J.Jpn. Surg. Soc.. 55(7): 795-814, 1954
宿題報告
Total Pancreatectomy
|
First Surgical Division, Kyoto University Medical School Ichio HONJO |
After having performed 8 total pancreato-duodenectomies including one case who is living a healthy life now, three years after the operation, I have come to believe that this operation may well be applied to humans.
Results obtained by us imply the very important physiologic criteria which can not be deduced from the knowledge of partial pancreatectomy.
Furthermore, I have performed a number of experimental investigations on dog (i.e., total pancreatectomy with or without duodenectomy, pancreatic duct ligation and others), and compared these data with those of total pancreato-duodenectomy on man.
I should like to avoid discussing well known facts which have already been clarified by other authors, and to report only the data which concern urgent and important problems related directly to the life of the patients.
I. Efficiency of the Gastro-intestinal Tract after Total
Pancreato-duodenectomy.
In human cases, I make it a rule to do total pancreatectomy combined with resection of the duodenum, because there is the possibility of necrosis of the duodenal wall if we try to resect the pancreas alone. Moreover, in case of cancerous disease, total pancreato-duodenectomy is preferable as far as the radicality is concerned.
In order to evaluate the efficiency of the gastro-intestinal tract, we adopted the digestion and absorption test, determining the amounts of organic constituents (protein, fat and carbohydrate) in the feces compared with those in the ingested food, and calculated the approximate percentage of food utilization.
After the operation the digestion was found to be so heavily impaired in these dogs that the feces resembled vomitus and were greatly increased in volume.
In spite of the administration of pancreatin together with methionine, the absorption rate revealed a marked fall. That is, the absorption rate of carbohyrate dropped about 20 per cent and protein about 54 per cent.
As regards fat, individuality of the dog influenced the rate of absorption considerably, and the absorption rate, in the worst cases, turned out to be negative indicating that a part of the fat in the feces is an endogenous excreation product. I tried, therefore, to calculate the average absorption rate of fat by recording the total amount of fat intake, together with the amount of fat in the feces in all the animals investigated. The result showed that the average absorption rate of fat dropped about 68 per cent.
In experiments in which pancreatin and methionine were not given, even lower valves were obtained.
In man, in our series, the digestion and absorption test was done in 3 cases after the operation.
Although the average absorption rate of protein and fat dropped 25 and 43 per cent respectively, it is remarkable that the rate of carbohydrate preserved almost the normal value.
From these data it is reasonable to presume that man retains a much better capacity for absorption after total pancreatoduodenectomy than does the dog.
I investigated also the capacity of absorption one year after the operation and compared it with the average value found relatively soon after the operation and found that there was no appreciable difference between the two. We cannot expect, therefore, that the postoperative absorption capacity may recover by compensatory functioning of the other organs.
II. Possibility of the Development of Fatty Liver after Total
Pancreato-duodenectomy
Some authors have reported that remarkably fatty livers usually developed after total pancreatectomy in dogs, and these dogs died of severe disturbances of liver function. And also, it was reported that after the operation there occurred a striking reduction in the amount of the esterified cholesterol in the serum even to zero. If these phenomena in the experiments on dogs are also true of human cases, we are obliged to hesitate to carry out this sort of operation in clinical use.
I want to note here that the fatty liver which I mentioned is not the kind which appears in all cases soon after the operation, and has its origin in postoperative diabetes mellitus. The fatty liver discussed now is the one which appears about 6 weeks after the operation notwithstanding the administration of insulin.
1) Totally Pancreato-duodenectomized Dog
i) With Administration of Pancreatin and Methionine
Under administration of 5 Gm. of pancreatin and 2 Gm. of methionine per day, 6 animals survived for more than six weeks. The cholesterol ester ratio was maintained within the normal range in all animals except 1, throughout the postoperative course.
ii) Without Administration of Pancreatin and Methionine
In dogs to which methionine and pancreatin were not administered the serum cholesterol ester ratio fluctuated widely, but there was no tendency of gradual decline in its value. Fatty liver was observed only in 1 dog out of 6 at autopsy.
2) Totally Pancreato-duodenectomized Man
The ester-cholesterol ratio was determined in 3 cases for a long time after the operation.
The first case is still living 3 years after the operation and in a satisfactory condition without receiving any medication except insulin. The serum cholesterol ester ratio has been within the normal range throughout the postoperative course ; consequently, there seems to be no possibility of developing fatty liver.
The second case had been suffiering from obstructive jaundice of three months duration and showed a marked disturbance of liver function at the time of admission. After the operation the serum cholesterol ester ratio returned to normal and maintained its level for about 30 weeks. But because of the progress of Iiver cirrhosis, sever infection of the biliary ducts and the development of jejunal ulcer, the serum cholesterol ester ratio began to fluctuate and decreased gradually and, at last, the patient died about one year after the operation.
The third case died of gradually increasing anorexia and emaciation five months after the operation, in spite of the administration of methionine, vitamine B12 and folic acid.
The serum cholesterol ester ratio began to decrease when the general condition deteriorated. At autopsy, this patient was found to have generalized tuberculosis with the formation of caverns in the left lung.
Fatty liver was found only in the last case, but, I could not detect any trace of fat accumulation in the other case and in 3 more cases whose livers were examined at autopsy. That is, fatty liver was found only in 1 case out of 6 who survived more than one month after total pancreato-duodenectomy.
3) Summary
To summarize these data on man and dog : I could prevent the development of fatty liver in dog after total pancreato-duodenectomy by the administration of pancreatin and methionine. Moreover, even when I did not give these drugs, I recognized fatty liver only in 1 case out of 6. Thus, in our experiments, fatty liver did not occur in dogs in such a high percentage as reported in the literature.
One of the reasons for these discrepancies in the results may lie in the mode of feeding, because the animals were fed with boiled rice and barley together with dried fish instead of raw lean beef and horse meat.
These facts indicate that the diet may play a great role in the pathogenesis of postoperative fatty liver.
Since a man retains a much better capacity for absorption than a dog postoperatively, it is reasonable to presume that the risk of developing fatty liver in man must be much less than in dogs.
Although I experienced the development of fatty liver in one case, this case, as stated previously, died of the aggravation of tuberculosis. It has been generally accepted that fatty liver is apt to develop in certain cases of tuberculosis. One can not, therefore, ascribe the occurrence of the postoperative fatty liver solely to the removal of the pancreas.
It would appear, therefore, that total pancreato-duodenectomy does not result in the development of fatty liver in man unless severe complication take place ; in other words, the fatty liver develops postoperatively only in exceptional cases.
III. Blood Sugar Level and Insulin Sensitivity after Total Pancreatectomy
1) Insulin Dose
It was pointed out by some authors that in totally depancreatized dogs the dose of insulin should be reduced day by day after the operation, in order to avoid hypoglycemia. They interpreted this phenomenon directly as the increases of sensitivity of animals to insulin and also stated that this sensitivity was a characteristic sign of the development of fatty liver,
i) Totally Pancreatectomized Dog
In our experiments, I injected a certain amount of insulin daily to keep the level of the fasting blood sugar at about 200 mg/dl in the early morning.
I observed, under this condition, 26 dogs during more than three weeks after the operation. In this series we found it necessary to reduce the insulin-dose only in 6 animals, that is, about 20 percent of all the dogs investigated. Moreover, fatty liver developed in only in 1 animal.
It seems, therefore, incorrect to explain this phenomenon solely on the basis of fatty liver.
ii) Totally Pancreato-duodenectomized Man
I have experienced 6 cases whoses level of blood sugar were investigated during more than one month after the operation.
A patient, who is still enioying good health now, three years after the operation, has been constantly receiving about 30 units of insulin per day, with no sign of hypoglycemia.
Summarizing the data of the other patients, I was led to reduce the insulin dose when the patient was attacked by severe complications (e.g. the development of jejunal ulcer, severe infection of the biliary ducts, liver cirrhosis, recurrence of cancer and aggravation of tuberculosis etc.) and lost his appetite. But, if the patient had good appetite and was not afflicted with any severe complications, I found no need of reducing the insulin dose.
These observations in man indicate that the amount of insulin need not be reduced after total pancreato-duodenectomy as long as an adequate food intake is maintained.
2) Insulin Test
I used the insulin test in order to estimate the sensitivity of the body to insulin at a certain point of time.
i) Totally Depancreatized Dog
I injected intravenously into a totally depancreatized dog in a state of fasting a certain amount of insulin, and then recorded the blood sugar level at certain intervals for four hours after the injection.
In the totally depancreatized dog, the time required to reach the lowest level bocame much longer and also the time required to return to the previous level was more prolonged than in normal dogs.
From the determination of the assimilation index, which has been said to show the grade of sensitivity numerically, we have been informed that the index had a lower value in totally depancreatized dogs than in normal ones, that is to say, the degree of insulin sensitivity was decreased after the operation. In this point, I am obliged to correct my previous idea.
ii) Totally Pancreato-duodenectomized Man
In man, I injected insulin subcutaneously, and measured the level of the blood sugar as stated above.
I was able to carry out this test several times on the same person at various intervals after the operation.
The blood sugar curves thus obtained were quite similar to each other and showed a unique figure when compared with that of normal persons. In other words, although the velocity of the decrease in value of the blood sugar was very slight, the level of the blood sugar steadily fell, and sometimes there occurred signs of hypoglycemia.
From the determination of the assimilation index, I have come to find that the patient became somewhat insensitive to insulin in quite the same way as did the dog.
Under such a special circumstance as a state of fasting, both man and dog show sometimes symptoms of hypoglycemia after insulin injection.
As we do not experience such an occurrence of hypoglycemia after insulin injection in normal persons, we are apt to misinterpret this phenomenon as being caused by the increase of insulin sensitivity in totally depancreatized individuals.
But the truth lies in the fact that both man and dog become somewhat insensitive to insulin after total pancreatectomy as indicated clearly by the assimilation index.
3) Appearance of the Anterior Lobe of the Pituitary Gland after Total Pancreatectomy
In order to investigate the disturbed balance of postoperative sugar metabolism more precisely, I have attempted to examine the histological findings of the anterior lobe of the pituitary gland which is considered to have the most intimate relationship with the pancreas in regard to sugar metabolism.
With the use of Cresazan's staining method, I calculated the number of cells of each type in the anterior lobe of the pituitary gland after the method of Rasmussen. In this way, I detrmined the ratio of the number of eosinophile and basophile cells to that of chromophobe cells. Comparing the ratios of totally depacreatized dogs with those of normal ones, I found that both the eosinophile and the basophile cells were remarkably reduced in their number after the operation.
In man, I had a chance to examine the pituitary gland histologically at autopsy. From this material I could also presume that the number of eosinophile and basophile cells was considerably reduced.
These findings in the pituitary gland undoubtedly show us that the endocrine function of this organ decreased in its activity.
It has been generally pointed out that the amount of insulin demanded after total pancreatectomy is an unexpectedly small dose compared with that required in endogenous diabetes mellitus. Moreover, we usually ascribe the genesis of insulin-resistant diabetes mellitus to the hypofunction of the pituito-adrenocortical system.
Then, it is natural to suppose that the pituitary gland which is regarded as the antagonistic organ to the pancreas in regard to sugar metabolism will come to display its full effect after total pancreatectomy.
We wonder, therefore why we do not need to use a large amount of insulin for the treatment of postoperative diabetes mellitus.
This discrepancy will be solved by the fact that the endocrine functioning of the anterior lobe of the pituitary gland is lowered after total pancreatectomy, although the disappearance of another hormone of the pancreae "glucagon" must be taken into consideration.
Postoperative decreased insulin-sensitivity will be explained by the fact that the numerically decreased, yet still existing chromophile cells will continue to fulfill their function confronting the absence of the pancreas.
Postoperative hypoglycemia which appears sometimes in a state of fasting of long duration may be due to undernutrition in general, particularly in the liver, caused by the decreased efficiency of the gastro-intestinal tract.
Be that as it may, it is ascertained by our study that the endocrine activity of the pituitary gland is lowered after total resection of the pancreas. At this point, one may say that a depancreatized dog is coming near spontaneously to Houssay's dog whose depancreatogenic diabetes mellitus is decreased in its severity by subsequent resection of the pituitary gland.
IV. Problem of the Development of Jejunal Ulcer after
Total Pancreato-duodenectomy
In totally pancreato-duodenectomized dogs, jejunal ulcers are apt to develop, particularly at the neighbouring site of the gastrojejunal anastomosis, and these dogs die sometimes of severe hemorrhage or perforation of the ulcer.
I have experienced this kind of ulcer in such a high percentage that 19 dogs out of 26 suffered from ulcer formation.
Thereupon, I tried to obtain some factors concerning the mechanism of ulcer formation after total pancreato-duodenectomy.
I could not find any difference between the dogs which were given pancreatin and methionine postoperatively and those which were not. And also, the percentage of ulcer formation was not influenced signigcantly by whether the antrum of the stomach was resected completely or not.
Then I attmpted to find some relationship between the postoperative blood sugar level and the ulcer fnormation. In our experiment, although we tried to control the dose of insulin by determining the blood sugar level in a fasting state early every morning, the blood sugar level fluctuated so widely throughout day and night that the dog was found sometimes to be in a state of hypoglycemia. We divided, therefore, these dogs into two groups ―those which did not show any sign of hypoglycemic shock throughout the postoperative course and the others which did.
As a result of our observations, we were able to determine that ulcers developed in all dogs whlch exhibited hypoglycemic shock, and the dogs in which ulcer did not develop belonged to the group in which hypoglycemic shock did not occur.
To confirm this finding, I performed an operation of total pancreatectomy on dogs without resecting the duodenum, and divided these pancreatectomized dogs into two groups ―the groud which was given a small dose of insulin maintaining the level of the blood sugar above normal constantly, and the other group which was given a large amount of insulin allowing occasional hypoglycemic shock.
We found that postoperative jejunal ulcer did not develop in the former group although it developed in 33 per cent of of the latter group.
These findings indicate that if one wants to prevent the development of jejunal ulcer, it is advisable to try to preserve the level of the blood sugar relatively high above the normal value after total pancreato-duodenectomy.
I ascertained, at autopsy, the formation of jejunal ulcer in 1 patient of our series.
V. Problem of Ascending Biliary-duct Infection after
Choledoch-jejunostomy
After total pancreato-duodenectomy, one must anastomose the common bile, duct or the hepatic duct with the jejunum. I experienced a severe ascending biliary-duct infection in 1 patient. After choledocho-jejunostomy on dogs, the gall bladder was usually found to be filled with intestinal contents and looked like a focus of infection in the biliary-duct system.
Thereupon, I extirpated the gall bladder at the time of choledocho-jejunostomy on dogs and found that the rate of infection of the biliary system was reduced from 73 per cent to 25.
Then I tried to investigate the functional activity of the gall bladder after choledocho-jejunostomy, even if the gall bladder was infected only to a slight degree.
As an indicator of the function of the gall bladder, I used the bile-concentration capcity.
After the ligation of the choledochus, the bile stagnates in the blood stream and the level of the serum bilirubin rises up. If we extirpate the gall bladder concurrently with choledocho-jejunostomy, the serum bilirubin content rises up much faster than before, because the bile-concentration capacity of the gall bladder is lost. By the use of this experimental method, we are able to estimate the activity of the bile-concentration capacity of the gall bladder of normal dogs.
Next I made the following experiment : first I performed a choledocho-jejunostomy, and then I reopened the peritoneal cavity more than one month after the first operation and determined the value of the serum bilirubin. In this experiment, the level of the serum bilirubin rose faster than in the previous one in spite of the existence of the gall bladder.
These results tell us clearly that the gall bladder can no longer display its normal activity of bile-concentration after choledocho-jejunostomy.
Because of this fact, I propose that extirpation of the gall bladder must be done concurrently with pancreato-duodenectomy for the purpose of removing the focus of infection.
VI. Calcium Metabolism after Total Pancreatectomy
I started to study the calcium metabolism after total pancreatectomy, as I had experienced one case of tetany after the operation.
I gave a test-diet which contained a certain amount of calcium both to normal dogs and to depancreatized dogs and then compared the amount of calcium excreted in the feces of the latter with that of the former.
I found that the amount of calcium excreted in the feces of the depancreatized dogs increased markedly and sometimes exceeded the amount of intake.
Nevertheless, the level of the serum calcium was almost within the normal range in the majority of cases of totally depancreatized dogs. Moreover, the level of the diffusible calcium of serum which probably is physiologically active was found to be within quite a normal range until nine weeks after the operation. Clinical signs of tetany, therefore, did not appear in the depancreatized dogs throughout the postoperative course of such a duration.
Next I measured the amount of calcium contained in rib of the dogs at various stages after the operation. I found that the amount of calcium contained in the rib of the depancreatized dogs was from one-fifth to one half less than the average normal value during from three to twelve weeks after the operation. Osteoporosis was found on histological examination.
The reason why he level of the serum calcium was preserved within the normal range in spite of the excretion of a large amount of calcium in the feces may reasonably be explained by the fact that the bone calcium was rapidly transported to the blood stream.
One patient of our series revealed, as stated before, symptoms of tetany eight months after the operation, and, at the same time showed a marked decrease of the serum calcium.
But this patient recovered soon after an adequate intake of calcium was instituted.
As a man preserves a better efficiency of the gastro-intestinal tract than a dog after total pancreatectomy, one cannot discuss the calcium metabolism in man as analogous to that in dogs. But it is advisable not to neglect the possibility of calcium deficiency in man after the operation.
VII. Changes in the Value for Serum Diastase after Total
Panrreato-duodenectomy
Although the source of serum diastase under in normal times conditions has been underinvestigation we have as yet no certain evidence.
In my experiments with animals, the serum diastase decreased somewhat after total pancreato-duodenectomy, but never to zero. But in man, I could ascertain the fact that the serum diastase disappeared completely, even if transiently, about two meeks after the operation. I propose, therefore, that the pancreas plays, even in the physiologic state, an important role as the source of serum diastase.
VIII. Vitamin A Metabolism after Total Pancreto-duodenectomy
One patient complained of transitory weakness of visual activity about eight months after total pancreato-duodenectomy and, at the same time it was disclosed that the value of his serum vitamin A was below the normal range. So, I decided to study the postoperative metabolism of vitamin A.
After operation the value of the serum vitamin A, both in dog and in man, decreased to below the normal range.
When fat-soluble vitamin A is given orally to the depancreatized dog, the absorption of it is found to be considerably disturbed. But water-soluble vitamin A is somewhat easily absorbed.
Then, I determined the value of serum vitamin A several times at intervals after the intravenous injection of the water-soluble vitamin A, and concurrently estimated the amount contained in the liver tissue.
Considering these data acquired from normal and depancreatized dogs, it is reasonable to presume that the destiny of vitamin A which enters the blood stream of depancreatized doge does not much differ from that of normal dogs.
In other words, the tissues of the depancreatized dog can utilize vitamin A which is injected into the body as adequately as the tissues of normal dog.
(author's abstract)
To read the PDF file you will need Adobe Reader installed on your computer.