Drs Brian Lacy and Kishore Iyer Discuss Short Bowel Syndrome - Part 2

In part 2 of this podcast, Drs Brian Lacy and Kishore Iyer shed light on treatment options for patients with short bowel syndrome.

Brian Lacy, MD, is a professor of medicine and gastroenterologist at the Mayo Clinic in Jacksonville, Florida. Kishore Iyer, MD, is a professor of surgery and pediatrics and director of the Intestinal Rehabilitation & Transplant program at Mount Sinai Hospital in New York City, New York.

---

Transcript:

Welcome back to part two of this podcast with doctors Brian Lacy and Kishore Iyer, as they continue their discussion on treatment options for patients with short bowel syndrome.

Dr. Brian Lacy:
Wonderful. Thank you. So now let's go back and let's start simply regarding treatment. How do we best address some of the nutritional issues you've already mentioned? Do all patients with short bowel syndrome need to be on TPM?

Dr. Kishore Iyer:
That's a great question. Perhaps the most important point to remember in thinking about management is recognition. So I think the biggest team in my perhaps quaternary level practice is unrecognized or under-recognized short bowel and intestinal failure. So I would say have a high index of suspicion perhaps for a gastroenterologist audience, high index of suspicion for your patient with IBD who's had multiple resections and who starting to complain of diarrhea, ask yourself over and over, could this be short bowel? Could this patient be on the cusp of becoming short bowel? Because this is not a binary decision. The patient doesn't one day not have short bowel and next day have short bowel. Yes. I gave examples of that, but in most practices that's not how it works. So there should be a low index of suspicion and it's safer for your patient to err on the side of assuming this is short bowel and intestinal failure, over treat, and then show to yourself and to the patient that treatment is not required and safely pull back on what you're doing.

So in reverse order, based on the brief discussion of physiology we had in reverse order, the priorities then become maintenance of fluid and electrolyte status, maintenance of nutrition, management of symptoms, maintenance of fluid aide status is easy in the very short term with intravenous fluids as appropriate. In the longer term, if their patients come in twice with dehydration, don't wait for a third time in kidney failure. I need a central line, secure central venous access, established provision at the minimum of intravenous fluids and then a decision can be made as to whether that should include provision of calories, macronutrients, micronutrients. The second issue, provision of nutrition, there are certainly situations where we can finesse this and say, could my patient tolerate intra-tube feeding? And that's a whole separate discussion in itself. But if you think the patient has short bowel or you've asked yourself, could I be dealing with short bowel, err on the side of presuming that you are. Have a low threshold to start parenteral nutrition. It's not dangerous. It's not lethal, contrary to popular legend and support the patient until you can establish for yourself that that's perhaps redundant.

And then prevention of symptoms. Overriding symptom is diarrhea, increased GI losses. We can reuse antidiarrheals and I tell clinicians we use them sequentially. We use them addictively. We use them appropriately. What does that mean? We might start with something like loperamide titrate up to maximal doses. You might have to tell the local pharmacist that this is for chronic use before the prescription starts getting denied. And then with continued symptoms instead of stopping the loperamide and saying it doesn't work, we might then consider adding a second agent such as diphenoxylate atropine and we would again titrate that up to maximal doses. I'm being a little facetious in saying I tell people that in my practice the patient with constipation does not occur.
And if that occurs there is some other underlying pathology or complication you are missing perhaps a stricture and unrecognized partial obstruction or a blind loop that requires further investigation. But the patient you're having with diarrhea, dehydration, increased ostomy losses should be treated with maximal doses and sometimes supra-therapeutic doses of anti-diarrheal for chronic use. And I'll make one point here. When you're recognized that you have a patient with short bowel or intestinal failure, for most clinicians it's relatively easy to understand malabsorption of macronutrients, fluid, electrolytes, macronutrients. We should therefore make the extension to understand orally administered drugs can also be malabsorbed and we should make allowances for that.

Dr. Brian Lacy:
Several great teaching points and I especially like the one two episodes of dehydration. Don't wait for the third. Jump into action. Let's not put our patients at risk. So thinking about GLP-2 agents, glucagon-like-peptide-2 agents has changed the management and kind of lives of many patients with short bowel syndrome. For our listeners here who may not be quite as familiar as you are, how do these agents work? And who should we give them to?

Dr. Kishore Iyer:
So this is a game changer in one phrase for the field of intestinal failure. So let me take a step back. Physiologically, if you have a normal GI tract as soon as one eats a big meal, there is immediately a postprandial secretion of endogenous GLP-2 from specialized cells, the L cells and the distal ilium and the right colon. Now naturally occurring GLP-2 has a very, very short half-life, but there is really phenomenal work done by an endocrinologist out of Canada, Dan Drucker, is showing that GLP-2 aids in the absorption of the meal that it was secreted in response to. So recombinant glucagon-like-peptide-2, alteration of a single amino acid in the GLP-2 analog, in the GLP-2 molecule, it was approved by the FDA now perhaps about 10 years ago as teduglutide I will use the brand name here just for convenience and reference called GATTEX distributed by Takeda.

But going forward I'll stick with the term teduglutide. Teduglutide has a slightly longer half life, about two hours or so, but it's administered by once daily subcutaneous injection and was shown in the confirm x-ray, randomized control trial, the steps trial to improve intestinal absorption in patients with short bowel syndrome associated intestinal failure. So that ultimately led to FDA approval. And I will just emphasize here that it is not simply one more antidiarrheal. Do not use it for your patient with short bowel syndrome, who can be managed with a simpler antidiarrheals that are much less expensive, that there's a lot more experience with, and have fewer side effects. GLP-2 as approved currently teduglutide is a very safe drug very efficacious drug if you safely and correctly. How does GLP-2 act? The obvious effects of GLP-2 are to increase villus height and crypt depth, but we do believe GLP-2 has other effects. It slows gastric emptying.

It increases portal flow and I'm no pharmacologist, but I do wonder to myself a drug with a half life of two hours that can be given by single daily injection. I have to believe this also exerts additional paracrine effects perhaps. And so it's a very interesting drug. In the steps trial about two-thirds of patients who got teduglutide were able to significantly decrease their PN volume, their parenteral nutrition volume. And what is significant for the purpose of that trial, a 20% reduction in intravenous fluid or parenteral nutrition volume, was accepted by the FDA as significant. Additional studies, post talk studies have shown that somewhere around 25%. In our own single center experience, close to two thirds of patients actually were able to come off parenteral nutrition completely, which of course is the holy grail of intestinal failure care. So GLP-2, this discussion would not be complete without at least mentioning one or two potential side effects.

I've alluded to the fact that it's a very safe drug, but given that technically it's a growth factor, it increases villus height and crypt depth, we should say there has been concern about the propensity to increase the size of colonic polyps and even more the concern about nuance and neoplasia. More recent post-hoc data, including some papers we have published have shown that perhaps the cancer risk is much less than originally feared. But nevertheless, the FDA requires and it is just sound practice to do baseline surveillance colonoscopy to make sure there are no polyps, to remove any existing polyps, and certainly the label requires that patients with active malignancy in the GI tract are not candidates for GLP-2 use. I will go a step further and say in my practice, anybody with an active malignancy, active being defined as within the last five years, is not a candidate for GLP-2.

Dr. Brian Lacy:
Wonderful. Thank you. Incredibly useful information. So as we start to wind down here, what about the role of additional surgery? You've cautioned our listeners about the risks of surgery, sometimes required, sometimes maybe not, but what about additional surgery? What about bowel lengthening techniques? Could these be used to wean people off TPM?

Dr. Kishore Iyer:
Great question. And finally I can speak to my really true roots. I am a surgeon after all. So that said, every operation I start in a patient with short bowel, I love to ask the trainees what is the most important thing we have to do? We have to not make the situation worse. The worst thing a surgeon can do for a patient with short bowel is to inadvertently or injudiciously lose further bowel length. So there with that as our sort of guiding beacon, perhaps there is a case for judicious and well considered surgical options. And the single most beneficial surgical intervention in many of these patients is perhaps I'll start at prevention of short bowel. Be very judicious about removing marginal bowel in Crohn's. I don't need to state this. Be extremely cautious. Use conservative strategies to deal with strictures and blind loops.

Be very careful about the decision to make a stoma. I tell people every time you create a stoma, you lose five centimeters a bowel. You take it down, you lose another five centimeters of bowel. Ask yourself, is that stoma really necessary? And it's much easier and safer in many situations to accept the need for additional second look operations. Multiple times I've needed that to make ill-advised decisions that are perhaps hasty and ultimately lead to a bad outcome. That said, perhaps the single most important operation is to examine whether there is any residual bowel that can be salvaged. And the single most important situation this occurs in is perhaps retained left colon, retained left transfers colon and beyond. The patient who has 30 centimeters of jejunal and and a high jejunostomy in my book, that patient nearly always, I cannot think of a situation where that patient would not benefit from putting that bowel back together again.

So is there risk to surgery? Of course. But is the benefit of recruiting that unused colon greater? A hundred percent. And especially in the current era of additional actual therapies if may call that such as GLP-2, the value of recruiting a unused bowel is massive. Then there are more specialized operations that you alluded to, the lengthening and tapering operations, the patient with a dilated loop of bowel and the whole issue of why does dilatation occur in patients with short bowel. You can take a teleologic view and say it's a compensatory mechanism. I suspect the answer is a little more complex. It may relate to watershed areas of marginal blood supply, but nevertheless, if that bowel has survived, it can be exploited. And without getting into technical details, there are different surgical strategies that are perhaps best performed its specialized centers to taper the dilated segment without loss of surface area.

And that ultimately is the lengthening. No true additional bowel is created, but what you've succeeded in doing is taper dilated bowel without losing surface area. And, yes, if we are so focused on length, if you do measure the length, you will record that you increase the bowel length and then that is the situation of the patient who has dilated bowel. What about the patient with rapid transit and no dilated bowel? This operation I think is underutilized, but there is a role for placement of an anti-peristaltic segment, a reverse segment. And I will do this, I don't usually do this as a single operation, but if I'm there for some other reason, the patient with 30 centimeters of jejunal left colon and I'm going to take down that stoma and restore continuity, I would consider placing an anti-peristaltic segment to reduce the risk of diarrhea. So there is a role for carefully considered exploitative surgery in short bowel, fully mindful, and this is not a simple decision, a careful risk benefit analysis.

Dr. Brian Lacy:
So let's consider as we wrap up here, that patient with persistent symptoms. They've failed all types of medical therapy. Maybe they've had complications from TPN. They're not a candidate for another surgery. Is that the patient we should refer for intestinal transplantation?

Dr. Kishore Iyer:
Great question. And you set the stage perfectly. That patient absolutely should be referred for transplant. So I will emphasize here that we don't simply offer intestine transplant for short bowel. And why is that? Intestine transplant outcomes have improved, have improved considerably. Their vastly better than say kidney transplant outcomes were at the same stage in the procedure's history, but they're still not quite ready for primetime. They're getting there. That is the reason the standard of care for the patient who's failing with short bowel syndrome is the provision of paraental nutrition and outcomes for paraental nutrition, for home paraental nutrition in the vast majority of adult patients are superb and we should expect 90, 95% five year survival for patients on home PN and so that has become the gold standard and rightfully so. However, it is important to emphasize that that's not the outcome in all patients.

And some patients sometimes for reasons that are not completely clear, are prone to associated complications most frequently in the form of catheter related complications, frequent catheter related sepsis. Medicare defined that as at least two episodes in a year or even a single episode of fungemia or loss of venous access. We have just four major veins to put in a central venous catheter. And if that, those have to be replaced frequently, some patients lose access. And then of course is the development of intestinal failure associated liver disease in the setting of PN. I still prefer the old-fashioned term of paraental nutrition associated liver disease, but fortunately that's become less frequent. But the occurrence, even the onset of liver disease should begin a conversation about whether intestine transplant is appropriate because for some patients, intestine transplant outcomes are really quite good and it's important to emphasize an intestinal transplant is a difficult and important decision. Referral for evaluation does not commit anybody, not the patient, not the transplant center to perform in the transplant. But that referral is important.

Dr. Brian Lacy:
Kishore, this has really been just an amazing conversation. I learned a lot. I know our listeners learned an awful lot. Any last thoughts for our listeners?

Dr. Kishore Iyer:
Look, I tell my patients and people who know me know that 50% of what I say is in fun. Unfortunately, many people can't tell which 50, but I will say this. Intestinal failure and short bowel devastating diseases. As one patient said to me as I was trying to improve his spirits and say, don't let your disease define you, he said to me, name one thing you do socially that does not involve food and drink. And there's a lot to be said for that. So, A, your patient who's not doing well with routine food and drink, you owe it to the patient and to yourself to start thinking about intestinal failure and short bowel. This is a devastating disease. I could not imagine living like this. Fortunately for my patients and for the field, this is a good time to have the disease. There are many new and exciting therapies, outcomes for surgery, outcomes for transplant are improving though I'm a transplant surgeon, I tell people I'm like a foreman in a Jiffy Lube. Yes. Transplants like replacing the engine, but we're now in a situation where perhaps a tweak of the oil and the change of the spark plug might be enough.

Dr. Brian Lacy:
Kishore, once again, thank you so much. To our listeners, this is another great conversation on gut check. You've been listening to Dr. Kishore Iyer, national and international expert in intestinal transplantation and professor of surgery in pediatrics at Mount Sinai Hospital in New York City. Tune in again and the near future for another great edition of Gut Check. Thank you so much.