I'd like to get started. We wanted to talk today about a patient with Crohn's disease. We asked Dr Sidney Barrett if he would discuss this topic for us and this patient dr barrett I think many of you know dr barrett is on our faculty but is I started to say stationed in roanoke but works in roanoke at the Veterans Administration Hospital there. And particularly many of the students have had an opportunity to work with him at Salem. The patient will be presented by dr lois smith. D. W. Is a 23 year old woman who began to have blood tinged mucus or diarrhea at age 19. Despite treatment with a Self Dean. Diarrhea and cramping, abdominal pain continued and a £20 weight loss ensued Over the next three years. She was first seen at the University of Virginia Hospital in july 1975 at which time practice copy was unremarkable, but X ray studies revealed an abnormal mucosa in the terminal ilium and seek um with a stricture of the mid descending colon. The diagnosis of granuloma. This colitis was made on the basis of the history and X ray findings. A sulfa Dean was discontinued because of a hemolytic anemia which subsequently responded to supplemental iron and folic acid predniSONE 40 mg per day was given for her colitis with clinical improvement and weight gain complications of her disease have included the following episodes number one. A left lower quadrant abscess presented in october 1975 as an abdominal mass. Barium enema at that time demonstrated officials tracked from the descending colon to the abscess cavity treatment with penicillin and gentamicin for two weeks and an increase in her pregnancy. Own dosage to 60 mg per day resulted in resolution of the mass. In september of 75 she presented with a dry scaly rash on her forearms and feet, which was felt to be peligro. This was a clinical diagnosis based on the appearance of the rash and resolution. After nice and supplementation. Number three are three. Ologists. By March of 1976 her predniSONE had been tapered to 15 mg a day and she developed arthritis in both knees which were partially responsible, partially responsive to rest and solicited therapy. Her present hospital admission on july the 12th was necessitated by three weeks of increasing diarrhea, fecal urgency and 10 isthmus. She has had no fever, chills nor recto vaginal fistulas, drainage. Physical examination revealed a thin young white female in no apparent distress temperature was 36.5 degrees centigrade. Post 30 respiration 18 blood pressure 1, 20/80 The skin was normal. H. E. N. T. Examination revealed no evidence of your itis. She was eventually, however, the chest was clear to percussion and ask rotation and the examination of the heart was unremarkable abdomen was soft to palpitation with no organa medley nor masses. The bowel sounds were normal. The rectum was extremely tender to examination but with no palpable areas of fluctuates. The pelvic exam was normal. The remainder of the physical exam was unremarkable laboratory data, hematocrit 47%. White blood count 16,200 A wreath recite sedimentation rate. 50 mls per hour, serum electrolytes and B. U. N. Un remarkable serum protein 6.3 with albumin. 3.4 g percent uric acid, 7.9 mg percent alkaline phosphate, 97 International units. L. D. H. 1 34 international units. S. G. O. T. 20 international units. X X rays will be subsequently shown hospital course patient symptoms were felt to represent exacerbation and rectal involvement of her underlying disease. Symptomatic treatment with six bass was instituted after which she was able to tolerate a practice practice ka pik examination on the 16th which revealed involvement of both rectal and anal mucosa. With March, granularity and free ability and overlying puss. A sonogram performed on the 13th was negative for any detectable abscess. The dosage of predniSONE was increased to 30 mg per day and her symptoms gradually improved. She was discharged from the hospital on july the 20th. Her discharged white count was 9500 with the urethra site sedimentation rate of 34 fine. Thank you very much. Dr smith. Any questions or comments dr bolton. Speak loudly please Not on this admission. She has had that previously. Yes. Without any positive results dr schafer you want to get set up for X rays? I wondered what happened to her teeth dr smith. Do you know what the occasion was that led to the extractions? I'm not sure I would assume. Poor dental hygiene but it was not this was not done in the last year too since the onset of her. Not that I'm aware of dr Whitby when the diagnosis of the niacin deficiency was made Villagra. Was she then continued on multivitamin supplementation? From then on. Yes on her admission even she was on multi vitamins niacin B 12 folate the works dr barrett. Has she been pregnant or tried to get pregnant any time during the course? No she has never been pregnant nor has she tried as far as I'm aware. Thank you very much. Dr smith schaefer. Okay I'm dr schaefer contrary to the program that says dr cooper we have the lights please. These are films from the upper G. I. Small bowel and colon examinations that were performed in july 1975 approximately a year ago. And I'm just showing you here the proximal small bowel which appeared normal except for the presence of some dilatation of the bow particularly. I want to emphasize that the duodenum appeared normal here. We can see that there is further dilatation more distantly in the genome but there is no mucosal edema, no strictures, no evidence of involvement of the small bow uh approximately. We did notice that there was tremendously delayed transit time. This is at three hours and still we haven't reached the colon. We're still in the terminal ilium and it took 5 to 5.5 hours before we actually reached the terminal ilium with the barium. These are spot films of the terminal ilium that show that the caliber of the terminal ilium is reduced. It's a regular. The terminal ilium was spastic. This is terminal ilium that we're seeing here and here we noticed that there was some Dema Dema speculation and there were changes consistent with inflammatory disease involving the terminal ilium. The most spectacular changes though are in the colon that were uh scene on the day before with the colon examination calling. We see tremendous the regularity of caliber of the bowel. There was no evidence of abnormality on other films uh in the region of the rectum or sigmoid colon. There was a very localized, very narrow stricture in the proximal descending colon. Uh The area of the spanish lecture was tremendously narrow and there was another area area of narrowing over in the region of the hepatic fracture with distension. Here we see a post evacuation film that gives us uh appearance here in the distal transverse colon. And I don't know whether you can appreciate it or not of both longitudinal ulceration and transverse ulceration here is a, can you see that stricture in that film dr schafer here is there is a localized structure here in the descending colon associated with what appears to be somewhat of official ist track, how common is that type of severe? That is. That is a severe. Well now I see the lumen is uh I was looking at that one thing on our left, but the lumen is much wider. Is that correct? Could you point out the lumen of the bowel there at that stricture point? The Lumen of the Bowel is here and it is approximately 2-3 mm in diameter. And how often do you see strictures of that severity? And granulomas? Uh enteritis involving the colon. It uh it's more common than we see in ulcerative colitis, certainly. And uh it's not a rare occurrence, but usually we don't see such severe strictures on our initial examination. Usually we do see skip areas of involvement. Like we see here, we do see the longitudinal and uh transverse alterations, but we don't. Normally, at first examination see a stricture this severity. So these changes all fit most compatible e with a diagnosis of brain alone. This colitis by actually fine, thank you very much. Uh This patient had to uh was ready for discharge from the hospital on monday or Tuesday and so she could not be here today and we felt that it was not uh justifiable to try to get her to come back. So we made a brief uh film uh a film clip to show you. We could run that now. Well, Mr West, thank you for coming over here today from the Towers, we've talked for a few minutes. You you call this problem that you have regional regional enteritis is that you've had this for a three year for three years. How was it initially diagnosed? Well, I was passing some blood in my stool and I went to an internist and he did photography and said that I had colitis. Did you have you had diarrhea then? Not really bad. Just slight diarrhea. Just the blood in my stool. What's been the major manifestation of this problem over this three year period? The diarrhea and throwing up vomiting. And how severe did the diarrhea get early On? It got very bad. I was going to the bathroom maybe 20 times a day and you know, just all the time I couldn't keep anything down. And that you're when when things were really at their worst. You started predniSONE. And was that did you attribute your improvement to that medication? Yes, it seemed almost instantly I started getting better less diarrhea. And You had lost 20-25 lbs by that time. And you started to gain your weight and things got better. Now have you continued on predniSONE since then for the past 2.5 or three years? Well I was on it for maybe a six month period and then they took me off because I was doing well. But then last july began to do the same thing. So after you stopped the pregnant sonia began to have a recurrence of put me back on it and I've been on it ever since. What's the dosage? Well, when I came in the hospital, I was on 15 mg a day. But now they've raised it to 30 to see if they could probably what brought you to the hospital this time? Well, the diarrhea and I have some infection in my victim. It's very sore. But you did you were having some diarrhea when you came in this time. That was sort of increase in the severity of your symptoms. How many stools were having a day? Well, that's six and very. Did you relate that to anything other than the fact that did you tell me that there are certain times of the year when this gets seems to get worse. It seems like in the spring my two major when it's hit me as being in spring. I don't know why it seems that way. So, did you actually have an infection in your rectum this time or was that was an abscess or No? I don't have an abscess. But they say from the disease, they have some infection and your symptoms have subsided since you've been in the hospital. And they're better than they were when I can you attribute your improvement to any specific therapists, they've been giving me a lot of sits baths and some kind of suppository. That does seem to have quite a bit, I'm not sure what it is. Have you had any other complications from your from this problem from this disease for the first time I came back for my checkup I had on my hands and my feet only it was very puzzled by it because I only had it on my hands and on and on my toes. But they cleared it up very fast with vitamins. And were you eating well then or was that related to eating constantly? When I started taking the presence on. My appetite was very good. But that was when your diarrhea was quite severe. Diarrhea was subsiding too. I thought I was getting better. I was gaining weight when I came back from my checkup but I had were you taking any supplemental vitamins then? No, I don't think I was taking vitamins. Thank you very much for coming over today. Thank you. Thank you. I'm sorry about the focus on that. Apparently there's some problem with the camera dr barrett and this pilot? Yes. The movie that dr Mandel showed a couple of weeks ago was very impressive with the white cells assassinating all the various bad guys. And I'm convinced that what the gastroenterologist who talks about regional enteritis needs in order to give a good presentation is a similar movie that shows as a thigh, a prion healing fistulas and predniSONE license granulomas and the like. But there is no such movie because we don't have any information like that. The story I'm going to talk about is the same dismal story that you've heard in previous grand rounds over many years about regional enteritis. There are some interesting things on the horizon. It'll be interesting in a few years to find out what they mean, where they fit into the whole picture. For instance, what is that uh side a toxic effect of the illegal infiltrate that occurs in cultures of human colonic cells that looks exactly like viral effects. Uh why do the lymphocytes of patients with Crohn's disease have a toxic effect on human colon cells and culture. But we don't have any of that information today. And I'm not going to say anything more about it. I also don't want to talk anymore about the extra intestinal parts of disease. Except to comment on pila gra uh DR Hook asked me to explain it and I certainly can't uh in reviewing the literature, I only find one case report in Dr bak is textbook which candidates 1940 he shows a patient with a typical rash, typical radiologic and pathologic findings and comments no more about it. I certainly can't explain this lady's disease. What I would like to talk about are some of the intestinal manifestations of the disease, particularly some of the physiologic arrangements that occur and what little we can do to redress the balance and I'll have a discouraging word or two to say about both medical and surgical therapy. We have the first slide please crones disease can affect the entire gut all the way from mouth to anus. It's not surprising if you think about it to realize that the presenting symptoms reflect generally the area of the ballot is involved. And as this slide reviews illegal disease and proximal colonic disease of the area's most frequently involved and I will get back to those in a moment after making a short digression to fill in this space between distal ilium and seek them. Yes, science patients who present with an acute onset of cerebral illness and right lower quadrant pain, glucose psychosis are often judged on clinical grounds to have acute appendicitis and indeed when they're operated on, this is usually what they have. But a minority of the time the surgeon will find something else, he may find just esoteric Adan itis, he may find an acute inflammation of just the terminal ilium or acute disease involving the terminal ilium. If we can believe reports from Europe, about 75% of this group will have an infection that's due to sort of tuberculosis or politica. This is an acute self limited disease in which no surgery needs to be done. There are no recurrences. The minority will turn out to have an acute onset to their Crohn's disease and will go on in the course of time to develop the full blown manifestations of the disease. The evidence that links yesenia infection to these diseases consists of culturing the organisms from the nodes and illegal contents. Not only that, but the illumination titus to the organism rise precipitously in these patients, you also need to know that if the disease does turn out to be an acute onset of what turns out to be chronic, the organism cannot be cultured. Nor is there any rise in illumination. Likewise, if retrospective reviews are made in patients who have already established disease, they have no um elevated titles to use any organism. Disease of the appendix uh is decidedly rare as are these others. Uh As I mentioned, most of this data is from the european literature. There are only a few scattered case reports in the United States. So it remains to be seen where in the total picture of acute Crohn's or also acute disease in the right lower quadrant of the abdomen. Where you see Nia Sioux, tuberculosis infection fits in. Let me turn now disease of the ilium and colon. There are too many numbers on this slide. I just want to make several points. The first point is that most patients in this is typical of several large series have small bowel disease, either alone or in concert with disease. In the colon, the minority perhaps 10-20% have disease of the colon alone. And this makes an important differential diagnostic point uh in making the diagnosis of Crohn's versus all sort of colitis, abdominal pain and diarrhea are almost universal when illegal diseases present, weight loss is often present. Um and there are several points which I would like to make about abdominal pain for moving on. First of all, when the disease starts and involves the terminal ilium. The pain is typically cramping and in the region about the umbilicus, this pain isn't relieved by defecation or passage of flatness. As disease in the colon often is later on as the disease progressive progresses and fiscally or inflammatory masses are formed. The pain may become continuous and move to the right lower quadrant. Next let me point out that anemia is present almost half the time, but that obvious bleeding is less common, suggesting that there are other factors involved. And I'll come back to that. Finally, when patients with Crohn's of the kolinahr granuloma colitis only in the colon are compared to patients with ulcerative colitis. There are some differences which are worth pointing out. First of all, diarrhea is common to both, but bleeding is virtually universal in patients with ulcerative colitis. Likewise, rectal involvement is almost universal, 95%, maybe too low a figure, it is very difficult if not impossible to make a diagnosis of all sort of colitis. If the rectum is normal and when this lady first presented, it's my understanding that her rectum was not involved. The last point I'd like to make here is that periodontal disease is significantly more common in patients with Crohn's or granulomas colitis. Uh and 70% maybe a low figure this presents as officially or fissures in the region and it's worth also pointing out that these peri anal manifestations may precede the full clinical picture by months or years. In some patients, the diagnosis will not be obvious. They don't present predominantly with abdominal pain and diarrhea. They may have a variety of other clinical syndromes. More than likely these clinical syndromes will complicate established disease, and I'd like to say a word about several of them, about anemia, about weight loss, about urinary stones and about gallstones. This is a series of 63 patients who had active Crohn's disease, 65% on investigation were found to have low serum iron. This probably resents the blood loss, which is usually a cult uh iron is well absorbed in the most proximal part of the gut and usually I would expect it to be absorbed normally. However, I have seen no data on uh iron absorption studies in these patients. It would not be surprising in today's patient to find that she malabsorption iron since she did have considerable abnormalities in the proximal small bowel. Next 22% had low iron binding capacities. Uh this may represent protein malnutrition or it may represent uh the part of the anemia of chronic disease 16% had low B 12 and B 12 levels. Most of these patients had extensive involvement of the terminal ilium or had extensive resection uh of the terminal ilium for disease. They're a minority had various strictures, blind or variations on the blind loop syndrome, in which overgrowth of bacteria bind the B 12 and make it unavailable for illegal absorption, somewhat surprising is that 64% had a low serum foley. This is surprising at first glance, because it is well absorbed in the proximal gut and usually the proximal gut is not involved. What is also more surprising is when they looked at the extent of disease in their patients, many of them had distal disease only know manifestations of proximal disease. However, more recently, it's been found out that absorption of label folate is abnormal in most patients with Crohn's disease, regardless of whether they have radiologic or even histological involvement of proximal small bowel. What is even more interesting is that a sulfa Dean further increases the malabsorption of folate, not only in patients with Crohn's disease, but even in normal patients, how this fits into the overall picture, I'm not sure, but it certainly is a warning that any patient with crones disease, mame al absorb folate, albeit in subtle fashion and they probably all probably ought to be supplemented with folate and other vitamins as well. Having heard that, I suppose it's not too surprising to see that in this series, 40% had a mega plastic anemia and most of them turned out to be do uh two full aid. The minority to be 12 and a few were mixed disorders. Moving on now to weight loss an intact ilium is necessary for the neuropathic circulation of bile salts. If the ilium is either diseased or removed assaults are lost, this results in a decreased concentration of bile salts in the proximal gut during digestion. Therefore the critical my seller concentration of bile salts is not reached and fat malabsorption of long chain triglycerides occurs. Therefore stool fat excretion goes up and also because the ilium is lost. The Schilling test is abnormal. Well, it's easy enough to correct the loss of B 12 with parental B 12. But in order to correct the malabsorption of fat, one needs to give a diet that is lower in the long chain triglycerides and supplement the diet with medium chain triglycerides. Portage in is one formulation of it, which do not require my cells in order to be absorbed. A variation on this function of the ilium is some sort of intestinal stasis, The common component of which is bacterial overgrowth. And here bacteria in the proximal small gut, the conjugate and di hydroxy lit the bile salts. Once again, the critical my seller concentration of bile salts is absent and fats are absorbed and as I mentioned earlier, the bacteria compete for B-12 binding it and making it unavailable for absorption further on. In this case, the simple thing to do is to treat with antibiotics, which decreases the intestinal contents of bacteria, returning fat absorption to normal and returning B-12 absorption to normal when bile salts aren't absorbed as in this situation here, I apologize for this slide, They get to the colon when they get to the colon, they turned the colon from its normal, efficient absorptive state into a secret ori state. And what I want to point out with this slide is that this line represents zero flux of water and electrolytes above indicates absorption below secretion when the bowel is refused. First with electrolytes, the net flux is absorption when bile salts are added, inhuman or in experimental animals, net secretion is the result. So the colon becomes an organ which is contributing to the diarrhea. The binding resin cola star mean, will bind bile salts and will certainly decrease the diarrhea. Although this may be at the expense of increasing Seattle area because if the bile salts are bound by the coolest are mean, they are not available for fat absorption. The patient with Crohn's disease really can't win when it comes to absorption gallstones. Uh bile salts are necessary to maintain cholesterol in the bile in solution when the ilium is lost and bile salts are not re absorbed. The ability of the bile to hold cholesterol and secretion diminishes. Therefore, cholesterol can precipitate and become the night is for stone formation. So we have an excellent theoretical reason to suspect the patients with Crohn's disease involving the ilium will have an increased incidence of gallstones. Patients with Crohn's disease involving or all sort of colitis involving only the colon have an incidence of gallstones in this series, which is roughly comparable to the hospital population. Those with illegal disease. Indeed do have an increased incidence of gallstones. The message here is to be aware that it happens inflammatory, rather inflammatory bowel disease is associated with the syndrome of cola static liver disease. The patient who has jaundice and elevated alkaline phosphate case may indeed have that form of perry cholangitis, but on the other hand, might also have a very treatable form of disease gallstones. Parenthetically, I also ought to remark that on theoretical grounds. Coolest Ira mean, which binds bile salts ought to predispose towards the formation of gallstones over the long run. But I know of no data to support this. I would just be aware of it. We're treating a patient for a long time with Co star mean, some arrows are missing on this. The slide was made hastily. You're aware of a number of renal complications which occur in uh Crohn's disease. There can be fiscally from involved bowel to ureter or to bladder. There can be obstruction of the ureter by an abscess. There can even be renal amyloidosis. These patients also develop stones which turn out to be in the main oxalate stones. The current thinking on why they develop oxalate stones is as follows in the normal situation. Dietary oxalate is bound by calcium in the gut. There should be an arrow here into an insoluble precipitate and is then passed out in the stool in the abnormal situation with illegal disease, dietary oxalate and calcium meet with un absorbed fat. Harold here somehow or presumably calcium complexes with the fat oxalate remains soluble, is absorbed and excreted Greenlee, where stones can form way to attack this. There are several plausible ways eat less spinach, decrease the dietary content of oxalate, increased calcium so it'll bind the oxalate. One can also add aluminum to the diet, perhaps in the form of something like an eagle, which has also been shown to bind oxalate or decrease the amount of fat in the diet, particularly long chain triglycerides. All of these will decrease the urinary excretion of oxalate treatment. Let me concentrate predominantly on these last two sections. What by comparison in all sort of colitis, there is excellent data to indicate that predniSONE is the best drug to induce a remission of the disease in its acute phase and that is alpha Dean is the best drug at maintaining the remission. Once it's gotten with predniSONE in this disease, whether of the large or small bowel, there is no such convincing data, although clinical observation for a long period of time has led most physicians to use a sulfa Dean as the first line drug, particularly in a patient who wasn't specifically who isn't terribly ill. Give it a trial of a month or two and then move on to predniSONE. If the A's alpha Dean doesn't work or to use a sulfa Dean in the sacred patient, essentially unresolved are the two questions of which is the preferable drugs in the acute situation, which is the preferable drug in the long term situation. There has recently been an attempt to answer some of these questions or at least to provide some data to provide the rationale for therapy. National Cooperative study of disease addressed itself to both of these part. One was an attempt to induce remission in patients with active Crohn's disease. 238 patients with active disease has defined by one of the references on on the sheet were treated for four months in double blind fashion. With one of the four options I listed on the other slide, hazel thodin predniSONE is a thigh aspirin and placebo results which were reported last month and there are more patients to come, so perhaps they may change no surprise. predniSONE is superior to placebo, is alpha. Dean is superior to placebo. This is what physicians have observed for a long time. Perhaps a little bit surprising is a tire print was no better than placebo dr Drucker of this institution published a report about six or seven years ago and this was also followed by others which indicate that Prince had a place in the treatment of some patients with active Crohn's disease. Indeed, one report suggested that fiscally closed when a tire print was used. This, these previous studies were almost all uncontrolled. Now, this study presents evidence that in a controlled situation is a thigh prin is no better than placebo. It follows on the heels of another. Another study, also listed in the reference sheet, which suggests the same thing. The group at Yale took patients maintain them on their usual dose of predniSONE and added easier either as a prince or placebo and studied the patients for four months at a time. The groups then crossed over and once again, no difference could be found between and placebo it seems then as of now, that is not for every patient with crones disease, there are a few in whom it might be tried. For instance, the patient who has is unable to tolerate high doses of steroid. It may exert a steroid, quote steroid sparing effect. It also might be used in a patient in whom surgery is unacceptable. There are those who still hold out and suggest that there is a sub population of patients with Crohn's disease who may benefit from a print. But this sub population has yet to be defined. Finally, let me turn to surgery and make several points. Once again, the data are conflicting and even the most optimistic results that you can find are none too cheerful. Several points. First of all, when disease involves a small bow, basically there are two options to remove it all or to bypass it in some fashion. Usually the surgeon will remove it if it's technically feasible. This study is taken from the last reference on the paper published in the new England Journal by Janowicz group from out Sinai last year. And it indicates that there is some minimal data in favor of resection. That is that with the passage of time, the cumulative recurrence rate is slightly less other authors in their day to have a more favorable swing towards resection. But what should be pointed out is that whatever the procedure, the cumulative rate of recurrence when patients are followed over the long haul is awfully high. The next point I'd like to make is that again, is that there is a lot of controversy over the recurrence rate after surgery for Crohn's disease. When the data is analyzed crudely, it is indicated in most series that the re operation rate or the recurrent and recurrence rate diminished after each successive operation. This data is open to criticism and is criticized in this paper because it fails to allow for decreasing time of follow up after each successive operation. When this is corrected for data like this appear and exactly the opposite conclusion is drawn. That is that after each successive operation, the chance of another operation becomes greater. The final point I'd like to make about surgery is that there were several reports in the early 1970s concerning granulomas colitis. Crohn's confined to the colon. They suggested that the recurrence rate after total collector me with Elias to me was much better than any kind of surgery for Crohn's that was confined to the small bowel. And indeed, that there was virtually no difference between the surgical results in ulcerative colitis and granulomas colitis. The group of Mount Sinai, which is Dr Kron's hospital, immediately replied to this report by coming up with 31 patients of theirs who had had recurrence after total collecting me and Elias to me for the colon. And this is not their data but data from a similar series. Again, both the patients with all sort of colitis in the colon have had total collector me and Elias. To me, the group with all sort of colitis have had far fewer operations and the cause of the operation has been predominantly recurrent disease proximal that is in the small bowel and more often in this group. Elias to me, reconstruction as somebody who doesn't have uh the long experience and expertise with disease. I take data like this with uh a note of caution. The outlook for the patient with surgery after crones after surgery for Crohn's disease is certainly guarded. Now, it maybe there's data which I haven't sighted to suggest that the course after Crohn's confined to the colon is better than confined to the small bowel. But it certainly cannot be said as far as I can see that Crohn's, which is limited to the colon has as good a prognosis as all sort of colitis patient with ulcerative colitis who has a total collectively can virtually be told he is cured. No such guarantee can be given to the patient who has had a collective for Crohn's disease. Let me mention one more point. Uh it was my understanding but not confirmed that pregnancy complicated uh this lady's course. At one point, you turn the slide off, please. Dr Crone has addressed himself to this point and he finds, first of all, that about a third of patients who become pregnant when their disease is inactive will have an exacerbation during that time again, those who become pregnant while the disease is minimally active, about a third of those will have an exacerbation. The majority, therefore, both in his series and in the more recent one and the british literature indicate that pregnancy can be safely undertaken in women who are either inactive at that point, from the crones disease, or only moderately active If pregnancy can be achieved in a period of active disease, the chances of carrying the pregnancy to a successful conclusion are considerably less. It's also interesting to note in the series, uh published in the British Medical Journal two or three years ago, that the fertility of women with Crohn's disease is considerably reduced and that half of their series of 80 women who attempted over a ten-year period to become pregnant or unable to do so. Thank you. Thank you. Sydney, you characterized your presentation at the beginning as the same old dismal story. And I don't know, perhaps, perhaps it was the same story in some respects. But I'd say that your presentation was notable for its factual content and for its clarity And thank you. Are there uh comments or discussions from the group? Dr Durant is holding up his hand undoubtedly to explain this occurrence of yersinia infection. Sorry. No. Uh to enjoy that very much, said I'm sure we all did. Uh but a couple of the things that you mentioned, one of them the your senior but the other the granuloma tissue response that characterizes the pathologic lesion in these patients uh raised the question of these patients immune status. Uh Can you comment on any information about their immune status, particularly cell mediated immune status or energy? I avoided that purposely because I find it very difficult to in reviewing the topic to make too much sense. And if there's somebody who can make more sense out of it than I can I would would welcome a comment, dr bolton. You asked a question in that area. You want to comment or does anyone No one wishes to comment on that or the other doctor. I wanted to to make a comment and ask a question. Said the problem of regarding iron deficiency anemia. Certainly agree with you that these people typically do have anemia of chronic disorder characterized by low serum iron, unusually low T. I. B. C. The percentages that you gave more of them had something like 40% at a low serum iron about 20% at a low T. I. B. C. But very often they may even be hipaa chronic. And then if you look at the bone marrow you will find storage giant. They tend to have thrombosis. Itto sis along as another evidence of inflammatory response and very often they are not iron deficient. Um I wanted to comment also about the hemolytic anemia here which did seem to be related clearly to a sulfa Dean which does in some way produce oxidant damage to the red cell, produces Heinz bodies and results in hemolytic anemia. And I think the statement here that the hemolytic anemia responded two supplemental iron and folate probably should say that the anemia improved as a sulfa Dean was withdrawn and possibly there was a component of full A deficiency. Um I wonder about the pill Agra whether or not this isn't like what is seen with some patients with blind loop syndrome. You characterized these patients with Crohn's disease as being, well they have components of the bacterial overgrowth problem possibly with B 12 malabsorption on that basis. And when there's bacterial overgrowth and I would have to go back to review the biochemistry of this but I think that the bacteria may do something to trip to fame. They certainly you get a lot of in Dole's Indal acetic acid is excreted into can excreted in the urine. And I wonder if with some borderline malabsorption of niacin. Perhaps uh an effect on breaking down trip to faint and the lumen of the gut that the requirements are increased perhaps uh in addition and that they developed Malaga on that basis. It's interesting that it's so rare that you I think that's a logical Step two Do I. I just couldn't find any definite um studies of particularly vitamin absorption or of effects of bacteria in intestinal stasis on vitamin metabolism. Now, if you recall in talking to her, I asked her specifically about that and it was she answered very clearly uh that she was eating well at that time and that her diarrhea was not particularly severe at that time. So perhaps some sort of intrinsic mechanism did what would account for it. Dr Owen, I said I may have missed it. But would you interpret this cooperative study to say that nobody is going to be using a Visa thigpen anymore for Crohn's disease? And also uh since this is part one, could you tell us what part two is going to be like? Part two involves a two year study in patients with inactive disease. To see whether any of those four possibilities will suppress the recurrence of the disease. And so the data is not available yet. Unfortunately, it's my understanding that has been deleted from that group because of a high incidence of side effects, unusually pancreatitis has occurred in four or five patients. Uh and I believe it's been deleted on those grounds. Uh no, people will not stop using as a tire print on the grounds of the study. I think people still believe although they haven't been able to prove that some people by golly do get better. It's just we're just not smart enough to define them. I wanted to ask dr will be related to the Himalayas. Sis understand that the fact that she did developed developed hemolytic anemia with a sulfa Dean. And I think dr Zirkle in dr keeling agree with your comments about the protocol. But the fact that she did develop that means that she's a rapid settle later of the compound. And how does that account for the Himalayas? Sis I don't really know. DR hook maybe Sid got his hand up can answer that. How that does all I can say is that there is an effect an oxidative injury to the hemoglobin molecule which forms Heinz bodies which then leads to him policies in the spleen uh presumably because of increased resistance and lack of reform ability of the red cell. Nobody knows how it works even in ulcerative colitis. But good results are best correlated with blood levels of self appearing the sulfur part of the of the molecule. And side effects are best correlated with the slowest settle later phenotype. It's not a rapid, slower satellites. Right. They have. Does that mean that there will be a slower settle later of for example, supposedly holds true. So it's added backwards I believe. So the molecule is split in the distal small bowel or large bowel into self appearing and five amino salicylic acid and after being absorbed in the sulfur is then set elated. And as I said, high blood levels of sulfur occurring more often and slower sata laters are associated with more side effects. Okay. I wanted to ask you uh that second slide where you showed a number of different conditions related to things in the right lower quadrant. I didn't quite understand. Um you said 75% of something would be explained by the larceny organism. What of what is that? The people of the non appendicitis group obviously uh those who have missing pericarditis, acute regional acute terminally itis not Crohn's and acute Crohn's but people presenting with with an acute illness with right lower quadrant discomfort and if it's not you're a genital disease and it's not typical acute appendicitis then it's one of those others, the patients presenting with the syndrome of acute appendicitis that don't turn out to have a large proportion of them will have the Athenian. If reports in this country bear out what Reports carries. I've been trying to recruit somebody down here to tell us more about your sena uh dr Grant. Do you want to did I succeed with you? I suppose. So uh you're saying it's certainly uh recognized cause of granulomas. This disease in the terminal small bowel as well as the peasant eric. And notice that uh further that said mentioned uh there gram negative enteric bacteria that really looked like proteus on usual. Something about you language try it now. The the the organism is a non lactose fermenter which is often missed in the routine uh bacteriology lab because it's expected to be a normal uh flora organism. Uh It also uh frequently will require growth that room temperature to isolate it. And it's been caused uh identified increasingly in Scandinavian countries as a cause of acute diarrheal disease as well. Uh It's an interesting organism because it tends to grow inside cells like salmonella and indeed its path of physiology may well be similar to an invasive process that gets inside cells and then is allowed to survive. Especially perhaps in patients with defective cell mediated immunity. Which is a good it would fit well with the granuloma. This process that we see uh that was why I asked the question about that. I don't know that anybody has looked at these people to find out that they have indeed do have defective cell community. Have they? I because they don't they don't, go on, go on to be. Well uh let me make one other comment that you raise. That's very interesting indeed. That is the toxic effect of illegal influence uh from these patients. Uh maybe due to a virus uh everything seems to be uh incriminating viruses these days. But another possibility are the site of toxic effects from products of certain bacteria. Shigella are fairly familiar to produce a site of toxin, but Clostridium preventions may also produce it and goodness knows what other bacteria might produce. Site a toxic products. And uh I think that's certainly an area that we need to look into more. The idea of the virus I think is pretty tenuous at this point. It's based purely on morphological changes in the cell culture. They look like it. Therefore it must be dr arora. See it's a very simple and I question I think I'm very ignorant. Why did you place right on the top of the list? Low fiber diet. Uh could you explain why do you rational this particular diet for patients in dr bak is textbook. He has a long section on diet which is I think very conservative and very restrictive. Most people don't believe or don't practice in that fashion, feeling that let the patient eat what the patient will as long as it doesn't upset the car owns. The only restrictions on this are patients with genetic lesion strictures who will find that increased fiber in the diet causes more pain and therefore they find if you don't tell them first, but they ought to decrease the fiber in the diet. Well, Dr Stone is coming to the microphone. I was surprised to see the uh the rectal involvement at 50%. I would have guessed that it would have been much lower. The figures vary from, I don't know, 25, to 50%. A couple of comments. One question I get asked continually. I'm sure you do too. Is this disease increasing? Are we seeing more actual cases or is it a question of of our better diagnostic capability? And two, what are your thoughts about the the filter bubble agent which is being now uh talented perhaps uh playing a role in ideology? Is this just a toxic effect? Or is there a better evidence than that that it is a is a living organism? The answer to the first question, I believe there is some epidemiologic evidence to cite that the incident is indeed increasing and equals that incidence of all sort of colitis personal experience which is brief. I've seen considerably more Crohn's than I have ulcerative colitis. I don't know what that reflects. Uh One of the other interesting things in the pathogenesis is that material from human granulomas in the intestine have been passed through a filter injected into rabbit ilium and it produced a similar pathologic picture and I believe this has been passed another generation. And what I know about dr I know you've seen this patient, you interested, you ever comment, Sir Dr Hunter. Is there anything to be learned from geographical epidemiology of this disease? Does it occur all around the world with equal frequency more common in whites than blacks? More common in jewish populations. More common in urban populations. Um probably in Israel as well. And other than that, uh, I don't think there are broad bands of geographical involvement versus non involvement to suggest certain viruses. Are there other questions or comments? Not. Thank you very much. Time's up.