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Chronic diarrhea, or diarrhea lasting longer than 4 weeks,
is a common condition affecting an estimated
5% of the adult population1; however due to variable definitions of
chronic diarrhea, obtaining an accurate estimate of the prevalence has been
challenging. The true prevalence is unknown, and may be higher than estimated
when considering multiple etiologies associated with chronic diarrhea. The
underlying cause of diarrhea can be challenging to diagnose, making symptoms
difficult to treat. Chronic diarrhea in adult patients frequently results from functional
gastrointestinal (GI) disorders, such as irritable bowel syndrome (IBS) and
small intestinal bacterial overgrowth (SIBO), but ongoing diarrhea may also
result from “organic” diseases, including inflammatory bowel disease (IBD) and celiac
disease.2,3 Often, patients with chronic diarrhea experience ongoing
symptoms for many years before they seek professional treatment for these symptoms.4 

The Burden of Chronic

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Chronic diarrhea can have a negative impact on
health-related quality of life (HRQOL).5 A study using an HRQOL
scale known as the Short Form (SF)-36 showed that patients scored lower in several
categories, including bodily pain, emotional well-being, fatigue, and social
functioning in comparison with the general US population.6


Chronic diarrhea is also associated both with higher health
care costs and with indirect costs due to loss of productivity. In the United
States, management of chronic diarrhea results in roughly 3.5 million health
care visits annually. The total direct and indirect costs associated with chronic
diarrhea were estimated to exceed $20 billion in the year 2000.7 Patients
with chronic diarrhea have more frequent doctor visits, require more diagnostic
tests, use more medications, miss work more often, have lower productivity
while at work, are more frequently hospitalized, and result in overall higher
direct medical costs than unaffected individuals.8 Therefore,
effective management of patients with chronic diarrhea, regardless of the
etiology, can reduce medical costs, enhance productivity, and improve the QOL
for those experiencing continual symptoms of diarrhea.


While the root cause of symptoms in some patients experiencing
chronic diarrhea may be unexplained, several potential underlying causes of chronic
diarrhea are described in Table 1.


Table 1: Potential underlying causes of chronic diarrhea.

Pathogen Infection
Postinfectious IBS (PI-IBS) may result from an infection
of the gut and persist for months to years following the initial infection. It
is more commonly related to a bacterial infection, but can develop after a
viral or parasitic infection as well. This condition is often seen following
international travel, where exposure to Escherichia
coli results in travelers’ diarrhea, which may persist in some
individuals as PI-IBS.9

Small Intestinal Bacterial
Small intestinal bacterial overgrowth (SIBO) is common in
patients with IBS and develops when an overgrowth of bacteria from the large
bowel infiltrates the proximal small intestine. Fermentation of dietary
carbohydrates by these bacteria leads to excess gas and symptoms consistent
with IBS.3

Celiac Disease
In patients with celiac disease, exposure to gluten
activates both innate and adaptive immune responses, leading to increased gut
permeability and damage to the lining of the small intestine.10 Patients
with celiac disease experience multiple GI symptoms, including diarrhea.11
Patients with non-celiac gluten sensitivity may also experience severe
ongoing diarrhea.12

Gut Inflammation
Inflammatory bowel diseases, such as Crohn’s disease and
ulcerative colitis, are chronic, relapsing GI disorders in which genetic and
environmental factors result in impaired barrier function in the intestinal
mucosa, leading to immune cell activation and gut inflammation.13 Like
patients with IBS-D, patients with IBD experience abdominal pain and
diarrhea, resulting in an impaired QOL.14

Bile Acid Diarrhea
Bile acid diarrhea (BAD) is typically seen in
patients with ileal dysfunction, which can cause impaired reabsorption, as
observed in patients with Crohn’s disease. BAD is also common in patients
with IBS-D, with estimates ranging from 17% to 35% of patients with IBS-D who
are affected by bile acid malabsorption. Other GI disorders that affect
absorption, including SIBO, celiac disease, surgery to the ileocecal valve and
chronic pancreatitis, are also associated with BAD. Finally, some patients
may experience BAD due to elevated bile acid (BA) production in the liver.15,16

Serotonin, primarily produced in the GI tract, is released
in response to chemical and mechanical stimulation and mediates gut motility.
The levels of serotonin remaining in circulation following food
ingestion  are elevated in some
patients with IBS-D in comparison with healthy individuals, leading to
accelerated colonic transit, which results in diarrhea.17


This newsletter will focus in detail on the mechanisms and
potential treatments for two of these underlying pathologies, bile acid
diarrhea and serotonin dysfunction.


Bile Acid Diarrhea

BAs are detergent molecules synthesized in the liver that
facilitate digestion and lipid absorption in the small intestine by solubilizing
fatty acids and monoglycerides. Roughly 95% of BAs are reabsorbed in the terminal
ileum for transport back to the liver. BA synthesis is negatively regulated by fibroblast
growth factor 19 (FGF-19) signaling that is induced by farnesoid X receptor
(FXR), which is activated in the presence of BA. Serum 7?-hydroxy-4-cholesten-3-one
(C4) is a surrogate marker of the rate of hepatic BA synthesis, and levels of
C4 inversely correlate with levels of FGF-19.  BAD predominantly results from the
interruption of the circulation of BAs between the gut and liver. Patients at
risk for BAD include those with resection of the ileocecal valve or resection
of the small bowel. Patients with IBS-D who fail standard therapy should be
evaluated for possible BAD.15

A study measuring levels of serum C4 and serum FGF-19 in
patients with IBS-D, IBS with constipation (IBS-C), and healthy volunteers
showed that patients with IBS-D had higher hepatic BA synthesis and higher
levels of BA excretion detected in their stool, which was collected over 48
hours, compared with healthy volunteers and patients with IBS-C. Serum C4
levels correlated positively with levels of BA detected in the stool and with stool
weight, and can therefore be used reliably to identify patients with bile acid malabsorption


In a small study of 12 patients with IBS-D, treatment with
the BA sequestrant colesevelam resulted in increased excretion of BAs at day 10
compared with baseline. Colesevelam also resulted in fewer bowel movements per
week and decreased scores on the Bristol Stool Form (BSF) Scale, indicating
firmer stools (Figure 1).  These results
support the hypothesis that by sequestering BA in the intestinal lumen, colesevelam
increases fecal excretion of BA, thus reducing diarrhea in patients with IBS-D
who have increased fecal BA excretion.19

 Serotonin Pathway Dysregulation20

The activity of the bowel is regulated by the enteric
nervous system (ENS), which, like the central nervous system (CNS), is composed
of a phenotypically diverse collection of neurons. To add to the complexity, enteroendocrine
cells within the GI lumen act as sensory transducers that sense conditions
within the bowel (eg, pressure, pH, nutrient concentrations) and relay
“messages” to nerve fibers.


Of these sensory-transducing enteroendocrine cells,
enterochromaffin (EC) cells have been well characterized as the primary
storehouse of serotonin in the gut. EC cells constitutively release high levels
of serotonin from their basolateral surface into the lamina propria, and even
more serotonin is released following food intake in order to ensure the signal
reaches neural receptors. To avoid desensitization of serotonin receptors and
toxicity associated with serotonin, reuptake is required. Enterocytes in the GI
mucosa express serotonin reuptake transporters (SERTs), which are responsible
for the reuptake of serotonin (Figure 2).


Neurons of the ENS that relay the messages of these luminal
sensors are known as intrinsic primary afferent neurons (IPANs). Once a signal
is received by IPANs, they transmit the information to processing neurons of
the ganglionated enteric plexus. In response to activation by serotonin, IPANs
secrete calcitonin gene-related peptide (CGRP) and acetylcholine (ACh) to mediate
peristaltic, secretory, and stretch-driven reflexes, as well as giant migrating
contractions in the mucosa.


In patients with IBS, the function of SERT in mucosal
enterocytes is deficient, resulting in impaired control of gut motility as
excessive levels of serotonin lead to potentiation and desensitization of
serotonin receptors. Therefore, selective serotonin receptor antagonists have
the potential to treat patients with IBS-D.

Management of
Patients With Chronic Diarrhea

Recommendations for
the Management of Patients With Chronic Diarrhea21

Due to the multiple, heterogeneous causes of chronic diarrhea,
a multidisciplinary approach to therapy, including pharmacologic intervention
along with behavioral and dietary modifications tailored to individual patients,
is ideal for managing clinical symptoms. In order to determine the optimal
treatment regimen for your patients with chronic diarrhea, a patient-centric
approach with effective patient-clinician communication is recommended.


The Cost of Delayed Diagnosis

Traditionally, determination of the cause of chronic diarrhea
involves sequential diagnostic testing, which is based on a carefully-taken
patient history and a physical exam. A workup may start with basic laboratory
tests (ie, complete blood count and metabolic profiling), followed by
additional blood work (eg, celiac serologies, hormone assays). If initial labs
are negative, treatment with an antidiarrheal may be initiated. For patients
who do not respond to the selected initial antidiarrheal treatment, stool
testing for bacteria or parasites, electrolytes, blood, leukocytes, fecal
calprotectin and pH may reveal the root cause. A parasite test may be
particularly applicable for a patient who has traveled to Asia or sub-Saharan
Africa and may have been infected by a hookworm. Electrolyte abnormalities
would suggest secretory or osmotic mechanisms. The presence of blood or
leukocytes in the stool may indicate inflammatory diarrhea, and a low stool pH
may result from carbohydrate malabsorption. In patients with abdominal pain and
diarrhea, BAM may be investigated as a common potential cause. In those with a
family history of IBD or celiac disease, duodenal biopsies may be necessary to
confirm diagnosis.1 Finally, assessment of serotonin levels may be
used to determine whether serotonin dysfunction is involved.20 


In the absence of a standard algorithm for the diagnosis of
chronic diarrhea, clinicians are tasked with independently developing
diagnostic frameworks to identify the underlying cause of chronic diarrhea in
each of their patients. Although the sequence and timing of specific tests may
vary among individual clinicians and be modified from patient to patient, based
on the patient’s medical history and initial physical exam, Figure 3 shows a
flowchart of a potential path to diagnosis for patients presenting with chronic
diarrheal symptoms. Some clinicians may perform stool studies initially as a
fast and cost-effective way to rule out potentially more serious pathologies,
whereas others may start with a complete blood count (CBC), either followed by
a complete metabolic profile (CMP), or in parallel with a CMP in cases in which
a patient presents with a lot of diarrhea. 

This series of empirical decision making and
diagnosis by exclusion is time consuming and may lead to initiation of an
inappropriate treatment regimen. Testing is further complicated by current
standards in stool sample storage. Studies show that levels of fecal
calprotectin, for example, significantly decline when samples are stored for 7
days at room temperature. More importantly, research has shown that fecal
calprotectin levels may not be accurate if samples are stored at room
temperature for more than 3 days.22 The integrity of DNA and RNA
within samples is also affected by storage conditions; analysis of the
taxonomic composition has shown that accuracy of identification of the
bacterial community in frozen stool samples is compromised after thawing for even
1 hour at room temperature.23 Simultaneous testing in a laboratory dedicated
exclusively to determining the potential underlying cause of chronic diarrhea may
lead to faster and more accurate therapeutic decisions, thus potentially
limiting the time during which patients suffer from ongoing symptoms, and protecting
against adverse consequences resulting from chronic diarrhea

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