Brian Lacy, MD, and Magnus Halland, MD, on Managing Chronic Diarrhea

Doctors Brian Lacy and Magnus Halland discuss the challenges of diagnosing and treating chronic diarrhea, including markers to distinguish it from irritable bowel syndrome and other gastrointestinal disorders.

Brian Lacy, MD, is a professor of medicine at the Mayo Clinic in Jacksonville, Florida. Magnus Halland, MD, is an associate professor of medicine at the Mayo Clinic in Rochester, Minnesota.

TRANSCRIPT:

Dr. Brian Lacy:  Welcome to this Gastroenterology Learning Network podcast. My name is Brian Lacy. I'm a professor of medicine at the Mayo Clinic in Jacksonville, Florida. I am absolutely delighted to be speaking today to Dr. Magnus Halland, associate professor of medicine at the Mayo Clinic in Rochester, Minnesota.

Our topic today is one that is important for every provider regardless of specialty -- chronic diarrhea. Dr. Halland, thank you so much for joining this podcast today. Let's begin simply to set the stage for our listeners. How common is chronic diarrhea?

Dr. Magnus Halland:  Thank you for inviting me to be part of the podcast today. It's a pleasure to be with you all. You would think, with a condition like chronic diarrhea, that we would have an excellent handle on answering the question of how common it is, but that's actually not the case. We lack high-quality population-based studies to fully understand this, but from the best of our current knowledge, we think that somewhere in the ballpark of 3% to 5% of people live a life troubled by chronic diarrhea.

Dr. Lacy:  That's a huge number of patients and explains why we're so busy in clinic. Magnus, we're going to focus today on chronic. How do you distinguish chronic diarrhea from acute diarrhea? Is there a cutoff in terms of days or weeks?

Dr. Halland:  It's a very important distinction to make. In clinical practice, we feel that the 4-week mark is a pretty important time point to determine whether somebody is having an acute diarrheal illness or whether they've moved into the territory of chronic diarrhea.

That doesn't mean to say that it's an absolute cutoff, and you have to judge each case on its own merits, but it's a good guideline to differentiate acute from chronic.

Dr. Lacy:  I like that point. So 4 weeks is a great cutoff for providers in all specialties. You mentioned that it's important, but why is it? Does it really make a difference if it's acute or chronic? Wouldn't the treatment be the same?

Dr. Halland:  It's a great question and it’s a really important question. As doctors, we help our patients the best when we can treat a specific pathophysiology. As it turns out, with diarrhea, there is a completely different set of pathophysiologies that commonly cause acute diarrhea from chronic diarrhea. This is a key point to get across.

Acute diarrhea, for example, is often infectious in nature or food poisoning-related. It's often self-limited, severe to begin with, and often gets better over time.

Chronic diarrhea is a whole different ballgame, and infections feature much less commonly in this scenario of chronic diarrhea, perhaps with the exception of C. diff, that should always be on your differential with chronic diarrhea, as well as giardia, and then rarer infections such as Whipple disease.

But more often in chronic diarrhea we are either dealing with a functional diarrhea, an irritable-type bowel, perhaps an inflammatory diarrhea, or a medication-induced diarrhea.

Dr. Lacy:  Wonderful. Great teaching points there about chronic diarrhea, whether irritable bowel syndrome with diarrhea, functional diarrhea, and oftentimes medications.

We're going to come back and visit it in a little bit, but one concern of many patients, and also many providers, is whether or not a patient has an inflammatory component, like inflammatory bowel disease, as a cause of their chronic diarrhea.

Are there noninvasive tests which we could use to accurately distinguish a chronic diarrhea not from inflammatory bowel disease, or does everybody need a colonoscopy?

Dr. Halland:  A few years ago, the answer to that question would have been maybe, but I feel like the answer now is heading more in the region of yes. I do think that noninvasive tests are helpful, and they're certainly getting better. Stool calprotectin comes to mind, and depending on the cutoff that you use, it can help rule out inflammatory bowel disease in the majority of cases.

Ultimately, still in 2021, noninvasive tests are either positive, inconclusive, or even negative in a small proportion of patients, and you have a high suspicion of inflammatory bowel disease, direct inspection of the mucosa with a colonoscopy test might be required. I think it can help us in that large proportion of patients initially in their workup to determine and avoid unnecessary colonoscopy.

Dr. Lacy:  Great, a good teaching point for our listeners is a very low fecal calprotectin and a low CRP would strongly argue against IBD and maybe more for something like IBS.

Magnus, you mentioned celiac disease earlier, and we know that celiac disease can be a cause of chronic diarrhea in some of our patients. Do you routinely evaluate all of your patients with chronic diarrhea for possible celiac disease, and if you do, what tests do you like to use?

Dr. Halland:  Yes, I do. I think it's useful to rule out celiac disease in chronic diarrhea, and again, noninvasive testing perform pretty well. For example, using the antitissue transglutaminase antibody, IgA, is pretty accurate in diagnosing celiac disease, although we know that about 2% to 10% of patients with celiac disease might have a negative antibody test.

Again, it's a highly useful screening test, and most of the time the test will get the answer right, but also keep in mind if you give into the refractory scenario, or if things don't simply add up, you may need to go to an invasive test like an endoscopy with a biopsy. Ruling out celiac disease makes complete sense in this patient population.

Dr. Lacy:  Perfect. Safe, not expensive, and can dramatically change treatment. You mentioned earlier on, Magnus, that many patients develop chronic diarrhea after an enteric infection. We know that giardia is a reasonably common cause of chronic diarrhea in many parts of the world, including the United States, and Europe. In Minnesota, a lot of people are hiking in the summer and going to camps, and lakes, and streams. For these patients with chronic diarrhea, do you think we should routinely check for giardia?

Dr. Halland:  Yes, I think it's reasonable. Again, I do adjust it a little bit depending on the duration of the diarrhea as well as risk factors. If somebody has had diarrhea for 10 to 20 years, it's less likely that you're dealing with giardia, but less than 6 months, I think it's very reasonable, and digging into some of those risk factors makes a lot of sense.

Asking questions about fresh water exposure, the drinking water source where somebody is using well water, male-to-male sexual behavior, and also parents who are exposed to diapers of children are at high risk of getting giardia. Adding those additional questions to your patient with chronic diarrhea can make it more less likely when you're dealing with giardia test.

Dr. Lacy:  Great tip, I like that. You mentioned earlier, too, Magnus, when thinking about the differential diagnosis of chronic diarrhea, you mentioned both functional diarrhea and IBS with diarrhea. For our listeners here today, who may not be quite as comfortable with this topic as you are, could you highlight a few key points that distinguish functional diarrhea from IBS with diarrhea?

Dr. Halland:  Yes, there are a few clinical features that can help differentiate. The one outstanding feature that I want to highlight is pain. In IBS with diarrhea, you have persistent loose and watery stools, that's exactly the same as a patient with functional diarrhea might report, but there should be abdominal pain present. Whereas patients who don't have pain, but they have loose and watery stools might be better characterized as having functional diarrhea. At least in my clinical decision making, the presence or absence of pain is one of the absolute key features.

Dr. Lacy:  We know that many of our patients take vitamins, and supplements, and herbal products because they believe they help promote good health for any number of reasons, but a lot of these can cause chronic diarrhea. Can you remind us of some of the worst offenders?

Dr. Halland:  This should also be part of the history-taking when you meet patients like this. The first one that comes to mind to me is magnesium. There's many different magnesium salts available, and many patients find them useful either for a muscular-skeletal indication or perhaps for aiding with sleep.

But you have to remember that magnesium is actually a laxative. It's present in some bowel preparations that we use to prepare patients for a colonoscopy. Asking about magnesium, I think, is prudent. We also should remember artificial sweeteners and items that are high in fructose, so high fructose items and artificial sweeteners that form part of the diet can also be very prominent in causing some susceptible people to have diarrhea.

Dr. Lacy:  Taking a great history and a dietary history is really important, and when people ask about medications, remember, for our listeners, ask about those supplements, as well. Kind of wrapping up this portion, Magnus, before we start talking about treatment, with regard to testing, what about breath tests? Controversial area—should we be doing breath tests to look for small intestinal bacterial overgrowth in all of these patients?

Dr. Halland:  Just speaking for my own clinical practice, breath testing doesn't play a large part in my evaluation of these patients. That's mainly related to the less-than-optimal sensitivity and specificity of breath testing for identifying small intestinal bacteria overgrowth. You can in fact have a false positive test due to rapid transit, and rapid transit through the gut can often be a pathophysiological factor in diarrhea. It can kind of lead you in the wrong direction in certain scenarios.

Now, if I have a very high clinical suspicion that this could be intestinal overgrowth of bacteria, then you could consider a duodenal aspirate, and in some cases, even empiric antibiotic therapy could be helpful. Patients with scleroderma, for example, that are at high risk of this condition may not need a confirmatory test. Perhaps an empiric trial would be reasonable in select cases like that.

Dr. Lacy:  Magnus, let's shift gears now, and focus on treatment for the next few minutes. What about dietary interventions for the treatment of chronic diarrhea? Should we be placing all of these patients on a low-gluten diet or a low-FODMAP diet?

Dr. Halland:  Coming back to the point of taking a good diet history, including food items, supplements, and artificial sweeteners, I think it's really, really important. There is no doubt that there's a very high level of interest in our patients to find a dietary solution to their diarrhea. Many patients are much more interested in that, rather than adding a medication or taking even more medications if they have other comorbidities.

There's been a lot of excitement that we finally had some robust evidence. We had some randomized trials indicating that the FODMAP diet might be helpful in reducing symptoms in irritable bowel syndrome.

That's really exciting, and it does add an additional tool that we can use in our patients. But the flipside to it is remembering that a very strict FODMAP diet is highly restrictive. It was never meant to be a lifelong diet, and there needs to be a reintroductory phase.

So even considering a gluten-free diet or a low-FODMAP diet, I would highly recommend involving a dietician to help give the patient practical advice beyond what we can do in a short clinic visit, and to also explain that it's not meant to be a lifelong restrictive diet.

In terms of a gluten-free diet in the absence of celiac disease, we do know that gluten can induce symptoms in some patients, although it doesn't cause the health harm that it causes in patients with celiac disease. So some patients do find that being a useful strategy. It's certainly something to discuss with interested, motivated patients while involving a dietician.

Dr. Lacy:  The probiotic market in the United States is now 6 to 7 billion dollars per year. Is there any role for the use of probiotics for treating chronic diarrhea?

Dr. Halland:  Again, this is a controversial area. We certainly have a number of studies that suggest benefit, even some meta-analysis of studies suggesting benefit. The drawback to many of these is that the methodology and the heterogeneity in the type of probiotics and supplements that are being used, makes it difficult to recommend a specific treatment or strain.

I want to say that this field is in its infancy. I think there is hope that probiotic therapy may become useful as time goes on. Some patients, empirically, find it helpful, but it's hard to make blanket statements and high-quality-based recommendations at this point in time.

Dr. Lacy:  Certainly interesting, certainly intriguing, but kind of a data-free zone. I agree. Magnus, loperamide has stood the test of time for the treatment of diarrhea. Some of our listeners may be old enough to remember that it was actually only available by prescription for a while. Is this still something you routinely recommend?

What about Lomotil or diphenoxylate-atropine? Is that something you prefer to avoid because of possible side effects, especially in the elderly?

Dr. Halland:  I like loperamide a lot, actually. To me, a treatment doesn't have to be the newest and the fanciest to be interesting. If I have a treatment like loperamide, which is cheap, effective, and very safe when used as prescribed with clinical monitoring, that is exciting to me.

One thing that I do want to mention about loperamide is patient education, because many bottles and over-the-counter preparations will say, "Take one after each loose stool." With chronic diarrhea, it's more important to be preemptive and use this before a meal, or preemptively first thing in the morning, or maybe at night if a patient is having nocturnal diarrhea.

Scheduled prescription of loperamide with a good explanation of the mechanism of action, and how to take it, can be very helpful. I have to say I use less Lomotil. In the elderly, I avoid it. The anticholinergic  side effects that are high potential in elderly patients makes it much less attractive in that population.

Dr. Lacy:  I couldn't agree more. There's been some interesting data over the last 5 to 9 years that some patients with chronic diarrhea may have a component of bile acid malabsorption as a cause of their symptoms. How do you identify patients with possible bile acid malabsorption, and should we be treating all these patients with bile acid sequestrants?

Dr. Halland:  Personally, I think this is a really interesting field because it highlights the diversity of pathophysiologies that might be present in our patients with irritable bowel syndrome. To me, it's chipping away and getting more specific when it comes to treating patients. So I do like considering bile acid malabsorption.

If somebody's had a cholecystectomy, it's not uncommon to have diarrhea, although it usually gets better. A post-cholecystectomy state would make me more suspicious than bile acid malabsorption could be going on.

In terms of testing, it can be challenging. At certain specialist centers, we are blessed with testing that can include detailed stool testing to measure the direct levels of bile acids in the stool. We have some serum testing, including the 7aC4 bile synthesis testing. In Europe, there's some breath testing that is available too, but this is not universally available.

What I want to say, though, is that bile acid sequestrants are also safe, and typically well-tolerated at low dosages. If this is suspected, again, if you don't have readily available testing, that wouldn't hold me back from having this in my personal armamentarium in trialing potential therapies for somebody with chronic diarrhea.

Dr. Lacy:  Magnus, I want to circle back to something you brought up 10 minutes ago, and that's the use of rifaximin for the treatment of IBS with diarrhea symptoms. We all know the data from TARGET 1, TARGET 2, TARGET 3 showing rifaximin had value for those IBS-D patients. What about the patients with chronic diarrhea?

You mentioned, should we just empirically treat with rifaximin, as an example?

Dr. Halland:  I've told you today I'm excited about loperamide. I'm excited about bile acids. I'm less excited about rifaximin, and here's why. We certainly have high-quality trials, TARGET 1, TARGET 2 trials, randomized studies showing a benefit. In my mind, the absolute benefit is still small. The numbers would suggest that you have to treat 10 patients with rifaximin for 1 patient to have a benefit that is temporary. When you then take into account the cost of rifaximin for many patients, and the fact that it's not a long-term fix — although some data, including TARGET 3, suggests that you can retreat patients — to me, it's certainly not my first go-to tool in treating this patient group.

I will often try and exhaust other treatment options before heading down that route.

Dr. Lacy:  Thank you. That's a very nice perspective. Magnus, as we wind down here, for patients who fail the treatment options we've discussed, what other treatment option is out there? What about 5-HT3 serotonin type 3 antagonists, or should we be using neuromodulators?

Dr. Halland:  The 5-HT3 antagonists makes me think of alosetron that entered the medical scene with a lot of promise and optimism because it's a highly effective medication. As we often see with very highly effective medications, there's also a higher potential for side effects.

Colon ischemia developed in approximate 4 in 1,000 people who used this medication and initially led to full withdrawal of this medication. It was later reintroduced under a limited access program for women alone. The use nowadays is only in severe cases of IBS-D where there has been nonresponse to other therapies because of this risk.

Even though the risk is low, the thinking was that IBS, even with diarrhea, although it significantly limits quality of life, it doesn't typically reduce life expectancy. Having a severe colon ischemia side effect wasn't an acceptable risk-benefit profile. So it's not often clinically used.

Neuromodulators are often used, and they're particularly tempting to use in IBS-D, because s we reflect back on functional diarrhea in IBS-D, pain is a major symptom in IBS. Certain neuromodulators, particularly tricyclics, have the ability to address both pain and also can have a positive impact on diarrhea due to the effect on gut motility.

Using a low-dose tricyclic antidepressant is safe, typically well tolerated and it can be a very useful therapeutic maneuver for many patients with chronic diarrhea, particularly if it's due to irritable bowel syndrome.

Dr. Lacy:  Magnus, this has been a wonderful discussion. I know I learned a lot, and I'm sure our listeners learned an awful lot, too. Do you have any last comments for our listeners?

Dr. Halland:  The only comment I would make is, listen to your patient. Dig in to try and understand the onset of this diarrheal illness. Inquire to find out about frequency and triggers, and spend a little bit of extra time to explore the dietary and supplement habits of the patients.

It would be a shame to add a medication to treat diarrhea when that's in fact a side effect of easy dietary or adjustment to supplementations.

Final comment on breath testing, too. You saw I was not too enthusiastic about SIBO breath testing, but I do think that fructose breath testing can be helpful. Fructose malabsorption, which is not really a disease, it's more a shades-of-gray, each human's ability to absorb fructose, can certainly be a contributor to diarrhea in a subgroup of patients. If you identify that, that can be a huge motivating tool to go on a fructose-controlled—not a fructose-eliminated diet, a fructose-controlled diet—and to understand what triggers of diarrhea might be.

Dr. Lacy:  Magnus, thank you. Once again, we can't appreciate all of your expertise that you've provided today. Thank you, Dr. Halland, associate professor of medicine of Mayo Clinic in Rochester.

Thank you to our listeners for joining in today. We look forward to having you join in on another podcast from the Gastroenterology Learning Network in the future.

Dr. Halland:  Thank you very much for having me on.