THE LIVER AND ITS RELATION TO CHRONIC ABDOMINAL INFECTION BY CHARLES GORDON HEYD, B.A., M.D. AND JOHN A. KILLIAN, M.A., PH.D. STRUCTURAL CHANGES IN THE APPENDIX, GALL BLADDER AND LIVER FROM THE SAME PATIENT BY WARD J. MACNEAL, PH.D., M.D. THE LIVER AND ITS RELATION TO CHRONIC ABDOMINAL INFECTION / A CLINICAL, PATHOLOGICAL AND CHEMICAL STUDY, WITH CLINICAL DISCUSSION OF THE AFFECTIONS OF THE APPENDIX, GALL BLADDER AND LIVER BY Charles Gordon M.D. PROFESSOR OF SURGERY K AND John A. Killian, M.A., Ph.d. PROFESSOR OF BIOCHEMISTRY, NEW YORK POST-GRADUATE MEDICAL SCHOOL AND HOSPITAL STRUCTURAL CHANGES IN THE APPENDIX, GALL BLADDER AND LIVER FROM THE SAME PATIENT by Ward J. MacNeal, Ph.d., m.d. PROFESSOR OF PATHOLOGY, NEW YORK POST-GRADUATE MEDICAL SCHOOL AND HOSPITAL BEAUMONT FOUNDATION ANNUAL LECTURE COURSE III 1924 Copyright, 1924, by The C. V. Mosby Company (All rights reserved) Printed in U. S. A. . Press of The C. V. Mosby Company St. Louis, Mo. THE BEAUMONT FOUNDATION LECTURES THE LIVER AND ITS RELATION TO CHRONIC ABDOMINAL INFECTION A CLINICAL, PATHOLOGICAL AND CHEMICAL STUDY, WITH CLINICAL DISCUSSION OF THE AFFECTIONS OF THE APPENDIX, GALL BLADDER AND LIVER BY Charles Gordon heyd, B.A., M.D. PROFESSOR OF SURGERY AND John A. Killian, M.A., Ph.D. PROFESSOR OF BIOCHEMISTRY, NEW YORK POST-GRADUATE MEDICAL SCHOOL AND HOSPITAL STRUCTURAL CHANGES IN THE APPENDIX, GALL BLADDER, AND LIVER FROM THE SAME PATIENT BY Ward J. MacNeal, Ph.D., M.D. PROFESSOR OF PATHOLOGY, NEW YORK POST-GRADUATE MEDICAL SCHOOL AND HOSPITAL SERIES NUMBER THREE AUSPICES OF THE WAYNE COUNTY MEDICAL SOCIETY, DETROIT, MICHIGAN, JANUARY 28 AND 29, 1924 Published by THE. C. V. MOSBY COMPANY ST. LOUIS Lectureship Foundation Committee Wayne County Medical Society Walter J. Wilson James E. Davis Harold Wilson Worth Ross William E. Blodgett CONTENTS PAGE Foreword. (Heyd.) 9 PART I The Liver and Its Relation to Chronic Abdominal Infection: A Clinical, Pathological and Chemical Study with a Clinical Discussion of the Affections of the Appendix, Gall Bladder and Liver. (Charles Gordon Heyd, B.A., M.D.) 11 Anatomy and Physiology 12 Clinical Pathology 18 Physiological Chemistry (Killian) 28 Tabulation of Chemical Blood Changes in Diseases of Liver and Gall Bladder 34 PART II Applied Physiology. (Heyd.) 37 Surgical Pathology of the Gall Bladder 45 Differential Diagnosis of Affections in the Right Upper Abdominal Quadrant 49 Summary of Symptomatology in the "Four Phases" of Disease of the Biliary Apparatus, with Differentia- tion of Pancreatic Neoplasms 50 Jaundice 52 Calculus 55 Neoplasms 58 Appendix Vermiformis 59 Peptic Ulcer 65 5 PART III • PAGE Structural Changes in Appendix, Gall Bladder and Liver Removed from the Same Patient at Surgical Operation. (Ward J. MacNeal, Ph.D., M.D.,) 68 Tabulated Changes in Six Patients under 30 Years of Age 70 Tabulated Changes in Six Patients from 30 to 39 Years of Age 89 Tabulated Changes in Six Patients from 40 to 49 Years of Age 109 Tabulated Changes in Six Patients above 50 Years of Age 136 Discussion 161 Summary 164 6 PREFACE The third series of the Beaumont Lecture Founda- tion is here presented by three active workers in the fields of surgery, pathology, and physiological chem- istry. A broad clinical research has been undertaken and carried on through excellent team effort which has resulted in the production of valuable data concerning the structural changes in the liver associated with, or dependent upon, infections involving particularly the appendix vermiformis, gall bladder and gastroduode- nal tissues. The clinical and pathological material studied has come almost exclusively and directly from the operat- ing table, thereby affording the best obtainable tissues in a fresh state and opportunities for the closest possi- ble association of the clinical symptomatology. At the same time the test of operation has been made, not as an experimental procedure, but as a therapeutic meas- ure indicated by the usual diagnostic guides and the assurance gained in the experience of well-controlled practice. It is indeed a valuable record when from the every- day work, there can be set down findings made in the course of the development and completion of case his- tories. The routine excision of biopsy sections from either the right or left sides of the liver during the time of laparotomy for other work has given tissue of unusual value and is a new departure in routine sur- gery that should prove of marked value in relating symptoms, morbidity and mortality with departures 7 from structural standards. The blood chemistry read- ings and interpretations, especially with the fatal cases when set alongside the liver cell changes often afford reason for death but the usual clinical diagnostic phe- nomena have not as yet set forth the patient's tolera- tion of the risk to life when submitting to abdominal operation. There is reason to believe that with this example of means for a more exacting study of clinical criteria progress has been made to greater protection of life by preservation of a greater margin in liver function. It is gratifying that we are able in this Beaumont series to preserve a certain unity and consecutive rela- tion for the entire work thus far given in this Foundation. July 1, 1924. James E. Davis, A.M., M.D. For the Committee. 8 FOREWORD Since 1910 we have been interested in certain func- tions of the liver and during the last few years have been working on the incidence and pathology of hepatitis. In considering hepatitis we define that form of hepatitis that is associated with or sequential to the more chronic inflammatory diseases of the abdo- men, particularly those involving the right side, includ- ing affections of the pelvis, appendix, gall bladder and gastroduodenal segment and to a lesser extent general- ized chronic infections of the abdomen. Abscess, in- farct and embolism of the liver as complications of suppurative conditions, either in the abdomen or else- where, are not included. Pathologically, we refer specifically to the low grade inflammatory changes in or about the small bile radicles, and about the peri- portal veins and characterized by hepatic cellular degeneration with fibrous tissue replacement. The finding of varying degrees and various types of hepatitis at autopsy has been of such frequent occur- rence that pathologists have accepted this finding as a commonplace of postmortem examinations. Hepatitis, using the word per se and distinct from either Laen- nec's or Hanot 's cirrhosis, is casually mentioned by one reference only in Moynihan's "Gall Stones and Their Surgical Treatment" under the head of Hepatitis Sequestrans and refers to hepatic slough incident to empyema of the gall bladder. Hepatitis is mentioned twice by Osler in his "Practice of Medicine," once under the head of Interstitial Cirrhosis referring to Laennec's Cirrhosis and again under the head Sup- 9 putative Hepatitis referring to Abscess. It will there- fore be noted that hepatitis as a pathologic or clinical entity in connection with abdominal disease has re- ceived but scant notice. Pathologically, it has received more extended notice but without any clinical data, for interstitial hepatitis is found repeatedly in post- mortem examinations without the presence of such condition being noted during life and without the presence of any symptoms pointing to its existence. Reidel in 1881 thought that the linguiform process of the right lobe of the liver depended upon disease of the gall bladder, such as inflammation, stones, disten- tion or traction through pericholccystic adhesions. 10 PART I. THE LIVER AND ITS RELATION TO CHRONIC ABDOMINAL INFECTION: A CLINICAL, PATHOLOGICAL AND CHEMICAL STUDY WITH A CLINICAL DISCUSSION OF THE AFFECTIONS OF THE APPENDIX, GALL BLADDER AND LIVER CHARLES GORDON HEYD, B.A., M.D. Professor of Surgery New York Post-Graduate Medical School and Hospital Apparently, there are at least four factors that bring about low grade liver changes. The first is infection, the second chronicity of infection, the third toxicity of the infectious by-products either by lysis of the bac- teria themselves or the toxins they elaborate, and the fourth, the catabolic by-products of metabolism. In nephritis we have a gradual degeneration of the kid- ney substance and coincidentally an inability of the kidney to eliminate certain intermediate by-products. We find on chemical examination of the blood certain characteristic changes in the quantities of the various chemical derivatives of protein metabolism and accord- ing to their retention in the blood we are able to deter- mine the extent of the renal lesion. In other words, in a degeneration of the kidney parenchyma we have an excellent example of dysfunction with the inability of the kidney to perform adequately its eliminative function and later, a complete cessation of kidney 11 function as manifested by uremia and the suppression of urine. It seems reasonable therefore to assume that the liver might exhibit certain disturbed states or func- tions. Tn other words, the liver may show an insuffi- ciency in function-hepatargia; or a perverted func- tion-dysfunction; or finally, a complete cessation or exhaustion of function. Probably the primary cause of some of the conditions that we consider metabolic diseases, gout, nephritis and arthritis, may be due to an inability of the liver to protect the body against certain toxic by-products. Anatomy and Physiology If we survey the liver from the point of view of its anatomic or physiological situation we are cognizant of certain outstanding characteristics. In the first place, the liver is an offshoot of the primitive foregut. The latter begins at the pharynx and terminates at the ampulla of Vater and within that segment of the gut tube every digestive enzyme is elaborated and excreted. In this particular portion of the primitive gut tube every chemical process for digestion is carried out, while the segment from the ampulla of Vater to the ascending colon is primarily concerned only with absorption. The liver weighs roughly fifty ounces. It represents about one-fortieth of the body weight in the male and one-thirty-sixth of the body weight in the female. An additional weight of ten per cent will represent hyper- trophy, while a diminution of ten per cent will repre- sent atrophy. The liver is a complete biochemic laboratory which is interposed between the portal and systemic circulation and transmutes the food into energy value. It is the chief of the metabolic workshops and regulates body metab- 12 olisin by enzyme action. Some of the enzymes are intrinsic and elaborated by the liver itself and others are extrinsic and brought to it from different viscera by the circulation. Hess and Serege ascribed various functions to different portions of the liver. It is inter- esting to recall that Silvestri and others attempted to specialize liver function in regard to the right and left lobes of the liver. It has been a frequent observation that when the liver is enlarged in diabetes the right lobe is more uniformly affected, while in Banti's dis- ease and other splenomegalias it has been observed that the left lobe participates more particularly, while trop- ical liver abscess is almost exclusively on the right side. The work of Glenard and Serege lends emphasis to this contention for in their experiments the left lobe of the liver is intimately connected with the stomach and spleen, while the right exhibited more definite relationships with the pancreas and small in- testine. The injection of staining fluids into the spleen invariably produced discoloration of the liver limited to the left lobe while injections into the superior mesenteric veins, as a rule, stained the light lobe of the liver more than the left. The liver has an unusual vascular supply, an ar- rangement of afferent and efferent blood that is found in no other organ in the body. The spleen and kidney perform their specific functions in the presence of a large supply of oxygenated blood. The liver, to the contrary, performs its functions with a blood that, except for a relatively small amount of arterial blood supplied by a minor portion of the hepatic artery, is entirely of a venous type. Two-thirds of the arterial blood via the hepatic artery is diverted to the gastro- duodenal, pyloric, supraduodenal and cystic arteries. One has only to compare the arterial blood of the liver with the arterial blood sent to the spleen or kid- 13 ney, the latter two organs performing their functions in the presence of an adequately or amply oxygenated blood. The liver, on the contrary, performs all of its functions with blood that is essentially nonoxygenated as the individual liver cells receive blood only from derivatives of the portal vein, the hepatic artery sup- plying the walls of the blood vessels, the bile ducts and the liver capsule. The blood supply to an organ is roughly an index of its metabolic rate. Inferentially, the kidney concerns itself with the terminal oxi- dative processes, while the liver apparently is con- cerned with an intermediate phase of metabolism where oxidation is not preeminently required. Synthesis and analysis, so far as they are intrinsic liver functions, are carried out by venous rather than arterial blood. Since the amount of blood supply to any tissue is an accurate index as to its metabolic activity it would follow that comparing the liver and kidney the meta- bolic activity of the kidney must be largely in excess of that of the liver. It would seem that the liver would represent a resting phase in glandular activity where materials are stored for partial catabolism in prepara- tion for the more active cellular oxidation taking place in the muscles and other tissues. It has not been definitely demonstrated whether any of the hepatic arterial blood goes beyond the interlobular septa; such transference of material from arterial blood to hepatic cells must be by osmosis and not by anatomical ar- terial canaliculi as the hepatic artery has no paralleling veins. Again, the venous blood entering the liver is diverse in its source and different in quality from or- dinarily considered venous blood. The portal blood represents (1) from one-sixth to one-eighth of the splenic venous blood, deprived of most of its oxygen after passage through the spleen; (2) the mesenteric venous blood is surcharged with products of absorption 14 from stomach, duodenum, pancreas, small intestine and the major portion of the large intestine. On the other hand, the hepatic veins carrying the blood from the liver to the vena cava, in addition to the above moieties, have the venous equivalent of the hepatic arterial blood. Biologically, the liver is probably the second oldest organ in the body, the oldest being the gut tube itself, with the liver developed as an early offshoot. The functions ascribed to the liver are diverse and repre- sent extreme variability in biochemical activity. Cer- tain functions, however, may be safely predicated at this time. The liver is the great reservoir for con- verted sugar, remaining in the liver in the form of gly- cogen. In association with this glycogenic storage the liver maintains a constant level of blood sugar.* In this latter activity there is an undoubted reciprocal relationship with the internal secretion (insulin) of the pancreas. Of equal ranking importance with the glycogenic function is the activity of the liver in the metabolism of proteins, the synthesis of urea, the catab- olism of purins, the maintenance of the ammonia bal- ance and the diaminization of the amino acids. The liver has some antimate chemical property whereby fat is stored or liberated, and that function is entirely distinct from the fatty degeneration that occurs in some diseases of the liver. The clotting of blood is in some way controlled or influenced by the liver. It is probable that the liver elaborates fibrinogen which is one of the essential elements in the mechanism of the clotting of blood. Then again, there is the more obvious function of the liver, that of the secretion and excretion of the bile. In addition to these specific functions ex- erted by the liver it at all times possesses a marked depurative and detoxifying power whereby noxious by ♦Mann, Frank C.: Amer. Jour. Med. Soc., clxi, p. 37, 1921. 15 products from the gastrointestinal tract, or derived from cellular activity in general, or from bacteria, are rendered inert or harmless. One of the outstanding features of the liver, aside from its specific functions, is its ability to regenerate. The liver cell is the simplest of all histological elements. When a highly specialized cell is worked there is an increase in the size of the cell and the phenomenon is knoivn as the work hypertrophy phenomenon. This never occurs with a liver cell. It is incapable of ex- hibiting compensatory work hypertrophy. What the liver cell does is to undergo hyperplasia and regenera- tion. Mann was able to remove seventy per cent of the liver and within three months the remaining portion of the liver had regenerated sufficiently to make appar- enty a normal liver. Rous and MacMaster were able to ligate nine-tenths of the bile ducts without produc- ing jaundice and in a very short time the unligated portion of the liver regenerated sufficiently to carry on all of the liver functions. It may be assumed therefore that when there is simply a degeneration of liver cells there is an immediate regeneration of near-by cells and that this process goes on year in and year out under normal conditions of health. This phenomenon of re- generation explains the clinical finding at laparotomy of the many cases of fairly well advanced cirrhosis of the liver without symptoms because the hepatic re- generation that has taken place is sufficient to carry on the functions of the liver. Bassler found that in 321 laparotomies performed during 1914 there were thirty-nine instances of definite cirrhotic changes in the liver. Up to the end of 1921, in 2567 laparotomies cirrhosis occurred 221 times, or roughly in about 8 per cent of the laparotomies. The cellular architecture of the liver cell is very sim- ple. It contacts, as it xvere, on one side with the portal 16 system and on the other side with the biliary system. As a cell it is capable only of reproduction, regeneration and degeneration-death and the pathological element that follows a degenerative condition is fibrous tissue replacement. The question naturally arises, By what mechanism is the liver injured? Adami has drawn attention to the fact that throughout the intestinal tract leucocytes bearing fatty globules and bacteria are constantly pass- ing out through the surface layers into the tissues and MacCallum after giving peptonate of iron to a fasting animal found leucocytes containing iron in the walls of the gut and in the liver and spleen. Bacteria in short are constantly passing into the system from the intestines and as constantly being destroyed, notably in the mesenteric and other lymph nodes and in the tissues. Under such circumstances there is no infection in the accepted sense of the term, but with the destruc- tion of the bacteria there is liberated their toxins which produce a low grade chemical irritation result- ing in degeneration of the hepatic cells with fibrous tissue replacement. Furthermore, Adami emphasizes that there is "a temporary proliferation of bacteria in the capillaries to which they have been carried, until such time as mechanically or otherwise they set up irritation and reaction: so soon as the tissues react the bacteria undergo lysis. It is not their proliferation but their death that liberates the toxic substances, which diffusing out, destroy the higher tissue cells in the neighborhood and simultaneously stimulate the lower connective tissue cells to proliferate and develop an area of fibrosis. We deal, that is, with something be- yond local capillary infarct formation: the area of necrosis extends beyond the limit of the territory of the blocked capillary: its extent can only be ascribed to the action of liberated toxins. What is char act eris- 17 tic of all these cases is recurrence, or, more accurately, they represent not simultaneous infection but the sum- mation of a succession of minute insults to the tissues, sometimes occurring within a few days or weeks but often extending over years, so that on examination lesions may be discoverable in various stages. What is more, it is evident that the incriminated bacteria gain this current entry into the blood stream from various points."* Friederich by ligation of the slender delicate veins of the omentum produced punctate hemorrhage in the stomach in thirty per cent of the animals and small hemorrhagic or anemic infarcts in the liver in five per cent of the animals. With an infected thrombosis of the portal system there were septic infarcts in the liver. Braithwaitef demonstrated the path of lymph flow from the cecal region to the third part of the duodenum and stated that some (of the lymph) passed upward over the head of the pancreas to enter the group of glands along the inner border of curled duodenum, while on two occasions the injected fluid passes higher, reaching the glands along the common bile duct and even the gland of the cystic duct. Clinical Pathology Peterman reported that in 130 unselected cases of gall bladder disease admitted to the surgical service of Barnes Hospital, St. Louis, Mo., there were 82 cases of reported liver involvement. Of these 69 were "en- larged" or "edematous," 5 showed adhesions alone and 8 were "atrophic" or scarred. Gandy drew at- tention to the fact that at autopsies made on patients suffering from simple gastroduodenal ulcer there were always present more or less advanced hepatic lesions. ♦Adami, J. George: Jour. Iowa State Med. Soc., ii, 6, p. 375. tBraithwaite, L. R.: Brit. Jour. Surg., July, 1923- 18 MacCarty and Arnold Jackson stated that in a series of 58 cases studied in relation of hepatitis 81 per cent showed chronic inflammation. The livers were studied independently of any knowledge of the conditions of the gall bladder. Peterman, Priest and Graham regularly produced experimental cholecystitis by injection of organism into the lumen of the gall bladder after liga- tion of the cystic duct and vessels. An associated hepatitis was invariably found associated with the cholecystitis. Fuettcrer was able to recover bacteria injected into the portal vein two minutes later in the bile. Charcot produced biliary tract inflammation and later cirrhosis of the liver with marked hepatic changes by ligation of the common bile duct in rabbits and guinea pigs. Adami has demonstrated that under nor- mal conditions colon bacilli may be present in the blood stream and eliminated from the liver in ap- parently normal bile. There is no anatomical connec- tion between the arterial blood of the gall bladder and liver; the only canalicular system common to both organs is the lymphatic system. From the appendix to the liver, from the stomach, duodenum and pancreas to the liver we have both the portal and lymphatic system. Theoretically the liver may be injured (1) by way of the general arterial system: (2) from con- tact with contiguous pathologic organs: (3) from as- cending infection through the external bile ducts: (4) by means of the abdominal lymphatics: (5) by means of the portal system. Injury to the gall bladder and liver by means of the portal system is probably the commonest mechanism of hepatic trauma. Surgical infection of the liver by way of the portal system has its mechanism well demonstrated in acute septic pye- lophlebitis following gangrenous appendicitis. Al- though this is an acute septic embolic process it illus- trates a pathway from appendix to liver that is 19 presumptively constantly utilized in low grade subin- fective conditions. The complications that may reasonably be expected after laparotomy for gall bladder disease are clear-cut and distinct and possess within certain limits a chrono- logical sequence. In the first twenty-four hours the complications are anatomical, such as hemorrhage, shock, gastric dilatation and embolism. In the suc- ceeding forty-eight to seventy-two hours the element of infection might possibly come into play with the production of a peritonitis and still later abscess for- mation. We have observed occasionally three clinical states that supervene after operations on the gall blad- der and biliary system, and more rarely after gastric, esophageal or intestinal surgery, and which cannot be attributed to any of these factors. Although these clinical complications are comparatively rare yet they are definite and apparently within their group and are rather characteristic in their symptomatology. For convenience of description we have classified them into three more or less distinct groups* The first group is represented by patients who have had comparatively simple gall bladder operations. As a rule, the surgery has been confined entirely to the gall bladder and the removal of the appendix. The patients are always obese and have a history of chronic gall bladder dis- ease extending over a long period of time. Preliminary study of the urine and blood has assured us as to the competency of renal function. They have been anes- thetized with gas and ether and a cholecystectomy and appendectomy performed. Following the operation the recovery from the anesthesia is delayed, in fact, it may be said that they never completely emerge from their anesthetic. They remain, for four to six hours *Heyd, Charles Gordon: Surgical Clinics of North America, New York Number, 1923, W. B. Saunders Co. 20 after being returned to the ward, in a semicomatose condition. They develop talking delirium, carphology, subsultus tendinum, which finally passes on into coma, with death. In view of the fact that the postoperative clinical syndrome suggested a distinct mental irritation spinal punctures have been made with comparatively negative findings. The cell count has been 10 or 11 cells per cu. mm.; globulin one plus; Wassermann neg- ative. Preliminary studies seemed to suggest that there was no renal element in these cases although co- incident with the development of the delirium there is gradual diminished urinary output both in fluid quan- tity and in chemical elements. We were in the habit of attributing this condition to the development of a postoperative acidosis incident to the poor metabolism represented by chronic biliary disease and plus the additional elements of anesthesia and surgical trauma. In making a complete study of these patients both be- fore and after operation Dr. Killian* was able to show that the carbon dioxide combining power of these patients was far in excess of the normal and ap- proached values of 70 to 80 and occasionally to 90 volumes per cent and that the condition chemically is that of an alkalosis. In none of the patients in this group had there been preliminary administration of alkalies and we can reasonably exclude the suggestion of sodium poisoning. In the last two years in the col- lective service of the attending surgeons at the New York Post-Graduate Medical School and Hospital we have been able to study six of these cases, four of which terminated fatally. The second group is essentially different in its clin- ical manifestations. These patients, as a rule, have *Heyd, Charles Gordon; MaeNeal, Ward J.; Killian, John A.: Trans. Amer. Assoc. Obstet., Gynec. and Abdom. Surg., xxxvi, 1923. 21 had a very severe type of biliary infection and there has been a history of jaundice and a previous gall bladder operation. The patients have had a choledo- chotomy with drainage of the common duct and the postoperative progress has been satisfactory until about the end of thirty-six to forty-eight hours when they become irritable and "nervous." Within a very short time the patient passes into a pronounced vaso- motor collapse with cold, clammy, "leaky" extremities. The condition is not associated with gastric dilatation and there has been ample renal function. The intra- venous administration of glucose and saline and con- tinuous Murphy proctoclysis with tap water has usu- ally brought about a recovery: we have considered these cases as due to the liberation of some pancreatic toxin with inadequate liver protection. These cases do not exhibit the alkalinization of the preceding group and their blood chemistry is only changed insofar as there is a change in the percentage of the rest nitrogen to urea nitrogen. The third group presents a still more difficult phe- nomenon in that the lethal complication occurs in pa- tients who were apparently progressing favorably up to the end of five or six. days after operation. They were all patients with a clinical picture of calculous cholangitis, pancreatitis, or rarely, malignancy of the head of the pancreas. At the time of operation their blood chemistry had been studied and the coagulation time when necessary had been brought within the normal range by blood transfusion or the intravenous administration of 10 per cent calcium lactate. The operation had been undertaken for the relief of the pathologic condition of the gall bladder and common duct and to institute biliary drainage either externally through the anterior abdominal wall or by the anas- tomotic union of gall bladder to stomach. The imme- 22 diate postoperative condition had been satisfactory. The icterus had begun to diminish appreciably in in- tensity and the dehydrated condition had been mani- festly overcome by continuous Murphy proctoclysis of ten per cent glucose. These patients had been fed their own bile, where there was external drainage, either by swallowing, or by means of a stomach tube, or by being added to the Murphy proctoclysis solution. It was reasonable therefore to suppose that lack of bile salts was not an element in their postoperative condi- tion. The maintenance of normal bile salt content is essential because Cokeman has shown that the salts in the bile gradually diminish with external drainage to approximately one-tenth of the normal quantity. This mechanism would seem to suggest a conservation ac- tion upon the part of the organism to retain the totality of bile salts present in the body. At the end of six or seven days, occasionally ten days, with a con- stantly diminishing' jaundice these patients become somnolent, sleepy, and pass into a pronounced state of coma, and die, irrespective of any remedial agents em- ployed. The clinical picture presented is essentially a coma occurring in a patient with a diminishing ob- structive jaundice. In its manifestations it is not un- like the terminal stage of a portal cirrhosis with com- plete liver exhaustion. Some of these cases at operation showed "white bile," both in the gall bladder and in the common duct. We have not regarded the presence of white bile as contributing to this condition but it tended to indicate an increase in the immediate opera- tive mortality. We have taken the explanation of Kausch that white bile represents a purely mucosal secretion and by and of itself has no deleterious qual- ities. We have long felt that these three clinical conditions were in some way connected with an impaired liver 23 function, either a disturbed liver metabolism, a liver dysfunction or a liver insufficiency. In the first type the rapidity with which the development of coma is brought about takes it entirely out of the infectious class and while it is possible that the operation may have liberated certain deleterious products the whole mechanism suggests a complete and rapid cessation of liver function. The second type of complication occurs too late for primary operative shock and occur- ring as it does in patients who have had a previous gall bladder operation with palpatory injury to the pan- creas might possibly be interpreted as due to inunda- tion of the system with operative and infectious by- products plus pancreatic enzymes and direct poisoning of the liver cells with cessation of their function. In the third group there must be considered the possi- bility of an infection. The operation itself has been conducted in an infected field and various encapsulated bacteria have been liberated, so that the mortality in this group might be explained by an increasing bac- terial infection, yet clinically there is no evidence of it. We have unfortunately not controlled these cases with repeated blood cultures, a line of investigation we propose to pursue, but it seems more probable that these patients have had sufficient liver function to maintain a certain degree of bodily welfare and ac- tivity. When this is interrupted by a surgical opera- tion or there is thrown upon an already compromised liver the increased burden of detoxifying a further increment of deleterious products, the liver is unable to do so and the interim between operation and death represents the period of increasing and progressive exhaustion of liver capacity. The liver is notoriously able to handle infection and the catabolic proteins that are the result of infection. If the dosage of these offending bodies is so great as to overwhelm the liver 24 or the toxicity is beyond the detoxifying power of the liver it is a question only of time before the liver fails to give that protection which under ordinary circum- stances and even in the presence of a chronic ab- dominal condition it has been competent to do up to this time. The question that presents itself for consideration is: what is the effect of long continued infection in the abdomen in regard to changes in the liver? The asso- ciation of gall bladder disease with histologic evidence of liver degeneration is conclusively proved. In every one of Graham's operative cases with demonstrable pathology in the external biliary system there were the macroscopic and microscopic evidences of liver change. Can we go further and demonstrate an hepatitis, either sequential to or concomitant with chronic abdominal infection in regions remote from the gall bladder? About eighteen months ago at the New York Post- Graduate Medical School and Hospital, with the assist- ance of Dr. Ward J. MacNeal, Pathologist, and Dr. John A. Killian, Biochemist, we undertook a threefold study: (1) a critical study of all of the organs ex- posed during the course of all laparotomies irrespective of the original abdominal condition; (2) the removal of a portion of the liver from both the right and left lobes wherever mechanically possible; (3) a preopera- tive and postoperative study of the blood in relation to the known elements of blood chemistry. We have assumed that a partially obliterated appendix or a com- pletely obliterated appendix represented the indubit- able proof of inflammation and that in this condition at least there must be continuous seepage of infective material or chemical by-products into the portal system and which being carried to the liver would manifest themselves in the histologic evidence of inflammation about the periportal system or the bile ducts. In this 25 we were not mistaken as is evidenced by the cases re- ported. We pursued the same line of investigation in regard to carcinoma of the stomach and again in ulcer of the stomach. While investigating this subject we removed two or three small pieces of liver during the course of an operation. The first section removed was usually from the neighborhood of, or adjacent to the gall bladder, the second piece from the superior surface of the right lobe and about five cm. distant from the gall bladder, and less frequently from the superior surface or anterior border of the left lobe, depending upon the accessibility of this portion of the liver. It occasionally happened that the liver changes were much more marked than the associated pathology in the gall bladder, appendix or stomach. In other words, the changes in the abdominal viscera were quite minimal as compared to those encountered in the liver. Insofar as the gall bladder was concerned as an etio- logical factor in hepatic change it did not seem to make much difference whether calculi were present or absent. The essential elements were apparently first, chronicity of the infective processes; secondly, the per- sistence of a certain degree of intensity of the offend- ing agent-chemic or biochemic. In catarrhal types of appendicitis and cholecystitis the macroscopic evidence obtained from inspection of the liver consisted in a thickening of the capsule, with occasional adhesions, with thickening of the anterior border, with crenation, swelling and surface dimpling. In disease confined entirely to the gall bladder the changes in the liver in the area of the gall bladder were more intense than elsewhere and the quality of the change varied in- versely with the distance from the gall bladder. In these cases the microscopic examination of the liver sections would show subscapular lymphocytic infiltra- tion and intercellular lymphatic infiltration. If there 26 were an acute inflammation in the appendix or gall bladder disease leucocytic infiltration would be merged with lymphocytic infiltration. When the abdominal condition was essentially chronic the surface changes on the liver would become more marked and more diffuse, together with an increase in the size of the liver. The liver was grossly enlarged in about 50 per cent of the cases and the enlargement, when present, was confined, in about 90 per cent of the cases, to the right lobe and particularly the outer and posterior half of the right lobe-the quadrate and caudate lobes not participating in gross enlargement. Microscop- ically the liver changes in the more chronic cases rep- resented an advance in pathologic intensity in keepmg with the chronicity of the abdominal conditions. Uni- form fibrosis was more marked, loose connective tissue would be found in abundance about the bile ducts and portal veins, bile stasis would be more apparent with hyperplasia and budding of immature bile ducts. Leu- cocytic and lymphocytic infiltration would extend be- tween flattened and distorted liver cells. Many of the latter would show vacuoles and disintegration; occa- sionally intra- and intercellular pigment, with some fatty degeneration and hepatic cell destruction, rarely hyperplasia of blood capillaries and an increase in syncytial cells of Kupffer. The histologic picture in this type of hepatitis is distinct and definite. It does not represent the pathologic changes that one observes in Laennec's cirrhosis. Occasionally during our inves- tigation we would find a liver showing a picture quite typical of Laennec's cirrhosis. Apparently so far as we could observe there was no definite parallelism be- tween the gross and qualitative liver changes and the pathologic condition of the associated abdominal con- dition. In some cases it was apparent that the force of the affection was spent on the originally infected 27 viscus remote from the liver; in other cases the force of the offending agent apparently exerted its greatest injury on the liver with minimal changes in the extra- hepatic viscus which frequently showed a well estab- lished repair. Physiological Chemistry JOHN A. KILLIAN, M.A., Pll.D. Professor of Biochemistry, New York Post Graduate Medical School and Hospital. Aii extensive investigation of the chemical changes in the blood coincident with disease of the liver and gal] bladder has been carried ont in the Biochemical Labora- tory. In twenty-five cases, of which thirteen were typical, reported in the table, fairly comprehensive studies of the composition of the blood from these have been made. From the chemical point of view the liver performs man- ifold functions. It is only partially an excretory organ, its main function being concerned with many essential syntheses and desyntheses for the blood. Experiments and technical procedures to determine hepatic function by the injections of foreign dyes and the study of their excretion have given no reliable information concern- ing liver function. In fact, such functional tests con- siders only the excretory function of this organ. The alimentary leucocytosis test, or the so-called Crise Hemoclasique of Widal has likewise not given us much information regarding liver function. In cases of mild liver insufficiency the data obtained from this test has been uniformly of little clinical value. Probably the most important role played by the liver in the physiological economy of the body is the diamin- ization of the amino acids and the synthesis of urea. As a preliminary to an intensive study of this function in the cases under observation a nitrogen partition of the blood has been made. It will be seen that in many cases the nonprotein nitrogen exceeds the upper nor- 28 mal level of 30 mg. per 100 c.c. The urea nitrogen, on the contrary, does not show a corresponding increase. This would indicate a rise in the rest nitrogen of the blood. Little is known concerning the nature of the compounds constituting the rest nitrogen of the blood, but we believe that a critical study of the nonprotein nitrogen partition promises more definite data on the chemistry of liver function than we have heretofore obtained. The normal uric acid content of the blood is from 3 to 4 mg. per 100 c.c. In a few instances an increase in the uric acid is noted. It has been pointed out by numerous observers that the uric acid is the first prod- uct to rise in the blood following kidney impairment. We have many reasons to believe that this increased uric acid is due to a mild secondary impairment of kidney function. Many cases of gall bladder disease show a definite increase in blood sugar. Tn fact, a blood sugar as high as 0.200 per cent is not uncommon. Frequently the clinician is inclined to believe these cases have a coincident diabetes. However, following adequate sur- gical therapy for the disease of the gall bladder or bil- iary ducts the blood sugar readjusts itself to normal. Case 2 is an excellent illustration of this fact. In many instances the high blood sugar is accompanied by an increased diastatic activity of the blood. Appar- ently the hyperglycemia noted in gall bladder disease may find its cause in an associated disturbance of pan- creatic function. On the other hand, in two cases we have found hypoglycemias. The reason for these hypo- glycemias is still obscure. The cholesterol determinations have been made by the method of Myers and Wardell. These authors place the normal cholesterol content of the blood be- tween 0.14 to 0.17 per cent. It will be observed from 29 an inspection of the figures in the table that the varia- tions in this blood component in pathological condi- tions of the liver and gall bladder are very great. An attempt to associate'a hypercholesterolemia with the presence of gall stones has proved disappointing. It has been asserted by some authorities that the hyper- cholesterolemia is a primary factor in the etiology of cholelithiasis, and consequently in the early stages of this condition a high blood cholesterol should be evi- dent. The association of cholelithiasis with the hyper- cholesterolemia of pregnancy is a well known fact. However, in the cases studied a wide range of choles- terol values of 1.180 to 0.300 per cent have been found in cases of cholelithiasis. It must be remembered, how- ever, that these cases do not represent the early stages of gall bladder disease. On the contrary, they were individuals who had recourse to surgery as a final measure. A greater degree of uniformity is noted in the asso- ciation of hypercholesterolemia with obstructive jaun- dice. Without exception all of these cases exhibit a high blood cholesterol varying from 0.209 to 0.952 per cent. It is of interest to note that the hypercholesterol- emia accompanies the jaundice whether the obstruction is due to gall stones, new growth, or any other mechan- ical factor. Cases 12 and 13 show a cholesterol con- tent of the blood of 0.313' and 0.410 per cent respec- tively and in both of these instances the obstruction was due to a neoplasm. Case 5 is of considerable in- terest in this connection. This patient entered the Hospital suffering from severe icterus and giving a history of an operation on the gall bladder a few months previous. At this time the blood cholesterol was 0.952 per cent. At laparotomy it was found that the common duct had been severed during the previous 30 cholecystectomy and the two portions of the duct li- gated. The severed ends of the duct were connected by a rubber tube. Two weeks later the jaundice was considerably decreased, and at this time the cholesterol had dropped to 0.545 per cent. After three months, when the patient was but slightly jaundiced, the cho- lesterol had decreased to 0.82 per cent. Subsequently, however, the rubber tube became obstructed and the patient was readmitted markedly jaundiced. At this time the cholesterol was found to be 0.643 per cent. In this case, and in fact, in all cases studied the variations of the blood cholesterol very closely approximated the clinical and operative evidence of biliary obstruction. Since Whipple has regarded the liver as the site of formation of the fibrinogen of the blood plasma, a study of the plasma fibrin was made by Wu's method. Miller has suggested that variations of the blood fibrin may be taken as an index of hepatic function. Wu's studies and our own observations place the nor- mal plasma fibrin between 0.200 and 0.300 per cent. All the figures obtained have shown a normal or an in- creased blood fibrin. Tn the three cases of extensive malignancy of the liver two showed a normal and one a definitely increased plasma fibrin. A study of the blood fibrin was also undertaken in an effort to throw some light upon the mechanism of the delay in coagula- tion time in cases of gall bladder disease associated with jaundice. The cases studied show no evidence of a lack of fibrinogen, and in vitro coagulation is prompt. In a few instances determinations of the calcium con- tent of the blood were made. The calcium content of the blood serum was well within normal limits. In Case 5, notwithstanding a normal concentration of fibrinogen in the plasma and of calcium in the serum, the coagulation time of the blood was delayed to 13 31 minutes. At first thought, these findings appear to contraindicate the use of calcium chloride solution in- travenously to decrease the coagulation time. Such, however, is not the case. The calcium to be of value in blood clot formation must be in an ionizable form. The determination of the calcium is for the total amount of this element whether it is ionizable, or not. It is conceivable that in cases of jaundice a portion of this element may be in combination with bile acids or bile pigments, which combination would not decrease the total amount of the calcium but would diminish the concentration of calcium ions. In this particular case the use of dilute (2 per cent) calcium chloride solution intravenously brought the coagulation time down to 7 minutes. From a practical standpoint the acid-base balance of the blood plasma should be accurately determined pre- operatively in all cases of gall bladder disease. It has been noted by us that these cases display lowered tol- erance for alkali as judged by the carbon dioxide com- bining power of the blood plasma. The determination of the alkali reserve of the blood plasma by calculating the volumes per cent of carbon dioxide that will com- bine with it according to the method of Van Slyke is the most practical method at hand. Under normal conditions 100 c.c. of blood plasma will combine with 50-70 c.c. of CO,. A decrease in the alkali reserve is indicated by a diminution of the carbon dioxide com- bining power below 50 volumes per cent. This indi- cates an acidosis. When the combining power of the plasma for CO2 drops to 40, a moderate acidosis is present; to 30 a severe acidosis, and to 20 an acidosis that will probably prove fatal. (Fig. 1.) The mech- anism of the production of the various types of acido- sis is well understood, and the methods for their relief 32 are matters of common knowledge. However, within lhe last few years our attention has been attracted to an entirely different disturbance of the acid-base bal- ance of the blood plasma, and that is an alkalosis. In this condition the alkali reserve of the blood is def- initely increased above the normal. The carbon diox- ide combining power may vary from 80 to 100 volumes per cent. The production of an alkalosis by the indis- criminate use of alkalies in the postoperative treatment of surgical cases is not uncommon. Of the twenty cases observed, all but'three terminated in death. Six of these cases were chronic disease of the gall bladder. In three of these cases no alkali had been administered and the question of sodium poisoning can be definitely Threshold of alkalosis Acid Acidosis Alkalosis Alkaline combining power Fig. 1.-An increase in the carbon dioxide combining power toward 80 indicates an alkalosis; the reverse, an acidosis. excluded. The mechanism for the development of the alkalosis is still a baffling question. However, we be- lieve that this alkalosis may explain some otherwise unaccountable postoperative deaths. Certainly, the cases included under the first group all exhibited a condition of pronounced alkalosis. For some time it has been questioned whether the toxicity of this con- dition was due to a decrease of hydrogen ions or to an increase of sodium ions in the blood plasma. Myers and Booher have recently shown that the increased carbon dioxide combining power is accompanied by an increased PH of the plasma, hence it is a true alkalosis. It is reasonable to expect that the administration of 33 NO. PATIENT AGE SEX NON- PROTEIN N UREA N URIC ACID SUGAR DIASTATIC ACTIVITY CHOLES- TEROL FIBRIN CHLO- RIDES CO„C.P. REMARKS Mg. PER 100 C.C. PEP CENT 1 M. D. 38 F. 54.7 10.1 4.2 0.093 20.4 0.146 0.53 47.1 Cholecystitis. No jaundice. 2 N.M. 52 F. 46.0 22.1 4.1 0.227 0.428 98.0 Cholecystitis. 24 hrs. after operation Na H CO3 given by rectum. 38.5 19.1 3.6 0.093 0.350 80.5 Na H CO3 discontinued. HCL by mouth. 49.0 One week later. 3 M. K. 60 M. 45.0 16.3 0.150 0.290 0.357 Ca. of liver. Marked jaundice. 4 L. Z. 57 F. 40.5 11.9 3.7 0.475 Cholecystitis. 5 H. T. 28 F. 40.7 11.0 3.7 0.082 20.4 0.952 0.396 46.2 Marked jaundice. Obstruc- tion of common bile duct. 37.5 11.7 3.8 0.091 16.0 0.545 Two weeks after removal of obstruction. Chemical Blood Changes in Diseases of Liver and Gall Bladder 34 44.1 26.4 36.2 12.3 10.8 10.9 3.7 2.9 0.098 0.182 0.643 0.360 0.364 0.633 0.734 Three months later. Patient improved; very slight jaun- dice. 6 A. J. 42 F. 43.6 14.4 4.3 0.300 47.1 Cholecystitis and cholelithiasis. Jaundice. 7 M. E. 41 F. 37.4 9.0 3.1 0.100 21.4 0.180 Cholecystitis. No jaundice. 8 E. S. 50 F. 36.3 10.1 3.4 0.104 0.160 0.449 Cholecystitis. No jaundice. 9 V. s. 41 F. 32.7 7.5 4.1 0.084 0.154 Cholecystitis. No jaundice. 10 A. M. 43 M. 38.5 14.8 5.3 0.180 26.4 0.216 65.3 Cholecystitis and cholelithiasis. 11 A. P. 37 F. 29.7 10.0 4.3 0.121 24.6 0.204 55.7 Cholecystitis and cholelithiasis. 12 B. M. 60 F. 21.9 8.9 2.4 0.148 14.8 0.313 Ca. of liver. Marked jaundice. 13 L.P. 50 F. 41.7 10.6 4.0 0.105 0.410 0.698 Ca. of gall bladder with ex- tensive metastases to liver and duodenum. Marked jaundice. 35 acid compounds will diminish the increased alkali re- serve. Such measures, however, have proved disap- pointing. Our experience has convinced us that alka- losis is more pernicious than acidosis, and although we have no satisfactory treatment to recommend for this condition, we wish to emphasize the fact that alkaline fluids should not be given by mouth, by rectum, intravenously or subcutaneously unless the acid-base balance of the blood has been previously determined. 36 PART II APPLIED PHYSIOLOGY The primitive gastrointestinal tract is a simple tube occupying the midline position. Embryologically it is divided into three portions: the foregut, the midgut and the hindgut. The stomach, duodenum, liver, bil- iary ductal system and pancreas are derivatives of the foregut and within this alimentary segment every di- gestive enzyme is elaborated and the chemical and attritional processes of digestion carried out. In attempting to interpret disturbances in function of the external biliary apparatus we must recognize that the gall bladder and its ducts are but one part of the alimentary system and physiologically conform to the fundamental neuromuscular mechanism that ap- plies to the entire alimentary system. The underlying mechanism of intestinal function of the gut tube is embraced in the so-called law of the intestine, a name given to it by Bayliss and Starling, sometimes called the law of contrary enervation of Meltzer. In simple language this law states that local stimulation of any segment of the intestinal tube induces a contraction above and a relaxation below the stimulated part. There is always a contracting impulse at the cephalic end and an inhibitory impulse at the caudal end. As a corollary to the rhythmicity of gastrointestinal move- ment it has been demonstrated that whenever there is an irritation of the gut tube, the portion above and below the point of irritation shows an aberration of its normal function. Meltzer maintains that "the law of 37 contrary innervation is manifested in all functions of the animal body and a disturbance of this law is a factor more or less important in the pathogenesis of many disorders and diseases of the animal body." Alvarez in a brilliant contribution on the mechanics of the digestive tract demonstrates that the gastrointes- tinal tract is largely autonomous and carries within itself the mechanism essential to peristalsis while the sympathetic function of Auerbach's plexuses and Keith's nodal points are for the conduction of stimuli and the coordination of movement. Furthermore, it may perhaps be stated as a general physiologic law "that the direction of transport of material in a tubu- lar organ depends upon gradients of rhythmicity, tone and irritability" (Alvarez). Increasing clinical and surgical experience demon- strates that ablation of the gall bladder is without any change in the health or metabolic processes of the individual. In order to have a clear conception of the surgical physiology of the gall bladder and biliary ducts it is necessary to consider some of its anatomical factors. The wall of the gall bladder contains non- striated muscle fibers and the presence of nonstriated muscle fibers presupposes a purposive activity. Doyen a number of years ago demonstrated, probably cor- rectly, that the gall bladder undergoes a series of peri- odic contractions, yet we know that the gall bladder is normally incapable of completely emptying itself. From personal observations on at least 1000 cadavers I have never seen a gall bladder that did not contain two-thirds of the amount of bile that it would ordinar- ily contain. So, if the muscle fibers of the gall bladder exercise a contractile power that contractile power does not possess sufficient expulsive force to adequately empty the viscus. It is rather interesting to note that all the organs in the body that contain fluid have their 38 outlet higher than their base. Tn the urinary bladder, stomach and gall bladder the orifice of exit is higher than the base of the reservoir and this arrangement presupposed a muscular apparatus for evacuation. The blood supply to the gall bladder is essentially a terminal blood supply, very similar to the blood ves- sels of the small intestine, or the appendix. Again it is of interest to observe that the lymphatic channels of the gall bladder pass without anatomical barrier di- rectly into the substance of the liver. Conversely, the lymphatics of the liver pass directly on to and into the substance of the wall of the gall bladder (Sudler). If there is anything clearly established in surgical pathol- ogy it is the uniform mechanism of lymph-borne infec- tion. If there is an area of infection drained by lymphatics, that infection always pursues the same course, so that if there is an infection of the gall bladder there is the lymphatic mechanism present for infection of the liver and infection of the liver has likewise an anatomical mechanism for infection as the gall bladder. In the upright position the fundus of the gall bladder is at a lower level than its outlet and ac- cordingly the bile within the gall bladder is in a condi- tion of normal stasis. It is noteworthy that the cystic duct has a series of valve-like convolutions-valves of Heister-and that in many cases it is impossible to empty the gall bladder by digital compression. The lymphatics of the cystic and common ducts do not pass upwards into the liver but downward toward the pancreas. It is a frequent surgical finding to observe an involvement of the glands along the common duct in carcinoma of the stomach yet it is impossible to affect these glands from carcinoma of the stomach ex- cept by the retrograde lymph flow. In the localization of lymphatic infection Cornet demonstrated that where infection occurs by means of 39 previously healthy lymph channels the infection al- ways travels from one regional group of glands to the next regional group in the direction of lymph flow (Braithwaite). The termination of the lymphatics of the cystic and common ducts is on the posterior surface of the pancreas and the actual terminal lymphatic gland group is in the triangle between the duct of Santorini and the duct of Wirsung and which is called the angle of pancreatic inflammation of Desjardins. Franke has experimentally demonstrated that the pan- creas can be infected through the lymph channels from the gall bladder. When we come to look at the termi- nation of the external biliary system we find that the duodenal outlet, called the ampulla of Vater, is sur- rounded by a sphincter called the sphincter of Oddi. The clinical association of pancreatitis and disease of the gall bladder has long been noted. In pancreatic disease Mayo found 72 per cent were associated with disease of the gall bladder. In 325 operations on the common duct they found palpatory evidence of disease of the pancreas in 22 per cent and in 168 operations for disease of the pancreas gall stones were present in 81 per cent. Many theories have been advanced to ex- plain the incidence of pancreatitis in gall bladder dis- ease, the most important hypothesis being that in about 50 per cent of cases it is possible by occlusion of the ampulla of Vater to convert theoretically the common duct and pancreatic duct into a continuous channel. In 1901 Opie in attempting to explain acute fulminat- ing pancreatitis, found on postmortem, a stone occlud- ing the ampulla of Vater and the evidence of retro- jection of bile into the pancreatic system. In some personal cases of pancreatitis where we have drained the pancreas we have found bile coming through the pancreatic drainage tubes. Flexner produced acute pancreatitis when he injected bile from the common 40 duct into the pancreatic duct. He also produced chronic pancreatitis when he injected bile from the gall bladder into the pancreatic duct. The only essen- tial difference between bile from the gall bladder and bile from the common duct is that the gall bladder bile has mucus incorporated with it. Flexner then stated that the presence of mucus in the gall bladder bile lessened the possibility of injury to the pancreas if by chance the bile obtained entrance into the pan- creatic duct. Archibald tried to prove that spasm at the sphincter of Oddi would cause a temporary influx of bile into the pancreatic duct. Mann, however, has shown by a series of dissections that it was physically and anatomically impossible in 98 per cent of cases to convert the two ducts into a continuous passage, so that pancreatitis could not be produced by the retro- jection of bile. The bile within the gall bladder is materially differ- ent from the bile secreted from the liver or from the bile contained within the ducts. The former is concen- trated, darker in color, has a higher specific gravity and is chemically changed by the addition of mucin and nucleoalbumins. Rous and McMaster recently demonstrated that the passage of bile through the cystic duct concentrated the bile from two or four times, while the gall bladder is capable of concentrat- ing the bile ten times in twenty-four hours. The secre- tion of bile is continuous yet it is delivered into the duodenum intermittently. Tn other words, we have a continuous secretion with periodic delivery. Corre- lated with this is the fact that the secretory pressure of the bile as it descends from the liver through the common duct is by and of itself insufficient to over- come the sphincter of Oddi; even the addition of the contractile pressure of the gall bladder is insufficient to overcome the normal tonicity of the sphincter. 41 There is required for relaxation an inhibitory impulse to allow the ejection of bile into the duodenum. Dur- ing the fasting state the duodenum is free from bile and it has been demonstrated that the introduction of acid chyme, peptones, albuminose or the irritation of the duodenal mucosa by a thread or a duodenal tube is sufficient to inhibit the sphincter of Oddi and cause the delivery of bile into the duodenum. From a neuromuscular point of view the muscle fibers of the gall bladder and the sphincter of Oddi at the ampulla of Vater are antagonistic in their action and the contraction of the former implies relaxation of the latter in a normal physiological biliary system. The moment food is introduced into the stomach the normal stimulation for bile production is present. The moment chyme passes into the duodenum you begin to have the ejection of bile into the duodenum. There- fore, the normal stimulation for biliary secretion is the presence of material in the stomach and the pres- ence of acid chyme in the duodenum is the normal stim- ulus for bile excretion. This dual activity, secretion and duodenal flow is the basis of the Meltzer-Lyon test. Meltzer and Lyon paralyzed the muscle of Oddi so that the intraduodenal placement of magnesium sulphate would give a continuous flow of bile into the duode- num. Lyon stated that the first bile appearing would be common duct bile, the second bile appearing would be gall bladder bile and the third bile would be normal liver bile secretion. The physiological effect of paral- ysis of the sphincter of Oddi is correct. The clinical interpretation of the bile sequence is not correct. The passage of bile through the gall bladder removes 90 per cent of the water present. If the gall bladder under ordinary circumstances holds 50 c.c. of bile and that is concentrated ten times we have in normal gall bladder an equivalent to a liver secretion represented 42 by 500 c.c. of bile. Therefore, the observation of in- spissated bile in the ball bladder during operation is of no importance because the natural condition of gall bladder bile is to be inspissated. It may be concluded therefore that the outstanding function of the gall bladder is to concentrate bile. Tf bile in the gall blad- der is concentrated and if that is the point of normal stasis it needs only one other element to produce path- ological change in the gall bladder and bile ducts and that clement is infection. In the gall bladder we have a point of normal stasis, we have a point of concentra- tion of chemical elements and the presence of an in- fectious element means the production of a patho- logical biliary system. At one time gall stones wer£ considered the only pathological evidence of a diseased gall bladder, and the finding of stones was interpreted as the essential pathological lesion. We know that this is incorrect and that it is the infective process in the gall bladder or the biliary system that produces the pathological changes and provides the surgical indication. It is the deeper tissues of the gall bladder that are more par- ticularly involved and 25 per cent of the lesions of the gall bladder that require surgical intervention are characterized by the absence of gall stones. An in- fected gall bladder, with or without stones, is an ex- pression of a pathological change more widespread and extensive than that which is represented in the gall bladder itself. It is possible to culture anaerobic bac- teria from the bile radicals of the liver almost at any time and occasionally aerobes. Again under normal conditions of health there are occasional bacteria in the blood stream and it is by no moans a rare occur- rence to have apparently normal bile contain patho- genic organisms in the process of being eliminated by the liver. The liver stands as an intermediate barrier 43 between the systemic and portal circulation and it is reasonable to suppose that there are very few cases of cholecystitis which are without liver involvement. These changes, when of mild degree, are in the form of hepatitis and Graham has demonstrated a microscopic picture of hepatitis in every operated case of cholecys- titis. There are four theoretical ways in which the gall bladder may be infected. Of these, one presupposes a mucosal infection, the infecting organism reaching the gall bladder either by ascent from the duodenum or descent from the liver. Laboratory experiments demonstrate that it is with the utmost difficulty that the gall bladder can be infected from within its cavity. The injection of virulent streptococci into the interior of the gall bladder does not produce gall stones. Other pathological factors must be brought into play which lessen the resistance of the tissues beneath the mucosa. Coffey has demonstrated that the duodenum will rup- ture under fluid pressure before there is a reflux of material up the common ducts. It does not seem prob- able that cholecystitis commonly arises from infection by way of the mucosa. Two other possibilities for in- fection of the gall bladder are the bringing of infec- tious material through the blood stream or by contact from contiguous viscera. If the blood stream is the means of infection we must distinguish a straight hematogenous infection and an infection by means of the portal system. If the vascular systems were at fault one would expect that the liver tissue itself would show uniform changes throughout its substance but this is not true as we find that in infections of the gall bladder it is the right lobe of the liver that is coincidentally involved and particularly that portion in intimate contact with the gall bladder. The fourth method for infecting the gall bladder 44 would be by means of the lymphatic circulation and it has been proved by Sudler and the work of Franke, Sweet, Deaver and Pfeiffer that there is a very inti- mate and extensive lymphatic connection between the gall bladder, liver, common duct and pancreas. Ana- tomically there is no separation between the extra and the intrahepatic system of lymphatics and a hepato- lymphatic infection would offer a reasonable basis to account for most of the cases of cholecystitis. Rose- now in a series of very beautiful experiments demon- strated the possible source of cholecystitis from in- fectious emboli in the walls of the gall bladder and drew attention to the relative affinity of certain types of bacteria for the tissues of the biliary apparatus. That this is a method of infection in certain cases can- not be reasonably denied but it must be relatively infrequent simply because of the comparative rarity of embolic processes of the gall bladder in any of the accepted forms of bacteremia. It seems logical to believe that in the majority of cases cholecystitis represents a direct infection of the wall of the gall bladder from an infected liver. Infec- tion reaches the liver by the portal vein, involves the periportal tissues and induces a pericholangitis with involvement of the intra- and extrahepatic lymphatics thereby bringing by direct extension an infection of the walls of the gall bladder. This would offer an explanation for the cholecystitis that is coincident with appendicitis, peptic ulcer, typhoid fever, suppurative hemorrhoids (Graham). Surgical Pathology of the Gall Bladder It has been our experience that the diseased gall bladders without stones are distinctly a greater menace to complete recovery and future well-being than is the less grossly changed gall bladder with stones. The 45 palpatory diagnosis of disease of the gall bladder in cases not characterized by the presence of stones is fallacious and an opinion as to the mortality of a gall bladder simply by palpation through a lower abdom- inal wound is seriously open to question. There are, however, certain criteria which in the absence of cal- culi may collectively be taken to indicate that a par- ticular gall bladder is pathological. Seriatim these may be defined as follows: (1) a loss of the normal color-under normal conditions the gall bladder is never white, brown or mottled, but always possesses its distinctly olivary green tinge. It is essential that the color of the gall bladder be noted upon opening the abdomen for upon exposure to the air it takes on a rather whitish appearance. (2) The walls of the nor- mal gall bladder are quite thin and any marked in- crease in the mural thickness bespeaks infection. (3) The deposition of saffron-colored fat well up to and on the fundus of the gall bladder is distinctly abnormal and represents infiltration of the wall. (4) The pres- ence of varying degrees of pericholecystitis is sugges- tive only. Personally, I have been unable to account for some of the many adhesions that exist between the duodenum and gall bladder, including the so-called cystico-duodenal and cystico-colonic ligaments, which Todd states are present in one out of four individuals. We have found adhesions so frequently in apparently normal persons without any disabling angulations and so far as we can determine in patients free from upper abdominal symptoms that the evidence of occasional adhesions between the gall bladder and colon in the absence of symptoms must be accepted as of minor value in determining the degree of pathology in the gall bladder. (5) The inability to express bile from the gall bladder by manual compression is of very little diagnostic importance and is not necessarily indicative 46 of pathologic change. By the peculiar "S''-shaped conformation of the cystic duct and ampulla the gall bladder can be distended almost to the point of rup- ture without allowing any bile to flow through the cystic duct. Adhesions angulating the cystic duct can bring about the same condition without intrinsic dis- ease of the gall bladder being evident. (6) The pres- ence of hyperplastic lymph glands along the course of the cystic and the common duct is indubitable evidence of infection, past or present, of the biliary system, for the mechanism of lymphadenitis is the same in the biliary system as it is elsewhere in the body and adenitic hyperplasia represents infective activity. (7) The presence of a small diverticulum at the fundus of the gall bladder usually about the size and color of a Delaware grape represents a weakening of the mus- cularis from infection with diverticular protrusion from pressure. (8) The finding of a papillomatous mucous membrane, rather than the normal smooth type, with minute cholesterin crystals imbedded in its substance is of primary importance in the diagnosis of the so-called strawberry gall bladder. We place little value in the so-called inspissated bile as an evi- dence of infection primarily, because it is the normal condition for bile to be inspissated or concentrated within the gall bladder. (9) The presence of white plaques extending from the serosal covering of the gall bladder to the under surface of the liver are of very great diagnostic importance as they represent, to our mind, fibrosis in liver tissue concomitant or sequen- tial to gall bladder infection. The symptomatology of disease of the gall bladder must necessarily include metabolic and systemic dis- turbances that are directly due to impairment of liver function. In an infected gall bladder and biliary duct system we do not only have a local infection but we 47 have had the attributes of a chronic focal infection with systemic intoxication. In grouping the symptoms of disease of the gall bladder we may classify the symptoms as those that are local, those that are remote and those that are general or systemic. Many of the remote symptoms are the symptoms that pertain to arthritis, to nephritis, to generalized arteriosclerosis and to endocarditis. It has not been an infrequent ob- servation that many supposed myocardial lesions with symptoms suggesting true angina or certain groups of patients with arrhythmias or tachycardias have their etiology in chronic focal infection of the gall bladder and the removal of the infecting focus has brought about an amelioration, if not a cure. Many of the patients incompletely cured after sur- gery on the gall bladder present a chronic tissue de- generation particularly a permanently damaged car- diovascular system with invalidism as a result of long persistent and recurrent infection of the biliary system. The general symptoms are an ill-defined group rep- resented by asthenia, neurasthenia, loss of weight, per- manent pigmentation and general constitutional in- stability. In considering the local symptoms of gall bladder in- fection, we may catalogue their exhibition with a fair degree of accuracy and while I admit there are some patients who may have gall stones or a supposedly in- fected gall bladder and yet exhibit apparently no symptoms this freedom from symptoms must certainly be a rarity. Of most importance in the diagnosis of disease of the gall bladder is the clinical history. A clinical history is the citation of the symptoms of disease in the order of occurrence. As a corollary to this, diagnosis may be defined as largely a correct in- terpretation of the clinical history aided by physical examination and special tests. 48 Differential Diagnosis of Affections in the Right Upper Abdominal Quadrant The differential diagnosis of affections of the right upper quadrant resolves itself essentially into an in- quiry as to the causation of the various forms of dyspepsia. Dyspepsia, however, arises from so many divergent causes that its translation into a clinical en- tity is ofttimes difficult. In the phylogenetic develop- ment of the gut tube there has come about a subdivi- sion in morphology, physiology and function and the stomach gives forth reflex symptoms from a variety of diseased organs more or less remotely situated. Of 100 persons complaining of gastric distress, or what may be collectively called dyspepsia, in only twenty persons will the cause of the symptoms be due to organic disease of the stomach. Tn 40 per cent the lesion will be within the abdomen but remote from the stomach, while in the remaining 40 per cent the patho- logic process will reside entirely outside of the ab- domen. The ordinary postmortem incidence of disease of the appendix is approximately 17 per cent. It is interest- ing to note that the appendix shows pathologic changes in 69 per cent, of the cases of cholecystectomy, whereas 55 per cent show disease of the appendix in cholecys- tostomy. Gastric ulcer is associated with disease of the appendix in 54 per cent of cases, while duodenal ulcer is associated with disease of the appendix in 66 per cent of cases, and in 15 per cent of all laparotomies there are two lesions sufficiently severe to warrant operation. It must not be forgotten that chronic disease of the appendix may occasion a rather severe hematemesis. Hutchinson records 24 cases of fatal hemorrhage from the stomach after operations of various kinds upon the abdominal viscera. Of these 24, 21 were cases of ap- 49 pendicitis with septic complications. I have records of 4 cases of pronounced gastric hemorrhage which on very extensive abdominal exploration revealed no mor- bid process except in the appendix, and following an appendectomy there was a cessation of the gastric dis- tress and gastric hemorrhage. Gastric hemorrhage has been experimentally produced by Rogers by injecting chemical irritants into the cecum and ascending colon, JAUNDICE GASTRIC SYMPTOMS A CHOLECYSTITIS CHOLELITHIASIS -BILIARY COLIC + SEPSIS A MECHANICAL B INFECTION SPASM -BILIARY COLIC + CHOLANGITIS ++80% "INTERMITTENT hepatic fever" -BILIARY COLIC -I- PANCREATITIS + + 100% COLIC SEPSIS ABSENT + CHOLEMIA + + bZ'f. Fig. 2.-Summary of symptomatology in the "four phases" of disease of the biliary apparatus, with differentiation of pancreatic neoplasms. while irritation of the colon, per se, has been shown to bring about a gastric stasis and the delayed passage of food material through the small intestine. Irrespec- tive of the presence of calculi in disease of the gall bladder the histories of a large number of cases will be found to present a composite picture in which four well-defined pathologic stages are evidenced and which clinically may be translated into four sequential clin- 50 ical pictures: (1) when the disease is confined to the gall bladder; (2) when there are attacks of biliary colic; (3) when calculous obstruction to the com- mon duct intervenes with or without jaundice, and (4) when, as a result of infection or trauma to the com- mon duct, there is an associated or coincident disease of the pancreas. The inaugural symptoms of cholecys- titis are those of a qualitative dyspepsia. This indiges- tion is due to motor and secretory disturbances in the stomach reflexly produced by infective changes in the gall bladder. In gastroduodenal ulceration the history reveals a distinct regularity in symptomatology, while in gall bladder disease the dyspepsia is vague, irreg- ular, with an ill-assorted grouping of symptoms of flatulency, heart-burn, eructations, belching', fullness, weight in the epigastrium, etc. This indigestion con- forms to no rule and exhibits no constancy. It is char- acterized by an absence of periodicity, and its most predominant symptom is gas production. There is usually some tenderness along the right costal margin. There may be a catch in the right side upon taking a full breath, and occasionally after large meals a slight sensation of chilliness or goose skin sensation. This gaseous indigestion is character- istically made worse by the eating of any fried foods or greases, or, less commonly, apples, nuts and cheese. There usually is some relief upon the raising or belch- ing of gas, and almost complete cessation of the symp- toms upon vomiting. Occasionally the history is ob- tained of the patient retiring after dinner and volun- tarily inducing vomiting with almost complete amelio- ration of the symptoms. It is noteworthy that the patient is relatively free from symptoms when the stomach is empty, in marked contra-distinction to duo- denal ulcer, where the patient is usually at his best when food material is in the stomach. This form of 51 indigestion may continue for a variable period of time and exhibit itself without any marked variation in the above picture. After a long or short period of the above qualitative dyspepsia there is introduced into the patient's history another symptom, different from any of the preceding symptoms and which is repre- sented in a sudden, acute attack of agonizing pain. The onset of the second phase of symptoms is quite characteristic-out of a clear sky, without any warn- ing or premonition the patient is seized, usually in the evening, with a sudden, intense, severe attack of cramp-like pain in the right upper quadrant. This pain comes on like a stroke of lightning, radiates through to the back, occasionally down the right side or up over the right chest and less frequently toward the left breast. It is of maximum intensity, is associ- ated with restlessness upon the part of the patient, and usually so severe as to require the presence of a doctor and an hypodermic injection of morphine. This agoniz- ing pain lasts a variable length of time, four to six hours, disappears almost as quickly as it came, leaving a residual soreness in the right upper quadrant or along the right costal margin. There may or may not be in addition some temperature during the height of the paroxysm. J aundice Jaundice is a symptom only and is due to the deposi- tion of bilirubin and biliverdin in the tissues. It is recognized clinically by the coloration of the skin and visible mucous membranes and by the presence of bile derivatives in the urine. In brief, the clinical phenom- ena associated with jaundice are due to the presence of bile pigments in the circulating blood tissues and to the absence of biliary constituents from the intestine. In its ultimate analysis jaundice is an interference 52 with the delivery of bile from the liver to the intestinal tract, and is due to the passage of bile pigments into the circulation by means of the hepatic capillaries and, to a less extent, by the lymphatics. Increasing experimentation and research proves that probably with the rarest exception jaundice is essen- tially an obstructive phenomenon. The obstruction CAUSES OF JAUNDICE GALL STONES "CATARRHAL JAUNDICE" CANCER OF LIVER CIRRHOSIS CANCER OF BILE DUCTS AND GALL BLADDER CANCER OF PANCREAS GASTRIC CARCINOMA CANCER OF DUODENUM MISCELLANEOUS- ICTERUS NEONATORUM.SEPSIS. + + + + 5587» .198*70 .0867' .07X7o ,0397° .OR5 7o .OI87« .OO17o Fig. 3.-Statistical tabulation showing the causative factor in the production of jaundice. (Modified from Cabot.) affects either the large extrahepatic bile vessels or the smaller intrahepatic bile vessels and therefore all jaun- dice is hepatogenous in that its site of production resides in the liver. The formation of bilirubin and biliverdin from henio- 53 globin is limited to the cells of the liver and nowhere can the elaboration of bile pigments be carried out ex- cept in the liver and in no place can this function be vicariously assumed. It is true, however, that in the neighborhood of large collections of blood there is a breaking down of hemoglobin with the formation of hematoidin which is chemically identical with bilirubin, while the presence of free hemoglobin in the blood- stream leads to an increase in the elaboration of bile pigments (or polyehromia-pleichromia) but does not, per se, gives rise to jaundice. Furthermore, jaundice is seen where marked hemolysis has occurred. This phe- nomenon is regarded as the conjoint result of two processes-the hemolysis destroying the red blood cor- puscles on the one hand and at the same time a cholan- gitis of the intrahepatic ducts. Exceptions to the general statement that all jaun- dice is obstructive are extremely rare but experiments have proved that bile pigments may be formed after an Eek fistula or after the removal of the liver, spleen and abdomen from the circulation and it seems prob- able that it is possible for the endothelial cells of the serous cavities to convert blood pigments into its biliary derivatives. In chronic splenomegalic hemolytic jaundice there is no pathological evidence that the jaundice is in any way associated with obstruction. In this condition the jaundice is essentially a dissociated jaundice as is in- dicated by the presence of bile pigments in the blood without bile salts. This predicates an independent extrahepatic origin for the bile pigments, for in pure obstructive jaundice they are never found in the cir- culation without the presence of bile salts. Statistical inquiry and analysis of a large series of cases exhibiting jaundice (6) demonstrates that ac- cording to its frequency jaundice may be classified In 54 the following order: (1) gall stones, (2) catarrhal jaun- dice, (3) cancer of the liver, (4) cirrhosis, (5) cancer of the bile ducts and gall bladder, (6) cancer of the pancreas, and (7) gastric and duodenal carcinoma. It will readily be seen that by eliminating catar- rhal jaundice and cirrhosis of the liver the diagnosis becomes one of differentiating between the jaundice due to gall stone disease and that from malignancy of the bile ducts. Calculus Jaundice is not a symptom associated with gall bladder dyspepsia nor is it ordinarily present in its early attacks of colic. In neither of these two types has jaundice been a symptom although in the latter phase of biliary colic there may be transient attacks of jaundice. After a variable period the third phase of biliary disease may be introduced by an attack of pain similar to the one outlined, to be followed in four to six hours with jaundice which reaches a maximum intensity within twenty-four to forty-eight hours and associated with this will be the evidence of a well- defined sepsis-chill, fever, and sweat, suggesting in its onset and periodicity a malarial paroxysm. Years ago this was known as intermittent hepatic fever (Charcot) and variously ascribed to malaria. The febrile reaction is marked, 104°-105°, with rapid inter- mission or remission of temperature variously called the "steeple chart" temperature, "the angle of cho- langic infection." The diagnosis of calculous disease of the common duct rests upon colic, icterus and sepsis and the symp- toms occur in that order. In cystic duct obstruction there is colic and fever and the symptoms occur in that order but there is no jaundice. In calculous disease of the common duct one is impressed by the fact that at 55 the time the patient presents himself jaundice is ab- sent in about 25 per cent of cases. Inquiry however, will reveal that in the larger proportion of cases (85 to 90 per cent) there is a history of a colicky jaundice. The first mechanical factor in calculous obstruction of the common duct is the production of acute biliary obstruction with alcoholic stools. After a variable period of cholangitis, distention of the duct behind the obstructive calculus occurs, the duct dilates, and the stone floats up into the more ample and dilated common duct, and biliary delivery into the duodenum is resumed. The diagnostic factors in this particular type of jaundice are (1) its onset with colic; (2) its association with sepsis; (3) its intermittency, "it ebbs and flows'' with the degree of obstruction; (4) its chronicity. Between attacks of calculous obstruction of the com- mon duct the patient may be apparently well but is practically never free from a subicteroidal tint or slight jaundice. The patient is designated as sallow when she is really suffering from a continuous and persistent low grade jaundice or a jaundice of remit- tent intensity. Many of these patients who are per- sistently sallow notice that the jaundice varies during the day, becoming deeper toward evening. With each attack of pain and jaundice there is a fever of a char- acteristic "steeple chart'' type, while early in calcu- lous obstruction the liver is enlarged and generally the spleen. The resultant pathological condition is a dilated and infected common duct with a calculus floating up and down-the ball-valve stone of Osler and Finger-and the mechanical factor is chronic intermittent intrinsic occlusion of the common duct. The pathological con- ditions are at the same time paralleled clinically by: (a) ague-like paroxysms, chills, fever and sweating; 56 the hepatic intermittent fever of Charcot; (b) jaundice of varying intensity which persists for months or even years and deepens after each paroxysm; (c) during the paroxysms pains in the region of the liver, with gastric disturbances. Stone in the common duct is preponderantly the result of a previous infection of the gall bladder and predicates a chronic cholecystitis with cicatrization and contracture. In 187 cases of obstruction of the common duct reported by Courvoisier (from the litera- ture) in 100 obstruction was due to causes other than stone and in 87 the obstruction was due to calculous impaction. Of the 100 cases in which obstruction was due to causes other than stone, in 92 there was a dila- tation or distention of the gall bladder and in 8 cases there was a normal gall bladder or an atrophy of the gall bladder. Of the 87 cases in which obstruction was due to stone, in 70 cases the gall bladder was atrophied and in 17 cases the gall bladder was dilated. Cour- voisier then enunciated his law: "In cases of chronic jaundice due to blocking of the common duct, a con- traction of the gall bladder signifies that the obstruc- tion is due to stone; a dilatation of the gall bladder that the obstruction is due to causes other than stone." In reporting the cases of the Massachusetts General Hospital, Cabot found 86 cases of obstruction of the common duct; 57 were due to calculous obstruction; in 47 the gall bladder was atrophied; in 8 it was nor- mal ; in 2 enlarged; 29 cases of obstruction were due to causes other than stone; in 27 the gall bladder was distended and in 1 the gall bladder was empty and 1 contracted around calculi. Four cases only of this series were exceptions to Courvoisier's law. With the exception of these four cases which constituted only 5 per cent of the total number examined every record of the Massachusetts General Hospital series in which 57 definite statements are to be found concerning the points at issue goes to confirm Courvoisier's law. In 84 per cent of cases with stone in the common duct' we find a contracted gall bladder. Therefore a case of obstructive jaundice with (1) history of colic; (2) distinct variations in the intensity of the jaundice (remittent or intermittent)-"ebbs and flows"; (3) absence of distention of the gall bladder; (4) presence of septic reaction-chill, fever, sweat, leukocytosis; (5) continuous or occasional presence of bile in the feces; (6) chronicity, then the diagnosis is almost positively calculous cholangitis. Ill neoplasms of the extrahepatic biliary system be- low the cystic duct there is a typical type of jaundice. Since the genesis of tumors requires time, the history of the onset of jaundice is distinct and characteristic. By slow growth a neoplasm produces minimal changes. There is insidious invasion or compression of the bil- iary passage; jaundice develops imperceptibly so that from day to day it hardly seems to advance in inten- sity, but without pause or hesitation, without intermit- ting or remitting, it progressively and continuously deepens in intensity from mild to severe, from lemon color to black, until it becomes a typical icterus melas. Tn its evolution it is not associated with colic and in its earlier stages it is usually devoid of pain. It is not associated with chills, fever or sweat or leukocytosis. This jaundice is the result of extrinsic compression or invasion and as there was no preexisting cholecystitis we have approximately in 90 per cent of the cases a dilated gall bladder. Tn addition the Courvoisier gall bladder is usually palpable, increases in size from day to day and enlarges downward toward the middle line about the umbilicus unlike the acutely distended gall bladder which enlarges upward and inward. Neoplasms 58 Appendix Vermiformis From the surgical standpoint the appendix repre- sents an organ with a naturally deficient drainage and a viscus that is at all times prone to low grade in- fections or irritations of bacterial origin. Adami and his coworkers, Nichols and Ford, have demonstrated the continuous passage of leukocytes through the in- testinal wall into the mesenteric lymph nodes. These migrating leukocytes carry within their protoplasm bacteria, ingested particles of pigment or fat droplets. Obviously, most of the bacteria and leukocytes undergo lysis or destruction in the first regional lymphatic group or in Peyers glands. Careful cultural experi- ments have obtained viable bacteria from these glands. If the transmigration of bacteria through an intestinal wall is found as an occasional occurrence in appar- ently normal or healthy individuals the frequency of this bacterial leukocytic migration must be exalted to a tremendous degree in inflammatory conditions of the gastrointestinal tract. Conditions of irritation of the mucosa, types of colitis and ulcerated conditions of the alimentary tract must facilitate and accelerate leukocytic transmigration through the intestinal wall. A chronic lymphadenitis means a blocked lymphatic channel and conductivity through a particular lym- phatic (or if the reaction involves a group) will be blocked and any further lymph conduction must de- pend upon circuitous routes or the development of new or aberrant lymph channels. Probably no organ within the abdomen is capable of producing such widespread peritoneal reactions and in so many diverse ways as an acutely infected appendix. The degree of peritoneal re- action is proportional to the acuity of the infection and obviously, minor degrees of infection of the appendix will produce the same character of peritoneal reaction which will vary only in quality and intensity from 59 those observed in the acute cases. Long before there is a perforation or an extravasation of intestinal con- tents from a diseased appendix we have a peritoneal irritation represented in an advancing zone of non- pathogenic anaerobic bacteria (lleyd), the purpose of which is to bring forth the normal fibrinoplastic re- action of the peritoneum. In and about the infected area the omentum becomes attached or contiguous with pathologic tissue. The intestinal coils are agglutinated and held together so that there is a resistant wall of fibrinoplastic material infiltrated with leukocytes. These plastic barriers in the ordinary nonlethal cases are ordinarily absorbed, leaving behind however me- morials in the form of adhesions and fixations which later become vascularized, and produce varying de- grees of aberration in function and motion of the upper gastrointestinal tract. The adhesive reaction that occurs in the region of an intraabdominal infec- tion may be divided histologically into two stages. The first stage represents the formation of adhesions that are reactive, consisting of fibrinoplastic material, do not contain blood vessels, are nonorganized, and from which no lymphatic absorption takes place. After a variable interval this fibrinoplastic material is organ- ized and converted into the absorbing, vascularized form of newly made peritoneal tissue. The omentum being peculiar in its vascularity and designated the "watch dog" of the abdomen (Moynihan) contains many converging veins of great length. These veins are thin walled and not adequately supported by fibrous sustaining tissue. Eiselberg demonstrated how rapidly the omental veins are thrombosed after injury or in- fection and in epiploitis (Hessert) after hernia opera- tions is a well substantiated clinical fact. Wilkie dem- onstrated the ease with which injury and thrombosis of the portal veins occurred. Upon mere ligation of 60 some of the omental veins there was produced puncti- form hemorrhages in the stomach in 30 per cent of the cases and in 50 per cent hemorrhagic infarcts in the liver. Wilkie in a measure repeated the work of Freidrich and again drew attention to the fact that healing as it occurred in the liver after the aseptic infarcts was usually a normal process with slight re- action. If aseptic thrombi in omental veins showed these preeminent tendencies towards upper abdominal embolism how much greater must be this embolic ten- dency in a septic thrombosis. There is no definitely established anatomical route for portal blood from the lower abdomen to the liver. Tn infancy the portal system contains valves which either disappear or be- come useless with the approach of adult life. The por- tal circulation is capable of being diverted from its usual route of conduction into other channels by varia- tions in blood pressure, posture, and by respiratory movement. Wilkie injected globules of oil into the omental veins and could trace the diversion of portal current from the right to the left gastro-epiploic vein and then to the transverse gastric vessels. This was particularly liable to occur following the ingestion of food for there is contraction and dilatation of the veins of the stomach and small intestine during the varied cycles of digestion. During digestion the gas- tric veins attain a diameter four times greater than that which obtains in a fasting state. According to Alvarez there is a spasmodic contrac- tion of the cardia, pylorus, ileocecal sphincter and anus whenever there is an ulceration or inflammation near by. This heightened irritability of the gastroin- testinal tube in the neighborhood of ulcer would bring forth an increased amplitude of intestinal movement both above and below the point of irritation. Fenwick drew attention to hypersecretion of the stomach and 61 its casual connection with latent disease of the appen- dix. Herbert Paterson writing on the "Appendix as a Cause of Gastric Symptoms," mentions certain symp- toms which may be accepted as criteria of a pyloric syndrome from chronic appendicitis. Categorically, these symptoms are: First, pain follows the ingestion of food, but which is variable and uncertain in regard to time of onset and relationship to the quantity and quality of food. It exhibits a diverse and variable se- quence and is capricious in its incidence. It is located in the epigastrium, usually to the right of the midline and radiates downward and to the right to the lower portion of the abdomen. This radiation never occurs in distinct gastroduodenal radiation. Second: hemor- rhage which is usually unexplained and may come from a variety of lower abdominal conditions. We have observed it following tuberculous salpingitis, fol- lowing diseased appendix, following tuberculosis of the ileocecal valve. Third: the periodic exacerbation of symptoms. The patient is entirely free from symp- toms over a considerable period of time. There is no recurrent symptomatology as exhibited in the gaseous dyspepsia of the gall bladder and there is not the pre- cision of onset of the periodicity that is exhibited in gastric or duodenal ulcer. Fourth: the chronicity of the symptomatology over long periods of time with but slight impairment of health. Fifth: an irritable colon. Alternating periods of diarrhea and constipa- tion, are not unusual. A characteristic history of hav- ing one normal bowel movement immediately after breakfast, and then two or three semiliquid stools at short intervals thereafter is very frequently obtained. Certain clinical associations stand out as pointing to 1he relationship of an ulcer syndrome and chronic ap- pendicitis. Primarily there is an ever increasing num- ber of patients who are cured of painful indigestion 62 following an appendectomy. The percentage lias been greatly increased in the last few years by reason of the marked tendency among surgeons generally to use a higher abdominal incision for an appendectomy and at the same time provide for a visual inspection of the stomach and gall bladder. During the days of the McBurney intermuscular incision the number of cases that were not cured after an appendectomy was greater than at the present time for the simple reason that many cases had ulcer of the stomach or duodenum and a mere appendectomy would in no way cure that condition. A large percentage of the patients who exhibit an ulcer symptom group without ulcer have had a history of an attack that could reasonably be interpreted as an acute attack of appendicitis. The appendix in the adult has a very definite ana- tomical conformation. It is a blind tube with its nar- rowest portion at the cecum, known as the valve of Gerlach. It is essentially an organ with a terminal blood supply, except in 16 per cent of females, where there is a connecting artery to the right ovary. It has a strong submucous layer which represents the disten- tion strength of the appendix. This submucous layer is absent in children and hence accounts for the ease of perforation in children. We believe that the symptomatology of acute appendicitis is one of the most fixed and well ordered of all abdominal condi- tions. Its symptomatology is precise and, within the first 24 hours of its evolution, embraces the following chronological order of symptoms: (1) pain: this pain is epigastric, confined to the region of the navel, and is colicky in type; (2) is followed by nausea or vomit- ing' or both; (3) generalized abdominal sensibility; (4) temperature; (5) leukocytosis and ascending poly- nucleosis. One can explain this chronological evolu- tion of symptoms by a consideration of the pathologic 63 sequence of events in the infected appendix. The in- fection arises on the mucosa in 95 per cent of cases; it is associated with tumefaction and tumescence and we have an angulation of the appendix with occlusion of the lumen or occlusion of the lumen at the valve of Gerlach. At this stage we have essentially an em- pyema, and the products of the infection are retained within the lumen of the appendix under pressure. One of three things occurs: (1) gangrene of the appendix; (2) rupture, or (3) resolution by intracecal drainage of the contents of the appendix. These pathological states distinctly parallel the symptomatology. At the time the infection begins in the appendix we have a point of irritation below the small intestine and we have a disturbance of the law of the intestine with small intestine participating in an exaggeration of its normal peristaltic activity. As a result we have colicky epigastric pain from hyperactivity of the small intes- tine. The exaggeration of the function of the small intestine brings about generalized abdominal sensibil- ity, and the activating agent in this trend of events is an infective process which produces the constitu- tional reaction of temperature, leukocytosis and poly- nucleosis. At the end of 18 to 24 hours the infection of the appendix has progressed to such a point that there is a peri-appendicitis with exudation or extravas- ation of appendiceal contents and the clinical picture is changed. The pain becomes constant, not colicky, is confined to the right lower quadrant, associated with local tenderness and spasticity over McBurney's point, while temperature may or may not be elevated. The leukocytosis and polynucleosis, however, remain present. Turning to chronic appendicitis one is confronted with an entirely different evolution of symptoms. The chronically infected appendix produces epigastric dis- 64 tress of indefinite intermittency. The symptoms are those of pain and distress more prolonged than similar occurrences in disease of the gall bladder, with in- creased acidity, vomiting, and eructations of sour ma- terial. Articles of food which at one time are asso- ciated with indigestion are eaten at other times with zest and relish. There is a long interval between the at- tacks in which the patient is free from symptoms. Each succeeding attack has a tendency to be more severe than the previous one by reason of the increased stenosis and stricture of the lumen of the appendix after each exacerbation. We believe that these symp- toms are due to pylorospasm associated with hyper- activity and hypersecretion of the stomach, and may be designated as the pyloric syndrome of chronic appen- dicitis. This variability in the indigestion from dis- ease of the appendix has been emphasized by Moyni- han, who states that the most frequent site for the pro- duction of the symptoms of ulcer of the stomach is in the right lower quadrant. The ingestion of food under normal circumstances is accompanied by a reflex process which is not per- ceived-a subconscious reflex-and when pain arises from the ingestion of food it points to an irritable proc- ess of the cord through which these reflexes pass as a result of oft-repeated painful stimuli. The epigastric region is essentially the place to which sensory symp- toms are referred and the upper part of the left rectus muscle usually contracts first in response to an irrita- tion from the stomach. Peptic Ulcer Peptic ulcer is a distinct organic ulceration of the gastroduodenal portion of the gut tube, and within its type the symptoms are constant, and, as a rule, char- acteristic. Variations in symptomatology depend to a 65 considerable extent upon the localization, and 70 per cent of all peptic ulcers are located so as to interfere with the emptying power of the stomach. In the diag- nosis the history is all important. Palpation, percus- sion and auscultation give evidence of very limited value; chemical examination of gastric contents gives some confirmatory value only. The gastric blood will be absent in over 75 per cent of cases while roentgen- ray examination is positive in 67 to 80 per cent of cases of duodenal and gastric ulcer respectively. Ulcer of the gastroduodenal segment is located ana- tomically in three main places: (1) In the silent area of the stomach with no pyloric involvement; (2) on the pyloric segment with obstruction from spasm or in- vasion; (3) in the duodenal segment. Eighty-eight per cent of all ulcers are characterized by a regular and uniform symptomatology and three symptoms stand out in unusual prominence: (1) Pain that bears some relationship to the time of ingestion of food; (2) chronicity-the symptoms extending over a consider- able period of time, and (3) periodicity-in that the symptoms recur in exact similarity day after day with almost unvarying precision. Eighty-five per cent of all ulcers of the stomach are situated on the pylorus, antrum or the adjacent three-fourths of the lesser curv- ature, and it is the regularity in the symptomatology of ulcer that makes the diagnosis possible. A loss of the periodic element with symptoms which suggest ulcer makes one suspicious of malignancy, for 99 per cent of malignant growths of the stomach show an absence of periodicity in their symptomatology. De- pending upon the localization of the ulcer we have cer- tain specific features that go with each one. The ulcer in the silent area of the stomach is, as a rule, charac- terized. in addition to the above-mentioned symptoms, by the early habit of vomiting, the vomiting of un- 66 digested food with a tendency to be blood-streaked. The pyloric nicer has early induced in its symptom- atology a motor insufficiency with stagnation of gas- tric contents and vomiting of large quantities of retained gastric content and food remnants of a pre- vious day's ingestion. The duodenal ulcer has charac- teristically added to these three major symptoms nocturnal occurrence, usually after 12 p.m., and the com- plete alleviation of symptoms upon the ingestion of food, while all three types of ulcer acquire early and independent of the physician's advice the bicarbonate of soda habit. The ulcer near the cardia frequently, but not invariably, produces pain almost immediately after the ingestion of food; the ulcer at or near the pylorus from an hour and a half to two hours, while the pain in duodenal ulcer is much more constant in the time of onset, being between two and a half to three hours after a meal. 67 PART III STRUCTURAL CHANGES IN APPENDIX, GALL BLADDER AND LIVER REMOVED FROM THE SAME PATIENT AT SURGICAL OPERATION WARD J. MACNEAL, Ph.D., M.D. Professor of Pathology and Bacteriology New York Post-graduate Medical School and Hospital The material which I purpose to lay before you deals chiefly with specimens removed from the human abdo- men at surgical operation, namely the appendix, gall bladder and small portions of liver. The first two of these are very frequently objects of surgical attention and have been abundantly studied by the histologist. Specimens of liver removed simultaneously with ap- pendix or gall bladder or both have been studied by a smaller number of observers, of greatest significance being the work of McCarty and of Graham and their associates. In general, these authors are inclined to regard inflammation of the appendix as an earlier man- ifestation in a sequence of associated disorders within the abdomen, this local inflammation tending to induce inflammatory changes in the liver, whence the gall bladder may become involved by lymphatic extension or through the bile stream. Indeed one finds even the suggestion that gastric or duodenal ulcer and gastric carcinoma may represent stages in this same sequence. While the surgical enthusiast will, perhaps, accept the suggestion that immediate laparotomy upon the first 68 sign of abdominal distress is the only insurance against this frightful train of disorders, it may be that the more skeptical would wish to await more adequate proof of this suggested interrelationship. Additional cases of human disease studied from this viewpoint would appear worth while. Our material for present discussion includes speci- mens from twenty-four patients, the youngest 17 years old and the oldest a man of 67 years. The six individuals under 30 years of age are listed in Table I. The first of these, J. P., male, aged 17, was admitted March 16, 1923, ambulatory, temperature 98.6°. lie had an initial attack of appendicitis in November, 1922, and repeated milder attacks since. At the operation on the following day, the gross findings were as follows: ap- pendix elongated, with slight external evidence of infec- tion ; gall bladder has lost its olive green color and its walls are thickened; on the overhanging edge of the liver there are a number of small discrete white plaques, the size of a pinhead, suggesting recent hepat- itis or possible tubercle; gastroduodenal segment nega- tive ; lymph nodes visible in mesentery of ileum. The appendix was removed and a caseated lymph node was excised from the mesentery of the ileum. A small piece of liver was taken. Peritoneal cavity was lavaged with equal parts peroxide of hydrogen and normal saline and closed without drainage. The postoperative tem- perature remained between 99 and 102° for six days except on the fifth day, when it reached ]03°. After the sixth day it remained low and the patient was dis- charged on the ninth day. The mucous membrane of the appendix is somewhat atrophic and contains brown blood pigment indicating a rather recent exacerbation of a low-grade chronic inflammation. Tubercles were not found in the appen- 69 PATIENT SEX AGE APPENDIX GALL BLADDER LIVER REMARKS 1 J. P. M 17 Chronic inflam., re- cently active. Negative, not re- moved. Slight insult. Duration 5 mos. Healing T. B. of mesenteric lymph nodes. 2 J. G. F 22 Chronic inflam., re- cently active. Chronic inflam., re- cently active. Moderate peribiliary cir- rhosis. Duration 8 days. 3 H. F. F 24 Chronic inflam., re- cently active. Thickened; not re- moved. Long-standing interstitial inflam. Duration 1 yr. (6 days). 4 J. D. M 26 Severe subacute puru- lent inflam. Slightly thickened; not removed. Irregular interstitial in- flam., hyperplasia. Duration 4 days. 5 F. P. F 27 Chronic inflam., mod- erately active. Chronic inflam., severe and active; concre- tions present. Early interstitial peri- biliary inflam, in both lobes. Duration 2 yrs. (14 days). 6 B. S. F 28 Chronic inflam., al- most quiescent. Chronic inflam., slight- ly active; small concretions. Portal congestion; slight diffuse hepatitis. Duration 1 yr. The Six Patients Under 30 Years of Age Table I 70 dix. The mesenteric lymph node did reveal the picture of healing tuberculosis. Fig. 4 represents a portion of the liver, which is al- most normal. In the fibrous trabeculae there is a slight excess of wandering cells, chiefly of the mononuclear (endothelial) type, but among them polymorphous Fig. 4.-Liver of J. P., Patient No. 1, aged 17. (a) branch of hepatic artery; (b) bile duct; (v) branch of portal vein; (hep. v.) intralobular branch of hepatic vein. With the microscope one can see mononuclear leukocytes in the connective tissue adjacent to the portal branches and mingled with these a few eosinophilic leukocytes. clear eosinophilic leucocytes are conspicuous. These details cannot, of course, be distinguished in the pho- tomicrograph. The numerous eosinophilic leucocytes 71 in the interstitial tissue of the liver may be related to the healing tuberculosis of the mesenteric lymph nodes. The second patient, J. G., female, aged 22, was ad- mitted March 2, 1923', ambulatory, with temperature of 98.8°, apparently comfortable. Eight days before she had general abdominal pain which eventually lo- calized in the right lower quadrant. She vomited at this time. The pain gradually diminished and had prac- tically disappeared. She was thin and undernourished. At the operation on March 3, 1923, the appendix was partly surrounded by adhesions and its tip was bulb- ous. The gall bladder was small with thickened wall which had lost the green color. The liver showed en- largement of the right lobe with formation of a Rie- del's lobe and the edge of the liver extended half way to the iliac crest. White fibrous spots were visible on the surface and there was diffuse whitening in the vi- cinity of the gall bladder. The appendix, gall bladder and a small piece from the edge of the liver were re- moved. Convalescence was somewhat stormy. On the second day there was moderate secondary bleeding from the wound and sanguinous discharge continued until the twentieth day, after which a purulent dis- charge continued until the fifty-first day. The tem- perature became septic in type on the twenty-ninth day and an abscess of the right breast required incision on the thirty-second day. The fever subsided on the thirty-seventh day and she was discharged on the fifty- second day after operation. A portion of the appendix is shown in Fig. 5. Irreg- ular thickening of the submucosa, occasional dense col- lections of round cells in it and collections of round cells and plasma cells in the subserous coat, indicate a recent moderate exacerbation of a chronic appendicitis, quite in conformity with the clinical evidence of an attack beginning eight days before operation. 72 A portion of the gall bladder wall is shown in Fig. 6. In this the inflammatory reaction appears to be of shorter duration than in the appendix but there is evi- dence of a moderate recent activity of the process. Fig. 5.-Appendix of J. G., Patient No. 2, aged 22; (Zw) narrow lumen of the appendix; (g) gland crypt; (/) lymph follicle; (cm) circular muscle; (Im) longitudinal muscle; (v) blood vessels in the submucous layer. The submucous and muscular layers are thickened by increase of their substance and by edema and there is a marked excess of round cells and polynuclear leukocytes in the edematous connective tissue about the blood vessels (v) in the submucous layer and at the border between the circular and longitudinal muscle layers. These finer details are not distinct in the photomicrograph. Fig. 7 shows a small portion of the liver. Here there is a distinct increase of connective tissue in the trabec- ulae, chiefly about the bile ducts and there are collec- 73 tions of wandering cells irregularly distributed. The changes here are far more advanced than in the first case and clearly indicate a chronic process extending over months or perhaps years. The changes in the Fig. 6.--Gall bladder of J. G., Patient No. 2, aged 22 ; (pl) plicae of the mucous membrane somewhat eroded and thickened ; (</) duct of Luschka (gland crypt) ; (m) muscle. The entire wall of the gall bladder is thickened and with the microscope one can see a large excess of round cells and moderately numerous poly- nuclear leukocytes in the mucous membrane and between the muscle bundles. These are evident even in the photomicrograph at low magnification. hepatic cells suggest a recent exacerbation of the toxic irritation. The third patient, II. K, female, aged 24, was ad- mitted October 20, 1922, ambulatory, with a tempera- 74 lure of 100°. She had an attack of pain in the right lower quadrant about one year ago. The present at- tack began six days before admission, with pain in the appendix region and vomiting; the pain persisted and there was some abdominal rigidity on admission. At operation the appendix appeared congested. The edge Fig-. 7.-Liver of J. G., Patient No, 2, aged 22 ; (a) branches of hepatic artery; (b) conspicuous and numerous bile ducts; (v) branches of portal vein; (cv) central intralobular vein; (ez) eosinophilic zone about the periphery of lobule; (n) unusually large nuclei in hepatic cells. The moderate increase of connective tissue about the portal branches and the increase in number of conspicuous bile ducts indicate a chronic inflammatory process. The marked variation in size and form of the nuclei of the hepatic cells and the irregular staining of the hepatic cells, which are more eosinophilic at the periphery of the lobule and paler in the interior, would appear to be related to a recent toxic insult to the liver, probably associated with the recent exacerbation of in- flammation in the appendix. 75 of the liver was thin and the right lobe was enlarged and showed a number of white spots on its surface. The gall bladder was blue in color and its wall some- what thickened. This was not removed. The appendix and a piece from the edge of the right lobe of the liver were taken. Recovery was uneventful and the pa- tient left the hospital on the seventh day after opera- tion. Fig. 8.-Appendix of H. F., Patient No. 3, aged 24 ; (/e) feces in the lumen, in which it is possible to identify fibers of striated muscle of the food; (e) epithelial lining of the appendix; (p) gland crypts irregular in size, form and arrangement and deficient in number; (/) lymph follicle; (fa) fat in the submucous layer; (cm) circular muscle; (Im) longitudinal muscle; (r) a small col- lection of round cells in edematous connective tissue just external to the muscle coat. This represents a chronic atrophic appendicitis with a very moderate recent exacerbation. 76 The appendix showed spots of inflammatory atrophy of the mucous membrane and large areas of recent hematogenous pigmentation, hardly adequate to ex- plain the preoperative distress. A portion of the wall is shown in Fig. 8. Fig'. 9.-Liver of H. F., Patient No. 3, aged 24 ; (cap) external capsule not entirely included in the picture, slightly indented in the vicinity of a branch of hepatic vein and showing an excess of wandering cells in its fibrous tissue; (hep) branch of hepatic vein; (iv) intralobular vein; (a) branch of hepatic artery; (b) bile duct; (v) branch of portal vein. The liver is shown in Fig. 9 and again in Fig. 10. Here there is evidence of a long-standing interstitial reaction with slight present activity. The fourth patient, J. D., male, aged 26, was admit- 77 ted November 9, 1922, ambulatory, with temperature 98.8°, and a leucocyte count of 15,000, polymorpho- nuclears 70 per cent. He had pain in the right iliac region, which began four days previously, after taking a cathartic. He had felt nauseated but did not vomit. Constipation had not been relieved. His temperature reached 99.4° on November 10. At operation on November 11, the appendix was Fig. 10.-Liver of H. F., Patient No. 3, aged 24 ; (a) branches of hepatic artery; (v) branches of portal vein; (b) bile ducts; (sv) sublobular vein; (ex) extravasated blood in a small area of central necrosis. Areas of central necrosis are very few in the sections. There is, however, a quite general thickening of the connective tissue about the central veins suggesting that slight central necrosis has been a frequent lesion in the past. (See the intralobular veins in Fig. 9.) 78 markedly thickened but free from adhesions. It was removed. The gall bladder was whitish and opaque and its wall slightly thickened. It was not removed. The surface of the liver showed a peculiar mottling. A small piece of liver was taken. Postoperative recov- ery was uneventful and the patient was discharged on the twelfth day after operation. Fig'. 11.-Appendix of J. D„ Patient No. 4, aged 26 ; (e) epithelial lining; (g) gland crypts; (/) lymph follicle; (cm) cir- cular muscle; (Im) longitudinal muscle; (s) subserous connective tissue; (r) dense collections of round cells; (v) congested blood vessels. The wall of the appendix is markedly thickened by in- crease of connective tissue and accumulation of inflammatory exu- date in all the layers. The deeply congested blood vessels appear black in the photomicrograph as do also the more dense collections of wandering cells. The subserous layer shows only in part at the edge of the picture. It also was enormously thickened by in- flammatory edema. The picture is that of severe purulent ap- pendicitis of about one week's duration. 79 Fig. 11 shows a small portion of the wall of the appendix, in which there is a severe subacute purulent inflammation, apparently of longer duration than a week. Fig. 12.-Liver of J. D., Patient No. 4, aged 26 ; (cv) central intralobular vein; (a) branch of hepatic artery; (v) branch of portal vein; (b) bile ducts. The periportal connective tissue is somewhat increased and contains an excess of wandering cells. The lobules are more distinctly marked than normal. The hepatic cells in the peripheral zone of the lobule stain a bluish pink with hematoxylin and eosin in contrast to the more central cells, which are paler but contain abundant minute brown granules just ad- jacent to the central vein. In the photomicrograph the lobulation is less distinct than in the stained preparation itself. The liver is shown in Fig. 12. Here there is a mod- erate but distinct thickening of the trabeculae and moderately numerous wandering cells in this connec- 80 tive tissue. The lobules are somewhat irregular in shape and in some places the columns of liver cells stain more deeply with eosin and the sinusoids between them are distinctly narrowed, suggesting an alteration Fig. 13.-Liver of J. D., Patient No. 4, aged 26 ; (a) branches of hepatic artery; (v) branches of portal vein; (b) bile ducts; (cv) central intralobular vein ; (es) eosinophilic zone of deeply- stained somewhat compressed hepatic columns containing deeply- stained nuclei of irregular size. The picture indicates a reaction to serious toxic injury, apparently derived from the diseased ap- pendix. of structure in some way dependent upon an earlier toxic insult. Such an area is shown in Fig. 13. The fifth patient, F. P., female, aged 27, was admit- ted December 2G, 1922, ambulatory, with a tempera- ture of 99°. During the previous two years she had suf- 81 fered three attacks with pain in the right iliac region, radiating to epigastrium and around the costal margin to the back. She had had four or five miscarriages but no living children. Patellar reflexes could not be elic- ited. The present attack began 14 days before admis- sion to the hospital and the pain was relieved after a few hours. At the operation on December 30, 1922, the appendix appeared thickened; gall bladder was mottled, dirty brown in color and contained a stone 20 mm. in diam- eter. The lymph nodes on the cystic duct and the common bile duct were enlarged. The liver was en- larged, particularly the right lobe. It appeared pale and there were numerous fibrous spots over the sur- face of the right lobe and a diffuse opacity due to fibro- sis adjacent to the gall bladder. The liver edge was irregularly indented. The uterus was bound down by posterior adhesions evidently resulting from an old pelvic peritonitis. The appendix and gall bladder and small pieces of liver from the right and left lobes were removed. The postoperative course was uneventful. The pa- tient left the hospital on the ninth day after operation, contrary to medical advice and on her own responsi- bility. A portion of the appendix is shown in Fig. 14. It has been the seat of a chronic inflammation which was still active at the time of removal. The gall bladder is shown in Fig. 15. Here the in- flammation has also been of long duration but evi- dently more severe. Furthermore, there was a moder- ately severe active purulent exacerbation present at the moment of removal. In the liver the changes are perhaps less marked than might have been expected. The trabeculae are thick- ened and they outline the lobules more completely than 82 in a normal liver. This connective tissue also contains an excess of wandering cells, apparently more inti- mately related to the bile ducts than to the portal branches. There was no evident difference between Fig. 14.-Appendix of F. P., Patient No. 5, aged 27 ; (/) lymph follicle; (cm) circular muscle; (Im) longitudinal muscle; (s) sub- serous coat in which there is increase of fibrous tissue ; (r) collec- tions of round cells in edematous connective tissue. The muscular and subserous layers are edematous and richly infiltrated by wandering cells. The picture is that of a chronic appendicitis in which there has been a moderate exacerbation of about two weeks' duration, now healing. the pieces from the right and left lobes of the liver. A portion of liver including the capsule is shown in Fig. 16. This does not include a portal branch and the increase of periportal connective tissue is, there- 83 fore, not shown. Collections of round cells in the liver substance and conspicuous large nuclei in the hepatic cells may be related to the recent illness of the patient. The sixth patient, B. S., female, aged 28, was admit- ted October 11, 1922, ambulatory, with a temperature Fig'. 15.-Gall bladder of F. P., Patient No. 5, aged 27 ; (p) thickened plicae of the mucosa; (p) ducts of Luschka (gland crypts) ; (pl) thickened and partly eroded plicae of the mucous membrane ; (r) areas of more abundant infiltration with wander- ing cells; (v) injected blood vessels. The hypertrophy of the muscle bundles, increase of connective tissue in the fibrous layer and between the muscle bundles as well as the thickening of the plicae indicate a chronic cholecystitis. The intense congestion and the abundant infiltration of the mucous membrane and the muscular coat with round cells mingled with smaller numbers of plasma cells, polynuclear leukocytes and eosinophilic leukocytes indicate an active exacerbation of the inflammation. The entire wall is about 4 mm. thick. 84 of 99°. For the previous year she had suffered repeated attacks of pain in the right hypochondrium, the pain radiating to the back and shoulders. She had been nauseated but had not vomited. She had suffered es- pecially during the preceding week. Fig. 16.-Liver of F. P., Patient No. 5, aged 27 ; (cap) Glis- son's capsule; (r) collections of deeply-stained round and poly- morphous cells, apparently endothelial cells, in the capsule and in the liver substance; (hep. v.) intralobular branch of the hepatic vein. The photomicrograph does not include the thickened trabec- ulae of Glisson's capsule, which were present in the section. At the operation on October 12, 1922', the appendix was thickened and turgid; the gall bladder was white with injected blood vessels extending to the fundus. It contained about twenty minute sulphur-colored 85 stones. Recently inflamed lymph nodes were seen on the cystic duct. The liver appeared slightly swollen but of normal color and without external markings. The postoperative course was uneventful and the pa- tient was discharged on the thirteenth day. Fig. 17.-Appendix of B. S., Patient No. 6, aged 28; (Zu) lumen; (f?) gland crypts in the mucous membrane; (/) lymph follicle; (r) dense collection of round cells in the submucous layer; (cm) cir- cular muscle; (Im) longitudinal muscle; (bl) injected blood ves- sels. The picture is that of a healing stage of a moderate exacer- bation of a chronic inflammation. Fig. 17 shows a portion of the appendix. Here there has been chronic inflammation with moderate recent activity. 86 The gall bladder is shown in Fig. 18. The muscle coat is thickened and there are abundant wandering cells in its interstitial tissue. The liver, shown in Fig. 19, presents evidence of a Fig. 18.-Gall bladder of B. S., Patient No. 6, aged 28 ; (pl) plicae of the mucous membrane; (g) duct of Luschka (gland crypt) ; (m) muscle bundles. In the connective tissue between the muscle bundles there are abundant round cells and moderately numerous polynuclear leukocytes. These are not distinct in the photomicrograph. rather mild interstitial hepatitis, inactive at the moment. In the decade from age 30 to age 39 we also have available six cases. These are listed in Table II. 87 The first of these, S. D., male, aged 30, was admitted December 29, 1923, with epigastric pain of 14 days' duration, accompanied by vomiting at first. He had lost ten pounds in weight during this time. The his- Fig. 19.-Liver of B. S., Patient No. 6, aged 28 ; (a) branches of hepatic artery; (v) branch of portal vein; (b) bile ducts; (/a) fat globules in hepatic cells. There is a very moderate increase of fibrous tissue about the portal branches and an excess of con- spicuous bile ducts, indicating a mild chronic interstitial hepatitis, doubtless secondary to the chronic inflammation in the appendix and gall bladder. In many of the lobules there is a very narrow zone of hyaline necrosis of the hepatic cells immediately adjacent to the central vein. These are not included in the photomicrograph. tory had to be obtained through an interpreter but apparently there had been indefinite indigestion for three years and more definite symptoms for one year. 88 PATIENT SEX AGE APPENDIX GALL BLADDER LIVER REMARKS 7 S.D. M 30 Chronic inflam., with recent severe exacer- bation. Not removed. Reaction of recent in- jury. Duration 24 days. 8 C. K. F 30 Chronic inflam., re- cently active. Chronic inflam., ' ' strawberry type. ' ' Peribiliary interstitial hyperplasia. Dyspepsia for 10 yrs., typhoid fever 2 yrs. ago. 9 E.W. M 31 Mild chronic inflam., acute congestion. Chronic inflam., with old erosion. Slight interstitial hepa- titis. Duration 2 yrs; ab- dominal cramps for last 6 hours. 10 J. F. M 34 Chronic inflam., par- tial obliteration. Negative; not re- moved. Negative. Recurrent appendicitis for 4 yrs.; present attack of 7 days' duration. 11 A. R. M 37 Chronic atrophic in- flammation. Chronic inflam., quies- cent. Interstitial increase; in- active. Chronic polyarthritis of infectious type. 12 C.W. F 39 Chronic inflam., slight recent activity. Chronic inflam., of moderate grade. Slight peribiliary fibrosis. Indigestion for 6% yrs. The Six Patients From 30 to 39 Years of Age Table II 89 The pain was relieved by food and by soda. At the op- eration on January 9, 1924, there was found a perforat- ing ulcer on the anterosuperior border of the duodeum, without adjacent adenopathy. The pyloric lumen was narrowed about 50 per cent. Distal to the ulcer at a Fig. 20.-Appendix of S. D., Patient No. 7, aged 30 ; (g) gland crypt; (/) lymph follicles ; (cm) circular muscle ; (Im) longitudinal muscle; (s) subserous coat. There is an excess of round pells throughout the entire thickness of the wall and these are especially abundant in and about the distended blood vessels in the edematous subserous coat (s). space of 5 cm. there was an adhesion of duodenum to gall bladder. A fine vascular granulation tissue ex- tended as a film over the ulcer and the pyloric end of 90 the stomach. The gall bladder was congested and dis- tended. The appendix was kinked at its middle and the lumen was obliterated at the tip. Adhesions were present about it. The liver showed mild Glissonitis, particularly in the gall bladder notch. The right lobe was enlarged and the consistency was more leathery than normal. The appendix and a small piece of liver were removed and a posterior gastroenterostomy was performed. Postoperative recovery was uneventful and the patient was up in a chair on January 19 (tenth day). Fig. 20 shows a portion of the wall of the appendix. It has been the seat of a chronic inflammation and was recovering from a quite severe exacerbation of this inflammation at the moment of removal. A portion of the liver is shown in Fig. 21. Here there is evidence of slight increase of interstitial tissue with a moderate excess of wandering cells in it. The hepatic cells them- selves are irregular in size and shape and exhibit marked irregularity in size, shape and staining prop- erty of their nuclei, evidently resulting from a recent toxic insult, apparently secondary to the inflammation in the appendix or to the duodenal inflammation. Patient No. 8, C. K., female, aged 30, was admitted October 29, 1922, ambulatory, with temperature 99°. For the last ten years she has had occasional attacks of vomiting and during the last eight months has been jaundiced three times. She had typhoid fever many years ago. At time of admission there was general ab- dominal pain, not severe. At the operation on October 30, 1922', the appendix contained seven fecoliths and its serous veins were injected. The gall bladder was mottled brown and white and its wall very thick and the lymph nodes along the cystic and common bile duct were much enlarged. Concretions were not found. The liver was dark in color and its right lobe enlarged, 91 the posterior half of the right lobe showing the great- est change. On the surface of this lobe there were many small white spots. The consistency was more leathery than normal and the edge of the liver was Fig. 21.-Liver of S. D., Patient No. 7, aged 30 ; (v) branch of portal vein; (b) bile duct; (hep. v.) intralobular vein; (n) un- usually large and deeply-stained nuclei of hepatic cells; (en) swollen and deeply-stained nuclei of endothelial cells lining the portal branches and the sinusoids between the liver columns. There is a moderate increase of fibrous tissue about the portal branches and in this an excess of wandering cells, indicating a mild grade of chronic interstitial hepatitis. The parenchymatous changes, namely, general swelling of hepatic cells, irregularity of hepatic- cell nuclei, swelling of the endothelial nuclei and narrowing of the sinusoids evidently represent a reaction to a recent toxic insult, probably related to the active appendicitis and the active ulceration in the duodenum. Unfortunately the photomicrograph lacks the clearness of the microscopic preparation and the magnification is hardly adequate to reveal the details distinctly. Compare with Fig. 24. 92 irregularly indented. Near the gall bladder the white plaques were more conspicuous. The appendix and gall bladder were removed; also a small piece of liver from the anterior edge 3 cm. to the right of the gall Fig'. 22.-Appendix of C. K., Patient No. 8, aged 30 ; (</) gland crypts; (/) lymph follicle; (/a) fat in the submucous layer; (cm) circular muscle; (Im) longitudinal muscle. The submucous layer contains scattered dense collections of round cells and there are occasional extravasations of blood in the mucous membrane, not seen in the photomicrograph. The picture is that of a mild chronic appendicitis, inactive at the moment. bladder. The postoperative recovery was uneventful and she was discharged on the seventeenth day. Fig. 22 shows a portion of the wall of the appendix. There is brown blood pigment in the mucous mem- 93 brane and also recent extravasations of blood. A slight excess of round cells in 1he outer coats indicates moderate recent activity of the chronic inflammation. A portion of the gall bladder wall is shown in Fig. 23. Here there is xanthomatous change in the stroma of the ruga1, which stood out as bright yellow marks in the gross examination of the mucous surface (strawberry Fig. 23.-Gall bladder of C. K., Patient No. 8, aged 30 ; (Zip) plicae of the mucous membrane showing extreme grade of xantho- matous change in the connective tissue, appearing bright yellow in the fresh state; (</) ducts of Luschka (gland crypts) ; (m) muscle bundles; (v) congested blood vessels. There is a moderate excess of round cells throughout the entire thickness of the wall. This is the picture of a chronic catarrhal cholecystitis of moderate severity producing the gross appearance of "strawberry gall bladder." 94 appearance). The muscle bundles are hypertrophied and there is inflammatory fibrous thickening of the entire wall. The liver is shown in Fig. 24. In it there is a moderate increase of connective tissue and of smaller bile ducts, evidence of a chronic inflammation prac- tically quiescent at the moment. Patient 9, E. W., male, aged 31, was admitted Octo- ber 13, 1922, as an emergency stretcher case, with fem- Fig. 24.-Liver of C. K., Patient No. 8, aged 30 ; (a) branch of hepatic artery; (b) bile ducts; (v) branch of portal vein; (cv) central intralobular vein ; (en) nucleus of endothelial cell lining a sinusoid; (fa) fat globule within a liver cell. There is a moderate increase of connective tissue about the portal branches and an increase in the conspicuous bile ducts, evidence of a previ- ous interstitial hepatitis of moderate grade. The liver columns, sinusoids and intralobular vessels appear normal. This figure should be compared with Fig. 18. 95 perature of 99.8°. The leucocyte count was 13,200, with 74 per cent polymorphonuclears. Six hours be- fore he had been seized with abdominal cramps and vomiting. The pain radiated to the right side. The pain and tenderness were most marked over the appen- Fig. 25.-Appendix of E. W., Patient No. 9, aged 31 ; (ep) lining epithelium; (g) gland crypt; (f) lymph follicle; (fa) fat in the submucous layer; (cm) circular muscle; (Im) longitudinal muscle; (v) congested blood vessels in the subserous layer. The mucous membrane is slightly atrophic, indicating earlier inflammation. The marked congestion of the subserous vessels and the accumulation of polynuclear leukocytes about them suggests a beginning active inflammation in the appendix but the inner coats do not reveal evidence of it in the sections which have been examined. dix region but the rigidity was most pronounced in the upper abdomen. For the past six years he has been subject to abdominal cramps, lasting several days at 96 a time, without apparent relation to food. The pre- operative diagnosis ("impression") was (1) ruptured appendix or (2) perforated duodenal ulcer. At the operation on the day of admission the gall bladder was adherent to the duodenum and transverse colon and its wall was thickened. The adjacent lymph nodes were Fig. 26.-Gall bladder of E. W„ Patient No. 9, aged 31 ; (pZ) plicae of the mucous membrane; (<jl) ducts of Luschka (gland crypts) ; (m) muscle; (er) erosion exposing the muscle, which is here infiltrated with wandering cells. enlarged. Concretions were not found. The appendix appeared swollen and turgid. Remainder of the abdo- men appeared negative. The gall bladder and appen- dix were removed; also a small piece of the liver. 97 The postoperative recovery was uneventful except for considerable oozing of blood during the first two days, lie was discharged on the fifteenth day. A portion of the wall of the appendix is shown in Fig. 25. The serous vessels are injected and there is some edema and a moderate excess of wandering cells Fig. 27.-Liver of E. W., Patient No. 9, aged 31; (&) bile ducts; (r) branch of portal vein; (hep) branch of hepatic vein; (cv) intralobular veins. There is a moderate increase of connective tissue about the portal branches. in the outer coats. The mucous membrane is negative except for atrophic changes consequent to earlier in- flammation. Fig. 26 shows a portion of the gall blad- 98 der. On the mucous membrane there are a few eroded spots, near which there is superficial inflammatory in- filtration. Fig. 27 represents a portion of the liver. There is slight increase of fibrous tissue in the trabec- ulae. At the edge of the liver there was an irregular Fig. 28.-Appendix of J. F., Patient No. 10, aged 34 ; (g) gland crypt of the mucous membrane ; (f) lymph follicle ; (cm) circular muscle; (Zm) longitudinal muscle; (fib) fibrous tissue of inflam- matory origin in the submucous layer; (r) dense collection of round cells in the submucous layer; (v) blood vessel. The distal third of this appendix was obliterated. fibrous scar infiltrated with wandering cells, evidently caused by lymphatic extension from the cholecystitis. This is not shown in the photomicrograph. The struc- 99 tural alterations do not very well explain the symp- toms, but possibly the congestion and edema of the appendix may represent an early stage of an inflam- matory exacerbation, to which the symptoms may be ascribed. Patient 10, J. F., male, aged 34, was admitted Decem- ber 19, 1922, ambulatory, with temperature 99.4°. He had pain in the right iliac region, of seven days' dura- tion, and has had similar attacks frequently for four years. In the initial illness, four years ago, he vomited every day for three weeks. lie has lost 20 pounds in the four years. A palpable mass was present in the right side at level of the umbilicus. The leucocyte count was 10,300 with 72 per cent polymorphonuclears. Preliminary diagnosis ("impression") was carcinoma of the colon. Subsequent roentgenologic study failed to support this impression and was essentially negative. Blood Wassermann was negative and the spinal fluid normal. Operation had been scheduled for December 20, but was postponed until December 28 to permit more complete preoperative consideration. At the op- eration on the latter date the liver and gall bladder appeared normal. The gastroduodenal segment was injected, without evidence of ulcer. The appendix was adherent to the right lateral abdominal wall and the right border of the omentum was adherent to the cecum and ascending colon. The lower border of the omentum was adherent to the mid portion of the sigmoid. The appendix and a small piece of liver were removed. The postoperative recovery was uneventful and the patient was discharged on the thirteenth day. The appendix was the seat of chronic inflammation only slightly active at the time of removal. The lumen was obliterated in the distal third. A portion of the wall is shown in Fig. 28. The liver is shown in Fig. 29. In it there is, perhaps, a slight excess of wandering 100 cells in the trabeculae but the appearance is practically normal. Fine granules of brown pigment and a very small amount of fat are present in the liver columns. Patient 11, A. R., male, aged 37, was admitted April 23, 1923, for pain in the left shoulder of two years' duration and more recent involvement of the fingers Fig. 29.-Liver of J. F., Patient No. 10, aged 34 ; (cap) external capsule of Glisson; (b) bile duct; (v) branch of portal vein; (w) intralobular veins. and toes (chronic polyarthritis). He had suffered from persistent diarrhea, painless, from 1918 to December, 1922, when it was relieved by treatment (apparently hydrochloric acid after meals). On January 2, 1924, 101 after seven months without improvement, a laparotomy was decided upon. At the operation on January 5, 1924, the appendix presented a constriction near its middle, obliteration at the tip and slight adhesions about the tip. The gall bladder contained about 150 Fig. 30.-Appendix of A. R., Patient No. 11, aged 37 ; (p) gland crypt; (/) lymph follicle rather poorly defined; (cm) cir- cular muscle; (Im) longitudinal muscle. The mucous membrane is atrophic and the lumen of the appendix had become obliterated at the tip. evidently the result of a chronic inflammation, inactive at the moment. small black facetted stones and its wall showed prom- inent blood vessels over the fundus. The liver was en- larged on the right side and there was moderate Glis- 102 sonitis, especially in the portion between the gall blad- der and the round ligament. The appendix and gall bladder and a small piece of liver were removed. Recovery from the operation was quite uneventful and the condition of the joints persists. Fig. 31.-Gall bladder of A. R., Patient No. 11, aged 37 ; (pZ) plicae of the mucous membrane somewhat dulled and thickened; (g) duct of Luschka (gland crypt) ; (wi) thickened muscle; (r) dense collection of round cells; (v) congested blood vessels. The gall bladder contained concretions and had evidently been the seat of chronic inflammation. Fig. 30 shows a portion of the wall of the appendix. It shows the changes of chronic atrophic inflammation 103 with only slight recent activity. The gall bladder is shown in Fig. 31. Here also there are the changes of chronic inflammation with evidence of only slight ac- tivity. The liver presents a rather marked increase of its connective tissue, evidently of long standing (Fig. 32). Fig. 32.-Liver of A. R., Patient No. 11, aged 37 ; (hep) branch of hepatic vein; (v) branch of portal vein; (a) branch of hepatic artery; (b) bile duct; (fib) fibrous tissue of the trabeculae greatly increased as a result of chronic interstitial hepatitis. It contains an excess of mononuclear cells. Patient 12, C. AV., female, aged 39, was admitted April 22, 1923', ambulatory, with temperature 98.6°. She had pain in the right hypochondrium of six years' 104 duration, with much nausea but no vomiting. At the operation on the following day the appendix was bent at its middle and the lumen was narrowed in the distal portion. The gall bladder was distended and its walls thickened. It contained about 15 calculi the size of hazel nuts. The right lobe of the liver was enlarged. Fig. 33.-Appendix of C. W., Patient No. 12, aged 39 ; (Zu) lumen of the appendix; (y) gland crypt; (/) follicle; (cm) cir- cular muscle; (Im) longitudinal muscle; (r) dense collection of round cells in the subserous coat. The appendix, gall bladder and a small piece of liver were removed. Fig. 33 shows a portion of the appendix, in which there has been a chronic atrophic inflammation with 105 evidence of slight recent activity. The gall bladder, Fig 34, also shows a severe chronic inflammation, but here more active inflammation persists. The liver is shown in Fig. 35. There is a slight increase of fibrous tissue in the trabccuhe, more dense about the bile Fig. 34.-Gall bladder of C. W., Patient No. 12, aged 39 ; (e) lining epithelium of the gall bladder; (m) muscle bundles; (v) congested blood vessels. There is almost complete loss of the plicae mucosae and a marked excess of wandering cells in the interstitial tissue of the muscle coat, evidence of a severe chronic inflam- mation. ducts, and a slight excess of round cells in this tissue. The next six patients to be considered fall in the age period from 40 to 49 years. They are listed in Table III. 106 Patient 13, M. S., female, aged 42, was admitted March 22, 1923, ambulatory, with temperature 100.2°. She had pain in the stomach of three years' duration and this has been practically continuous for the last Fig. 35.-Liver of C. W., Patient No. 12, aged 39 ; (cap) Glis- son's capsule; (hep) intralobular vein, sharply defined; (t>) branch of portal vein; (a) branch of hepatic artery; (b) bile duct. There is a moderate increase of connective tissue in the trabeculae about the portal branches and an excess of wandering cells in this tis- sue, evidence of a chronic interstitial hepatitis, almost quiescent at the moment. six months. She appeared emaciated. The preopera- tive diagnosis ("impression") was malignant growth of stomach. The gastric juice after Ewald test meal 107 contained no free hydrochloric acid. The leucocyte count was 5,800 with polymorphonuclears 56 per cent. At the operation on March 24, 1923, the stomach and duodenum were negative. The appendix was obliter- ated for the distal two-thirds and near the appendix the omentum was adherent to the parietal peritoneum. Fig. 36.-Appendix of M. S., Patient No. 13, aged 42; (fa) fat in the obliterating tissue filling the site of the lumen ; (cm) circular muscle; (Zm) longitudinal muscle; (ad) fibrous adhesion; (ic) wrinkle in the section (artefact). The lumen is completely obliterated as a result of earlier inflammation. There were also some adhesions in the pelvis. The gall bladder appeared thickened but without calculi. The liver was moderately enlarged with fibrosis of the cap- 108 PJ TIENT SEX AGE appendix GALL BLADDER LIVER REMARK 13 M. S. F 42 Old complete oblitera- tion. Slight thickening. Extensive irregular scar of right lobe. Duration 3 years. 14 K. H. M 43 Slight chronic inflam- mation. Entirely negative. Mild interstitial hepatitis. Acute peptic ulcer of pylorus; post-opera- tive death. 15 T. M. M 45 Acute gangrenous exacerbation of chronic inflam. Thick and red; not re- moved. Enlarged; sub-acute peri- portal hepatitis. Clinical duration 3 days; death 5 wks. after operation. 16 A. M. M 46 Chronic atrophic in- flam., slight recent activity. Acute phlegmonous e x a c e r bation of chronic inflam. Chronic peri-biliary inter- stitial hepatitis. Death 33 hours after operation. 17 M. N. F 47 Chronic atrophic in- flam., with mild ac- tivity. Chronic atrophic in- flam., with moderate activity. Subacute interstitial hepatitis, rather recent. Duration 7 years. 18 J. S. F 47 Chronic inflam., inac- tive. Mild chronic inactive inflam. Long-standing interstitial thickening. Duration l years. The Six Patients From 40 to 49 Years of Age Table III 109 stile and crenation of the free edge, especially of the right lobe. The appendix and gall bladder and two pieces of liver, one from the right lobe and one from the left lobe, were removed. The postoperative recov- ery was uneventful and the patient was discharged on the fourteenth day. Fig\ 37.-Gall bladder of M. S., Patient No. 13, aged 42 ; (pZ) plicae mucosae; (m) muscle bundles. There is irregularity of the plications of the mucous membrane and hypertrophy of the muscle bundles with a slight increase of fibrous tissue. These indicate a chronic cholecystitis, inactive at present. A portion of the appendix is shown in Fig. 36. The specimen did not reveal a Inmen nor any remnant of mucous membrane. The obliteration was evidently of 110 long standing. Fig. 37 shows a portion of the gall bladder. Here there is slight thickening from old in- inflammation but only slight evidence of any recent activity. A portion of the liver specimen from the right lobe is shown in Fig. 38. Here there is extensive Fig. 38.-Right lobe of liver, near gall bladder, of M. S., Patient No. 13, aged 42; (fib) fibrous tissue of inflammatory origin; (Zi) distorted hepatic lobule. fibrosis intermingled with groups of hepatic cells ir- regularly arranged, indicating an old inflammation, probably extending through the lymphatics from the gall bladder. The specimen of liver from the left lobe 111 shows much less alteration although here there is a definite increase of connective tissue about the bile ducts. Patient 14, K. H., male, aged 43, was admitted Janu- ary 11, 1923, ambulatory, with temperature of 99.6°. Fig. 39.-Left lobe of liver of M. S., Patient No. 13, aged 42 ; (hep) branch of hepatic vein; (b) bile duct in thickened fibrous trabecula; (v) branch of portal vein. The fibrosis is less exten- sive here than in the section from the right lobe but the changes are of a similar character. lie complained of severe pain in epigastrium, nausea and some vomiting, during the preceding seven days. He was ill from "meat poisoning" in 1915 and had 112 stomach trouble in 1919 and 3920 but was free from symptoms from 1920 until January, 1923'. For the last week he has avoided solid food because of the distress caused by it. Physical examination revealed moderate rigidity on the right side. The preoperative diagnosis ("impression") was duodenal or gastric ulcer and subacute appendicitis. At the operation on January 13, there was found an area of vascularization, stip- pling and infiltration on the superior curvature of the stomach, just proximal to the pylorus, evidently due to a subacute gastric ulcer. The appendix was nar- rowed by inflammatory fibrosis in the distal third. The gall bladder and the liver appeared normal. A poste- rior gastrojejunostomy was performed; the appendix and a small piece of liver were removed. After this operation the patient vomited reddish brown fluid on the first and second days and yellowish green fluid after the third day. His temperature remained 99 and 101°. On the eighth day vomiting became very fre- quent and the abdomen was distended. At a second operation on this day (January 21) the small intestine was found completely paralyzed and greatly distended. The peritoneum was generally injected and discolored by hemorrhage and there was free fluid in the perito- neal cavity. Jejunostomy and ileostomy were per- formed and the peritoneal cavity was drained. The patient died 18 hours later. At the autopsy, performed six hours after death, the significant findings were acute ulcerative enteritis of severe grade; localized purulent peritonitis about gas- troenterostomy and about appendix stump and gener- alized hemorrhagic serous peritonitis; bronchopneumo- nia and marked pulmonary edema; cardiac dilatation; severe acute nephritis; a recent peptic ulcer in the pyloric ring. The appendix presented the features of chronic in- 113 flanimation, practically inactive at the moment. Illus- tration of it has been omitted as unimportant. The pylorus, removed six hours postmortem, is shown in Fig. 40. The structure is not well preserved but the deep defect in the pyloric ring can be discerned. This ulcer was deep and narrow and extended in a circum- ferential direction about one-third of the way around the pylorus. It is evidently of very recent origin as there is no evidence of scar tissue about it and very lit- Fig. 40.-Pylorus of K. H„ Patient No. 14, aged 43 (autopsy) ; (m)muscle; (br)glands of Brunner; (uZ) ulcer extending- into the muscular coat; (p) pyloric glands of the stomach; (zv) wrinkle in the section (artefact). The magnification here is very much lower than in the preceding photomicrographs. tie local inflammatory reaction. The gall bladder re- moved at autopsy is shown in Fig. 41. It appears entirely negative except for postmortem change. Fig. 42 shows a portion of liver removed at the first operation. In this there is an excess of wandering cells in the trabeculae and a moderate increase of connective 114 tissue in them. On the whole the liver appears almost normal. The liver removed after death (Fig. 43) shows a very extreme edema and a marked degeneration of the liver cells, evidently a manifestation of the ter- minal infection but in part, doubtless, a postmortem change. Patient 15, T. M., male, aged 45, was admitted as an emergency for operation at 1:45 p.m., November 27, 1922, with temperature 99.8°, suffering from severe Fig. 41.-Gall bladder of K. H., Patient No. 14, aged 43 (autopsy) ; (li) liver substance; (m) muscle of gall bladder; (pl) plicae mucosae of gall bladder. The magnification is same as in Fig. 40. pain in right iliac region, of three days' duration and accompanied by nausea and vomiting. He had never been ill before. The leucocyte count was 10,400 with 81 per cent polymorphonuclears. Preoperative diag- nosis ("impression") was acute appendicitis. At the operation, at 4 :50 p.m., November 27, the appendix was found near the under surface of the liver. The appen- 115 dix was gangrenous near the tip and there was local- ized peritonitis about it. The gall bladder was hemor- rhagic and thickened, apparently as a result of reaction to the severe inflammation in the neighboring appen- dix. The liver extended about 3% inches below the costal margin and appeared to be in the hypertrophic stage of portal cirrhosis. The appendix and a small piece of liver were removed. Fig. 42.-Livei' of K. H., Patient No. 14, aged 43 (surgical speci- men) ; (a) branch of hepatic artery; (b) bile ducts; (v) branch of portal vein; (n) enlarged nuclei of hepatic cells. There is a considerable increase of connective tissue in the trabeculae of Glis- son's capsule and an excess of wandering cells in this tissue, evi- dence of a chronic interstitial hepatitis. The excessive number of large nuclei in the hepatic cells suggests active toxic irritation which may be related to the acute disturbance for relief of which the operation was undertaken. 116 The postoperative course was rather stormy with bronchopneumonia for two weeks and later a small pleu- ral effusion. A very few tubercle bacilli were found in the sputum after repeated long search. There was continued fever, reaching 103° almost every day. Death occurred on the thirty-seventh day after opera- tion. Postmortem examination was not permitted. Fig. 43.-Liver of K. H., Patient No. 14, aged 43 (autopsy) ; (cap) edematous Glisson's capsule; (Ze) liver column surrounded by edematous fluid which has separated the endothelium from it completely. The tissue is poorly differentiated by the stain, in part because of postmortem change (autopsy 6 hours after death). The extreme edema of the liver would appear to have resulted from the fatal postoperative enteritis and peritonitis. This picture should be compared with Fig. 42 representing the same liver at the time of operation. 117 The structural changes in the tissues removed at operation are interesting and apparently of great sig- nificance. A portion of the appendix is shown in Fig. 44. Here there is a very severe purulent inflammation with considerable gangrene and extension of the proc- ess to the peritoneum, evidently supervening upon a chronic appendicitis. The gall bladder was not re- moved in this case. Fig. 45 shows a low-power view of Fig. 44.-Appendix of T. M., Patient No. 15, aged 45 ; (s) subserous coat distended by hemorrhagic inflammatory exudate; (Im) longitudinal muscle; (cm) circular muscle richly infiltrated by inflammatory exudate; (sm) purulent exudate in the gangrenous submucous coat; (g) gland crypts; (p) pus in the lumen of ap- pendix; (ba) dense masses of bacteria in necrotic exudate. This is the picture of gangrenous appendicitis. 118 a portion of the liver. The trabecula of Glisson's cap- sule are everywhere richly infiltrated with wandering cells, particularly endothelial leucocytes, lymphocytes and conspicuous polymorphonuclear leucocytes. The striking feature, however, is the enormous swelling of the inner coats of the portal branches and the prolif- Fig-. 45.-Liver of T. M., Patient No. 15, aged 45 ; (v) portal branches; («) branches of hepatic artery; (&) bile ducts. The periportal connective tissue is edematous and richly infiltrated with polynuclear leukocytes, eosinophilic leukocytes and especially abundant mononuclear (endothelial) leukocytes. Mitotic division figures are present in the endothelial cells. The endothelium of the sinusoids is swollen and in many places separated from the liver columns by a coagulable exudate in which there are poly- nuclear leukocytes. There is an enormous collection of mononuclear cells in the walls of the portal branches. The picture is that of a severe acute diffuse hepatitis of portal origin. 119 eration of the lining endothelium. The bile ducts are obviously less related to the inflammatory exudation although one occasionally finds a polynuclear leuco- cyte in the lumen of a bile duct. Fig. 46, at a some- what higher magnification, shows severe lesion of the portal vein in contrast to the more normal bile ducts. Fig. 47 is a photograph of a thin section stained with Fig-. 46.-Liver of T. M„ Patient No. 15, aged 45 ; (v) branches of portal vein showing in some places a marked accumulation of deeply-stained mononuclear cells beneath and in the intima; (a) hepatic artery enormously injected; (b) bile ducts with sharply defined lumen and orderly epithelial coat, obviously less involved than the portal branches in the inflammatory reaction. The thick- ened trabeculae of the capsule are edematous and richly infiltrated with wandering cells. The hepatic cells are swollen as are the endothelial cells lining the sinusoids. The picture is that of a rather acute diffuse hepatitis of portal origin supervening upon a chronic interstitial hepatitis. 120 resorcin-fuchsin and carmine. The thick endothelium internal to the elastic coat of the vein is clearly shown in the stained specimen and can be discerned in the photomicrograph. A careful search for thrombosed portal branches has failed to reveal any. The hepatic cells themselves appear swollen and there is an excess of polymorphonuclear leucocytes in the sinusoids. Patient 16, A. M., male, aged 46, was admitted De- Fig. 47.-Liver of T. M., Patient No. 15, aged 45 (section stained with resorcin-fuchsin and carmine) ; (re) branch of hepatic artery; (b) bile duct; (el) subendothelial elastic layer in the wall of portal vein. In the microscopic preparation this layer of some- what frayed elastic fibers is sharply differentiated in dark blue in contrast to the adjacent cells stained rose color by the carmine. In the photomicrograph the red appears as dark as the blue. There is a thick layer of cells, chiefly endothelial cells, internal to this elastic layer. 121 cember 22, 1922, ambulatory, with temperature of 99.0°. He complained of severe pain in the stomach with belching of gas, of 18 months' duration. There was no nausea or vomiting and no definite relation to meals, the pain appearing frequently at midnight. He has been twice jaundiced in the past year. For the last week the pain has been more severe and jaundice has returned. The patient had pneumonia in 1917 and after it an empyema which was drained surgically. The preoperative diagnosis was (1) cholecystitis and cholelithiasis, (2) noncalculous cholangitis, (3) associ- ated pancreatitis and possibly hepatitis. At the operation at 2 :50 p.m. on December 27, 1922, the appendix was retrocecal, surrounded by inflamma- tory membrane and turgid. The gall bladder was mark- edly thickened (wall 2 to 5 mm.), of a dusky brown color without any green tinge. It contained about 350 very small sulphur-colored concretions. There was considerable reddening about the base of the gall blad- der and marked infiltration in the neighborhood of the cystic duct. The lymph nodes along the common duct were enlarged. The liver, as a whole, was smaller than normal but the right side of the right lobe was elongated into a Riedel's lobe, extending to the mid- axillary line 5 cm. below the level of the ribs. The liver edge was retracted and fibrous and, near the gall bladder, the liver surface was opaque and white in a zone about 2 cm. wide. Over the dorsal surface of the right lobe there were many white fibrous spots, the largest about 3 mm. in diameter. The liver, as a whole, was pale ochre in color. The appendix, gall bladder and a small piece of liver were removed. After operation the patient rallied in a normal man- ner. In the evening of the next day the pulse became imperceptible; there was a chill and the temperature rose to 105° at 11 p.m. He became noisy and irra- 122 tional and died at 1 a.m. that night. Postmortem ex- amination was not permitted. Fig. 48 shows a portion of the appendix, in which there is atrophy due to chronic inflammation and some brown blood pigment in the mucous membrane, indi- cating a recent slight activity of the inflammation. A Fig. 48.-Appendix of A. M., Patient No. 16, aged 46 ; (</) gland crypt of the mucous membrane; (/) lymph follicle; (hf) hemor- rhagic lymph follicle.; (sm) submucosa; (cm) circular muscle; (Im) longitudinal muscle; (v) congested blood vessel. portion of the gall bladder wall is shown in Fig. 49. Here there is an active purulent, and in part phlegmon- ous, exacerbation of a severe chronic ulcerative inflam- 123 mation. Eosinophilic leucocytes are found in small numbers, suggesting a tendency to subsidence of the active process. The liver specimen appears to be of considerable sig- nificance. Here there is general fibrous thickening of the trabeculae of Glisson's capsule and an evident in- crease of the bile ducts. This connective tissue con- tains an excess of wandering cells which occur in Fig. 49.-Gall bladder of A. M., Patient No. 16, aged 46 ; (pZ) plicae mucosae denuded of epithelium; (m) muscle; (w) wrinkle in the section; (a) artery with enormously thickened wall; (i) edematous fibrous tunic markedly thickened by inflammatory fibrosis; (h) recent hemorrhage; (p) peritoneum. There is a moderate excess of wandering cells throughout the wall but they are more abundant in the interstitial tissue of the muscle layer and in the mucous membrane. The picture represents a severe chronic cholecystitis, still active. 124 dense collections and are more intimately related to the bile ducts than to the blood vessels. The hepatic lobules are frequently somewhat small and distorted with the intralobular vein displaced from the center. These changes may be interpreted as chronic. In addi- Fig. 50.-Liver of A. M., Patient No. 16, aged 46 ; (a) branch of hepatic artery; (b) bile ducts; (v) branch of portal vein; (c-r) central intralobular veins; (bi) bile thrombi in distended bile capillaries near the central veins ; (r) localized area of round-cell infiltration in vicinity of bile ducts. tion there are evidences of acute disturbance. Many of the bile capillaries are distended with bile thrombi, especially evident near the intralobular veins (Fig. 50). In some of the bile ducts one finds bile-stained exudate 125 (Fig. 51). After considerable search it has been possible to find a few of the smaller bile ducts which are filled with polymorphonuclear leucocytes and sur- rounded by inflamed fibrous tissue. This patient, therefore, had suffered from a severe chronic chole- cystitis with repeated attacks of icterus and at the time of operation there was an active phlegmonous exacerbation of the gall bladder disease associated Fig. 51.-Liver of A. M., Patient No. 16, aged 46 ; (cap) external capsule of Glisson; (n) large nuclei of hepatic cells; (Tiep) intra- lobular branch of hepatic vein : (bt) bile thrombi near the intra- lobular vein; (v) branch of portal vein; (b) bile ducts; (bt') bile duct containing bile-stained exudate. This picture and the preced- ing one illustrate the hepatic changes in recurrent cholangitis and icterus associated with severe chronic cholecystitis, changes which evidently represent a stage in development of biliary cirrhosis. 126 with an ascending cholangitis, purulent in some places, extending along the lumen of the bile passages and their lymphatics, to which the bile stasis and icterus may be ascribed. Patient 17, M. N., female, aged 47, was admitted September 26, 1922, ambulatory, with temperature of Fig-. 52.-Appendix of M. N., Patient No. 17, aged 47 ; (g) gland crypts; (cm) circular muscle; (Zm) longitudinal muscle; (/e) feces in the lumen. Atrophic appendix. 98.6°. She complained of pain in the right upper quadrant, of seven years' duration. She had given birth to 14 children of whom ten are alive and well; four are dead. There were also four miscarriages. 127 The last child was born seven years before and the abdominal discomfort has existed since that time. Dur- ing the three months preceding admission the pain was more severe. She was somewhat jaundiced. The pre- operative diagnosis ("impression") was cholelithiasis and cholecystitis. Fig. 53.-Gall bladder of M. N., Patient No. 17, aged 47 ; (pl) plicae mucosae shortened and thickened; (m) hypertrophied muscle bundles. At the operation on September 27, 1922, the appen- dix appeared distended and there were adhesions about it; ovaries and uterus were atrophic and the latter contained five small fibroids. The gall bladder was 128 enlarged, devoid of green color. The wall was thick- ened, 1 to 1.5 mm., and the cavity distended with white bile in which there were about 75 stones, 10 to 20 mm. in diameter. The cystic duct was obstructed but the common duct patent. The liver appeared about 50 per cent larger than normal and there was a marked Rie- del's lobe, the right edge extending as far down as the crest of the ileum. Extending from the gall blad- der fossa were lines of white fibrous tissue. There was Fig-. 54.-Gall bladder of M. N., Patient No. 17, aged 47 ; (e) somewhat atypical epithelium remaining on an area largely de- nuded; (in) hypertrophied muscle bundles; (v) vein; («) artery. This represents a thicker portion of the wall at a higher magnifica- tion. general slight dimpling of the Glisson's capsule and at various points on the edge there were deeper retrac- tions, particularly in the region near the gall bladder. The appendix and gall bladder and a small piece of liver were removed. The postoperative recovery was uneventful and the patient was discharged from the hospital on the twelfth day. 129 Fig. 52 shows a portion of the wall of the appendix. In it there is evidence of old chronic inflammation still slightly active. A portion of the gall bladder wall is shown in Fig. 53 and another portion in Fig. 54. Its mucous membrane is atrophic and in some places de- nuded, as a result of chronic inflammation and pressure Fig. 55.- Liver of M. N., Patient No. 17, aged 47 ; (v) branch of portal vein; (b) bile ducts; (cv) central intralobular veins. The dense round-cell infiltration about the bile ducts is emphasized by the deep staining. This liver appears to be in an earlier stage of development of biliary cirrhosis than that of the preceding case (Fig. 51). of concretions. The muscle layer is hypertrophied and there is moderate infiltration with wandering cells. A portion of the liver is shown in Fig'. 55. The trabeculae 130 of Glisson's capsule are moderately thickened and in this connective tissue there are excessive numbers of bile ducts and abundant mononuclear wandering cells. The columns of liver cells are well preserved, but among the liver cells are some with very large nuclei. Fig. 56.-Appendix of J. S., Patient No. 18, aged 47 ; (.9) gland crypt; (/) lymph follicle; (cm) circular muscle; (Im) longitudinal muscle ; (a) congested artery in mesoappendix. Mild chronic ap- pendicitis. The endothelial cells lining the sinusoids are some- what prominent and deeply stained and in these endo- thelial cells one finds an occasional mitotic division figure. There is also an excess of leucocytes in the 131 sinusoids. The changes indicate a moderate active exacerbation of a chronic hepatitis which appears to be more closely related to the bile ducts than to the por- tal branches. Patient 18, J. S., female, aged 47, was admitted June 15, 1923, ambulatory, with temperature 99.0°, suffer- ing from pain in the epigastrium of 18 months' dura- tion. She had received medical treatment for duodenal ulcer some months before and in March, 1923, she left the hospital feeling much better. About May 1, 1923, the pain returned, more severe than before, and she thought that her stools contained blood. On the day of admission she was nauseated but had not vom- ited at any time. There was rigidity and tenderness in the upper abdomen. Preoperative diagnosis ("impres- sion") was upper abdominal disease. At the operation on June 16, 1923, the appendix was found angulated and thickened, with a bulbous ex- tremity containing feces and mucus. The gall bladder was somewhat contracted and its wall thickened (2 to 3 mm.). In the cystic duct there was an enlarged lymph node, 15 mm. in diameter, but the nodes along the common duct appeared normal. The liver was markedly enlarged, extending 3 to 4 cm. below the costal margin in the anterior mammary line. Its sur- face was white and opaque about the gall bladder notch in a zone 5 cm. wide. The under surface of the right lobe presented a mosaic of depressed white bands, between which the liver tissue projected somewhat. Over the upper surface of the right lobe there were adhesions between Glisson's capsule and the abdominal wall. Everywhere the liver was more leathery than normal and the edges crenated. The left lobe partici- pated in these changes almost to the same degree as the right. The alterations in the liver appeared to be of a more severe grade and of longer standing than 132 the changes in the gall bladder. The other abdominal organs were negative. The appendix and gall bladder and a small piece of liver from the right lobe and an- other from the left lobe were removed. The post- operative recovery was uneventful. The patient was Fig. 57.-Gall bladder of J. S., Patient No. 18, aged 47 ; (pl) plicae mucosae; (m) muscle bundles.. Mild chronic cholecystitis in- active at present. up in a wheel chair on the ninth day and was dis- charged from the hospital on the sixteenth day. Fig. 56 shows a portion of the appendix. In it there is the atrophy of old inflammation and some recent extravasations of blood. The gall bladder wall is rep- 133 resented in Fig. 57. Here also there is evidence of old inflammation, the rugae being somewhat irregular in thickness and the muscle bundles somewhat hyper- trophied. There is no evidence of recent activity of the inflammatory process. Fig. 58 represents a portion of liver. There is a distinct general thickening of the trabecula of Glisson's capsule and the liver lobules are more completely outlined than normal. This increase Fig-. 58.-Liver of J. S., Patient No. 18, aged 47; (v) branch of portal vein; (a) branch of hepatic artery; (b) bile duct; (hep) sublobular branch of hepatic vein showing a marked and some- what irregular increase of hyaline fibrous tissue in its wall. Study of other portions of this specimen show scattered narrow zones of necrosis about many of the central veins. Here the degenerat- ing hepatic cells are invaded by numerous polymorphonuclear leukocytes. 134 of connective tissue is evidently of long standing. It contains only a moderate number of wandering cells. Scattered small spots of healing central necrosis indi- cate a recent toxic insult and the almost general thick- ening of fibrous tissue about the intralobular veins would suggest that similar injury had previously occurred. This group of six cases in the age period 40 to 49 years presents, in general, more severe disease of the liver than the preceding groups of younger patients. In the next group, patients over 50 years of age, there are also six individuals. They are listed in Table IV. Patient 19, B. K., female, aged 50, was carried into the hospital in an armchair on October 5, 1922, with temperature of 101.0°, pulse 120, respiration 28. She gave a history of indigestion of many years' duration and she had occasionally induced vomiting for relief. She had taken soda habitually. About two years ago she had a severe attack of epigastric pain in the night, with vomiting, which required hypodermic medication for relief. Several days before admission she suffered a similar attack. Upon palpation there was definite tenderness under the right costal arch. The leucocyte count was 8,800 per cubic millimeter, polymorphonu- clears 82 per cent. The preoperative diagnosis was cholecystitis, probably calculous. During the 48 hours preceding operation the temperature remained between 99.6° and 100.4°. At the operation on October 7, 1922, the appendix showed chronic inflammatory change. The gall blad- der was markedly thickened, the wall measuring from 1 to 6 mm., and was acutely distended but free from adhesions. A marked red blush was present. The lymph nodes about the cystic duct were enlarged. Gall bladder cavity contained about 100 sulphur-colored 135 PATIENT SEX AGE APPENDIX GALL BLADDER LIVER REMARKS 19 B. K. F 50 Inactive atrophic in- flammation. Chronic ulceration; moderate. Chronic interstitial hepa- titis. Many years ' duration; death 4 days after operation. 20 A. L. M 51 Chronic inflam., slight activity. Phlegmonous exacer- bation of chronic inflammation. Chronic hepatitis and acute catarrhal chol- angitis. Duration 2 days, sur- vived. 21 E. C. M 53 Chronic inflam., inac- tive. Not removed. Perihepatitis and chronic interstitial thickening. Inoperable carcinoma of pylorus. 22 M. A. F 59 Chronic inflam., severe exacerbation. Chronic inflam., quies- cent, gall stones. Fibrous nodule, slight in- terstitial hepatitis. Duration 10 yrs., pres- ent attack 3 weeks. 23 H. T. M 61 Not removed. Not removed. Chronic interstitial hepa- titis with terminal re- action. Gastric carcinoma, postoperative death. 24 A. A. M 65 Not removed. Not removed. Moderate fibrous increase. Inoperable carcinoma of stomach. The Six Patients Above 50 Years of Age Table IV 136 stones. The liver was slightly enlarged, extending 2 cm. below the costal margin. Adhesions extended from the left lobe to the anterior abdominal wall. Glisson's capsule was unusually dense and in it there were white lines extending upward and backward from the gall bladder region, more particularly along the right edge of the liver. This edge was distinctly fibrous and indented. There were adhesions between the hepatic flexure of the colon and the omentum. On the anterior portion of the duodenum, traction re- vealed a white spot which suggested ulcer. There was no sign of stippling nor of infiltration at this place, however. The appendix and gall bladder and a por- tion of the edge of the right lobe of the liver were removed. Subsequent to the operation the temperature mounted, reaching 103.4° at 4 a.m. the following morn- ing. At 8 a.m. she became irrational and attempted to get out of bed. Spinal puncture yielded a clear fluid containing 10 cells per c.mm. and a slight excess of globulin. At the following midnight the temperature descended below 103° for the first time and for 24 hours remained below 101.6°. The patient remained delirious, noisy and was controlled with difficulty. On the third day after operation the temperature mounted again, reaching 105.6° in the afternoon. She became comatose. Spinal puncture at 10:30 p.m. obtained 40 c.c. of clear fluid, under pressure. This contained 15 cells per cubic millimeter and a small excess of globulin. Cultural examination for bacteria was nega- tive. Death occurred at 7:25 the following morning. Postmortem examination was not permitted. Fig. 59 shows a portion of the wall of the appendix in which there has evidently been a chronic inflamma- tion only slightly active at the moment. A portion of the gall bladder wall is shown in Fig. 60. This is 137 enormously thickened by increase of connective tissue and by inflammatory edema. On the internal surface the rugae are preserved for the most part but there are numerous small ulcers, 1 to 3 mm. in extent, beneath which the wall is deeply and richly infiltrated with Fig. 59.-Appendix of B. K., Patient No. 19, aged 50 ; (</) gland crypt cut across ; (/) lymph follicle ; (i) inflammatory fibrous tissue; (r) dense collection of round cells; (cm) circular muscle. The lumen was completely obliterated in the distal portion of this appendix. Chronic obliterative appendicitis with evidence of a rather recent exacerbation, now subsided. polymorphonuclear leucocytes. These ulcers may have been produced by pressure of the concretions against the inflamed wall. A portion of the liver is shown in 138 Fig. 61 and another field in Fig. 62. There is a quite irregular but very marked increase of connective tis- sue in the trabeculte of Glisson's capsule and the fibrous tissue is distinctly more dense about the bile ducts than about the portal branches. In some places the columns of hepatic cells have almost disappeared in the abundant scar tissue. These changes appear to have resulted from chronic recurrent hepatitis arising chiefly by lymphogenous extension from the gall blad- Fig. 60.-Gall bladder of B. K., Patient No. 19, aged 50 ; (pZ) plicae mucosae ; (<7) duct of Luschka (gland crypt) ; (m) muscle bundles; (u) hemorrhagic bile-stained exudate on the surface of an ulcer; (gr) granulation tissue richly and deeply infiltrated with wandering cells, especially polymorphonuclear leukocytes. A large number of these ulcers occurred over the mucous surface, prob- ably as a result of pressure upon the contained concretions. There is also a general phlegmonous inflammation of the entire thickened gall bladder. der. There are scattered dense collections of round cells, sometimes in the trabeculae of connective tissue and sometimes near the midzone of a lobule (Fig. 61, r), which suggest a rather recent exacerbation of the inflammation. 139 Patient 20, A. L., male, aged 51, was admitted Octo- ber 9, 1922, with temperature of 103.2°, pulse 88, respiration 20. He complained of pain in the right hypochondrium of two days' duration. The attack began with severe pain, which radiated to the back, a chill, nausea and, after drinking warm water, vomiting. There has never been any jaundice. Palpation re- vealed definite tenderness and rigidity in the upper Fig. 61.-Liver of B. K., Patient No. 19, aged 50 ; (v) branch of portal vein; (a) branches of hepatic artery; (b) bile ducts; (cv) central intralobular vein; (hep) sublobular branch of hepatic vein; (r) dense collection of wandering cells. The bile ducts are increased but relatively to a less extent than in Patient 16 (Fig. 51). The arterioles in the trabeculae are very conspicuous. The picture is that of a chronic interstitial hepatitis arising by lymphog- enous extension from the inflamed gall bladder. 140 right quadrant. The leucocyte count was 15,800 per c. mm., polymorphonuclears 87 per cent. Preopera- tive diagnosis ("impression") was acute cholecystitis. At the operation, at 8:55 p.m., October 9, the appen- dix was found submesenteric, kinked, with marked thickening of the wall and narrowing of the lumen in Fig. 62.-Another portion of liver of B. K., Patient No. 19, aged 50; (a) branches of hepatic artery; (b) bile ducts; (v) branches of portal vein. Numerous red blood cells are visible in the sinusoids. This picture approaches that of biliary cirrhosis. the distal 20 mm. About it were abundant adhesions. The gall bladder was large and red in color. The wall was thickened, 1.5 to 6.0 mm., and the side adjacent to the liver was gangrenous. It contained about 100 c.c. 141 of brown mucopurulent fluid, in which there were 15 dark brown calculi. The omentum and hepatic flexure of the colon were adherent to the liver so as to enclose the gall bladder, but there were no adhesions to the gall bladder itself. There was some free flaky lymph in the right upper quadrant. On the anterior surface of the liver, extending back from the area of the gall bladder, there was a yellowish-green mottled area, 3 x 5 cm. in extent, covered on its surface with fine red fibrinous exudate resembling fur. This area did not fluctuate. The liver, as a whole, was about normal in size and on it there were numerous fibrous spots, espe- cially near the gall bladder. The mucous membrane of the gall bladder was dis- sected out and the cavity reconstructed by suturing the serosal flaps together (intravesical cholecystec- tomy), a rubber drain being sutured into the cystic duct and iodoform gauze inserted into the recon- structed cavity of the gall bladder. The appendix and a small piece of liver were also removed. The post- operative recovery was very satisfactory and the pa- tient was discharged from the hospital on the fifteenth day. Fig. 63 shows a portion of the wall of the appendix. Its mucous membrane is in part atrophic and also con- tains recent extravasations of blood. It has evidently been the seat of chronic inflammation, only slightly ac- tive at the moment of appendectomy. A portion of the gall bladder is shown in Fig. 64. The mucous mem- brane has been destroyed and the internal surface is covered with partly necrotic fibrino-purulent exudate. The entire thickness of the wall is edematous and ex- tensively infiltrated with hemorrhagic purulent exu- date. In the wall outside the thickened muscular coat, there are microscopic abscesses. Sections of the liver are of peculiar interest. Here 142 there is slight thickening of the trabecula) of Glisson's capsule, which are everywhere infiltrated with wan- dering cells. Evidently there has been repeated dam- age to the liver in this region adjacent to the gall blad- der with resulting increase of connective tissue (Fig. Fig-. 63.-Appendix of A. L., Patient No. 20, aged 51 ; (e) lining epithelium; (g) gland crypts of the mucous membrane; (/) lymph follicle; (cm) circular muscle; (Zm) longitudinal muscle; (s) sub- serous coat; (per) peritoneum (serum coat). The appendix shows atrophic changes of a mild chronic inflammation almost inactive at the moment. 65). One of the larger bile ducts shown in this figure is partly filled with exfoliated epithelium. The smaller bile ducts also show evidence of cholangitis (Figs. 66, 143 67 and 68). It is evident that an acute inflammation has supervened upon the chronic process. The infec- tion has evidently extended from the gall bladder along the lymphatic channels in close proximity to the bile ducts. The endothelial lining of the portal branches (Fig. 68) and of the sinusoids and the struc- ture of the hepatic columns within the lobule are little disturbed and the entire liver, as observed at operation, Fig. 64.-Gall bladder of A. L., Patient No. 20, aged 51 ; (m) muscle bundles; (/«) fat in the fibrous coat; (hp) hemorrhagic purulent exudate. The plicae mucosae have been lost and there is a general thickening of the wall from chronic inflammation, of which a severe active exacerbation is actually in progress at the moment of operation. The acute abdominal disease of this patient is in the gall bladder rather than in the appendix (in contrast to Patient No. 15). 144 was of normal size. In contrast to the condition in Patient No. 15, a hematogenous origin of this present inflammation appears less probable. We are inclined to regard this as a definite instance of acute ascending lymphogenous hepatitis originating from the gall blad- der, supervening upon a chronic milder inflammation, which may have been originally derived from a focus in the appendix, but later aggravated by recurrent ex- Fig. 65.-Liver of A. L., Patient No. 20, aged 51 ; (&) large bile duct with intact lining epithelium but with lumen partly filled with columnar epithelial cells which have been shed, probably in smaller tributaries; (fib) inflammatory fibrous tissue of long standing, evidently produced in earlier and probably milder exacer- bations of the cholecystitis and consequent hepatitis; (li) preserved liver substance in the scar tissue. There is no active inflammation in this portion of the liver section. 145 tensions from the gall bladder. The history of the patient indicates that there had not previously oc- curred any such severe attack as this last one. The fact that the patient survived the operation and made such a prompt postoperative recovery indicates Fig. 66.-Liver of A. L., Patient No. 20, aged 51 ; (fib) fibrous trabecula of Glisson's capsule, greatly thickened as a result of chronic interstitial hepatitis and now richly infiltrated by wander- ing cells; (a) branch of hepatic artery; (v) branch of portal vein; (b) bile duct plugged by exfoliated epithelial cells; (fa) fat globules. The picture is that of a catarrhal cholangitis and acute ascending exacerbation of a chronic interstitial hepatitis. the remarkable ability of the liver to overcome infec- tion within its substance. The free drainage of the region of most severe inflammation doubtless contrib- uted in a decisive manner to permit this outcome. 146 Patient 21, E. C., male, aged 53, was admitted Novem- ber 8, .1922, ambulatory, with temperature of 100°, pulse 78, respiration 20. lie complained of frequent attacks of vomiting during the last two years, becom- ing worse recently. About six weeks ago there was blood in the vomitus and at this time his stools were black. lie did not recall any previous illness of note Fig-. 67.-Liver of A. L„ Patient No. 20, aged 51 ; (v) branches of portal vein; (fa) fat globule; (sin) sinusoids between the hepatic columns; (nu) swollen and hydropic nucleus of hepatic cell; (b) bile duct partly disorganized by exfoliation of epithelial lining and invasion by wandering cells; (leu) polymorphonuclear leukocyte invading the wall of a minute intralobular bile duct. The inflam- mation is evidently a cholangitis and peri-cholangitis rather than a portal peri-phlebitis. The endothelial lining of the portal branch to the right is clearly defined and thin. This figure should be compared with Fig. 45 and Fig. 46, Patient No. 15. 147 nor had there been any surgical operation. There had been no pain at any time and only moderate discom- fort from accumulation of gas in the stomach. In the last three months he had lost 30 pounds in weight. Fig. 68.-Liver of A. L., Patient No. 20, aged 51 (preparation stained with resorcin-fuchsin and carmine for demonstration of the relation of elastic tissue) ; (a) branch of hepatic artery; (b) bile ducts; (Z) compact group of polymorphonuclear leukocytes in lymph space in the wall of a bile duct; (i>) branch of portal vein with well preserved endothelial lining in normal relation to the elastic tissue of the venous wall. Compare this picture with Fig. 44, liver of Patient 15, in which there was marked portal phlebitis. Roentgenologic examination revealed an obstruction at the pylorus. Palpation revealed no mass or tender- ness of the abdomen. The stomach was distended and 148 easily outlined. The preoperative diagnosis (''impres- sion") was carcinoma of stomach. At the operation on November 11, 1922, there was revealed an infiltrating annular tumor of the pylorus, the opening of the latter being about 75 per cent ob- Fig. 69.-Appendix of E. C., Patient No. 21, aged 53 ; (s) sub- serous coat; (</) gland crypts in the mucous membrane; (/) lymph follicle; (sm) submucous coat; (cm) circular muscle; (Im) longi- tudinal muscle; (fe) feces in the lumen. The appendix shows atrophic changes of a mild chronic inflammation, almost quiescent at the moment. structed. There was no evident enlargement of regional lymph nodes. The tumor extended backward toward the head of the pancreas. The liver showed mild 149 mottling on its surface but was otherwise negative. (The gall bladder is not specifically mentioned in the recorded operative notes.) The appendix was long and narrow. A posterior gastroenterostomy was per- formed. The appendix and a portion of the liver were removed. Postoperative recovery was uneventful and the patient was discharged from the hospital on the 13th day, with wound entirely healed. Fig. 70.-Liver of E. C., Patient No. 21, aged 53 ; (cap) ex- ternal capsule of Glisson; (b) bile duct; (a) branch of hepatic artery; (v) branches of portal vein; (w) central intralobular veins. This is a low-power view of a section stained by hema- toxylin-Van Gieson method. There is marked irregular thickening of the external capsule and general thickening of its trabeculae within the liver. Fig. 69 shows a portion of the wall of the appendix. The mucous membrane is in part atrophic and it con- tains extravasations of blood, indicating mild chronic inflammation. A section of the liver is illustrated in Fig. 70. There is a marked thickening of the external capsule and of the trabeculae extending through the 150 liver substance. This fibrous tissue contains an excess of wandering cells and conspicuous bile ducts (Figs. 71 and 72). Within the lobules themselves there is con- siderable hyperplasia of the fibrillar connective tissue about the central veins. The liver changes suggest ex- tension of inflammation from the gall bladder, but they Fig. 71.-Liver of E. C., Patient No. 21, aged 53; (&) bile duct; (v) branch of portal vein; (cv) central intralobular vein. may be related in part to the mild chronic appendicitis or to the pyloric tumor. The case is of interest in part because the neoplastic disease has developed without symptoms or signs of any earlier serious abdominal 151 disease. The conception of carcinoma of the digestive tract as a terminal phenomenon in a train of disorders beginning with appendicitis would hardly be supported by this case. Patient 22, M. A., female, aged 59, was admitted Sep- tember 26, 1922, ambulatory, with temperature 100°, pulse 76, respiration 20. She complained of belching Fig'. 72.-Liver of E. C., Patient No. 21, aged 53 ; (cap) irreg- ularly thickened external capsule of Glisson; (v) branch of portal vein surrounded by an excess of fibrous tissue. The lobules near the capsule are small and almost completely outlined by the fibrous tissue, much more than are the lobules more deeply situated (Fig. 70). Apparently these changes have resulted from an old peri-hepatitis and localized interstitial hepatitis arising by lymphat- ic extension from an adjacent organ, possibly the gall bladder. Metastatic neoplasm was not recognized in the liver sections. 152 and pain in the right upper quadrant, of about 15 years' duration. Hemorrhoidectomy was performed in 3900 and tonsillectomy in 1917. The present attack be- gan three weeks before admission. She had vomited in the attacks but had never been jaundiced. The abdo- men was tender to palpation over the appendix and Fig'. 73.--Appendix of M. A., Patient No. 22, aged 59 ; (e) epithelium lining the lumen; (g) gland crypts; (/) lymph follicle; (r) dense collections of round cells in the submucous layer; (cm) circular muscle. The distal portion of the lumen was obliterated by fibrous tissue. Chronic appendicitis with recent exacerbation. gall bladder. The preoperative diagnosis was chronic cholecystitis and chronic appendicitis. At the operation on September 27, 1922, the appen- 153 dix was found submesenteric in position and bound down by adhesions. Its lumen was partly obliterated by soft fibrous tissue of comparatively recent origin. The gall bladder appeared markedly inflamed, with di- lated blood vessels over its surface and enlargement of the lymph nodes along the cystic and common ducts. Clinging to the mucous membrane were innumerable cholesterol granules. The wall was slightly thickened, measuring 1 to 2 mm., and was adherent to the omen- tum and to the hepatic flexure of the colon. The omen- tum was also adherent to the anterior wall of the stom- ach, to the ascending colon and to the appendix. The liver was about one-fifth larger than normal and on its upper surface there were adhesions to the anterior abdominal wall. The surface presented minute opaque fibrous depressions, about 1 mm. in diameter, and there were white fibrous lines on the surface of the liver near the gall bladder. All the adhesions were freed. The gall bladder and the appendix and a small piece of liver were re- moved. The postoperative recovery was uneventful and the patient was discharged on the 17th day. Fig. 73 shows a portion of the wall of the appendix. Here there is a chronic inflammation which has led to a rather recent obliteration of the distal portion of the lumen and an inflammatory atrophy of the mucous membrane in the patent portion near the base. There are dense collections of round cells in the submucous layer and an excess of such cells in the thickened sub- serous coat. There is here, therefore, evidence of a re- cent active exacerbation of a chronic inflammation, sufficient to account for the clinical symptoms of the last few weeks. A portion of the wall of the gall blad- der is shown in Fig. 74. Here there is thickening and partial loss of the corrugations of the mucous mem- brane. The muscle layer is moderately thickened and 154 there is an excess of wandering cells in its interstitial connective tissue. These are evidently the result of chronic inflammation, relatively quiescent at the mo- ment. Fig. 75 shows a portion of the liver, in which there is an area of necrosis outlined by a dense fibrous Fig. 74.-Gall bladder of M. A., Patient No. 22, aged 59 ; (pZ) plication of the mucous membrane showing abundant lipoid in the stroma at its swollen tip; (m) irregularly thickened muscle bundles. Chronic cholecystitis almost quiescent at the moment. capsule and an incomplete zone of round-cell infiltra- tion. The nature of this area is somewhat uncertain but its appearance suggests a parasitic cyst. The liver substance in general shows a moderate thickening of 155 the fibrous trabeculae and an increase of wandering cells in them, indicating a mild grade of chronic inter- stitial hepatitis such as is usually associated with chronic disease of the appendix and gall bladder. Patient 23, II. T., male, aged 61. was admitted No- vember 25, 1922, ambulatory, with temperature 99°. Fig. 75.-Liver of M. A., Patient No. 22, aged 59 ; (n) necrotic material filling a cyst cavity; (ft) fibrous wall of the cyst; (?•) compact collections of round cells forming an irregular wall be- tween the cyst and the adjacent liver tissue (Zi). The nature of this cyst has not been determined. He complained of pain in the epigastrium, of one year's duration. Aside from lumbago two years ago there was no important previous illness. More recently the 156 pain has appeared at night, about two hours after eat- ing, usually associated with nausea but without vomit- ing. He has never been jaundiced. In the preceding seven months he has lost 25 pounds in weight. There was pain on pressure throughout the entire abdomen, most severe in epigastrium. A mass was felt in the Fig-. 76.-Liver of H. T„ Patient No. 23, aged 61; (cap) ex- ternal capsule of Glisson, edematous and infiltrated with wander- ing cells in its deeper layer. left inguinal region which gave impulse on coughing. The preoperative diagnosis was carcinoma of the stom- ach and inguinal hernia, left. At the operation on November 28, 1922, there was 157 revealed an infiltrating neoplasm at the midpoint of the stomach on the lesser curvature extending a distance of 5 cm. to either side and about 7 cm. toward the greater curvature on the posterior wall. The gastro- hepatic omentum was infiltrated but otherwise there was no evidence of metastasis to the lymph nodes or Fig. 77.-Omental lymph node of A. A., Patient No. 24, aged 65 ; (ca) groups of carcinoma cells in the lymph node and in the omental fat outside of it; (/) follicle in the lymph node. The group of cancer cells outside the node is richly infiltrated by polymorphonuclear leukocytes as is also the adjacent fat. liver nor was there any interference with the lumen of the pylorus. Resection of the stomach was performed. The patient died on the third day following the opera- tion. At a partial autopsy a portion of the liver was 158 obtained. This shows chronic interstitial hepatitis, ap- parently of equal grade in the right and left lobes of the liver, and an acute perihepatitis, possibly part of a more generalized peritonitis. A portion of one of the sections is shown in Fig. 76. Patient 24, A. A., male, 65, was admitted March 16, 1923, ambulatory, with temperature 99.6°. He com- plained of indigestion of 25 years' duration, pain in epigastrium for two years and difficulty in swallowing food for the last three months. The pain appeared about 2% hours after eating and has been relieved by eating or by taking soda. More recently the pain has appeared directly after eating and for the past two years it has been aggravated by the taking of food. The patient has vomited occasionally but never raised any blood. The preoperative diagnosis impres- sion") was carcinoma of the stomach engrafted on old ulcer. At the operation on March 19, 1923, there was found a scar of an old ulcer on the anterior surface of the stomach about 3 cm. from the lesser curvature and oc- cupying the mid-position. Extending from this in all directions was an infiltrating new growth reaching al- most entirely around the stomach. The lymph nodes along the greater curvature were involved and there was an extension of the infiltration through the gastro- colic omentum. On the peritoneal surface of the uri- nary bladder there were several small metastases. The liver was enlarged, apparently as a result of an inter- stitial hepatitis. Numerous metastases of the tumor extended toward the central fissure of the liver. A portion of omentum, including a small lymph node, and a piece of liver were removed. The postoperative re- covery was uneventful and the patient was discharged from the hospital on the eighth day. Fig. 77 shows a portion of the small lymph node. 159 Here there is extensive infiltration of the node and of the adjacent fat by adenocarcinoma. A portion of the liver is shown in Fig. 78. In this there is a moderate and irregular thickening of the fibrous trabeculae with occasional collections of wandering cells in the trabec- ulae and in the liver substance. Metastases of the tumor have not been found in the liver.. Fig. 78.-Liver of A. A., Patient No. 24, aged 65 ; (cap) ex- ternal capsule of Glisson; (b) bile duct; (a) branch of hepatic artery; (v) branch of portal vein; (cu) central intralobular vein. The increase of connective tissue in the fibrous trabeculae is only moderate in degree, not very remarkable for age 65. There is a moderate excess of wandering cells in this connective tissue. Ap- parently the changes here are much less than in some of the younger patients in this series, in spite of the history of digestive disturbance for twenty-five years and the evidence of chronic ul- ceration and advanced malignant disease of the stomach. 160 Discussion The changes in the liver are related in some degree to the age of the individual. It is well known that fibrous tissue is more abundant in the liver of older individuals. In part this may be considered normal. In this present series the individuals over 40 years of age all showed thickening of the fibrous trabeculae suffi- cient to suggest a previous serious hepatic insult from active inflammation somewhere in the region of portal drainage. One is inclined, therefore, to regard the overcoming of these repeated injuries as a part of the physiologic function of the liver. At any rate the border line between normal and pathological reactions is not clearly discerned at the present time. While our own work has not included bacteriological studies, there can be no doubt that bacteria frequently pass from the intestine into the portal system to be carried to the liver. This may be accepted as a demon- strated phenomenon during normal digestion. When there is inflammation in the portal territory, such bac- terial invasion is probably facilitated and certainly the microbes entering the portal stream at such times may be believed to possess an augmented virulence. In any case the liver substance evidently is endowed with a remarkable ability to overcome such microbes. That bacteria are removed from the blood stream through phagocytosis by the endothelial cells lining the hepatic sinusoids has been abundantly demonstrated and it is also known that bacteria may pass through the endo- thelium and the hepatic cells to be excreted with the bile, apparently without exciting any definitely recog- nizable inflammatory reaction in the liver itself. Such temporary microbic invasion of tissues has been desig- nated by Adami as subinfection. When, however, an inflammatory reaction is produced in the liver, the con- nective tissue of the periportal trabeculae becomes 161 edematous and infiltrated with wandering cells. It is obvious that lymphatic extension of the infection along these trabecuhe must readily occur under these circum- stances. We are, therefore, inclined to accept the view of Graham, namely that the gall bladder may become infected by lymphatic extension from the liver as well as through the bile stream and also the converse exten- sion of infection from the gall bladder wall to the adjacent liver substance through the lymphatics of the capsule and its trabeculae. HMost of the irregular fibrosis of the liver substance adjacent to the gall bladder would appear to have resulted from repeated lymphatic extensions of inflammation from the gall bladder accompanying recurrent exacerbations of cholecystitis. The extension of inflammation from the appendix through the portal system is illustrated by our Patient 15. The survival of this patient for five weeks after the operation at which his gangrenous appendix was removed, indicates a remarkable capacity for defense on the part of his liver. Similar extension of inflamma- tion from the appendix, but somewhat less severe, is exemplified by Patient 4. The extension of inflammation along the lymphatic channels from the acutely inflamed gall bladder to the liver is illustrated by the tissues of Patient 20. In this case a possible extension along the bile ducts them- selves has to be considered, but such an extension, if present, would appear to have been of less importance than the spread through the lymphatics. Other exam- ples, in which the inflammation in the liver was less active at the moment of operation, are presented by Patient 16 and Patient 19. Catarrhal cholangitis, with extension of infection along the lumen of the bile ducts as well as by the adjacent lymphatics is exemplified by the liver of 162 Patient 16, in which icterus was also evident. The specimens from Patients 2, 8, 16, 17 and 19 present various stages in the development of biliary cirrhosis and contribute evidence of an intimate relation be- tween severe chronic recurrent cholecystitis and biliary cirrhosis. While we are inclined to accept the idea of a rela- tionship between appendicitis, hepatitis and cholecys- titis, in which it is assumed that inflammation extends from the appendix to the liver, thence to the gall bladder and from this to the liver again and again in the repeated exacerbations of the cholecystitis, it is not by any means clear that this is the only source of such inflammation. In fact Patient 14, in whom there was an acute ulcer of the pylorus, showed some evi- dence of hepatitis at the time of operation and the post- operative peritonitis was associated with an enormous edema of the liver, although his gall bladder appeared normal and the appendix only slightly involved in a chronic inactive inflammation. In regard to the possible relation of this compara- tively frequent combination of appendix, liver and gall bladder inflammation to malignant neoplasm of the stomach, we are not at all convinced. In so many in- stances carcinoma of the stomach appears without any history of preceding serious abdominal disease, as for example in Patient 21 and Patient 23 of this present series, that one is inclined to question whether the de- velopment of a malignant neoplasm must justly be considered to have other than an accidental relation- ship to preceding abdominal disease and especially is one reluctant to ascribe more than an accidental rela- tion to gastric neoplasm to inflammation of the appen- dix, gall bladder or liver. The examination of the tissues removed at operation throws some light upon the subsequent behavior of the 163 patient and especially upon the postoperative fatalities. Whenever an active purulent exacerbation of cholecys- titis is encountered at operation the inflammatory in- volvement of the adjacent liver substance would ap- pear to be an important consideration. Fatal post- operative infection by extension into the liver sub- stance and beyond it to the lungs or general systemic blood stream appears to be a more imminent danger than is a generalized peritonitis. Free drainage of the gall bladder fossa, if the cholecystectomy is carried out, or free drainage of the gall bladder itself, without removal at the time, would appear to afford the patient a better chance to escape such a fatal complication. Summary 1. Specimens from different abdominal organs, usu- ally the appendix, gall bladder and liver, of twenty- four surgical patients, from 17 to 65 years of age, have been briefly described and figured. 2. Severe inflammation in the region of portal drain- age frequently is associated with inflammation in the liver which leads to fibrous thickening' of the trabec- ulae of Glisson's capsule. Such primary inflammation is most common in the appendix but may occur in other organs. 3. The inflammation may frequently extend from the liver to the gall bladder, either through the bile or through the lymphatic channels and the cholecystitis thus initiated may subsequently in its repeated exacer- bations bring about localized or even general hepatitis by lymphatic extension of the infectious process. 4. The probable presence of infection of the liver substance during active exacerbation of a cholecystitis should be taken into consideration whenever operative intervention is undertaken in such a condition. 164