Healio Hot Topic

IBS: Transitioning from a Syndrome to a Disease

William Chey

Irritable bowel syndrome is a symptom-based condition defined by the presence of abdominal pain and altered bowel habits. The clinical phenotype can be quite diverse so while all patients have pain, some patients can have problems with diarrhea, others can have problems with constipation, and still others can have a mixture of both constipation- and diarrhea-related features.

IBS is a very important condition on several different levels. First is due to its prevalence. The population-based estimates in the United States reveal that around 14% or one in seven people have symptoms that would be compatible with a diagnosis of IBS. When you look at the prevalence of IBS symptoms worldwide, you come up with a very similar number although it varies from country to country.

The good and bad news is that not all those people who are symptomatic go to see a physician. Obviously if everybody experiencing IBS symptoms were to go to seek medical advice, it would overwhelm the health care system. Probably fewer than half the people that have GI symptoms compatible with a diagnosis of IBS actually seek care for their GI problems. That being said, IBS is the most common diagnosis rendered by gastroenterologists and one of the most common diagnoses managed by primary care physicians.

Thus, it is not surprising that IBS accounts for a tremendous economic burden in the United States on an annual basis. It’s estimated that we spend $20 billion to $30 billion a year in caring for patients with IBS. IBS exacts a tremendous impact on patients’ quality of life and work productivity. Patients with IBS have a measurable and clinically meaningful detriment in their quality of life. When you break down quality of life into physical and emotional domains, IBS crosses all those boundaries. IBS patients miss more work and are less productive at work even when they go to work, affecting both absenteeism as well as presenteeism.

With IBS, we see a burden to the health care system, a financial burden to society, and tremendous personal burden to patients affected by the condition.

Importance of Heterogeneity

IBS – being a symptom-based condition – isn’t one disease. It’s likely several different diseases that happen to present with the same symptoms. Yet, given our current understanding and a lack of validated biomarkers, we cannot parse IBS patients on the basis of pathophysiological abnormalities. Instead, we rely upon symptoms to establish a diagnosis and choose a treatment.

As science advances, our level of sophistication will improve both in terms of our understanding of what causes IBS symptoms and our ability to identify subgroups of patients based upon pathophysiology rather than symptoms alone. When we are able to separate IBS patients into pathophysiological subgroups, we hope to improve the chances of selecting the right treatment for the right patient. The candidate pathophysiological factors that are felt to contribute to IBS fall into a wide range of different categories, but some durable themes include alterations in motility, visceral sensation, brain-gut interactions, the gut microbiome, intestinal and colonic permeability, and the gut immune activation.

We often discuss these factors as if they were independent variables, but they’re almost certainly not independent but rather, co-dependent variables. In other words, they interrelate and influence one another to varying degrees in different patients with IBS. For example, one could envision alterations in the microbiome leading to changes in permeability which could increase antigen exposure to the gut immune system, leading to activation of the gut immune system, which interacts with neural pathways involved in motility, visceral sensation, and brain-gut interactions. All these factors may or may not be interrelated, but the discussion of these various factors and how they might interplay really highlights a central theme: heterogeneity.

Heterogeneity is an important concept because it helps one to understand the various factors that could lead to the range of IBS symptoms and provides an explanation for why virtually all of the available therapies — whether you’re talking about diet, behavioral, or medical therapies — typically improve symptoms in only 40% to 60% of treated patients, with a therapeutic gain over placebo of 7% to 15%.

There’s no silver bullet as far as treatment because the treatments target specific pathways and there are a wide range of different pathways that might lead to the symptoms of IBS. As long as we define IBS based on symptoms alone, we are unlikely to do much better than this. The real step forward will be identification of biomarkers that allow us to parse patients based on pathophysiology. This will allow us to take a personalized medicine approach by choosing a targeted therapy for a specific patient.

Diagnosing IBS

My previous comments may lead readers to conclude that the time for symptom-based criteria has come and passed. Given the lack of validated biomarkers to rule in the diagnosis of IBS, that is definitely not the case. It’s important to recognize that in 2018 and for the immediate future, symptoms will remain our most reliable gateway into the diagnosis of IBS. At present, we use symptoms to identify patients in whom we suspect IBS and we consolidate the diagnosis by ordering selected diagnostic tests to exclude organic diseases that can mimic IBS.

For example, we’ll do serological testing for celiac disease which can present with symptoms that are very similar to IBS. Celiac disease has been described as the great mimicker. It can present in a wide range of ways including GI and non-GI symptoms. From a GI standpoint, celiac can present with abdominal cramping, bloating, flatulence, and altered bowel habits such as diarrhea.

It important to address a couple of misconceptions regarding the clinical spectrum of celiac disease. Though less common, a small proportion of patients with newly diagnosed celiac disease are now endorsing complaints of constipation.

Many patients, particularly in the United States, being diagnosed with celiac disease are now obese. So, the dogma of celiac patients presenting with wasting and diarrhea no longer holds true.

We recently published a systematic review and meta-analysis looking at the prevalence of celiac disease in patients with IBS symptoms, and found an increased prevalence of celiac disease worldwide amongst individuals with IBS symptoms. But when you look at the small number of studies from the United States, this association is not as clear.

I would still strongly recommend that patients with IBS symptoms be screened for celiac disease because celiac disease is a specific genetically-mediated disease with a highly effective diet-based therapy. Missing the diagnosis can have serious consequences for affected patients. All that said, it is important to realize that you’re going to do about 100 to 150 tests to find one patient with celiac disease. It’s not going to be a diagnosis that you commonly make.

We will test for inflammatory markers like fecal calprotectin or fecal lactoferrin to exclude inflammatory bowel disease in our IBS-D patients. Having a negative fecal calprotectin or fecal lactoferrin virtually rule out inflammatory bowel disease in patients who present with IBS symptoms and no warning signs or alarm features. Inflammatory bowel disease is always a concern, but the good news is that the prevalence of IBD is no greater in individuals with IBS symptoms and no warning signs or alarm features than it is in the general population. It can happen but it’s very rare.

Depending on where you are in the United States, screening for giardia infection can be very helpful when evaluating patients with diarrhea-related symptoms. In Maine or Michigan where giardia infection is more common, screening for giardia should be a routine part of the workup of any patient with diarrhea-related symptoms.

Another concept gaining popularity is screening for bile acid diarrhea. Recent studies have shown that somewhere between 20% and 30% of patients with IBS-D will have evidence of bile acid malabsorption. There are now commercially available assays that can allow a provider to measure the quantity of bile acids in a 24-hour stool collection. There are also blood-based biomarkers like C4, which have recently become available commercially in the United States.

Lastly, age appropriate colorectal cancer screening is always very important. In patients with typical IBS symptoms and no warning signs or alarm features there doesn’t appear to be an increased risk for colon cancer. Yet, with all of the recently reported data reporting an increased prevalence of colorectal cancer amongst younger individuals, we may need to take a step back and re-study what the prevalence of colorectal cancer is in patients presenting with IBS symptoms to see if this still holds true or whether we need to be a bit more vigilant about performing colonoscopy in patients with IBS symptoms. Currently, there is no justification for performing colonoscopy in all patients presenting with IBS symptoms but no warning signs such as GI bleeding, unintentional weight loss, progressively worsening symptoms, or a family history of organic diseases such as colon cancer, inflammatory bowel disease or celiac disease.

There’s overlap in symptoms and a number of studies which report an increased prevalence of microscopic colitis in individuals with diarrhea with or without abdominal pain. Thus, when performing colonoscopy in patients with unexplained diarrhea, obtaining random biopsies to exclude microscopic colitis should be considered.

The discussion in this section makes clear that nearly all of currently available biomarkers are used to exclude organic diseases that can mimic IBS.

There has been a recently released biomarker that claims to identify patients with IBS. That is anti-cytolethal distending toxin B (CdtB) and anti-vinculin antibodies. The Cedars-Sinai Group presented interesting preliminary data to suggest that individuals who experience an enteric infection respond by producing anti-CdtB and anti-vinculin antibodies. They showed patients with IBS have persistently elevated levels of these antibodies while in individuals who don’t have IBS, the levels of antibodies wane and disappear very quickly after the resolution of the infection. They have shown in some preliminary studies that anti-CdtB and anti-vinculin antibodies can distinguish IBS patients from patients with IBD, celiac disease and healthy controls. To date, most of the validation studies are cohort studies and not real-world studies that have evaluated individuals with IBS symptoms coming in for an evaluation and going through a workup including anti-CdtB and anti-vinculin antibodies. To determine the true performance characteristics – sensitivity, specificity, and positive or negative predictive value – of the interesting and novel test, we will need to see how it performs in a real-world setting.

Despite the weaknesses of the data, it’s exciting to think that we may be entering an era where an improved understanding of pathophysiology will lead to the development of biomarkers which can help providers to establish a confident diagnosis of IBS provide insights into the pathogenesis of a patient’s IBS symptoms.

The Future

The future of IBS lies in combining symptom-based criteria with biomarkers that allow us to subgroup patients based on pathophysiology and then linking diagnostics to targeted treatment. In other words, applying diagnostics that allow us to subgroup so that we can shorten the time to effective treatment and improve clinical outcomes.

That really does represent a paradigm shift compared to our current symptom-based, empiric treatment model. This paradigm shift is not going to be easy and quick, it is going to be a slow process driven by vision, rigorous science, and likely, a bit of luck. There are great examples of this concept emerging in the literature. In the diet space, there are very interesting studies that identify patterns in the microbiome or metabolome, which identify patients who are more likely to respond to the low FODMAP diet. If that turns out to be true, we should be able to leverage that concept in a variety of different ways to identify patients who are more likely to respond to microbiome-based therapies including antibiotics, diet interventions, prebiotics, and probiotics.

Though this paradigm shift will not be easy and will undoubtedly upset the apple cart, it is something to which we as a community of scientists and care providers should and can aspire. We need to create a future in which we can identify an effective solution for some IBS patients to a more personalized medicine approach, which offers prompt identification of an effective solution for all (or at least the vast majority) IBS patients.

Disclosure: Chey reports consulting for Allergan, Biomerica, IM Health, Ironwood, Nestle Health Sciences, Outpost, Ritter Pharmaceuticals and Salix, research grant funding from Biomerica, Ironwood, Nestle Health Sciences, True Self Foods and Zespri, and is a patent holder of My GI Health and My Nutrition Health.

William Chey

Irritable bowel syndrome is a symptom-based condition defined by the presence of abdominal pain and altered bowel habits. The clinical phenotype can be quite diverse so while all patients have pain, some patients can have problems with diarrhea, others can have problems with constipation, and still others can have a mixture of both constipation- and diarrhea-related features.

IBS is a very important condition on several different levels. First is due to its prevalence. The population-based estimates in the United States reveal that around 14% or one in seven people have symptoms that would be compatible with a diagnosis of IBS. When you look at the prevalence of IBS symptoms worldwide, you come up with a very similar number although it varies from country to country.

The good and bad news is that not all those people who are symptomatic go to see a physician. Obviously if everybody experiencing IBS symptoms were to go to seek medical advice, it would overwhelm the health care system. Probably fewer than half the people that have GI symptoms compatible with a diagnosis of IBS actually seek care for their GI problems. That being said, IBS is the most common diagnosis rendered by gastroenterologists and one of the most common diagnoses managed by primary care physicians.

Thus, it is not surprising that IBS accounts for a tremendous economic burden in the United States on an annual basis. It’s estimated that we spend $20 billion to $30 billion a year in caring for patients with IBS. IBS exacts a tremendous impact on patients’ quality of life and work productivity. Patients with IBS have a measurable and clinically meaningful detriment in their quality of life. When you break down quality of life into physical and emotional domains, IBS crosses all those boundaries. IBS patients miss more work and are less productive at work even when they go to work, affecting both absenteeism as well as presenteeism.

With IBS, we see a burden to the health care system, a financial burden to society, and tremendous personal burden to patients affected by the condition.

Importance of Heterogeneity

IBS – being a symptom-based condition – isn’t one disease. It’s likely several different diseases that happen to present with the same symptoms. Yet, given our current understanding and a lack of validated biomarkers, we cannot parse IBS patients on the basis of pathophysiological abnormalities. Instead, we rely upon symptoms to establish a diagnosis and choose a treatment.

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As science advances, our level of sophistication will improve both in terms of our understanding of what causes IBS symptoms and our ability to identify subgroups of patients based upon pathophysiology rather than symptoms alone. When we are able to separate IBS patients into pathophysiological subgroups, we hope to improve the chances of selecting the right treatment for the right patient. The candidate pathophysiological factors that are felt to contribute to IBS fall into a wide range of different categories, but some durable themes include alterations in motility, visceral sensation, brain-gut interactions, the gut microbiome, intestinal and colonic permeability, and the gut immune activation.

We often discuss these factors as if they were independent variables, but they’re almost certainly not independent but rather, co-dependent variables. In other words, they interrelate and influence one another to varying degrees in different patients with IBS. For example, one could envision alterations in the microbiome leading to changes in permeability which could increase antigen exposure to the gut immune system, leading to activation of the gut immune system, which interacts with neural pathways involved in motility, visceral sensation, and brain-gut interactions. All these factors may or may not be interrelated, but the discussion of these various factors and how they might interplay really highlights a central theme: heterogeneity.

Heterogeneity is an important concept because it helps one to understand the various factors that could lead to the range of IBS symptoms and provides an explanation for why virtually all of the available therapies — whether you’re talking about diet, behavioral, or medical therapies — typically improve symptoms in only 40% to 60% of treated patients, with a therapeutic gain over placebo of 7% to 15%.

There’s no silver bullet as far as treatment because the treatments target specific pathways and there are a wide range of different pathways that might lead to the symptoms of IBS. As long as we define IBS based on symptoms alone, we are unlikely to do much better than this. The real step forward will be identification of biomarkers that allow us to parse patients based on pathophysiology. This will allow us to take a personalized medicine approach by choosing a targeted therapy for a specific patient.

Diagnosing IBS

My previous comments may lead readers to conclude that the time for symptom-based criteria has come and passed. Given the lack of validated biomarkers to rule in the diagnosis of IBS, that is definitely not the case. It’s important to recognize that in 2018 and for the immediate future, symptoms will remain our most reliable gateway into the diagnosis of IBS. At present, we use symptoms to identify patients in whom we suspect IBS and we consolidate the diagnosis by ordering selected diagnostic tests to exclude organic diseases that can mimic IBS.

PAGE BREAK

For example, we’ll do serological testing for celiac disease which can present with symptoms that are very similar to IBS. Celiac disease has been described as the great mimicker. It can present in a wide range of ways including GI and non-GI symptoms. From a GI standpoint, celiac can present with abdominal cramping, bloating, flatulence, and altered bowel habits such as diarrhea.

It important to address a couple of misconceptions regarding the clinical spectrum of celiac disease. Though less common, a small proportion of patients with newly diagnosed celiac disease are now endorsing complaints of constipation.

Many patients, particularly in the United States, being diagnosed with celiac disease are now obese. So, the dogma of celiac patients presenting with wasting and diarrhea no longer holds true.

We recently published a systematic review and meta-analysis looking at the prevalence of celiac disease in patients with IBS symptoms, and found an increased prevalence of celiac disease worldwide amongst individuals with IBS symptoms. But when you look at the small number of studies from the United States, this association is not as clear.

I would still strongly recommend that patients with IBS symptoms be screened for celiac disease because celiac disease is a specific genetically-mediated disease with a highly effective diet-based therapy. Missing the diagnosis can have serious consequences for affected patients. All that said, it is important to realize that you’re going to do about 100 to 150 tests to find one patient with celiac disease. It’s not going to be a diagnosis that you commonly make.

We will test for inflammatory markers like fecal calprotectin or fecal lactoferrin to exclude inflammatory bowel disease in our IBS-D patients. Having a negative fecal calprotectin or fecal lactoferrin virtually rule out inflammatory bowel disease in patients who present with IBS symptoms and no warning signs or alarm features. Inflammatory bowel disease is always a concern, but the good news is that the prevalence of IBD is no greater in individuals with IBS symptoms and no warning signs or alarm features than it is in the general population. It can happen but it’s very rare.

Depending on where you are in the United States, screening for giardia infection can be very helpful when evaluating patients with diarrhea-related symptoms. In Maine or Michigan where giardia infection is more common, screening for giardia should be a routine part of the workup of any patient with diarrhea-related symptoms.

Another concept gaining popularity is screening for bile acid diarrhea. Recent studies have shown that somewhere between 20% and 30% of patients with IBS-D will have evidence of bile acid malabsorption. There are now commercially available assays that can allow a provider to measure the quantity of bile acids in a 24-hour stool collection. There are also blood-based biomarkers like C4, which have recently become available commercially in the United States.

PAGE BREAK

Lastly, age appropriate colorectal cancer screening is always very important. In patients with typical IBS symptoms and no warning signs or alarm features there doesn’t appear to be an increased risk for colon cancer. Yet, with all of the recently reported data reporting an increased prevalence of colorectal cancer amongst younger individuals, we may need to take a step back and re-study what the prevalence of colorectal cancer is in patients presenting with IBS symptoms to see if this still holds true or whether we need to be a bit more vigilant about performing colonoscopy in patients with IBS symptoms. Currently, there is no justification for performing colonoscopy in all patients presenting with IBS symptoms but no warning signs such as GI bleeding, unintentional weight loss, progressively worsening symptoms, or a family history of organic diseases such as colon cancer, inflammatory bowel disease or celiac disease.

There’s overlap in symptoms and a number of studies which report an increased prevalence of microscopic colitis in individuals with diarrhea with or without abdominal pain. Thus, when performing colonoscopy in patients with unexplained diarrhea, obtaining random biopsies to exclude microscopic colitis should be considered.

The discussion in this section makes clear that nearly all of currently available biomarkers are used to exclude organic diseases that can mimic IBS.

There has been a recently released biomarker that claims to identify patients with IBS. That is anti-cytolethal distending toxin B (CdtB) and anti-vinculin antibodies. The Cedars-Sinai Group presented interesting preliminary data to suggest that individuals who experience an enteric infection respond by producing anti-CdtB and anti-vinculin antibodies. They showed patients with IBS have persistently elevated levels of these antibodies while in individuals who don’t have IBS, the levels of antibodies wane and disappear very quickly after the resolution of the infection. They have shown in some preliminary studies that anti-CdtB and anti-vinculin antibodies can distinguish IBS patients from patients with IBD, celiac disease and healthy controls. To date, most of the validation studies are cohort studies and not real-world studies that have evaluated individuals with IBS symptoms coming in for an evaluation and going through a workup including anti-CdtB and anti-vinculin antibodies. To determine the true performance characteristics – sensitivity, specificity, and positive or negative predictive value – of the interesting and novel test, we will need to see how it performs in a real-world setting.

Despite the weaknesses of the data, it’s exciting to think that we may be entering an era where an improved understanding of pathophysiology will lead to the development of biomarkers which can help providers to establish a confident diagnosis of IBS provide insights into the pathogenesis of a patient’s IBS symptoms.

PAGE BREAK

The Future

The future of IBS lies in combining symptom-based criteria with biomarkers that allow us to subgroup patients based on pathophysiology and then linking diagnostics to targeted treatment. In other words, applying diagnostics that allow us to subgroup so that we can shorten the time to effective treatment and improve clinical outcomes.

That really does represent a paradigm shift compared to our current symptom-based, empiric treatment model. This paradigm shift is not going to be easy and quick, it is going to be a slow process driven by vision, rigorous science, and likely, a bit of luck. There are great examples of this concept emerging in the literature. In the diet space, there are very interesting studies that identify patterns in the microbiome or metabolome, which identify patients who are more likely to respond to the low FODMAP diet. If that turns out to be true, we should be able to leverage that concept in a variety of different ways to identify patients who are more likely to respond to microbiome-based therapies including antibiotics, diet interventions, prebiotics, and probiotics.

Though this paradigm shift will not be easy and will undoubtedly upset the apple cart, it is something to which we as a community of scientists and care providers should and can aspire. We need to create a future in which we can identify an effective solution for some IBS patients to a more personalized medicine approach, which offers prompt identification of an effective solution for all (or at least the vast majority) IBS patients.

Disclosure: Chey reports consulting for Allergan, Biomerica, IM Health, Ironwood, Nestle Health Sciences, Outpost, Ritter Pharmaceuticals and Salix, research grant funding from Biomerica, Ironwood, Nestle Health Sciences, True Self Foods and Zespri, and is a patent holder of My GI Health and My Nutrition Health.

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