 2. PANCREAS AND HYPOTENSIVE SUBSTANCES With the intraveous injection of Kallikrein, the fall in blood pressure was rapid ; with the intramuscular injection both fall and recovery were gradual, and the degree of fall was lower than with the intravenous injection. Emulsions of the pancreas and the salivary glands were treated by dialysis in a cellophane bag, and precipitated by the addition of pure alcohol in a ratio of 805'C. The solution thus obtained contained a substance similar to the above in lowering the blood pressure. Saline extracts of the pituitary, purified by precipitation with alcohol, lowered the blood pressure slowly, but the action was prolonged. However, this substance differed from Kallikrein in various aspects. Also even when the pituitary was completely removed, the substance responsible for lower ing the blood pressure could still be demonstrated in the urine. The hypotensive substance in urine was precipitable by 30 60,9C alcohol (mainly by 50-60°;;') in the case of humans, and by 60-80JC alcohol (mostly by 70-805'.;') in dogs. In the latter with complete pancreatectomy, and in patients with total pancreatectomy, the hypotensive substance in urine decreased from the first day of operation, (Fig. 19, 20), having no relation to administration or non-administration of insulin after operation. After complete pancreatectomy there was no recovery of the hypotensive substances for a long time. This substance coincided with Kallikrein in its being not dialysable through sheep skin menbrane, in the degree of destruction by heat, in its inactivation by mix ture with blood and in being destroyed by acid and alkali. 94 S. AOYAMA r t l I Ur rn<:: of- [)"'f"'''Cto>ufiz<'d Do'J Uron£ ol norrr1ul D(lg Urine of Dcpanueatfzed Urine o+ Depan- D 0 10 '" 20 30 35 40 Minut'='~ ------···-~----···----- FIG. 19. Influence of urine of depancreatized dogs to blood pressure. --·~t'"~------~---,~~~------1 Nurm 10 I o 20 i • FIG. 20. Influence of urine of depancreatized patients to blood pressure. In nephritis and hypertension, the amounts of this substance in urine were frequently lowered, and sometimes too, in pancreatic diseases. It was recognized further that the pancreas is not just a reservoir of Kalli krein, and in its mechanism of production cannot also be compensated by the salivary glands and others. Also, the pituitary could be considered to have only a secondary significance. However, the role of this substance in the living body presents many problems that require clarification. In other words, this sub stance is intimately connected with the pancreas, but patients affected by a pan creatic impairment do not necessary have hypertension, neither do people with high blood pressure especially show pancreatic disturbance. 3. PANCREATIC IMPAIRMENT AND SWEAT Sweat was collected 2 or 3 times every 20 minutes from patients exposed to a dry bulb temperature of 38-46° C and wet bulb temperature of 30-35° C. The amounts recovered and the concentrations of the Na and Cl were examined. The results were as follows (Fig. 21). DISORDERS OF THE PANCREAS 95 In those with part of the pan mM creas resected, Na and Cl concen 130 - trations were somewhat lower than normaL In chronic relapsing pan !GO creatitis, they were higher than the controls during the acute aggra 140 Panucus vation stage. In the intermittent 0--·-Q FJmrcrenflii~ rrrAcl•te stage the values were almost nor txou-rLH1fiun maL The fluctuations in the amount o-----o f\mcreolrti,-, rn ]rrlurrnttcrd ~tuqe of sweat ran parallel with the con 100 centrations of Na and Cl; no spe 80 cial relationship was noted between Na and CL Gu ~ 401_ ~!O ;2~-o------0------0---~ FIG. 21. Perspiration and pancreatic disease (Sodium-concentration). f) ~--·--·-·- ______L_ 0 ~\) 4( 1 (,0 80 f'1rrrut-e') 4. PANCREATIC INP AIRMENT AND CHANGES IN THE BLOOD i. The blood in experimentally induced pancreatic impairment The specific gravities of the whole blood and plasma, the amounts of water in the blood and the plasma, Ht value, oxygen combining power, proteins and their fractions,-all these in case of partial (1/3, 2/5, 1/2, 8/10 and 9/10) resec tion of the pancreas, ligatures of the pancreatic duct, total pancreatectomy and allergic pancreatitis were examined. A description is given here of allergic pancreatitis. It was found that the GB began to rise from the first day, and returned to the preoperative level on about the 3rd day. It then decreased till about the lOth day, after which it returned to the preoperative level, to be followed later by a slight rise. GP showed a rise from the start and returned to the pre operative level about the 30th day. The plasma protein amount was proportional to the GB, while WGB increased and decreased in inverse proportion to GB, and WGP to GP. The Ht content rised in the earliest stage, but fell gradually to rise again during the 2nd week. Oxygen showed a change similar to Ht. ii. Pancreatic inPairment and antithrombin In patients with partial resection of the pancreas the antithrombin content showed a slight increase, and in experimental necrosis of the pancreas and in alloxan glycosuric dogs increased markedly. In ligature of the pancreatic duct, the antithrombin content was slightly increased, while the prothrombin value in plasma was slightly decreased. In total pancreatectomy the antithrombin value increased markedly. This ran parallel with the decrease in plasma pro thrombin, but did not necessarily coincide. The mechanism of this antithrom bin increase cannot simply be attributed to the pancreas alone. 96 S. AOYAMA iii. Pancreatic impairment and electrolytes When observations were made on the fluctuations in inorganic substances in the blood serum in case of pancreatitis due to E. coli (Fig. 22), or Candida, and partial resection of the pancreas, Ca began to decrease after operation, and reached a minimum during the period from the 5th to the 7th days. Na fell to a minimum between the 5th and lOth days. K and Cl decreased immediately after operation, and dropped to a minimum by the 5th day, while inorganic phosphorus decreased between the 3rd and 5th days. All the above recovered by the lOth or 14th days. Mg did not show a definite change. TABLE 22. Serum inorganic substances in experimental Coli-bacterial pancreatitis of dogs ------ ---- - op:/aet-ive! ~~~/iiive I op~~FeF:!~liv:l:p~j~iv:l:pu~i~:l:~~t~ri~e- ClNa ~ii----~~~ - ig~ ---~--iig ·--, -i~~---! i!~-----ici~ - K 4.85 4.35 4.40 I 4.35 4.35 4.95 5.40 Ca 5.55 5.15 5.30 5.35 4.35 5.60 5.25 Mg 1.70 I 1.70 1.50 1.60 1.65 2.40 1.25 p 3.80 3.45 ___':~ __ 3.80 ___!.75_l_~s ____3.8~-- iv. v. Pancreatic impairment and Pictures of the hlood and the bone marrow, etc. In experimental allergic pancreatitis, (Table 23), erythrocytes and Hb in creased immediately after the operation, and after a transitory decrease, returned to the preoperative level. The reticulocytes especially showed a marked increase between the 1st and 4th days, and the diameter of the red cells began to increase suddenly from the 1st day. The maximum increase was seen on about the 7th day. In the early stage there was a marked increase of leucocytes and blood platelets which decreased somewhat between the 7th and lOth days, after which there was a return to the preoperative level. Shift to the left in leucocytes was slight in general. Lymphocytes decreased rapidly on the 1st day, later in· creased gradually to surpass the preoperative value. Acidophils increased marked ly on about the 3rd, 4th and 5th day, and sometimes there appeared plasma cells and toxic granules. When the pancreatic duct was ligatured, erythrocytes and Hb decreased markedly, but began to recover in the 3rd week. Reticulocytes showed a clear increase up to the 4th day, while the diameter of the erythrocytes became en larged from the 1st day. Leucocytes and blood platelets increased from the second day, but began to recover a few days later. Neutrophils showed a slight movement of the nuclei to the left. Lymphocytes increased from the 1st day, while acidophils decreased. Basophils and toxic granules did not appear. With the exception of acute severe pancreatitis and cases of marked general impairment, the pictures of the blood and the marrow in pancreatic disease did not generally show any special changes in the number or type of leucocytes. However, in chronic pancreatitis there was frequently seen an increase in eo sinophils. Attempts were made to find the cause of this, but no satis- TABLE 23. Hemogram of experimental allergic pancreatitis on dogs (f) Differential count ( J()') <1J (f) (f) >. u _ Neutrophils Lymphocytes <1J » +-' ro » 0 u :§~ ~ 1..o [ Segmented form ~.g_ 0 8 8 s:: 0 ~ ,~_sbLs J -r--r-'i_r_n____,l_r_v_ 1'v~o-r'_i_T_~~~~~j ~ 1 :;s . over • I - I Pre-operative 6.41 [12 200[298000[ 88 i 0.6111 1 o 1 o 26.001 23.251 7.751 1.00 I 58.oo[ 2.50 1 3.25] 5.751 12.25 24.00: 0 \ I ' ------~-~--~-~,~------~ 1 I 7.41 127 800 318630 93 0 43.25! 1 71.75 1.50 0.50 2.00 3.75 1st dayl 0.61 20 I 2.50[ 27.751 5.751 0. 75 14.251 + 2nd day 7.24 24 200 340 280 95 0.6, 16 0 1.00 29.00 9.0011. 75 i 68.00 1.50 2.50 4.00 5.751 21.251 - 28.251 75 ! 3rd day 7 37 13 200 479 050 82 0.6i 13 I 0 0.75 I6.50 18.00] 5.50 0. 40.75 4.75 5.50 10.25 8.00, 40.25 ~I- Post- 4th day 7.10 114 000 795 200 82 0.5 10 0 0 14.00 19.251 7.001 0. 75 I 41.00 5.25 7.75 13.00 7.001 39.00 0 - 5th day 6.28 12 000i602 880 77 0 1.00 20.251 5.25 0. 50 ! 45.00 5.00 12.25 17.25 29.25 0 - operative 0.61 4 19.001 7.501 7th 0.5 6 22.75 5.25 0. 50 47.75 6.75 14.25 21.00 20.25 0 day 6.61 ! 118001568240[ 76 0 1.501 19.2!11 9.501 - lOth 6 82 000306900 78 0.5 3 I 5.25j 0. 57.50 7.25 6.75 14.00 11.00 17.50 day III 0 o 29.oo1 22 50, 75 0 - 15th day 6. 79 [12 600f360 690j 87 0.6: 10 I 0 0.25: 18.501 31.251 11.251 0. 75 61.75 3.251 8.00 11.25 10.50 16.50 0 - 30th day 6.92 • 12 600i356 500 92 0.6[ 8 I 0 o 1 13.75 23.751 8.25[ 0. 50 46.25 3.25 14.25 17.50 9.251 27.00 01 - - -- _!___ I I I TABLE 24. Peripheral blood findings in patients with pancreatic diseases ·------Coagulation ! (f) -s:: I v (f) Differential count (f) I <1J ~ K : _§_ time <1J I Fragility of I I +-'8 I <1J '+-'Cfl I ~'t:l (f) 2 't:l l'l t', erythrocytes I ~ '.o <1J I <1l ~a <1J » Gu I - tl.()- u_ ·- <1J u o..___I 0' 1 bLJ...... , bll (f) . 0 :E ..0'-< ..c~- 6 ~ .s s:: ~ >. 0 ... s:: ] !=:2 . - 10.8 4.8 28.0 15 755 3.44 35 518'2.3o I 7.5 0.50 Tumor of pane reas 3.31 53.31 68.5 ' 0.9971 4.451 11.151 0.3651 IA~"""'I, Max. 8.0 20.5 70.5 11.0 4.71 90.0 ' 1.16 1/ 2.30' 5.0 14 8.0 0.35 0.50 (10 cases) 44.o I 84oo ' Min. 1.0 0.5 45.5 0 18.0 4 oco 2.53 50.0 0.74 2.30 I 4.30 8.30 7.0 0.38 0.50 I " ·------·- -·------·---~------' s.oo 90-100 1 1-3 ._'Average] 3.0 I 4.5149.0 ' 5.6138.0 17 000 II 1.00 224 000 I Normal values 1.05 35 000 3 14 25 9.0 I 0.321 0.46 (by Komiya) Max. 5.0 7.5 55.0 7.0 45.0 8 000 5.75 no I 1 2g.o I Min. I 1.0 2.0 45.0 2.0 25.0 , 6 000 I 4.00 90 i 0.90 13000 1 5 12 o.3o 1 0.42 ------I -----·-·------'---- -~--'---'__ I TABLE 25. Bone marrow findings in the patients with pancreatic diseases Reticulum cells ' Erythrocyte series ! Myeloid series en <1) v I S I ~-~-]----r-~·-i .·-!!l--_;--- ~N'e-uc-tr-o-p'h-ci'ls--..... :>, I u 1 1 0 .g :0 ;o ~(/)I'l~ooo~ ~eo ]~~~~~-, .g i i boo 1::1 . 0. ~ s ~ I ~ v i - I ~ 0 0 0 8 ~ ~ (ij ?-! i ~a)2 '+-1 s ..' 0 , S- 1 - ...., u 1 ro I ..<:: S - '" ~ S- ~- 1 ~ ~ - - I en - 0 I bll , <1l " ·;;: :>, '. ~ » ..,. ~ :>, "'0 bll ~ I » <1l I ro v "'0 , v >, I 8 ~ ro o 8 u ·. ~ u :"" S u 1::1 v "'0 , ....1 u I p:;u_.:_~ ~ ·~-_3·-""-- CO ~ o. i I Q3 rn 2 Average o.8511.o2 ! o.o2 5.31. 14.5 o.6 o.o2 6.17! 1.2 ! 16.6 -~7.9 13.4115.7 I o.721 15.7 Chronic pancreatitis Max. 1.4 22 : 0.2 9.6 19.2 1.2 0.2 15.2 i 2.0 i 21.2 13.8 16.5 20.211.4 21.6 Min. 0.2 0.4 I 0 1.2 7.2 0.2 0 1.8 i 0.2 I 11.4 4.0 8.2 10.0 0.2 11.4 Ca~cer:~:creas-1-ABiE.:~:llHrr n:l ti ~!!i !:ll8:!1 H-1-fgI ~:r i~!ll!:8 l!!-·~--~-:~---+-~-g-:!- 3.1 16.8 6.0 32.6 : ABi1:; ~-~ 1 ~fl.!:!1· 1 ~il~l -~~~) !!-lzl 1g:, 1 ·:: 1g: H ~nu1,:J 0.7 5.0 TABLE 26. Insulin sensitivity and functions of adrenal-pituitary system on the depancreatized dogs ==----·===----- __ ._---__:__ __:___~~---.:- ....~.::.--===~. -----· Values after ACTH ~ii1ti--aVenous------· Insulin test Urinary 17-keto injection ( 10 mg) 1 Operation Insulin 1 unit/kg intravenously steroids ( 24 hours ·· ] Glycogen in Experiment No. (total pan- --- ...... -- specimen before Eosinophil Variation of urinary the liver decrease 17 -ketosteroids on 24 . crcatectomy) i Blood sugar I Maximum ACTH injection) hours specimen 1 i decrease index decrease rate (mg/day) percentage ( mg/day) . I 0.51 ~o~.7=o2~---+--~68 +6:51'~z----+---"2"'6o~ 1 50 52 0.82 0.500 29 +0.555 20 0.4:1 0.384 64 +0.032 276 2 Before 35 After 74 0.78 0.1Y8 40 +0.861 58 2 089 ------72 - +0.647 I • 286 ·- .. 3 Before 54 0.54 After 62 0.70 0 160 16 +0.949 I Minute amount Before <:9 0.44 0.230 50 -0.020 242 4 After 113 0.77 0.543 30 +0.029 70 Before 39 0.45 1.610 50 -0.412 358 5 After 82 0.74 1.810 12 -1.007 180 41.4 0.48 Average ' Before 1.003 60.8 +0.132 284.4 76.6 __ 0.78 0.642 25.4 +0.275 82. L __ -~!.t~--- j __ _ DISORDERS OF THE PANCREAS 99 factory explanation was available. Many cases showed a slight decrease in erythrocytes and Hb, while in general no marked changes were found in the number of the platelets, the bleeding time, the coagulation time and the re· sistance of erythrocytes. Regarding the marrow, there were a good number of cases where the reticulum cells, especially the plasma cells, showed a slight increase (Table 24, 25). 5. PANCREATIC IMPAIRMENT AND GASTRIC FUNCTION From considerations of the reports by various writers and of the experi mental results obtained by the present researchers regarding the gastric function in pancreatic disturbance, it can be stated that there is a decrease in the acidity of the gastric juice in an acute pancreatic disorder. In its subacute stage there was a slow recovery and fluctuation, but sometimes there was seen a contrary excitation. When the disease develops into its chronic stage, there resulted a slowing down of the function and in many cases there was seen a decrease in its acidity. But in the case where the impairment was slight there was a return to the normal. In its early stage pepsin assumed a similar attitude as HCl, but later tended to dissociate from it. 6. PANCREATIC IMPAIRMENT AND SUGAR METABOLISM In monilial pancreatitis the great majority showed the conversion of Staub's effect to the negative, and with the alleviation of the inflammation, slowly be came positive. There was no marked change seen in the fasting blood sugar level, and glycosuria was not usually seen. In other cases of experimentally induced pancreatitis, the same general tendency was seen. When 8110 of the pancreas was removed, there was transitory hyperglycemia after the operation, and after some fluctuations there was finally a return approximately to the pre operative level. Hyperglycemia continued in about one half of the cases where 9/10 of the pancreas was excised, while the remaining half tended to behave similarly as the 8/10 excised group. When complete pancreatectomy was per formed, all the cases showed hyperglycemia which was abnormally sensitive to insulin administration. The degree of fall was far greater than in normal dogs, and not only did it not recover easily, but there were cases that ended fatally in a state of hypoglycemia. Such insulin hypersensitivity was recognizable in humans, too. The attitude of the pituitary-adrenal system, after complete pancreatectomy, indicated that a living body can be rendered unstable to stress. For example, (Table 26, 27), in the 24 hour specimen of urine there was seen a marked decrease in 17 ketosteroids, as well as in the blood acidophils. By the administration of ACTH, the rate of decrease of acidophils was lowered and the urinary 17 ketosteroids showed a greater increase in both frequency and degree, when com pared with normal cases. Histologically, the principal changes in the pituitary were found in the anterior lobe, and basophilic cells increased in number which could be differentiated into two types. The adrenals showed dilatation of the cortical capillaries, and showed tissue disintegration in the zona reticularis. In 100 S. AOYAMA the reticular layer the cells in general lost their regular arrangement, and in many cases the cells became contracted or flattened out. However, the factors responsible for the insulin hypersensitivity must be further investigated from various angles, and though here special attention was paid to the attitudes of not only the pituitary and adrenals but to the liver, it seems well to refrain from drawing a definite conclusion regarding this. TABLE 27. Thorn's test in depancreatized dogs I !i Pre-operative rn r .....~I , Post-operative Case No. ! Eosinophil I Eosinop~~EOsinophil 8~ ~Eosinophil].EoSlnophiT_I_E_osinophiC !count before count after decrease : "-~count before count after 1 decrease I ACTH ACTH ratio I o ACTH ACTH 1 ratio 1 356 118 68% 10 1C6 74 299.;' 2 524 142 729;; 10 38 30 169;; I 3 418 174 569.;' 10 50 42 I 129.:; 4 250 125 50% 5 43 30 309;;" 5 106 36 64% 6 30 18 I 409<1' I I ------~------ When cobalt chloride was injected repeatedly subcutaneously into guinea pigs, the a cells sometimes appeared stimulated but in most cases showed de generation. The chromatin granules became indefinite. The cells showed fusion or vacuolization, and further, might dilate or fuse into a mass, or assume a form where the cell margin was only faintly recognizable. In the case where the injec tions were made into the heart, the picture of stimulation of the a cells appeared very early. The {3 cells showed no change or might show degeneration some what later. In this particular case the blood showed (Fig. 22, 23) a transitory hyperglycemia, followed later in most cases by hypoglycemia, and ending as such finally. The liver showed in most cases a slight fatty infiltration, but sometimes it was marked, and the fatty liver resulted. The liver glycogen, in the great majority of the cases, disappeared or showed a marked decrease. 200. Ill Days FIG. 22. Variation of fasting blood sugar values after subcutaneous administration of cobalt 0.03 gr. DISORDERS OF THE PANCREAS 101 ,..._ I ..._..._ I I ---- J--~--~------~ 0 1 3 FIG. 23. Variation of blood sugar values after 0.05 g of cobalt subcutaneously. Regarding the a cells and their significance, at the present stage of in vestigations, the writer feels that they, together with the {3 cells, partake in the regulation of the blood sugar. 7. PANCREATIC IMPAIRMENT AND BLOOD PROTEINS In a pancreatic impairment experimentally induced by the ligature of the pancreatic duct, necrosis of the pancreas and complete or partial pancreatectomy, the blood proteins showed somewhat different pictures, depending on the method employed (Table 28). But in general albumin decreased and globulin, especially a and {3 globulin, increased. The individual changes that occured later are om mitted here. In general, when the changes were slight, they were reversible, but when great in degree, did not recover or did recover with difficulty. These changes were influenced by factors other than those in the pancreas. For example, the state of the liver and the degree of general impairment could not be neglected. In experimental allergic pancreatitis the picture was somewhat different, and the albumin decreased a little till the 2nd day after the operation, later showing an increase instead. a globulin increased markedly for 1 or 2 days after the operation, after which it slowly returned to the preoperative level. {3 globulin tended to decrease slightly and a globulin to increase a little after the operation, while fibrinogen increased somewhat on the day of the operation, decreased on the 2nd day, later returning to the preoperative level. In clinical cases, the total proteins were increased slightly in acute and chronic pancreatitis, or might remain almost normal. In pancreatic tumour, in most cases there was a decrease, with albumin showing generally a decrease and globulin an increase. a globulin was increased in all cases but {3 globulin, though indefinite, was increased in most cases. r globulin almost always showed a medium degree of increase, while fibrinogen sometimes decreaseed and some times showed a slight increase. The albumin globulin ratio was lowered in almost all cases. When there was complication by diseases of the liver or the biliary tract, the above changes became more marked. 102 S. AOYAMA TABLE 28. Findings of plasma protein in experimental pancreatitis Plasma Pre- Post-operative Experiment 42nd p~~e)in operative --J~~~ I _I~~ I 1;;; _;_j~t~ -~-~ ---T-Al~umin--j ___4~.6___ 36.o- [~ ~5.4 41.1 I, 43.0 460 Plasma protein of the II. IX I 12.1 7.9 7.8 8.1 I 10.0 10.7 dog with 2 mg of Sta (3 Globulin i 9.5 19.6 20.0 15.4 I 12.6 10.1 phylococcus aureus in i y 19.8 22.4 22.3 23.3 23.3 20.7 1 Total 41.4 49.9 50.1 46.8 i 45.9 41.5 jected into the pancre- atic duct I !!~;ino~~-~-~~ 12.1_,_ 14.2_ I 14.5 i 12.2 I 11.5 12.5 A/G 1.13 1 o.72j--0.71[-o~88 1-o-.9-4 l-i-1J-- I Albumin ! 42.1 I- 30.6 I protein of the Plasma I IX I 12.4 dog with 5 mg of Sat- (3 Globulin 9.3 i 2~:6 I phylococcus au reus in- y 17.9 I 16.6 i Dead 4th day post-operative Total 39.6 1 47.5 i jected into the pancre- Fibrinogen I 18.3 atic duct 21.9 I A/G 1.06 1.55 ------I Albumin 44.4 35.1 47.3 ! ------~-- Plasma protein of the 10.2 12.8 12.1 11.2 I 12.3 19.0 14.0 10.5 dog with 5 mg of Esche- ~Globulin 22.4 18.7 20.6 20.2 richia coli injected into Total ! 44.9 50.5 46.7 41.9 -I the pancreatic duct 10.8 14.5 11.4 12.1 1 10.1 ------ 1.03 1 0.12 1 o.77f ;~92 1 o.91 1.17 ~4.9 --- 37.2l-38.9]-40.4 -~-~1:7 10.6 9.3 I Plasma protein of the /3 Globulin I ~:~ 1~:~ ~~ 1~:fT 10.6 9.9 dog with ligation of Y 26.0 22.5 26.6 I 25.6 26.7 45.5 ! 47.2 the pancreatic duct ~ot.::__ ___i _ 43~.9-- ~~5____ 4_7.9 I I Fibrinogen 11.2 15.4 13.2 1 11.9 1 11.2 1 1 A/G 0.8!]_ o.s7 0.981 __ ~-89 8. DIGESTION AND ABSORPTION OF PROTEINS DURING PANCREATIC IMPAIRMENT In dogs with complete pancreatectomy, the fecal volume was greatly in creased, and the daily variation was great when compared with normal dogs. The proteins were also excreted in abundance, and the absorption rate was less than one half of the normal (Table 29). In dogs with the pancreatic duct ligatured, or with 8/10 of the pancreas removed, the absorption of protein was temporarily disturbed, but later returned to normal. DISORDERS OF THE PANCREAS 103 TABLE 29. Digestion and absorption of protein in experimental pancreatic impairment ··· 1 Protdn · Nitr=og=·e=n=!c=cA=vc~e=ra=g=e=p=r=o=- =c:IA=v=er=a~g=e=n=:ic=tr=o=:-~P~r=otc=e""'in= I Da~s [ intake intake per'tein excretion gen excretion absorption Case . No. pos : :per day i day j per day per day ratio per !operative, (g) ·. (g) 1 (g) , (g) day (%) 1 8 30 4.8 19.79 3.11 34.0 2 5 30 4.8 26.21 4.11 12.6 Total [ 3 10 30 4.8 17.04 2.73 43.9 pancreatectomy ! 4 8 30 4.8 16.55 2.65 44.8 5 14 30 4.8 16.81 2.69 43.2 19.28 35.7 Average 9 j_~ 4.8 Ligation of the I 1 22 30 4.8 8.18 72.3 pancreatic duct , 2 15 30 4.8 5.93 80.2 I -Pari:Tal (8/10J ··~· 1 'r 20 r 30 4.8 4.55 0.73 80.2 pancreatectomy I In chronic pancreatitis, clinically, the excretion of nitrogen in the stool was in most cases within the normal range, while in pancreatic cancer was slightly increased. The amount of feces was also increased in cases of tumour, especially in those accompanied by jaundice. 9. PANCREATIC IMPAIRMENT AND FAT METABOLISM i. Changes in plasma lipids When the pancreatic duct was tied (Table 30), the total fats in plasma in creased markedly on the 2nd day after the operation, and attained a maximum on the 4th to 6th days. After this there was seen a slow decrease, though on the lOth day was still higher than the preoperative level. The changes in neutral fats resembled the above. The phosphatides increased slightly after the oper ation, and within a limit of 2 to 6 days began to decrease and recover. Free cholesterin and total cholesterin both showed no marked changes, while chol esterin ester decreased after the operation. In allergic pancreatitis total fats increased after the onset of inflammation, but not markedly. The neutral fats were the main constituents involved in the increase, and the remaining fractions showed almost no variation. When 9/10 of the pancreas was removed, total fats already increased on the 2nd day after the operation, and attained to a maximum on the 6th day. After this there was a gradual decrease, which still remained comparatively higher than the preoperative level even on the 12th to the 14th day. The neu tral fats also showed a similar tendency. In complete pancreatectomy (Table 31), the total fats were increased, most conspicuous of them being neutral fats, followed by cholesterin in a free state. The total cholesterin increased in all cases, but the degree was slight. Phos phatides and cholesterol ester showed only slight changes. When the changes in the fat fractions were observed daily, phosphatides, cholesterin, free and total, and cholesterin ester showed some increase, though slight, while neutral fats already markedly increased on the 2nd day after the operation, and still more so on the 6th to the 8th day. Later they sometimes increased and sometimes decreased, but in general, were high. 104 S. AOYAMA TABLE 30. Variation of plasma lipids after ligation of the pancreatic duct in dogs (mg%) Experi-j -~·-Ph··· h ~-Free I Total fEsterifiediCholeste-INe t 1 1 Total ment I Days . ~s~d o- choleste-! choleste- 1 choleste-, rol I f~[a I. lipids No. p rol 1 rol 1 rol I ester ! ----~era~i;~[_ 125 I_ 52_=L 128 ! 76 ~- 123 l04 .';--_4_0_4_ o; I 2nd day 137 54 ' 116 62 I 101 143 435 1 I ~ l; 4th day 124 58 114 56 , 91 119 392 l gj ~I 6th day 111 67 120 53 ' 86 165 429 10... ~ 8th day 119 65 109 44 71 124 379 i o lOth day 128 64 116 52 84 127 403 -----c- Pre-operative 113 66 134 68 o; I 2nd day 124 73 145 72 117 189 503 2 ~ ·13 4th day 121 71 129 58 94 203 489 gj r; 6th day 143 81 138 57 92 215 531 o... ~~ 8th day 128 69 U7 48 78 171 446 o 1 lOth day 123 67 124 57 92 153 435 54 119 I P~e~~;;~:: 65 132 109 158 486 3 , • .;: [ 4th day 62 134 117 172 499 ~~~6thday 67 129 101 136 450 1 0... ~ 8th day 61 130 112 129 437 1 o lOth day 58 123 105 117 418 . ---~---·--.. TABLE 31. Variation of blood plasma lipids in depancreatized dogs ( mg 0ii) ---~------.~=~----=-----===------=-=- 1 Days Phos- I Free I Total I Esterified Cholesteroll Neutral I Total _ 1 pholipid ,_c~ole:_teroll cholesteJ"_ol, cholesterol ester fat . _, lipids_ Pre-operative I 107 52 92 40 65 95 319 Post-operative 2nd day 128 66 104 38 61 239 494 4th , . 124 70 111 41 66 246 506 6th ,, 1 119 81 124 43 70 287 557 8th II I 135 77 118 41 66 264 542 120 251 525 ~_" ___1:6 74 46 74 ii. Omitted here. uz. Digestion and absorption vf fatty substances When a diet consisting of 30 gr of protein, 20 gr of fat and total caloric value of 1,000 was given to healthy dogs, more than 95% of the ingested fat was absorbed, and the proportion of the fatty acids to the total fats was on an average 52.6JC. When the pancreatic duct was ligatured, the total fats excreted in the first week became extremely increased, and consisted principally of fatty acids. In the second week the total fats approached the normal level, and the proportion of the fatty acid to the total fat became high. In the third week both returned to normal. After the ingestion of fats, the fats in the lymph of the thoracic DISORDERS OF THE PANCREAS 105 duct increased slightly, to decrease markedly shortly after. After the loading of vitamine A and fats, the rise in the lymph of the thoracic duct was markedly less than in the blood plasma. In other words, by the ligature of the pancreatic duct, the absorption of fats was markedly obstructed. No noteworthy changes were seen in allergic pancreatitis. By the excision of 8/10 of the pancreas the total fats in the first week were almost normal. During the second and third weeks they slowly increased, but compared with the case of total extirpation, the degree of increase was slight. The proportion of fatty acids to the total fats was high in the first week, but fell slowly, and in the third week there was seen a digestion impairment of fat. When the pancreas of the dogs was completely removed (Table 32), the total fat excreted in the first week often indicated its normal quantity during that period, and in the fifth week an amount corresponding to about 70?C of the fat ingested was excreted. The proportion of fatty acids to total fats was greater than normal in the first week, but decreased in the second and third weeks, and in the fifth week the amount of neutral fats conversely became greater. Thus in complete pancreatectomy, from the beginning there was a dis turbance in both the digestion and the absorption, but at first the impairment due to the absorption was greater, while later that due to the digestion became more marked. An examination of lymph from the thoracic duct also revealed an impairment of the fat absorption (Fig. 24 ). After complete pancreatectomy, methionine, pancreatin and insulin were administered, and it was found that compared with the untreated group, both the digestion and the absorption were fairly well preserved. The fasting blood vitamine A content (Table 33) showed marked decrease, and even after the loading of vitamine A, its absorption was markedly disturbed. When a low fat content diet was given to dogs with the pancreas completely removed, the total fats excreted were somewhat greater than in normal dogs. This pointed to an increased excretion of fatty substances from the intestinal wall. However, when compared with cases where ordinary TABLE 32. Digestion and absorption of fat in depancreatized dogs , ...... grams of fat grams of fat excreted in feces daily I ___ _j~ve~ge,) __ _ Fatty acid Exp. , Weeks intake daily No. Totafw (average) Fatty acids Neutral fat [ Total fat (%J --~------~------1st 18.3 2.65 1.22 3.88 68.4 2nd 21.7 3.43 1.65 5.08 67.5 1 3rd 22.2 3.28 3.39 6.67 49.2 4th 20.0 3.07 3,44 1 6.51 47.1 5th 20.0 6.21 7.87 1 1st 20.8 2.o3 I 2 1.62 ,~~-r 2nd 20.0 I 4.04 4.06 i ;;·; 1st 2nd ·----l--!f-~----~--~1!-- -HI_I_l~-~!-- 3 3rd l!__ .. 4th ·------~--- ·------106 S. AOYAMA ,) Hour:, FIG. 24. Total fat of thoracic duct lymph in dogs (1 gram of butter given per 1 kg of weight). TABLE 33. Vitamin A absorption test in dogs Adminis 1 Vitamin A concentratioTl.;lOO ml Exp. tered Analized ! (l.U.) No. Condition of dogs vitamin A specimen (l.U.) Fasting lst~o-ur I -=~d hour 1 Normal 40000 Plasma 208.5 480.2 2 Depancreatized 40000 II 99.2 3 II 40000 II Ligation of the pan I 4 creatic duct ( 3rd 40000 II -_____c!axJ - - - I Lymph from the: 121.3 843.9 thoracic duct ' 5 Normal I 40 000 ------,------Plas~--~-191.1 475.5 Lymph from thel 232 g 165.5 Ligation of the pan ! thoracic duct I • 6 creatic duct (6th 40 000 ~------~- .... day) 1 Plasma ' 423.0 729.0 -'----c~=c J._ Vitamin A concentration/lOOm! (LU.) Maximum Exp. No. 3'-r'd-,----"'4-t"hc---,----c5"'t-,-h ' 6th 8~-9th-- 1 ----wth-- 12th variation hour hour ! hour I hour I hour i hour hour I hour --1--,------694.3 1 - 1 8i4:3Jl 051.9 1 8-13-.3---'-.1----',---8-43-.4 ~2- ----~ 291.0 1 --1 403.2_1_128.3 1------104.41 344.7 -3- ---~-204.61------282.6J ---~ -----~--- 190.7 1 -4 __ 1______24i.5 225.41 349.4 127.2 l=i--408:7 1 1 i 2 o76.o ! 1 2 581.4 1 3 112.2 f --~~-2018.6 1 1 670.61 2 990.9 5 -----~--3o6.9!----~--352.8j-4o2.2_! ___ _ 252.0f ------zs.u- 1 182.31 230.5 1 --- -91.51 1 130.8 6 1185.1 I I - 11143.5 1 483.0 1 957.6 1 I______7_~~.5 ---"----- DISORDERS OF THE PANCREAS 107 amounts of fats were being given to completely pancreatectomized dogs, the amount was far less. In other words, the fats in the feces do not seem to consist solely of those excreted from the intestinal wall. In patients with chronic impairment of the pancreas, the fecal fatty sub· stances were within the normal range in case of pancreatitis, while in tumours of the pancreas there was frequently seen clear evidence of disturbance. This was especially so when jaundice was complicated. 10. PANCREATIC DISORDER AND HEPATIC IMPAIRMENT i. Fundamental items In various pancreatic impairments, such as bacterial and allergic pancre atitis, an impairment produced by the ligature of the pancreatic blood vessels and partial or complete pancreatectomy, the blood proteins, laevulose disposing function, serum and visceral phosphatase, bromsulphalein test, cephalin chole· sterol flocculation test and prothrombin value were examined to test the hepatic function. At the same time the histological changes in the liver were examined. Various degrees of hepatic impairment were demonstrated. Most marked changes were found in complete pancreatectomy and when 9/10 of the pancreas was ex· cised. In the other cases the changes were in general slight and transitory. In the liver cell were seen various changes such as degeneration, vacuole formation, dissociation, or cellular infiltration and other changes in the interstitia. In complete pancreatectomy, the glycogen in the hepatic cells decreased markedly, and in about 60JC of the cases, the fatty liver was demonstrated. Sometimes the fatty liver was also found in the cases where the pancreas was partially excised. The distribution of fats in the liver lobules was mostly peripheral; sometimes there were seen a centripetal fatty degeneration. The fat droplets varied much in size, but in the same specimen were comparatively uniform, and in most cases were neutral fats ; lipoidal fats and cholesterin were both poor in amount. In complete pancreatectomy, the frequency in the production of the fatty liver was less in the group of complete pancreatectomy cases treated by insulin, methionine, dehydrocholic acid, glucuronic acid and cyanocobalamine, than in the untreated ones. But it could not be stated that such a treatment could absolutely pre· vent the formation of the fatty liver. Centripetal fatty degeneration was seen more in the thus treated group. In disorders of the pancreas, such as pancre· atitis due to the bacteria, allergy, Candida or virus, produced by the ligature of the pancreatic duct, alloxan glycosuria, from the obstruction of the vagus nerve and the pancreas transplanted with chicken sarcoma, the production of fat in the liver cells was not in general marked. However, in some allergic pancreatitis there was seen a marked fatty infiltration in the periphery ; and in virus pancreatitis a slight degree of diffuse fatty infiltration was seen at a comparatively early stage of the disease. ii. Clinical items In chronic pancreatitis, cancer of the pancreas and pancreatic cirrhosis, various tests such as the serum bilirubin content, alkaliphosphatase, hippuric acid synthesis, cephalin-cholesterol test, thymol turbidity test, prothrombin 108 S. AOYAMA amount, congo-red index, sugar metabolism, and serum protein were made in order to observe the hepatic function (Table 34). Histological examinations were also made. A clear hepatic impairment was observed in 9 out of 40 cases of chronic pancreatitis, in 6 out of 11 of pancreatic tumours, and in 1 out of 2 cases of pancreatic cirrhosis. The frequency of hepatic impairment was greater in pancreatic cancer than in chronic pancreatitis, and in general was more serious. The functional and morphological findings in the liver were compared with the degrees of inflammation in the pancreatic tissue and the changes in the islets, but a definite relationship could not be found. Among 3 cases where acidophils were recognizable in the hepatic tissue, there was one in which the histopatho logical picture of the pancreas showed tuberculous infiltration of the interstitia, while in the rest there was seen an old allergic pancreatitis characterized mainly by changes in the interstitia. In pancreatic tumour and rarely in chronic pancre atitis there was sometimes seen the formation of the fatty liver. In addition there was frequently recognized centripetal fatty degeneration or peripheral fatty infiltration. The frequencies were almost equal for the two. In cachectic diseases due to factors other than the pancreas, such as in gastric cancer and ulcer or pulmonary tuberculosis, the fatty liver was found in about 20°~ of cases, and frequently fats appeared in the peripheral zones. TABLE 34. Liver function tests in patients with pancreatic diseases Chronic pancreatitis Pancreatic tumor Abnormal -Abnormal Total cases cases cases Serum bilirubin (Total) .... . 38 3 13 2 Serumbilirubin (Direct) .... 1 38 4 13 2 Serumbilirubin (Indirect) ... 1 38 2 13 2 Serumalkaline phosphatase . , 40 12 13 6 Hippuric test ...... 35 6 5 3 Bromsulfalein test ...... 36 8 8 5 Cephalin cholesterol} 6 7 floculation test · · · · · · · 39 13 Thymol turbidity •...... 40 4 13 3 Prothrombin •.....•...... 38 6 12 3 Con gored index .•.•.•...... 12 0 '----- Number ofatmormaitest-_:;-r·· o 2 3 4 I Mor\ than Disease ~ 1 1 Chronic pancreatitis ...... 1 14 11 10 2 -~-+-I 2 Pancreatic tumor ...•...... 4 2 1 1 2 iii. Summary From the above mentioned results, the following considerations may be possi ble regarding the fatty liver: In both experimental and clinical cases of pancre atitis, there is seldom seen a marked incidence of the fatty liver, and even in complete pancreatectomy or cases of serious pancreatic cancer where the pan creatic tissues are completely destroyed, the fatty liver does not necessarily result. Methionine, dehydrocholic acid, glucuronic acid and cyanocobalamine are not DISORDERS OF THE PANCREAS 109 absolute in preventing the formation of the fatty liver. Continuous intra venous injections of fresh pancreatic juice cannot also prevent it. When a cells are disturbed the fatty liver occurs, but the rate of the occurrance is not high. Ex periments with the ligature of the pancreatic duct and complete pancreatectomy indicate either a disturbance in the digestion and the absorption of fats, or a difference in the proportion of the total fats in the lymph of the thoracic duct. The fatty liver is of interest from the aspect of problems related to the pan creas, and there are many reports on it. However, to the writer the decom position and absorption of lipids in the intestinal tract and synthesis in the in testinal wall present a significance of higher value. But, if there occurs an abnormality in the intermediate metabolism of sugar in connection with a marked impairment of the pancreas, and especially if there exists a disorder in TCA cycle, it is to be expected that there will result an inhibition of the decomposition of the fatty acids that are oxidized in TCA cycle via acetylphosphate. And the disturbance in the decomposition of fatty acids produces an effect on the synthesis, decomposition and balance of the body fats, and as a result it is natural that there be an accumulation of neutral fats. It is considered that the problem of the fatty liver should be investigated with due consideration to the above aspects of metabolism. In other words, the problem should be considered not in the light of one involving fatty substances alone, but as a chain in the whole metabolic cycle involving a serious disorder of sugar metabolism. IV. Changes in the Pancreas during Impairment of Various Organs In diseases of various organs the pancreas may show many abnormalities. The abnormality noted may etiologically be indistinguishable from that of the primary disease, or may be the result of a functional or anatomical relationship existing between the organs involved. Or the pancreatic disorder may be one phenomenon of the generalized disturbance resulting from the primary disease. The literature on the findings in the pancreas in such cases is extremely scarce. Hence, the results of the writer's investigations on the state of the pancreas in various diseases, especially regarding its external secretory aspect, are described below, based on the examinations of the duodenal fluid. 1. IN CARDIAC DISORDERS Obstructions of the pancreatic function seen in acute cardiac diseases such as endocarditis, myocarditis and pericarditis, and in conditions characterized by decompensation, such as valvular endocarditis and myocardial degeneration, showed a decrease, but rarely an increase, in 1 to 3 enzymes. The enzymes involved are not a definite single one but an intermixture of each other, and with the disappearance of the acute signs or recovery in compensatory function, the pancreatic function also showed improvement. However, when the compen satory obstruction became repeated or prolonged, the pancreas showed organic changes, and there occured a high degree of secretory disturbance, or the dis turbed secretory function might not recover (Table 35, 36). 110 S. AOYAMA TABLE 35. External pancreatic secretion in patients with acute heart diseases (Findings of duodenal fluid, kilo-units per 3 hours) Case Acute stage Postacute stage No. Trypsin j Amylase I Lipase -T;ypsi~lAmylase_j_Lipase- .~ -~~~f-,~--~~~i ~~~ ~-~- 1-~-i-f~-g--c,--i-i6-~-~-~---',~--53_8_8_8_c--_9_8_0_7_5 ----i---1-2-1-18_0_ ;a 3 53 068 102 919 92 407 84 312 184 316 123 641 :; 4 36 225 106 855 94 681 g 5 24 413 58 688 89 696 41450 100 771 146 523 '0 6 46 933 30 548 25 898 35 810 98 790 79 576 ~ 7 7 048 57 856 59 624 84 930 143 812 147 147 8 13 505 46 348 33 689 18 268 86 548 49 837 1 35 000 97 507 II 83776 52714 166 501 128 330 2 21092 51967 50 289 33500 51476 50 736 3 23900 63766 67687 30938 64 953 70 816 1 41100 84 284 69 862 I 2 33430 87087 94 958 56018 168 317 105 474 3 16 048 51416 52 269 32 364 66423 39 714 4 11750 14 951 22 931 36 543 58 248 66 245 5 14 524 32 561 29 290 29740 43718 43320 ------~------'------'------'------ TABLE 36. External pancreatic secretion in patients with chronic heart disease (Findings of duodenal fluid, Kilo-units per 3 hours) Stadium of decompensation Stadium of perfect compensation Di~"" Ic.:. No. Trypsin __ [_!-mylas_:__[~pase __ _ ~ryp~~--~--~my}~;~~T_~ Lip~ Q) 1 I 36 950 66 537 82 319 rn C1l 2 61300 137 913 141234 Q) rn 3 56483 111 745 83 040 :0 4 84165 181682 213 809 Q) 5 62 520 103126 116192 > ~ > 6 44 356 93869 93 54'2 7 105 05 0 446 404 277138 ~ 8 20 93 5 30603 54 284 53 945 98898 96004 .~ 9 24440 57134 67 401 44 230 88612 103 501 ::s 10 17 09 6 45 686 44389 14392 44489 40 827 ----·-- I -- Q) 1 33110 80405 72681 (J) C1l 2 33 563 67 536 98436 Q) rn 3 52 930 106 744 98724 :0 4 89273 148116 158 059 Q) 5 16 815 32 827 76862 > ~ > 6 30945 64 354 21093 49 325 161685 96668 7 33 81 5 45 744 47 438 43 444 92 514 85234 .;:l..., 55 371 15 490 57 298 56760 .... 8 1395 1 42 917 0 9 8729 44458 46391 16945 13038 47 228 -< 10 84490 161221 178 181 - I 6 ~-~ 1 59 790 27 530 I _roPs .... 0 ::l p Q) 2 1919 6018 2~ ;:~ j______I -~. _Q)_ ..... 1 30 500 58344 58157 0 b ~ s +--" Cl) ...... ::l I ~>Bco. 2 33 910 75 849 54 787 '+-~ v·.-~ v ~~boo 3 I 47790 66 258 60701 I ------DISORDERS OF THE PANCREAS 111 TABLE 36. (Continued) ------1 - St;diu~~f decompensation I Stadium of perfect compensation Disease Case - No.I Trypsin Amylase Lipase ~-T~~;~~-Amylase I Lipase 1 : 1 r--- ::: ,:::: r- ,:: 1 44 420 60412 !12 448 2 33 746 106 038 123114 3 20 513 64697 63 650 4 13100 51551 28395 5 48624 128122 118 089 6 17100 33 866 37 333 ------'------'------ 2. IN ABNORMALITIES OF BLOOD PRESSURE In cases of essential hypertension the pancreatic secretion was at times slightly disturbed, a few of them indicating hypersecretion. It was more subject to a disturbance in the stable stage of hypertension than in the fluctuation stage, and generally resulted in a small decrease. Cases of hypertension with marked arteriosclerotic changes were frequently attended by a secretory impairment often of a high degree. In cases of essential hypotension there was sometimes observed a slight impairment characterized mostly by a lowered secretion (Table 37). TABLE 37. External pancreatic secretion in patients with abnormal blood pressure (Findings of duodenal fluid, kilo-unit per 3 hours) i Case No. Trypsin Amylase Lipase I 1 i 101450 147 810 I 177 477 I Fluc.tu· 2 I 57 250 I 105 015 116 667 atwn I I 3 54970 118139 80602 stage I J 4 123 000 I 335 530 202780 Essential ! ------~ I hypertension I 5 40745 62622 60 207 Stable 6 42 510 63 248 59 574 stage 7 I 47 210 80 070 79 323 8 12795 57 331 58 424 i ----- I 1 27720 65 618 61176 I 2 63 510 97 343 94 885 Renale hypertension I 3 83 600 156 713 158 957 4 32 995 70094 67 010 5 40330 73895 70157 -1----~------54193 133 904 113 021 Arteriosclerotic 2 33079 97 278 80534 hypertension 3 25 480 50 820 55 549 4 I 14340 39 607 40 575 5 I 42200 97 283 93821 I ------! 1 I 43180 78753 91950 2 i 36366 57 017 58262 Essential hypotension 3 22190 56097 78789 4 40760 75 702 ! 77 342 I 5 I 39740 92632 93 552 112 S. AOYAMA 3. EXTERNAL SECRETION AND HISTOPATHOLOGICAL CHANGES OF THE PANCREAS IN PULMONARY TUBERCULOSIS Various degrees of impairment of the external secretory function of the pancreas were observed in pulmonary tuberculosis (Table 38, 39, 40). In general, marked impairment was seen often in the exsudative and mixed forms, and in the hematogenous fresh disseminated lung type and pneumonia! type, the lower ing in the pancreatic function was often marked. In chronic cases with static foci, the impairment was in general not so marked, but it was not unusual to find dissociation of the enzymes. By observations of bi- or autopsy cases of pulmonary tuberculosis (Table 41), changes in the external secretory system were seen to be mostly degenerative, and the condition was more conspicuous in chronic than in acute cases of pulmo- TABLE 38. External pancreatic secretion in patients with light pulmonary tuberculosis (Findings of duodenal fluid, kilo-units per 3 hours) Case No IVol~me \ Trypsin\ Amylasel Lipase [\ CN~e I Volume I Trypsin IAmylas~~~--Li;a-s~ 1 130.0 i 48760 214 8091165 556 ~~~ 12 111.5 73 228 145 500 174 615 2 106.0 i 52 350 160 435 102 750 13 42.0 29110 51466 48373 3 86.5 74 282 158 660 100 122 •I 14 76.5 66 300 87 512 90018 4 158.0 102 440 198 998 i 202 552 15 184.0 103 250 178 806 214 339 5 78.0 39 950 125 749 I 94 403 I 16 141.0 106 135 324 518 285108 6 95.5 27 310 84 584 90 334 17 280.0 145 300 424844 328009 7 68.0 31030 78 888 92 123 18 55.5 31839 66395 78016 8 254.0 104 690 282107 1 269 386 19 111.0 50 530 162 586 108866 9 120.5 30 660 12 s1o 1 48 336 20 63.0 37 413 46679 59766 10 114.5 63 200 182 510 1 167 518 21 78.0 46 710 89326 90403 106.0 74 330 121522 146 330 ~11 I 140.0 _ 56 ~0~- 155:2:__1_~4~3~~_,___2_:_ __ -· ------'-----·---'-----~ TABLE 39. External pancreatic secretion in patients with moderate pulmonary tuberculosis (Findings of duodenal fluid, kilo-units per 3 hours) c~~~ I Volume I Trypsin I Amyla~-el Lipase II~~~ I Volume ITrypsin I Amyl;~~-~ipase- 1 47.0 23 810 68472 74 518 I 19 70.0 30320 68148 72510 2 72.0 51240 84666 79413 20 I 62.0 43 510 86605 78433 3 50.5 60 500 76 873 86 536 21 I 41.0 29120 51112 49 301 4 67.5 47 322 92630 78534 22 22.5 20150 42148 38090 5 124.5 72530 133 668 169 306 23 45.0 24 800 167 515 144182 6 110.0 62 880 102 010 126 866 24 99.0 69740 123 518 I 162 990 7 52.0 27 819 70 445 83 550 25 124.0 74220 108 916 122 531 R 40.0 25 320 72 808 48 418 26 65.0 53100 96 222 90183 9 62.0 48 366 96 314 98444 27 52.5 45 058 120 218 126 558 100125 80874 10 1080 33100 60024 61533 i 28 87.0 52120 11 82 28 610 52 836 64015 I 29 76.0 29960 86880 56718 12 34.5 19 320 48 908 1 42 537 30 103.0 27 220 56 306 60224 13 241.5 118 000 274 506 256 377 31 42.0 12670 32 517 34866 14 40.6 24 370 52 039 47 351 32 59.0 52940 74346 88042 15 72.0 60 826 93 283 86 552 33 72.0 50180 132108 106 009 16 63.5 43 709 72226 34 64.5 22010 86963 I 78427 90 0881 I 17 100.5 121329 121329 82 537 35 I 168.0 98220 243 2491 238607 18 53.0 88 977 88977 103 412 I DISORDERS OF THE PANCREAS 113 TABLE 40. External pancreatic secretion in patients with severe pulmonary tuberculosis (Findings of duodenal fluid, kilo-units per 3 hours) ~~:~v~~~~e I Trypsin I Amylase[ Lipase II ~~-e I Volume i Tr~psinj Amylase[ Lipase I 1 56.0 26620 l 78416 86 224 13 92.0 54000 78188 96 518 2 79.0 50240 l 84128 108 416 14 78.0 48310 96506 111275 3 62.5 28 644 ! 42871 43032 15 62.5 27 446 72 319 82998 4 64.0 13480 44784 40672 16 36.0 24760 46522 45 333 78.5 I 98906 5 15 845 ! 13016 32126 17 71.0 44420 78893 6 55.0 18400 48768 44 010 18 53.0 20100 87204 73566 7 50.0 33260 67 432 39624 19 124.5 79267 151219 210100 8 39.5 18550 45 754 47118 20 76.0 45120 126120 90266 9 61.0 38090 46 893 ' 60 917 21 106.7 I 41450 100771 146 523 10 103.5 49 642 1321241 118122 22 102.0 52 360 94 626 132 008 11 82.5 47 338 148 715 106 749 23 92.0 43890 138666 107028 12 130.0 80590 243 741 212184 ' ------I TABLE 41. Histopathological changes of pancreas in patients with pulmonary tuberculosis Histotha;~~~~gical ~ -Pa~~~hy~a of pancreas----~- Is-l~ts-of Langerhans ~~~~~e~sof r Res~ults Degene~~~ion I Fibrosis I in~~~~~~f~n I Vacuolisation I Fibrosis . (±) 30.99;;' 54.49;;' 41.1% 19.0% 11.7% Head 7.3 25.0 17.6 5.9 4.4 (+) I ! (3) (2) (1) (3) (1) ------I I I - I ( ±) I 40.6 50.0 48.3 20.3 6.2 Body 9.3 28.1 10.8 9.3 3.2 (+} (2) (1) (3) (1) (3} I I I ( ±) 31.1 47.5 42.6 9.8 9.8 Cauda 9.8 16.2 14.7 6.5 3.0 (+) (1) (3) (2) (2} (2) nary tuberculosis, and the same held true for the proliferation of the interstitial connective tissue. Cell infiltration and fibrin formation were seen more in the periphery of the parenchyma. In the islets were sometimes seen vacuolization, fibrin formation, or the islets may hypertrophy or increase in number while the a: cells might decrease. These changes were in general marked when complicated by intestinal tuberculosis. When the lymph glands adjacent to the pancreas showed marked tuberculous changes, changes in the parenchyma of the pancreas were also marked, and it seemed that in such cases the changes spread into the pancreas from the tuberculous lymph glands in that area via the lymph ducts to the capsular membrane and into the parenchyma of the pancreas (Table 42). In cases when tubercles were seen in the pancreas, they were either miliary tuberculosis, or one further complicated by tuberculous meningitis. In chronic pulmonary tuberculosis, tubercles were never seen in the pancreas. In other words tuberculosis of the pancreas was basically hematogenous in its origin. In one case there were seen tubercles in the pancreas in the absence of tuberculosis of the lungs and other viscera, but such a case was extremely rare. 114 S. AOYAMA TABLE 42. Histopathological changes of the pancreas and its regional lymphatic glands in patients with pulmonary tuberculosis Changes in the lymphatic glands Chages in the pancreatic tissue ------Caseation Increase of the collagen fibres 1 Tubercle Cirrhosis of the pancreas 1 Sinus catarrh (-It) Cellular infiltration 2 A 11/11 ne,tructiun of tho ""n Tubercle Vacuolisation of the parenchy- mal cells B } 1 Sinus catarrh (-It) Cellular infiltration ~ 5/6 Inflammation of the perilymphatic No changes 1 node I Sinus catarrh ( 1+) Increase of the collagen fibers 1 I} 2/2 c Cellular infiltration 1 Sinus catarrh ( +) No changes 4 I 0/4 Increase of the interlobular Sinus catarrh ( +) connective tissue D 1 I I 2/2 Increase of the reticulum cells Edema of the interlobular connective tissue 1 I ----··-~------~------ 4. FEVER AND EXTERNAL SECRETION OF THE PANCREAS Comparisons were made during the febrile and afebrile stages of 37 cases of pulmonary tuberculosis, cholecyctitis, pyelitis and malaria, and of 20 cases subjected to artificial fever once or repeatedly induced. The results showed that the fever itself influenced the external secretion of the pancreas ; in many cases the action was an inhibitory one. When a secretory impairment had al ready existed the tendency for the secreti~n to decrease was greater. With a single artificially induced fever impairment was not seen, after a repeated in· ducement of fever, an impairment was registered. Generally, the pancreatic impairment due to fever, was usually reversible (Table 43, 44, 45). 5. ANEMIA AND EXTERNAL SECRETION OF THE PANCREAS Anemia due to an injury, ancylostomiasis, chlorosis, or aplastic or pernicious anemia proved to cause, purely by itself, an impairment in the secretion, and the degree of such an impairment corresponded generally to the nature and the length of the anemia. An impairment in the external secretion brought on by anemia always resulted in a decrease of secretion, and an abnormal excitation was exceptional (Table 46). DISORDERS OF THE PANCREAS 115 TABLE 43. Pyrexia and external pancreatic secretion (Findings of duodenel fluid kilo-units per 3 hours) , 80.0 70.5 52 310 60 020 87 866 58443 79512 70 880 13 a s2.o 44.o 21 si9 211so 10 445 46689 83 550 47 520 14 ~ 48.0 39.0 40 120 32 530 66 308 58100 80233 78989 15 -a 65.0 52.0 55 240 40 000 88 606 58 783 II' 90228 76340 16 ll< 94.o 38.5 1 88 960 5o 2so 102 320 78660 100 223 84 553 17 65.0 50.5 I 53100 48 270 4968 920282 'I 101301 90183 102 003 18 34.5 36.5 19 320 22 150 . 43122 42 537 36148 19 41.0 56.0 18 920 27 600 68 540 i 74640 44141 78580 20 45.0 32.5 24 800 20 360 167 5151 83166 144182 74 530 21 76.0 58.0 45 120 40 660 126 120 65 887 90266 80099 ----~----~----~----~----~-----~ 1 103.5 78.0 73 330 58 270 121 514 ! 83738 148 642 120 355 2 -~ 124.0 50.5 68 860 28 520 124 472 89 684 166 024 79 436 3 ·So 84.5 80.0 48 240 50 180 36 243 67118 82145 76903 4 § 54.5 62.5 22 010 20 000 76 968 50180 70427 42 350 5 0 48.0 42.0 44 310 38 200 60 258 52 768 77 493 80021 6 ..c: 29.5 38.0 46 220 30 690 67 514 60220 72533 68404 7 u 53.5 39.0 65 480 50 840 88 825 72 388 90326 89 388 8 46.0 38.0 24 120 20 800 36 488 50147 60012 49833 1 ·.: 63.o 4o.o I 34 33o 40 000 88 251 69 358 103 456 86 522 2 ~ 71.5 52.0 62 470 I 50860 96 514 78 303 100 947 74999 3 OJ 68.0 50.5 61 290 44 310 121807 83 596 99180 96288 4 d:' 68.5 48.0 48 780 I 24180 92226 68 346 96 688 88245 5 52.0 40.0 64 400 50270 88213 69 330 148 516 136104 1 145.0 43.5 86 530 20 100 1148 806 621551150 122 52100 2 74.0 43.0 28840 20100 96 512 46 532 100 241 84122 3 63.5 40.0 28280 32 550 124 533 70 254 186 524 120 058 ----~--·------~-----'------TABLE 44. External pancreatic secretion in simple artificial attack of fever (Findings of duodenal fluid, kilo-units per 3 hours) ·-· - Volume of fluid Trypsin Amylase Lipase ~~-~ Case No. - ·-··------~~ ------~~ Afebrile ) Febrile Afebrile I Febrile Afebrile I Febrll~ Afebril~)_Febrile I 1 86.0 66.0 78340 46200 146 5131 70888 196 040 83123 2 48.0 62.0 50810 42318 66318 74024 68914 80022 3 76.0 42.0 58 920 26670 99645 83166 120 326 72 536 4 95.0 55.0 83400 51000 123 518 110 674 135 168 80066 5 82.5 41.0 67 440 28130 150 211 80 534 128 650 93612 6 48.5 42.5 44180 38920 68718 68 528 72506 78123 7 66.0 70.0 73 520 50430 96871 83 522 101606 63514 8 110.0 83.5 64 210 50320 78 515 58343 94518 60023 9 80.5 54.0 50180 43160 72 416 68938 70 516 69323 10 50.0 40.5 22390 20860 52876 44 215 61903 60648 116 S. AOYAMA TABLE 45. External pancreatic secretion in repeated artificial attack of fever (Findings of duodenal fluid, kilo-units per 3 hours) No. of 1- Trypsin Case No. attacks Volume -~ Amylase Lipase 1 75.0 38 530 124 270 146 533 1 5 40.0 30120 78 530 94 265 8 41.0 28 380 60544 88776 1 83.0 I 52000 96328 134 530 2 5 32.0 24340 80076 102 278 8 40.0 28530 83 524 99 806 I I ---- 1 97.0 78630 120 556 112 385 3 5 72.0 66400 74271 96 233 10 80.5 53720 86468 94869 1 67.0 63860 93496 86203 4 5 80.0 72140 88273 90146 10 52.5 51020 51311 52388 1 60.0 85 330 112 224 130 291 5 5 42.0 32140 73060 71333 8 38.0 32060 60278 51808 1 68.5 68320 126 612 186978 6 5 32.0 18400 52768 83990 10 I 56.0 22310 50 834 48650 1 52.0 28120 67 310 72018 7 5 39.5 30 880 52270 40130 10 30.0 24560 52996 46322 1 40.5 20860 48215 60648 8 5 42.5 22360 42513 74 468 8 44.0 16440 42008 47 322 1 50.0 I 51220 78 522 88828 9 5 32.5 32140 58 382 60534 8 52.5 30660 54439 50806 I 1 46.0 58 880 68566 74 533 10 5 58.0 38240 78235 60816 8 42.0 36660 80 006 56398 TABLE 46. External pancratic secretion in patients with anemias (Findings of duodenal fluid, kilo-units per 3 hours) ======~======~===== I Case No.j I Volume Trypsin I Amylase I Lipase I 1 I ~~~,~---~6-3-.1~.---~4-0-2-80- --122 9771 ____ 92 987 I I 2 1 1 1 125.0 49 270 1 136 621 139 808 52 840 i 48492 3 51.0 27 006 I I After recovery I 88.0 49 640 107 036 110 848 ~~~~~~~~- ~~1~--~~------~------~~~~~~~7_0._1_- _---_-_4_4_4_so~~~~-8_5_9_04~7-~7_7_1_21__ 42363 68659 2 I I 51.7 13 364 I 1 After recovery 69.5 39 640 85 985 77753 62.0 23 261 I 94 289 60940 3 After recovery I 76.5 56238 102 785 102 881 DISORDERS OF THE PANCREAS 117 TABLE 46. (Continued) I Case No. j Volume i Trypsin Amylase j Lipase I ' -T - -~68-8-39~ ·;;;lfJ 1 75.5 42 580 64 039 0 )... 0 58 5 33 870 32 55!1 51355 .:2 2 u After recovery 77.5 47 000 107 168 101655 64.5 30 413 87 432 83 055 I 41809 52618 I 36 274 39 365 69 88R 67 830 48 878 56 056 .l. ro u ·- 1 36 339 26 497 ·- lfJ s p.,e:""" 0 <=:ro 2 43.5 5 963 40 306 37 217 6~10. DISORDERS OF THE LIVER, THE BILIARY TRACT AND THE GALL BLADDER IN RELATION TO PANCREATIC EXTERNAL SECRETION, ETC. In diseases of the liver, the biliary tract and the gall bladder, there was fre quently seen an impairment of the external secretion. It was nothing serious and appeared to be only a dissociation of the enzymes. Sometimes the three en zymes showed a marked decrease, indicating a high degree of impairment (Table 47). In such pancreatic disorders, the patient did not necessarily show special signs. This indicates that in these diseases, though there may be no signs other than those due to the primary disease, an impairment of the pancreas has to be considered. An examination of the results of experiments with animals, in the case of hepatitis due to the introduction of bacteria into the liver, brought out the fact that the duodenal juice and the ferments showed a marked decrease in most cases. In such cases there were seen a degeneration in the parenchyma, hy pertrophy of the islets, slight edema of the interstitia, thickening of the wall of the pancreatic duct, focal necrosis and derangement of the cell column. These changes were marked in the head and body and extremely slight in the tail. When the sarcoma was transplanted into the liver of the chicken, the blood diastase rose slightly, and when transplanted into the right lobe this rise lasted for a longer period than when transplanted into the left lobe. In both cases, however, there resulted a fall afterwards, and the value became less than the pretransplantation level. In such cases there was not seen any special change in the pancreas from the histopathological point of view. Experimentally, when a solution of copper was given orally or the powder inspired into the lung continuously for a long period, there resulted ultimately a high degree of liver cirrhosis. In these cases there resulted, though very late, cellular infiltration and parenchymal degeneration in the pancreas. In clinical cases of liver cirrhosis, there were seen atrophy of the gland acini in the pan- 118 S. AOYAMA creas, proliferation of the connective tissue, cellular infiltration and formation of false lobuli. TABLE 47. External pancreatic secretion in patients with liver disease or cholecystopathia (Findings of duodenal fluid, kilo-units per 3 hours) ------Disease Volume of Trypsin 1 Case No. i fluid 1 163.2 63 594 312 735 205153 2 48.8 183 396 43 699 37003 100.2 37 815 100 610 90991 Infectious hepatitis 3 4 146.9 43 632 95 219 91536 5 39.0 20 550 37185 32367 6 170.5 i 23 490 133 258 113 915 ------1 55.5 21810 57 881 56 543 2 29.5 7680 23 569 19447 Hepato-cirrhosis 3 590 30400 61725 39959 4 81.2 35 890 58 090 98024 5 44.. 0 28405 49 926 47 243 1 4036 34 836 33667 Primary carcinoma 2 6306 33 729 25 251 5138 21973 559 of the liver 3 22 4 36450 74 516 118 984 5 5 315 36 337 50 430 1 59 582 Metastatic carci 2 49659 noma of the liver 3 24777 4 69887 5 76 805 1 34.2 31350 88 327 65 582 2 91.1 36 575 109119 140 307 3 602 20032 95 852 28 286 88 970 139 645 443 Cholecystopathia 4 579.5_ 649 1 5 164 6 56 020 200 862 232146 6 150.2 34 053 147122 156 587 7 55.8 8664 42 348 41414 8 57.2 10 332 37744 33 750 ---- _____! ______ 11. GASTRIC DISEASE AND EXTERNAL SECRETION OF THE PANCREAS In severe acute gastritis there resulted an impairment of the external se cretion of the pancreas, and when enteritis became complicated there was greater tendency for pancreatic impairment to occur. Chronic gastritis showed comparatively frequently pancreatic impairment, sometimes reaching a high degree. In atrophic gastritis there was especially seen a tendency for great impairment to occur. In general, in these cases, though the external secretion of the pancreas might be within the normal range, the ferments tended to be low in content. In gastric ulcer, especially in fresh cases, the secreted volume was compara· tively large and the amounts of the enzymes were also high in many cases. There were, however, some showing a slight secretory impairment, while at times there were others with a serious one. In gastric cancer there was seen an impairment of the pancreatic secretion fairly frequently. DISORDERS OF THE PANCREAS 119 In the case of a pure gastric secretory impairment, it was rare to find pan creatic secretory impairment in hyperchlorhydria, but rather there was an exci tation in the secretion. In achlorhydria there was relatively frequently seen a low degree of impairment. In this case there was no special relationship demon strable in the reactivity or nonreactivity of the stomach to histamine (Table 48). TABLE 48. External pancreatic secretion in gastric patients (Findings of duodenal fluid, kilo-units per 3 hours) j Case No. I Volume of fluid I Trypsin Amylase Lipase , I ------~ ------~ 1 80.1 31570 80 572 86798 2 74.4 28 582 90 500 73 393 3 89.6 30320 93116 94 986 4 140.1 77 690 238 730 208173 5 170.8 105 310 208 941 224823 6 62.5 19 043 73 027 70356 7 206.0 59 420 113137 125 067 8 97.0 67 430 116 833 127150 9 173.5 93 350 139 145 147 054 10 80.0 34 450 76626 79135 1 22.6 5 432 37 921 26953 2 54.0 26 778 62 812 78453 3 69.2 33 441 84418 82 552 4 58.4 32 238 80014 77 938 5 111.7 39149 117 993 121972 6 46.5 16 338 279~8 37 540 7 107.5 51840 110 515 100 878 8 77.5 69 900 i 93 509 77702 9 82.1 52 002 I 81370 128 420 83 366 10 11_6·~-~----16043 __ _l_ 74627 1 114.1 52190 113 220 287 577 2 145.2 124 720 234 812 238147 3 97.0 35 810 98790 79 576 4 53.5 33 500 51476 50736 5 26.3 19 542 51553 37067 6 74.5 47 465 53955 72 320 7 88.5 50 932 54390 81489 8 101.5 59446 109189 77 874 9 129.5 45 490 71450 79 520 10 72.5 37 560 84670 82 726 1 64.7 36 256 138 745 84 203 .... 2 41.6 19130 65143 58172 u"' 3 192.4 108 290 276 927 229 382 .: 4 177.5 85 513 209 391 196 299 u"' 5 33.0 20950 34455 39 907 ..r:: u 6 39.4 17 562 34 445 24071 "' 7 44.1 30 438 45 406 56039 s0 8 59.3 28290 109 478 64 797 +-' (/) 66.6 30825 126 282 57172 46 310 78 778 16 1 71.5 99858 ----'---- 1 241.0 84 320 189 043 295 477 2 334.7 78989 148118 230165 3 209.5 33135 60791 371479 4 83.0 48 960 114 625 95 837 5 182.5 84 855 170 148 287 577 6 r: 83.0 54419 ·r 142 475 112 294 7 :.0 73.0 41812 ' 179 706 58797 8 ·;:; 58.9 24 278 173 703 65 959 9 .:"' 60.2 18268 86 548 49 827 10 166.8 66476 185 763 207088 < i --~--~----~ ------~~------120 S. AOYAMA 12. THE AUTONOMIC NERVOUS SYSTEM AND THE PANCREAS In experimental vagotomy the blood diastase and sugar showed a transitory abnormality, but when the anterior branch was severed immediately below the diaphragm, or when a left cervical vagotomy was performed, there resulted an atrophy and a degeneration of the cells of the parenchyma and a diminution in size and an atrophy of the islets. Continued administration of atropine sulphate, acetyl choline and pilocarpine hydrochloride caused changes in the blood sugar and diastase. Also there were seen a degeneration, an atrophy, an edema and a destruction of the pancreatic parenchyma or the islets. When the hypothalamus was destroyed or stimulated experimentally, the islets showed a hypertrophy, an atrophy and a degeneration in both cases, followed later by a mechanism of regeneration. The glandular cells of the pancreas became atrophic after a week or so. 13. BLOOD DIASTASE, ESTERASE, SUGAR METABOLISM AND BLOOD PICTURE AFTER SPLENECTOMY Omitted here V. Clinical Cases 1. CHRONIC PANCREATITIS a. Clinical observations The results of the observations, in which histopathological findings were also available, are described in the following. In most cases the past history of the patients showed no special disease. But there were some who had suffered from gastritis, gastric ulcer, acute pan creatitis, peritonitis, appendicitis, jaundice, congenital dyspepsia, gastralgia, inter mittent adbominal pains. It was not clear whether these conditions had existed as completely distinct from pancreatitis or as chronic pancreatitis in themselves misdiagnosed as above. It was not possible to demonstrate a definite tendency in taste or diet com mon to all the cases, but sometimes there was noted clear evidence that specific diets, such as fats or a large amount of sugar, stimulated the onset of the dis ease. More than half of the cases led a regular regimen in their daily meals, and those with marked irregularity in their food habits were much fewer than expected. The numbers of spare and heavy eaters rivalled each other, but they did not amount to many. With the greater haU of the cases the onset of chronic pancreatitis was sudden. The early signs consisted of abdominal pain especially in the epigastrium. Other complaints consisted of nausea, vomiting, fullness in the epigastrium, vertigo, headache, fever and diarrhea, hematemesis, and chills. The complaints associated with this disease, when arranged in the order of their frequencies, were as follows : languor or general malaise, abdominal dis tension, headache, loss of weight, nausea, gastric or epigastric pain, feeling of oppression in abdomen, vomiting, rigors, abdominal pain, thirst, belching, fever, anorexia, heartburn, hyperperistalsis, vertigo, borborygmus, and abdominal dis- DISORDERS OF THE PANCREAS 121 comfort. Thus it will be noted that in this disease, the onset is marked by epigastric or abdominal pain followed later by general and neurotic symptoms, intermixed with symptoms traceable to the abdomen. Frequently, there are repeated at· tacks of pain indicative of the chronic relapsing type, but, on the other hand, it may take an uneventful course. In some cases the disease may first be seen as a chronic case, without the evidence at all of the early symptoms. The pain was in most cases localized and deep in abdomen and was over· whelmingly in the upper abdomen. The point to be noted is that the fre· quencies of pain in the entire upper abdomen, in the right and in the left upper abdomens were almost equal, and this characteristic was common to acute pan· creatitis, pancreatic tumour and other diseases of the pancreas. The so-called pancreatic pains, though of diagnostic value when presented, accounted for only half of the pains accompanying pancreatic disease. The nature of the pain might be slow of aggravating, intermittent, or colicky, and in most cases was radiating. In some cases it was continuous and dull. There was not seen any significant relationship between the registration of pain and the time of meal when considered generally, but there were some cases with pain coming 3 hours after meal, immediately after meal, during hunger and atter the drinking of spirits. About one half of the cases complained of constipation, the other half being free from it. Diarrhea was comparatively rare. On abdominal palpation tenderness was noted in the epigastrium, and in more than one half of the cases a swelling or resistance was felt. The tumour was hard and in most cases the surface was rugged. They were mostly mobile. It was more usual to feel a resistance in the epigastrium at the center of a line joining the xyphoid process to the umbilicus, than to palpate a definite tumour. In the great majority of the cases there was some tenderness in the tumour or resistant area. The liver was usually palpable, but the increase in size was not marked and the consistency was not great. A palpable liver did not, of course, neces sarily indicate a liver impairment. The fasting blood diastase showed a maximum value of 972.3 mg/dl, and a mininum of 52.5 mg/dl, with an average of 214.3 mg/dl. Many cases showed normal values, and those showing abnormally high or low figures were few in number. Of course the values varied with the stage of the disease, so that during or immediately after an acute onset, it was usual to find high values, and during the intermittent stage, normal or comparatively low values. The Vagostigmin test showed that in about 3/5 of the cases an abnormality could be demonstrated, and in about one half of the cases disturbance in the blood sugar regulatory function was noted. Of the abnormal Vagostigmin reactive cases about one half showed disturbance in the carbohydrate metabolism, and of those presenting no abnormality in the Vagostigmin test, about one half showed an impairment in the blood sugar regulation. In the case of chronic pancre atitis, abnormalities in the blood diastase content and in the blood sugar regu lation were seen in about one third of the casPs a nil a hnnt one half showed 122 S. AOYAMA one or the other abnormality, and about one sixth did not show either of the abnormalities. More cases showed abnormalities in the Vagostigmin test than in the sugar disposal function. From the above findings it must be said that the existence of the disease has to be considered not only when changes are seen in both the blood diastase and the blood sugar test, but also when either one of the above shows a change. Further it must be noted that pancreatic impairment cannot be ruled out even when both tests do not show an abnorm ality. Points to be noted in the picture of the peripheral blood in this disease, were a low grade of anemia indicated by decrease in erythrocytes accompanied by a parallel lowering in the blood hemoglobin content, and the comparative frequency for acidophils and neutrophilic stab cells to increase. The increase in acidophils was seen fairly frequently and the point that calls for attention was that in the bone marrow of these patients there were seen increases in the acidophils and neutrophilic marrow cells. As a cause for the increase in acido philic cells an allergic factor could be considered. Actually the pancreas showed histologically the picture of allergic inflammation, and there were cases where the blood acidophils increased, but there were also cases where it did not. Further, the pancreas did not show histologically allergic changes though the blood picture showed increase in acidophils. Hence, this change could not be attributed in its entirety to an allergic inflammation. In fact, the writer and his research colleagues have not been able to clarify satisfactorily all the causes for the increase in acidophils. The main changes in plasma proteins were the decrease in total proteins and albumin and the increase in globulin (especially of r and a globulins). The blood sedimentation rate in most cases showed no abnormality, and even when it was present, was represented by only a slight acceleration. The changes in the liver function have been described in III and therefore are not described here. The gastric juice showed generally hypoacidity in most cases, though some might show hyperacidity. The duodenal juice in most cases showed the volume and content of ferments to be within the normal range, but there was seen a fairly large difference between the maximum and minimum values, and in cases where the pancreatic impairment was widespread and serious, most of them showed a decrease in value. Of the three ferments trypsin showed the most marked fall. Stool findings: In chronic pancreatitis the occult blood was frequently posi tive, and in about one half of the cases fat drops and muscle fibers were demon strable. In a few cases starch was seen. The contents of the three ferments in the stool were in general lower than the normal amount, though sometimes they might be abnormally high. The urine showed sometimes proteins and urobilin bodies ; the sugar was negative in all cases, and urinary diastase in almost all the cases showed normal values when examined by Tarnai's method. The X-ray pictures revealed in most cases no marked abnormal findings, hut in some there was seen a derangement of the duodenal mucosa, enlarge- DISORDERS OF THE PANCREAS 123 ment of the duodenal opening, stasis of the duodenal contents, dislocation of the stomach and deformity of the pylorus. In 44 cases where pathohistological examinations were made, the changes in chronic cases showed an inflammation of the pancreatic interstitia or duct, and a degeneration of the parencyma, but in most the main change was inflam mation in the interstitium. Of these, nine showed histological changes of al lergic pancreatitis. Of those showing mainly an inflammation of the pancre atic duct, there were some that exhibited an increase in acidophilic cells in the blood. In general, no specific relationship could be demonstrated between the degree of the pathological changes and that of the abnormality of the clinical function test of the pancreas. As the cause of pancreatitis various factors can be considered, and many theories have been advanced. In an acute necrosis of the pancreas the signifi cance of pancreatic ferments and the conditions for its onset have been discussed from various angles. In this country many experiments have been performed by Matsuo, Mizuta, and Tsuda, while the relationship of the diseases of the liver and biliary tract to pancreatitis has received great attention in Europe and America, and, in this country, from such researcher as Miyake and others. The role of intestinal parasites, especially Ascaris, has lately been investigated and reported by Maki et al. An infection of the pancreas may be due to an ascending infection via the pancreatic duct, by direct spread from neighbouring viscera via the lymphatic vessels, hematogenously as a result of a generalized infection. The affection may be due to bacteria, virus and other micro-organisms, or may be due to various toxins, such as a pancreatitis due to diphtheria toxin or d/ ethionine. The allergic changes in the pancreas can sometimes be intimately related to a generalized allergic state, but the changes may be limited to the pancreas. The antigen in such cases may be varied, and as have been experi mentally demonstrated, in both pancreatic vessel and duct types, special changes are produced in the pancreas. For example, in the case of allergic human pancreatitis, allergy from a food or focal infection seems to have a special sig nificance. Clinically it is not easy to clarify the cause, the nature of the changes in the pancreas, or the pathological findings in each case encountered. Hence, Heinsen has termed pancreatic changes due to an inflammation, an intoxication and a degeneration as "Pancreopathie." Such a name is probably convenient clinically from the standpiont of nomenclature. The relation between acute and chronic pancreatitis is also never simple. There are many types of acute pancreatitis, while acute inflammation may con tinue as a chronic one, there may be the chronic case which begin as a chronic one ; while there are chronic relapsing pancreatitis, in which case each relapse may be rightly considered as an aggravation of the chronic inflammation, but there may also be cases which can be better considered as acute repeated in flammation. Thus in the case of pancreatitis, depending on whether it is acute or chronic, on the content or nature of the edema, hemorrahge, necrosis and degeneration, as well as on the clinical aspect, there are many points that require further 124 S. AOYAMA investigation. Katsch examined 467 cases of pancreatic disease between 1928 and 1937, and stressed that the disease is not rare. Heinsen, in 1952, pointed out that the disease has shown a tendency to increase, which cannot be attributed merely to the improvement in diagnostic methods. In recent years cases of chronic pan creatitis have been increasingly reported in this country and the writer's clinical investigation showed that it is the most frequently encountered disease among disorders of the pancreas. Only, as has been described above, its diagnostic confirmation is not simple; generally only after various tests have been dis cussed, in conjunction with the clinical findings, and diseases of other viscera have been ruled out, is it possible to make a definite diagnosis. When due at tention has not been paid, the condition may mistakenly be diagnosed for ex ample as gastritis, gastric or duodenal ulcer, cholecystitis, gastroptosis, or chronic enteritis. "The first thing to be recalled in the diagnosis of an acute necrosis of the pancreas is the presence of this disease," has been considered to hold true for a long time since Gulecke, but today this saying can no longer be ap plied to chronic pancreatitis. b. Clinical cases Below are described the findings from a few interesting cases. Case 1. T. M., 63 years old, male. Present condition: For about 20 years, diarrhea after a heavy meal, con tinuous belching, heart burn ; has resorted constantly to "stomach medicine." For about 3 years past has suffered from violent attacks of epigastric pain ac companied by nausea occurring about 3 times a year. No fever. Before the attack of abdominal pain became conscious of tumour above umbilicus. The attack of abdominal pain increased in frequency from about 1 year ago; debility gradually increased in its degree. At about this time urticaria was seen after the abdominal attack. At present bowel movement once in every 3 days; appetite slightly affected. Fatty foods often caused abdominal attacks. Smokes about 30 cigarettes daily, takes about 5 to 10 cups of coffee daily; does not drink liquor. Chief complaint: Attacks of violent pain in the upper abdomen. Objective findings and results of laboratory tests: Nothing abnormal noted in the chest ; hard tumour about the size of a goose egg palpable in the upper abdomen. Blood picture almost normal, showed leucocyte count of 6,400; ery throcytes, 4,510,000; hemoglobin content, 71% (Sahli); bleeding time, 3 minutes (Duke's method); coagulation time, start 3 minutes, end 8 minutes (Sato's method). Blood diastase content, 16 units; urinary diastase, 25 units (both by Wohlgemuth"s method). Fasting blood sugar (the Hagedorn-Jensen method), 108 mg/dl. Gastric juice showed maximum free HCl of -10 and minimum of -40; total acids, maximum 20, minimum 2, and showed hypoacidity. Lactic acid (the Ufferman method) and occult blood (benzidine method), both posi tive. Ascaris ova in stools; fecal occult blood negative. X-ray of the stomach immediately after a barium meal showed large amounts of the meal in the body of the stomach, and at or near pyloms was seen the picture of defect, apparently due to pressure. Two hours after meal, no picture of abstruction to passage seen. DISORDERS OF THE PANCREAS 125 Laparotomy findings : Ascites practically not seen ; no changes in the sto mach itself. Tumour of cartilaginous hardness seen in the body of the pancreas. Resection of the body of the pancreas with main secretory ducts made. Histological findings: Pancreatic interstitia generally showed edema. Around blood vessels was seen an infiltration, especially by lymphocytes, acidophils, and large mononuclears. Practically no polymorphonuclear neutro phils found. In one part was noted a marked proliferation of the interstitial connective tissue accompanied by a round cell infiltration. Hence, parenchyma of the pancreas appeared spotted, and areas found where glandular cells became atrophied. In part of the pancreas were seen large areas of granulation tissue surrounded by connective tissue containing large mononuclears and lymphocytes, and with the central part undergoing necrosis. No marked changes in the epi thelium of the pancreatic duct, but the small ducts showed in parts an adeno matous proliferation. Some of the blood vessels, especially arteries, showed thickening of the intima, resulting in an extensive narrowing of the lumen (in timitis). Many showed a decrease in the size of the islets, but no changes m the structure (Fig. XV). Diagnosis: Allergic relapsing pancreatitis. Case 2. T. I., aged 46 years, female. Past history : Cholelithiasis about 15 years ago, cured after about a month by allopathic treatment. Since then is said to have occasionally suffered from urticaria of an unknown origin. Operated for ectopic pregnancy 8 years ago. Present disease : Attack of the colic in the epigastrium on March 10, 1954, which lasted for 3 days. Had fits accompanied by nausea, vomiting, chills and fever; dull pain radiated to the left anterior chest, but not to the back. Ex amined by many physicians and vaguely informed that the disease may be cholelithiasis, gastric ulcer or hepatic disease. The patient is a spare eater, and prefers diets consisting of carbohydrates. Does not drink liquor, nor smokes. Bowels move 3 times a day, diarrheal in nature. Chief complaint : Pain in the epigastrium. Objective findings and results of tests : Medium physique, facies showed distress, debility not so marked. Nothing abnormal in chest. Upper abdomen slightly distended, marked tenderness from right costal arch to epigastrium, also resistance felt. Blood findings: Leucocytes, 8,600; erythrocytes, 3,920,000; hemo globin content, 83~~, showing slight anemia; acidophils not seen. Fasting blood diastase, 347 mg/dl (Tamai-Kobayashi's method); maximum deviation after Va gostigmin test, -103 mg/dl, and both showed abnormality. Urinary diastase, 211.4 mg/dl (Tarnai's method) and almost normal. Fasting blood sugar, 84 mg/dl; Staub's effect after double loading with glucose given orally, negative. Total serum bilirubin (Jendrassik-Cleghorn's method), 0.45 mg%; direct biliru bin value, 0; indirect value, 0.45 mg%. Cephalin-cholesterol flocculation test positive. Prothrombin content, 90% (Mune's modification method); alkaline phosphatase, 1.98 Bodansky units; thymol turbidity test, 3.6 units; hippuric acid synthesis test (Ishiyama's modification, orally administered), 49.0836' and ap proximately normal; bromsulphalein test after 45 minutes, 5-103o'. Gastric juice showed hypoacidity ; trypsin in duodenal fluid slightly decreased (Charney- 126 S. AOYAMA Tamarelli's method), diastase within normal limits (Okada's method). Lipase somewhat decreased. Stools showed positive occult blood, no parasite ova, muscle fibers abundant. Urinary urobilin and urobilinogen positive, no other marked changes. Blood sedimentation rate accelerated. Gall bladder X-ray after administration of Priodax showed no clear presence of gall stones. Laparatomy findings : Inflammatory changes in the gall bladder and pan creas, the latter especially showing increase in hardness. Histological findings : The pancreas showed proliferation of the interstitia in lobules and interlobular spaces, proliferation of connective tissue around blood vessels, intermixed with infiltration by acidophils. Around small ducts also seen increase in connective tissue, while the gland cells either showed decrease in size, lost the nuclei, or showed vacuole formation. The islets were generally normal, but in some areas showed production of hyaline-like substances (Fig. XVI). The hepatic interstitia showed throughout a fairly well-marked round cell infiltration, intermixed with lymphocytes and acidophils. Hepatic cells are somewhat dilated, but nuclei generally normally stained. No changes in the Kupffer cells. Fat stains showed more or less a diffusion of fat droplets in the peripheral regions. Diagnosis : Chronic cholecystitis and chronic allergic pancreatitis. Case 3. M. N., aged 27 years, female. Past history : Operated upon for appendicitis about 3 years ago. Present condition : In August 1953, about 2 hours after meal, had violent pains in the left costal margin. Since then has had repeated attacks of such pain, almost every evening at about the same time. Pain not radiated to other areas. During that time had fever throughout, about 37.5° C during the day and about 38.2 during the night. Obstinate constipation, with bowel movements once every 4 or 5 days. That greatly improved about the middle of December, and almost no distress was felt. Early in May 1954, completely lost of appetite owing to over fatigue, and since then, has had continuous violent pains in the left costal margin, with nausea and vomiting. Bowels constipated, with about one move ment every 2 days. Urine volume decreased, but reportedly not turbid. During the day pain was slight and tender to touch, but at night there was a violent attack of colic in the left costal arch which was directed to the back. During the attack limbs became cold, sometimes accompanied by rigor. From early May, for about a month received daily injections of 600,000 units of penicillin, Chloromycetin for 3 days and injections of glucose solution and methionine. But diagnosis remained indefinite with no improvement in general condition. Hence was hospitalized at the writer's Department on May 27, 1954. Chief complaints : Pain in the left costal arch, nausea. Obejective findings and results of tests : A belt of resistance and tenderness in the area to the left of the center of line joining the umbilicus and xyphoid process. Blood findings : leucocytes, 4,600; erythrocytes, 4,602,000 ; hemoglobin content, 90%; acidophils, 45!6'. Fasting blood diastase, 138.6 mg/dl; maximum deviation after Vagostigmin test, -42 mg/dl; fasting blood sugar, 97 mg/dl; and approximately normal. Staub's effect after double loading with glucose orally, negative. Serum bilirubin, 0.42 mg%; direct bilirubin content, 0; indi- DISORDERS OF THE PANCREAS 127 rect, 0.42. Blood prothrombin amount, 85%; thymol tubidity reaction, 1.9 units; bromsulphalein test after 30 minutes, 0-55'()'; alkaline phosphatase, 6.0 Bodansky units; congored index (the Adler-Reimann method), 73.3. Nothing abnormal noted in the urine and feces. Blood sedimentation rate, midvalue 7. X-ray of gastric region revealed the stomach to be Holzknecht's form ; no obstruction to emptying, but stasis of barium in the duodenum noted, and edema of the mucosa seen. After an injection of 1 mg of histamine chloride there appeared urticaria not only at the site of the injection but over the entire body. After an inspi ration of 205'.;' acetyl choline for 3 minutes there appeared dyspnea and a marked lowering in vital capacity. Laparotomy findings : Slight swelling of the head of the pancreas, and small regional adhesion of the peritoneum at the cecum. Histological findings : Parts of the pancreatic parenchyma showed a partial atrophy, intermixed with other areas showing hypertrophy of the gland cells. In the latter the blood volume somewhat increased. No marked changes in staining of nuclei noted, but in the atophied areas nuclei stained well, and the cell itself became smaller and elongated. Between them slight infiltration by lymphocytes noted, while in the atrophied cell tissue foci of necrosis noted. The boundary between healthy part was not clear and near such areas nuclei of some of the gland cells showed destruction. In the interstitia were noted irregular growths of the connective tissue which invaded the lobules and made the gland tissue coarse in appearance, but infiltration by round cells compara tively slight. In general there was noted growth of the ductules, but no changes noted in the blood vessels. The islet cells atrophied and their number decreased markedly (Fig. XVII). Diagnosis : Chronic relapsing allergic pancreatitis. Case 4. G. F., aged 54 years, female. Past history : Had rheumatic arthritis about 10 years ago, and has suffered occasionally from knee joint pains. Also frequent attacks of urticaria. Present condition : In early May last year, had feeling of fatigue and pain in the right arm. Feeling of obstruction in the esophagus, thirst, oppression in the epigastrium and feeling of inflation in the stomach area about 30 minutes after meal. Bowel moved once in about 2 or 3 days. Consulted many physicians, but diagnosis remained indefinite. From early June had diarrheal stools about 3 times a day. Chief complaints : Oppression in the epigastrium and inflation of the stomach 30 minutes after meal, slight thirst and feeling of esophageal blocking. Objective findings and results of tests : Physique and nutrition medium. Resistance over the entire epigastrium, especially in the center of a line joining the umbilicus and the xyphisternum. A thumb head sized tumour, hard and with irregular surface, felt. Blood showed : erythrocytes, 3,200,000 ; hemoglobin, 80J Case 6. S. T., aged 48 years, female. Present condition : Oppression, especially fullness in the epigastrium for several months. Vomiting sometimes, but no attacks of violent pain. Chief complaint : Fullness in the epigastrium. Objective findings: Between the epigastrium and left costal arch an im· mobile tumour palpable ; tenderness marked. Blood showed : erythrocytes 3,820,000; hemoglobin content, 70?.;'. Stools showed Ascaris ova, occult blood negative. Urinary diastase was 256 units and increased. Blood diastase (Wohlgemuth's method), 16 units. Laparotomy findings: No marked changes in the gall bladder and stomach; the pancreas showed some generalized hardening. Histological findings: The interstitial connective tissue of the pancreas showed a marked proliferation and invaded the interlobular spaces and lobules, resulting in an atrophy of the parenchymal gland cells, and a production of scattered false lobules marked by the infiltration of cells, mainly of lymphocytes and acidophils. The islet cells appeared large and edematous ; no special changes seen in the pancreatic duct and walls of the blood vessels. Diagnosis: Chronic allergic pancreatitis (Old form). Case 7. S. N., aged 38 years, female. Past history: Laparotomy 5 years ago for an inflammation of the oviducts ; frequent attacks of urticaria. Present condition : Two days ago had pain in the left lower abdomen radiating to the left back. No nausea and vomiting. Fever of about 37o C, slightly constipated. Urticaria appeared with abdominal pain. Chief complaint : Pain in the left costal margin. Objective findings: Tenderness over the entire abdomen, especially in the epigastrium. Tumour not palpable. The blood showed no special changes, no anemia; acidophils, 2.?C; fasting blood diastase, 1,213.8 mg/dl, and specially raised. The maximum deviation after the Vagostigmin test, -319.2 mg/dl, and showed abnormality. Fasting blood sugar, 81 mg/dl. Double loading by an intravenous injection of glucose solution showed the numerical value of -51, and abnormal. Urinary diastase, 1,024 units (Wohlgemuth's method), and in· creased. Laparotomy findings: No change in the stomach and gall bladder, an in· crease in the hardness of the entire pancreas noted. Progress after operation : Frequent attacks of abdominal pain accompanied by urticaria, but cured by oral or parenteral administration of anti-histamine drugs. Histological findings : Arrangement of gland cells in the parenchyma of the 130 S. AOYAMA pancreas almost normal, but some showed dilatation while others atrophied. There was a production of the connective tissue in the parenchyma, which in vade the interglandular spaces. Closely adjacent to the blood vessels were seen nodosities consisting of lymphocytes, acidophils and fibroplasts. The islet cells may be larger or smaller than ordinary ones, and the former became vacuolized, but hemorrhage and necrosis not seen. No special changes seen in the blood vessels and the pancreatic duct. Diagnosis : Chronic allergic pancreatitis. Case 8. Y. S., aged 23 years, male. Present condition: From about 7 years ago has had dull pains in the epi gastrium after drinking liquor, after taking meals and after labor. In February and September 1953 had sudden pain in the right costal margin that radiated to the right back and the chest. Was diagnosed as cholecystitis by a certain physician and received injections of analgetic for about a week, and the condition became better. In January of last year about 4 hours after supper had sudden violent pains under the right costal margin that radiated to the right chest and back. Nausea registered but no vomiting. Was not relieved by injections of analgetic, and was admitted to the writer's Department on the following day. Stools once a day, and normal in nature. Chief complaint : Pain in the right epigastrium. Objective findings and results of various tests: No marked findings in the chest, muscular defense below the right costal margin characterized by extreme tenderness. Blood findings: erythrocytes, 4,170,000; leucocytes, 8,200. Acid ophils slightly increased. Fasting blood diastase, 98.0 mg/dl; maximum devi ation after the Vagostigmin test, +62.0 mg/dl. Fasting blood sugar, 86 mg/dl; after double loading orally with glucose, Staub's effect negative. Urinary dia stase, 398.7 mg/dl, and slightly increased. Total serum bilirubin, 0.80 mgJ{; the direct, 0.47; and the indirect, 0.33. The thymol turbidity test, 1.45 units; cephalin flocculation test, after 24 hours, ( + ) ; after 48 hours, ( * ). Hippuric acid synthesis test, 28.209{; bromsulphalein test after 30 minutes, 5-10JC. Blood prothrombin content, 93%; alkaline phosphatase, 2 units; and the direct serum bilirubin amount, hippuric acid synthesis and bromsulphalein tests were there fore abnormal, but no marked changes noted otherwise. Urinary urobilinogen markedly positive, otherwise no change in urine. Ascaris ova positive in stool. Blood sedimentation rate was 34.5 (midvalue) and accelerated. Gastric juice showed hypoacidity, lactic acid and occult blood negative. Duodenal juice showed lowering in diastase, trypsin and lipase, and after the intramuscular injection of Vagostigmin slight increase in concentration of ferments. X-ray of the gastric area showed slight atony of the entire stomach, and though no retention noted in the pyloric region after the barium meal, emptying into the duodenum slug gish, and slight widening of the duodenal opening recognized. Though tender ness marked in the gall bladder region, there was seen, when pressure was ap plied to this region, acceleration of passage of meal from the stomach to duo denum. Laparotomy findings: The gall bladder slightly increased in size and con gested, but no stones found. No marked changes in the biliary tract. Increase DISORDERS OF THE PANCREAS 131 in hardness noted over the entire pancreas, from the tail to head, and especially the neck and body surfaces were characterized by ruggedness and appeared cirrhotic. No marked changes in the stomach region. After discharge from hospital progress was satisfactory for some time, but after about 6 months, returned for examination with complaints of gastric dis tension, loss of appetite and dizziness. After the cortisone therapy the symptoms disappeared. Histological findings: In pancreatic lobules were found in places fibrotic changes, and in areas most markedly affected glandular cells showed an atrophy and a decrease. Pancreatic ductules possessing cavities collected together, and in between were seen proliferations of a large amount of connective tissue. No changes in size noted in the isles, but in some parts were seen darkly stained islet cells. Necrosis and hyalinazation not seen. Interlobar connective tissue showed fair grade of proliferation, accompanied by infiltration by round cells intermixed with acidophils. Especially adjacent to the blood vessel walls were found nodosities characterized mainly by basophilic cell infiltration. Giant cells were not seen. Proliferation of the connective tissues also seen around the pan creatic duct (Fig. XX). Diagnosis: Chronic allergic pancreatitis. Case 9. H. K., aged 48 years, male. Present condition: Epigastric distension for about 3 years. No pain, nausea, vomiting or loss of weight. Was diagnosed as gastritis by several physicians, and given digestives, but with no improvement in condition. Received X-ray examination of the gastric region at a hospital and operation was recommended for suspect gastric cancer. Bowels slightly consitpated, moved once in about 2 days ; appetite good. Chief complaint : Epigastric distension. Objective findings and results of tests : Immobile, relatively firm swelling running horizontally in the epigastrium felt. Tenderness noted. Blood findings : erythrocytes, 4,420,000; hemoglobin content, 825'1>'; leucocytes, 6,400; no acidophils. Fasting blood diastase, 81.9 mg/dl. Maximum deviation after the Vagostigmin test, -14.7 mg/dl; fasting blood sugar, 98 mg/dl; after the double loading with glucose given intravenously, +20; urinary diastase, 8 units. Hepatic function test showed thymol turbidity test to be 2 units, and bromsulphalein test atfer 45 minutes, 5-0%. No special findings in urine and stool. Blood sedimentation rate, 5.5 (midvalue). X-ray examination of the gastric region showed a hori zontally running markedly tender swelling by the side of the duodenal bulb, otherwise no changes were noted. Laparotomy findings: The stomach almost normal. The neck of the pan creas slightly hardened, and adherent to the duodenum. No other marked changes. Histological findings: Gland lobules of the pancreas irregular in arrange ment, and a proliferation of the interstitial connective tissue seen fairly fre quently. No changes noted in size and morphology of gland cells. No changes also noted in staining of nuclei. Close to the blood vessels and capsule, in the interstitia were seen some cellular infiltrations consisting chiefly of lymphocytes, 132 S. AOYAMA mononuclears and acidophils. No changes noted in the pancreatic duct. Near to the walls of the blood vessels were seen small necrotic foci in the connective tissue. Diagnosis : Chronic allergic pancreatitis. Case 10. S. H., aged 48 years, female. Since last June has complained of colicky pains, accompanied by vomiting, in the area extending from the epigastrium to the right hypochondrium. Ascaris was vomitted out, and the patient was treated under the diagnosis of chole lithiasis and ascaridiasis. However, the complaints remained, and was admitted to the Yamada Red Gross Hospital. In the epigastrium was noted a swelling of the size of an egg, which was hard, rugged on the surface and mobile, mov ing with the movements of respiration. Tenderness was noted. The liver, spleen and kidneys were not palpated, and there was no ascites. Gastric juice showed almost achlorhydria. Parasitic ova and occult blood negative in stools. No special abnormal findings in the urine. Serum bilirubin showed, total biliru bin, 1.21; direct, 0.77; indirect, 0.44. Thymol turbidity reaction, 2 units. Cephalin reaction negative. Alkaline phosphatase value, 1.63 Bodansky units. Roentgeno graphy of the stomach showed generalized gastroptosis. Relief picture was regular, with the gastric border smooth, and no abnormalities in the pylorus and duodenum. The swelling was therefore outside these organs. When Katsch's test was made there resulted complaint of burning sensation in the region midway between the umbilicus and xiphisternum, and hence the test was posi tive. Blood diastase showed abnormal rise, and the maximun deviation exceeded markedly the normal range. Staub's effect was positive with a double sugar loading test, but the fasting blood sugar level was abnormally high. Histological findings : A type of granulation tissue with nodules in various parts, and composed of epithelioid cells and very few lymphocytes. Giant cells were also seen. In the nodule there was seen no caseation ; instead there were seen one, sometimes two small bodies that appeared to be amoeba. There was leucocytic infiltration around the nodules; acidophils were present. The area around was rich in the connective tissue, with marked destruction of the pan creatic tissue, leaving only some ductules. In parts there was seen partial enlargement of the ductules. In other words, the swelling could be considered to be granulation tissue composed of collections of nodules formed by the in vasion of ameba (Fig. XXI). Diagnosis Chronic parenchymatous pancreatitis (amebic). 2. TUMOUR OF THE PANCREAS a. Clinical observations Of malignant tumours of the pancreas, carcinoma is the most frequently seen and is found mainly in the head of the pancreas. Jaundice appears as a result of the obstruction of the biliary flow by the growth itself, or by an edema, inflam mation of the biliary duct, swelling of the lymphatic gland, or a connective tissue proliferation accompanying or resulting from the tumour, and the picture presented is one of congestive jaundice. DISORDERS OF THE PANCREAS 133 Jaundice which associated with cancer of the pancreatic head is said to be characterized by its permanency and unchanged constancy in grade after ap pearance, but carefull observations of the serum bilirubin during the course of the disease revealed fluctuations. This is related to the state of flow in the biliary tract and hepatic function. The degree of jaundice does not necessarily run parallel with the size of tumour ; also though the jaundice might gradually and increasingly made its appearance, there were cases where it appeared sud denly as a high grade of jaundice. However, it must be specially noted that jaundice may not be associated with cancer of the pancreatic head. A cancer that causes difficulty in its differentiation from the one in the pancreatic head is that situated at the papilla of Vater. Ross and Klinge have stated that papillary cancer is associated with jaundice in all cases, and that it predates pain, while pain predates jaundice in cancers of the pancreatic head. This is a point that deserves attention, but was found not to hold true for all of the writer's cases. In cancer of the ductus choledochus an almost similar clinical picture was pre sented, but this type of cancer is relatively rare. Pain is an early and important characteristic. It differs in intensity with change in body position, and has been said usually to be intensified in the supine position. This was found to be generally true. Pain has been said to be most marked in cancers of the pancreatic body, and that its characteristics are pain in the upper abdomen, early and rapid wasting not accompanied by jaundice. Pain was mostly fulminating, sometimes dull. But it might sometimes be in the form of a feeling of heavy pressure, lassitude, inflation or oppression, or oppres sive discomfort. Reinhoff and Lewic has stated that pain of pancreatic cancer is not related to intake of meals, and can be differentiated from gastric pain, but we have found this not necessarily to hold true. In cancer of the pan creatic tail, with the exception of terminal cases, pain was usually slight. When the gall bladder swells as a result of pressure on the biliary tract, the so-called Courvoisier's symptom appears. According to the writer's findings at operation and autopsy, dilatation of the gall bladder was seen in almost all cases of cancer of the pancreatic head, but only in less than one half of the cases could it be palpable by an external examination. Metastasis from cancers of the pancreas was seen most in the adjacent lymph glands and the liver. It was usual for the metastases in the liver not to attain giant size. Abnormalities in the fasting blood diastase, in the Vagostigmin test, in the fasting blood sugar and in the blood sugar regulation might or might not be seen. As Malinowski has pointed out, the fasting blood diastase was markedly raised in cancer of the head of the pancreas, and this was also recognized, as has already been described, in the experiments on the transplantation of sar coma into the pancreas. Also in cases where the general condition was very poor, the value was low and the Vagostigmin test was often negative. Rise in the fasting blood sugar was seen seldom, and it was rarer to find glycosuria. Abnormal lowering of the blood sugar was seen as a special feature in cases of tumour of the islets, but in tumours of the external secretory portion of the pan creas, in the early stage, when there was stimulation of the islets, a lowering 134 S. AOYAMA in the blood sugar level with accompanying hypoglycemic symptoms sometimes took place. This fact deserves attention. Disturbance of the pancreatic secretion was often seen, but in the early stage such disturbance was not too apparent. In an organ like the pancreas where compensation is high, such findings may be considered to be expected. Only when the tumour had grown to a comparatively large size, were seen the typical signs of indigestion and diarrhea. b. Clinical cases As tumours of the pancreas, descriptions will be made here of only a few of the rare cases. Case 1. S. I., aged 59 years, male. Chief complaint: Pain in the left costal margin. Findings : In the left costal region was seen a tender hard tumour of the size of an infant's head, which appeared as if the spleen had swollen. Fasting blood diastase was 1,468.5; the Vagostigmin test, -121 and abnormal. Fasting blood sugar normal, Staub's effect positive. Laparotomy findings : In the left upper abdomen was seen an extremely hard oval flesh -coloured tumour. The spleen was pushed upwards and to the left, but the tumour consisted of the body and tail of the pancreas. Histological findings : Parenchyma of the pancreas was completely de stroyed, and spindle-shaped cells presenting a typical proliferation were abun dantly seen. The liver was congested, and showed fatty degeneration in the center of the lobule (Fig. XXII). Diagnosis : Sarcoma of the pancreas. Case 2. S. T., aged 64 years, female. Chief compalint : Epigastric pain. Past history: Violent pains in the upper abdomen 7 years ago. Clinical findings: In the center of the line joining the xyphoid and um bilicus was felt a tumour ; tenderness and pain present. Anemia not marked, acidophils, 4%. Fasting blood diastase value, 66 (lowered); the Vagostigmin test value, -24.15. Fasting blood sugar, 150; Staub's effect negative. Almost achlorhydria. Laparotomy findings : Gastric region normal. Almost the entire pancreas hardened. The gallbladder dilated. Histological findings : Pancreatic parenchyma destroyed. Proliferation of spindle shaped epithelioid cells seen, intermixed with lymphocytes, large mono nuclears and plasma cells. Blood vessels in general dilated (Fig. XXIII). Diagnosis : Squamous cell carcinoma of the pancreas. Case 3. I. I., aged 63, female. Chief complaint: Epigastric pain. Past history : Gastritis. Clinical findings: Tender tumour of size of hen's egg felt in the epigastri um. Erythrocytes, 2,780,000; hemoglobin count, 505'6'. Acidophils, 5%. Fasting blood diastase value, 30.4 (lowered); the Vagostigmin test value, +34.6. Fast- DISORDERS OF THE PANCREAS 135 ing blood sugar, 148; Staub's effect negative. Hypochlorhydria. Laparotomy findings : Almost the entire pancreas hardened and presented picture of cancer. Adherent to the pyloric portion, and infiltrated. Histological findings : Pancreatic parenchyma destroyed. Tumour with cancer nest structure containing numerous round columnar cells and in parts squamous cells seen (Fig. XXIV). Diagnosis : Adenocancroid of the pancreas. VI. Therapy The treatment must naturally vary with the individual patient and according to the nature of the case. Hence, discussion is limited here to problems com mon to all cases, and to some of the more important aspects. 1. TREATMENT OF SHOCK, 2. TREATMENT OF PAIN Omitted here 3. EFFECTS OF VARIOUS DRUGS ON THE EXTERNAL SECRETION OF THE PANCREAS When inflammatory changes are seen in the pancreas, there is need to keep the pancreas at rest. Pancreatic secretion is influenced by neurotk, humoral or humoroneurotic factors. Hence to stimulate or inhibit pancreatic secretion, these routes can be employed. Of the drugs those that have been experimentally or clinically clarified regarding their actions have been ommitted here, and what is described below is limited only to results obtained by the writer in experiments with dogs, and considered to have clinical significance. 1. Pilocarpine : After injection there resulted rapid increase in secretory volume, but there was not seen a tendency for the concentrations of enzymes to become lowered because of this. 2. Acetycholine : Showed almost the same tendency as the above. 3. Vagostigmin: Marked increase in both the volume of juice and the con centration of enzymes noted. 4. Imidalin (Benthylimidazolin): The volume secreted increased after the injection, and continued for a relatively long period. With this increase, there resulted a lowering in concentrations of both enzymes and bicarbonates. 5. Histamine : Clear increase in volume after the injection accompanied by a contrary lowering in the concentration of enzymes. 6. Secretin (According to Friedman-Thomas' method): Shortly after the injection there resulted a marked increase in volume which reached a maximum in 6 to 10 minutes, followed later by a gradual lowering. 7. Finalin (Diethylaminoethylbenzilate methobromide): After the injection there resulted clear decrease in volume accompanied by lowering in concentra tions of both enzymes and bicarbonates. The recovery in the enzyme concen tration preceded the recovery in the volume. Most of the secretion inhibitory preparations produce with decrease in volume secreted, no change or a slight rise in enzyme concentration, but this drug produced both decrease in volume 136 S. AOYAMA and lowering in enzyme concentration. This deserves attention from the clinical point of view. 8. Methobromine (Hexamethylene-1.6-bistrimethylammonium bromide): The volume secreted clearly decreased after the injection, accompanied by lowering in the enzyme concentration. However this lowering was not so marked as the decrease in the volume. 9. Pentamethionium bromide : The inhibitory action of this on the gastric juice secretion had been confirmed by Yamaguchi et a!., but it also inhibited the volume secreted and also lowered the concentration of enzymes in pancreatic juice. 10. Tebron (Tetraethylammonium bromide): Shortly after the injection the volume decreased but there appeared a tendency for a slight rise to occur in the enzyme concentration. 11. Banthine ( $-diethylaminoethylxanthene-9-carboxylate methobromide): The volume markedly decreased after the injection. The concentrations of fer ments and bicarbonates either became lowered or remained unchanged. 12. Proban thine ( P'·diisopropylaminoethy lxanthene-9-carboxylate methobro· mide): The same tendency as the above was seen, but more markedly. 13. Anticholine preparations (Adopon; a:-[N·(P'-diaethylaminoethyl)]·amino· phenylacetic·isoamylether-HCl): This acted as an anodyne and antispasmodic on smooth muscles, but produced a decrease in the volume of pancreatic secretion and a slight lowering in the concentration of enzymes. 14. Antihistamine drugs (Restamin; P'-dimethylaminoethyl benzhydryl ether): No marked changes noted. 15. Sex hormones : Both male and female hormones produced no definite effects on the pancreatic secretion. Sometimes there were no changes seen at all. 16. Vitamine A : Injections of this produced no change in the secretory volume, but there was seen a rise in the enzyme concentration. 17. Thiamine : There are various views regarding the influence of thiamine on the pancreatic secretion, but with doses usually employed clinically, no special changes resulted. 18. Riboflavin : 19. Vitamine Bs : 20. Vitamine Br2 : 21. Ascorbic acid: 22. Vitamine K: 23. Vitamine P : All the above produced no clear changes. 24. Kallikrein : Slight decrease in secretion after the injection, and a tend en cy seen for the concentrations of ferments and bicarbonates to increase some what later. 25. Umor: No changes in both the amount and the concentration of fer- ments noted. 26. ACTH: No special changes noted. 27. Penicillin : 28. Aureomycin : No marked changes produced. 29. Dihydrostreptomycin : Tendency for secretion to decrease but no changes noted in the concentration of ferments. 30. INAH: Appeared to be inhibitory. DISORDERS OF THE PANCREAS 137 4, THERAPEUTIC EFFETCS OF VARIOUS DRUGS ON PANCREATITIS For acute pancreatitis chemotherapeutic drugs, such as sulfonamide and anti biotics, such as penicillin have lately been used clinically, and different views have been presented regarding the action and effectiveness. In pancreatitis ex perimentally induced by E. coli in animals, it was recognized from observations based on the fluctuations in blood sugar and diastase, and from the histological findings, that Chloromycetin, Aureomycin, Streptomycin and Ilotycin produced good results, while Diazine, Irgafen and homosulfamin were not especially ef fective. Sulfathiazol and Damian given orally had some effect, while penicillin and the usual quantities of glucose solution produced no special differences from the controls. In pancreatitis due to staphylococci, sulfadiazine and Irgafen produced an early improvement in the blood sugar regulatory function, and the histological changes were also slight, and the disappearance of the acute symptoms rapid. Sulfathiazole, Damian and homosulfamin were also effective. Chemotherapeutic drugs and antibiotics both possess specific effects of their own, so that, as has been stated above, they are bound to differ depending on the causative organism. Next, concerning the question whether these drugs act specifically on pan creatitis itself regardless of the causative organisms, the writer's experiments have proved to the contrary. Hence these measures should be applied when it is suspected that a primary or secondary infection exists. What must be considered further in such cases is the presence of intestinal bacteria. In experimentally induced impairment of the pancreas, it was found that though a problem does not arise from the type of organism, there was a marked increase in the number of both aerobic and anaerobic bacteria especially in the duodenum and upper portions of the small intestine. Hence when drugs are administered in cases such as above, this factor requires consideration. Besides the above, in pancreatitis experimentally induced by various methods, from fluctuations in blood sugar and diastase values, as well as from histological findings, methionine, adrenalin, Finalin and ascorbic acid acted effectively, while vitamine K was somewhat of value in the early stage of inflammation and effec tive in the later stages. Thiamine, cyanocobalamine and atropine seemed to have some value, but insulin, pilocarpine and acetylcholine were not effective when compared with the controls. However, on considering the therapeutic effects of drugs, there is not only need for attention to be paid on the amount and method employed, but also on the effects on the subjective symptoms, and the influence on viscera other than the pancreas. Unless all these conditions are sufficiently weighed, it is not possi ble to give a definite view regarding their effects. 5. ON THE DIET AND 6. OTHERS In acute cases it is essential that the diet be such that it will not stimulate or be a burden to the pancreas as well as to the entire digestive tract. As the 138 S. AOYAMA secretion of gastric juice influences the pancreas via secretin, the diet should consist of abstinence from eating or drinking, or be one such as is given in the early stages on gastric ulcer. For pancreatitis, easily digestible carbohydrates are least stimulating, and to be recommended as the best, followed next by easily digestible proteins. Fats should receive the strictest consideration. Reagarding the influence of glucose and amino acids on the secretion of the pancreas, various investigations have been made, but the results obtained by the writer and his research colleagues revealed that the usual amount injected clinically had no special influence on the pancreatic secretion. Also from the viewpoint of the histology and the fluctuations of the blood sugar and diastase, the amount did not influence the inflammation in various experimentally induced pancreatitis. In chronic cases with stabilized symptoms the main aim of therapy is the pre· vention of the aggravation and recurrence of the disease, and the strengthening and discipling of the pancreatic function. For this the administration of a secretory excitant has to be considered, and in such cases secretin was preferred because of its selective action on the pancreas. The clinical investigations by the said researchers have proved that pancreozymin is not satisfactory. It is, of course, necessary to avoid diets that lead to the aggravation of the disease, but beyond this it is not necessary to resort to protective foods. Good results have been obtained by the administration of high protein foods. This is believed to have been due to the direct influence on the pancreas of the pancreatic se· cretion being dimished by the scarcity of amino acids, to the indirect influence on the pancreas of the gastric juice via secretin, and to the improvement in the hepatic function. However when the grade of the hardening of the pancreas was high, overburdening by diets was not desirable. The use of pancreatic enzyme preparations was, of course, necessary from the view point of supplementary therapy, but they should be given continuously not only after meals but in between meals too. In the case of pancreatic im pairment, observations on the state of the blood diastase and sugar, the changes in duodenal enzymes, and the nature of digestion and absorption of foods, are of help in recognizing the pathological changes. Hence during therapy, it is necessary to make these tests at frequent intervals to observe the progress of the disease. 7. ON SURGICAL TREATMENT Walter Hess states that "necrosis of the pancreas has been transferred from the surgical to the medical, and chronic pancreatitis from the medical to the surgical field." This statement cannot be accepted in its entirety. However when an operation to be performed, consideration has to be made on the con dition of the disease from the standview of pathogenesis, besides the problem of removing the affected part or the entire pancreas. The following techniques can be employed, namely : removal of the gall bladder and biliary and pancreatic calculi ; anastomosis of the gall bladder to the duodenum, or the biliary tract to the intestine; partial removal of the stomach to suppress gastric hyperacidity, and hence the production of secretin ; excision of Oddi's muscle for hypertony DISORDERS OF THE PANCREAS 139 of the sphincter ; excision of the visceral nerves for hypotony ; excision of the left visceral nerves from the viewpoint of pain transmission and control of the pancreatic blood circulation ; excision of the thoracic sympathetic nerves ; re moval of the solar plexus ; and excision of the vagus nerve with a consideration of its influence on the pancreatic secretion and action on the muscles of Vater's papilla. The operation to be considered will, of course, vary with the individual case. But so far literature on the applicability and therapeutic effects is scarce, and the experiments by the writer also could not help to present a definite con clusion. The practical aspects of this problem remain to be clarified. Regarding the limits of the pancreatic excision there have been various views. Complete pancreatectomy, as has been described above, leaves behind many disturbances which have to be considered. Of these the most important is the regulation of the hepatic impairment and sugar metabolism. The insulin sensitivity becomes extremely unstable, and attention has to be paid to hypogly cemia more than hyperglycemia. The extent of a partial resection where special care is unnecessary, after the operation, has to be considered from the aspects of the functions of the external secretion, carbohydrate metabolism, the powers of digestion and absorption, and the attitudes of the other organs, especially the liver, and the possibility of their reversibility. From a consideration of the results obtained, the extent of maxl mum removal seems to be eight-tenth. 8. SUMMARY The above statements regarding the therapy have been made from the aspect of the pancreas itself. However in pancreatic impairment, as has been described above, there are also seen various changes in the other body organs, especially in the gastrointestinal tract, the liver, the gall bladder and the biliary tract, all of which show very intimate correlationship with the pancreas. Hence, it is necessary that considering all these factors the treatment should be per formed from a wider angle. LIST OF REFERENCES Omitted here 140 S. AOYAMA EXPLANATION OF FIGURES FIG. I. Pancreatitis due to Candida albicans. Seventh day after the injection into the pancreatic duct of normal dog. Numerous Candida masses seen in the necrotic portion. Mycelial propagation seen in abundance in healthy peripheral region, but comparatively few in the center of the necrotic foci. McManus staining. 200 x FIG. II. Pancreatitis due to the Candida. Injection into the pancreatic tissue of normal dog (11th day). Widespread infiltration by cells, with gland cells scattered in shape of the islets. Cell infiltrations mostly by monocytes ; giant cells also seen. H. E. staining. 100 x FIG. III. Pancreatitis due to the Candida. Injection into the pancreatic duct of normal dog (17th day). Characteristic nodule formation with proliferation of leucocytes in the central zone, of epithelioid cells in the intermediate peripheral zone and of the connective tissue in the outermost zone. H. E. staining. 100 x FIG. IV. Pancreatitis due to the Candida. Fifth day after the injection into the ear vein of normal rabbits. The pancreas shows masses of the Candida in Langherhan's islets. McManus stain ing. 200x FIG. V. Experimentally induced viral pancreatitis. Coxsackie virus Connecticut-5 strain injected into the peritoneal cavity of the nor· mal mouse (72nd hour). Marked destruction of the gland cells, with majority showing necrosis. H.E. stain· ing. 400x FIG. VI. Experimentally induced allergic pancreatitis. Normal dog sensitized with horse serum followed by the reinjection of the same serum into the pancreatic artery (48 hours). In the pancreatic interstitia, especially close to the blood vessels, are seen round cell infiltration, especially by acidophils, and high degree of serous inflammation accompanied by fibrin formation. H.E. staining. 400 x FIG. VII. Experimentally induced allergic pancreatitis. Normal dog sensitized by horse serum followed by the reinjection of the same serum into the pancreatic artery (7th day). In the pancreatic interstitia are seen giant necrotic foci, with a part extending into parenchyma. H.E. staining. 100 x FIG. VIII. Experimentally induced allergic pancreatitis. Normal dog sensitized with emulsion of the normal dog pancreas, reinjection with the same emulsion into the pancreatic tissue (24 hours). In lobule of the pancreas are seen small necrotic foci containing giant cells, and with the central portions showing hyalinization. HE. staining. 400 x FIG. IX. Experimentally induced allergic pancreatitis. After sensitization of normal dog with emulsion of Langherhan's islets cells of the Bonito, reinjection of the same emulsion made into the pancreatic artery (5th day). Small necrotic foci in the pancreatic interstitium, formation of granulation tissue consisting of acidophils, polymorphnuclear leucocytes intermixed with fibrin, and formation of the partly organized thrombus seen. Also noted vacuole formation of the gland cells and basification. H. E. staining. 100 x FIG. X. Experimentally induced allergic pancreatitis. After sensitization of normal dog with horse serum, reinjection of the same serum made into the large pancreatic duct (48 hours). Desquamation of the pancreatic duct epithelia, cell infiltration around the duct DISORDERS OF THE PANCREAS 141 mainly by acidophils and monocytes, and fibrin formation. H.E. staining. 400 x FIG. XI. Experimentally induced allergic pancreatitis. After sensitization with emulsion of Langherhan's islets of the Bonito, the same emulsion reinjected into the pancreatic artery (5th day). Vacuole formation in Langherhan's islets cells, or destruction of the nuclei noted. No picture of regeneration. H. E. staining. 900 x FIG. XII. Reinjection of the dead bacilli into the pancreatic artery of dog with chronic abscess produced in the joint cavity by previous injection of hemolytic streptococci (24 hours). Near the hemorrhagic fatty tissue is seen the picture of a growing rheumatoid nodosity. The pancreatic parenchyma and Langherhan's islets show edema. FIG. XIII. Dog with chronic abscess produced in the joint cavity by injection of hemolytic streptococci and sensitized by the horse serum, reinjected by the same serum into the pancreatic duct (48 hours). Around the fatty tissue are seen many acidophils, monocytes and other cells showing nuclear degeneration. Marked fatty necrosis. FIG. XIV. Pancreatic impairment from dl-ethionine. d!-ethionine injected into the peritoneal cavity of normal guinea pig (4th day). Vacuole formation in the gland cells with part showing necrosis. Slight round cell infiltration in the interstitia, dilatation of Langerhan's islets and degeneration of the islets cells. H.E. staining. 200 x FIG. XV. Clinical case. Name: T. M. Diagnosis: Chronic interstitial pancreatitis (allergic). Oedema of interstitia, especially near the blood vessels seen round cell infiltration, consisting mainly of lymphocytes. acidophils and mononuclears. The parenchyma of the pancreas shows a trophy. H.E. staining. 200 x FIG. XVI. Clinical case. Name: T. I. Diagnosis : Chronic interstitial pancreatitis (allergic). Gland cells atrophied ; interstitia, especially around the blood vessels, shows pro lieferation of the connective tissue with infiltration by acidophils in the some parts. H.E. staining. 200 x FIG. XVII. Clinical case. Name: M. N. Diagnosis : Chronic interstitial pancreatitis (allergic). Irregularity of the lobules with necrotic foci in some. Proliferation of the connective tissue seen in the interstitia, but the round cell infiltration slight. H.E. staining. lOOx FIG. XVIII. Clinical case. Name: G. F. Diagnosis : Chronic interstitial pancreatitis (allergic). Granulation seen in the pancreatic lobules consisting of giant cells, monocytes and fibroplasts. Part of the gland cells shows atrophy. H.E. staining. 200 x FIG. XIX. Clinical case. Name: M. S. Diagnosis : Chronic interstitial pancreatitis (allergic). Marked proliferation of the connective tissue in the interstitia, invading also the pancreatic lobules and isolating the gland cells. In some parts are seen shapes of duct formation. Infiltration by cells mainly of lymphocytes seen in the pancreatic duct, especially around periphery of the blood vessels. H.E. staining. 400 x FIG. XX. Clinical case. Name: Y. S. Diagnosis : Chronic interstitial pancreatitis (allergic). Fibrin formation in the lobule<>, with some showing adenoma-like changes. Pro liferation of the interstitia and round cell infiltration, principally by basophils, around the blood vessels. H.E. staining. 100 x 142 S. AOYAMA FIG. XXI. Clinical case. Name : S. H. Diagnosis: Chronic parenchymatous pancreatitis (amebic). Parenchyma shows loss of lobular structure and becomes fibrosed throughout. The interstitia shows infiltration by acidophils, lymphocytes, fibroplasts, plasma cells and monocytes. Numerous nodules containing the parasites in the central position. H.E. staining. 400 x FIG. XXII. Clinical case. Name : S. I. Diagnosis : Sarcoma of the pancreas. The parenchyma shows complete destruction and numerous atypical proliferation of the spindle shaped cells. H.E. staining. 200 x FIG. XXIII. Clinical case. Name: S. T. Diagnosis : Squamous cell carcinoma of the pancreas. The parenchyma shows complete destruction, and proliferation of the spindle shaped squamous like cells. Dilatation of the blood vessels seen. H. E. staining. 400 x FIG. XXIV. Clinical case. Name: I. I. Diagnosis : Adenocancroid of the pancreas. Destruction of the parenchyma, with cancer nests containing numerous columnar and in parts squamous cells. H.E. staining. 400x THE NAGOYA jOURNAL OF MEDICAL SCIENCE. VOL. 18 PLATE 8 . FIG. I FIG. II FIG. III FIG. VI Shingo Aoyama : Clinical and Exp·erimental Study of Disorders of the Pancreas. THE NAGOYA JOURNAL OF MEDICAL SCIENCE. VOL. 18 PLATE 9. FIG. V FIG. VI FIG. VII FIG. 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