Chronic unexplained diarrhea: a logical and cost-effective approach to assessment

Dosanjh, Grace; Pardi, Darrell S.

Current Opinion in Gastroenterology: January 2016 - Volume 32 - Issue 1 - p 55–60
doi: 10.1097/MOG.0000000000000232
LARGE INTESTINE: Edited by Eamonn M.M. Quigley

Purpose of review: The workup of chronic unexplained diarrhea can be equally frustrating for care providers and patients. It carries a physical, financial, and social toll. In this review we provide a sensible approach to evaluating and managing chronic diarrhea.

Recent findings: Bile acid diarrhea is becoming increasingly recognized as a potential cause behind some cases of chronic diarrhea.

Summary: A detailed history and physical examination can provide clues that guide a logical approach to the evaluation. We suggest a cost-effective approach to the workup and management of chronic diarrhea based on individual patient factors related to clinical history and physical exam. We find that this approach leads to initiation of treatment in a time-efficient fashion and avoids unnecessary testing.

Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, USA

Correspondence to Grace Dosanjh, MD, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55902, USA. Tel: +1 507 266 4347; fax: +1 507 284 0538; e-mail: Dosanjh.PrabhjotGrace@Mayo.edu

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INTRODUCTION

Acute diarrhea, defined as lasting less than 4 weeks, accounts for the majority of diarrhea episodes. Most of these acute episodes are self-limited and last less than 24–48 h, especially in an immunocompetent host [1]. Diarrhea lasting longer than 4 weeks is deemed to be chronic, and can be quite difficult to diagnose and treat. This study serves to help guide the clinician caring for patients with chronic diarrhea and offers a logical approach to a potentially debilitating disease.

Approximately 5% of the adult population suffers from chronic diarrhea [2]. However, the definition of chronic diarrhea is variable, and therefore the true prevalence is not precisely known. In general, diarrhea means decreased consistency, increased frequency, or increased volume of stool. Patients most commonly use the term diarrhea to describe loose or unformed stools [3] but also can mean bowel movements with urgency or having more than one stool/day. ‘Pseudodiarrhea’, frequent defecation but with a normal stool consistency and volume, can also be misinterpreted by some as diarrhea [3], and some patients use the term diarrhea to mean fecal incontinence. Thus, it is imperative for physicians to inquire from patients what the term diarrhea means to that individual. Given this variability of meaning between individuals, it is recommended that the Bristol stool form scale be used when discussing diarrhea with patients, with types 6–7 being used to describe diarrhea.

Chronic diarrhea can be debilitating and have a negative impact on quality of life. Therefore, physicians should ask about the social burden of chronic diarrhea on their patients. Patients with urgency often report feeling fearful about having an ‘accident’ and avoid traveling, visiting unusual locations, and even working in an environment where urgently finding a bathroom maybe difficult. Others feel that their food choices have become particularly narrow because of their fear of making the diarrhea worse. High volume, bloody diarrhea or malabsorptive diarrhea can leave patients feeling exhausted and not able to complete daily routine. In addition, the cost of chronic diarrhea to society is great. In an older report, health related costs of chronic diarrhea were estimated to be $492 million/year directly with an additional $129 million/year in indirect costs [4].

With careful inquiry into the history and symptoms of the illness, assessment of epidemiologic factors, and a detailed physical exam, the clinician then decides which tests to employ (if any) and develops a treatment plan. A ‘shotgun’ approach, where a large battery of tests is undertaken indiscriminately, is discouraged as it leads to superfluous testing and unnecessary costs of time and money. Physicians are also left with a large number of test results to follow-up, which may lead to confusion and/or additional unnecessary testing.

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HISTORY

Historical clues, symptom clustering, and physical findings can help differentiate chronic functional causes of diarrhea from that which may have organic roots. Although reviewing these features, keeping broad etiological categories in mind, such as infectious, inflammatory, vascular, neoplastic, dietary/malabsorption, iatrogenic/drug induced, and endocrine causes of diarrhea is helpful.

An early distinction used by many clinicians is that of organic vs. functional diarrhea. Irritable bowel syndrome (IBS) with diarrhea is considered when a change in stool form or frequency occurs in association with recurrent abdominal pain which improves after defecation [3]. Predominant diarrhea (>75% of stools) without significant abdominal pain or discomfort is termed functional diarrhea [3].

Nocturnal diarrhea usually occurs with organic causes. Similarly, weight loss and bleeding are less likely to be present in IBS or functional diarrhea. Fever, bleeding, and abdominal pain suggest underlying inflammation. Additionally, tenesmus and small frequent bowel movements can be seen in proctitis. Systemic symptoms, including fatigue, night sweats, fevers, and weight loss suggest lymphoma, whereas pencil thin stools, anemia, and significant weight loss can be seen in colorectal malignancy. Overconsumption of caffeine can also result in diarrhea. If fasting leads to resolution of symptoms, an osmotic cause for diarrhea is suggested. Fructose or lactose malabsorption may occur when there is a noted relationship between dietary intake of particular foods with diarrhea; gas and bloating may also be prominent. Similarly, patients should be probed about consumption of poorly absorbed sugar alcohols, such as sorbitol, mannitol, and xylitol which are abundant in ‘diet’ or sugar free drinks, snacks, and confectioneries.

Weight loss, anxiety, palpitations, tremors, and diarrhea may be a sign of hyperthyroidism. Chronic fatty diarrhea can indicate fat maldigestion, such as in pancreatic insufficiency or with inadequate duodenal bile acid concentration, or fat malabsorption, such as in celiac disease or other small intestinal mucosal disorders. Small intestinal bacterial overgrowth (SIBO) can cause fat maldigestion and malabsorption. Patients with steatorrhea should be asked about current and past use of alcohol, since chronic alcoholic pancreatitis is a leading cause of pancreatic insufficiency. Whenever possible, past or ongoing alcohol use should be quantified as some patients may underestimate their consumption. In addition, place of employment, such as in a daycare, or risk factors for HIV would suggest a possible chronic infection with Giardia or other organisms. Similar to social history, family history and travel history are also potentially useful. Family history of inflammatory bowel disease, celiac disease, or thyroid abnormalities can help elucidate a diagnosis. Those with significant exposure to tropical climates should be ruled out for tropical sprue.

When a patient with a lifelong history of constipation develops diarrhea, impaction with overflow diarrhea or incomplete evacuation with frequent defecation must be considered. Opportunistic infection with parasites, including Giardia, Cryptosporidium, Cyclospora, and Isospora can cause chronic symptoms particularly in an immunocompromised host. SIBO may be the culprit in those with a relevant systemic illness, for example, scleroderma or long-standing diabetes where gastrointestinal motility is compromised, or in inflammatory bowel disease or prior gastrointestinal surgery where a stricture might occur. Similarly, patients with surgically altered anatomy are at an increased risk of SIBO, for example, a patient with Crohn's disease or a history of appendicitis who no longer has an ileocecal valve to keep colonic bacteria from migrating into the small bowel. Once should also consider bile acid malabsorption in patients with Crohn's disease with distal ileal involvement or resection. Physicians should inquire about a history of pelvic radiation as that can cause diarrhea because of bowel damage even years after therapy.

Careful review of a patient's medication list is imperative, including not only current prescription medications but also past medications and use of over the counter medications, vitamins, minerals, herbal, and nutritional supplements. Weight loss promoting teas or supplements may contain laxatives and thyroxine-like thyroid replacements. Although the list of medications that can cause diarrhea is exhaustive, frequent offenders include acid reducing medications (proton pump inhibitors, magnesium-containing antacids, and H2 blockers), antibiotics (antibiotic-associated diarrhea and Clostridium difficile infection), selective serotonin reuptake inhibitors or NSAIDS (NSAID enteropathy and microscopic colitis), antihypertensives (olmesartan resulting in celiac sprue like enteropathy, beta-adrenergic receptor blocking drugs), and chemotherapy agents.

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PHYSICAL EXAMINATION

Physical exam can occasionally present clues to the severity and underlying cause of chronic diarrhea. Hypotension, particularly orthostasis, and tachycardia can indicate hypovolemia. Loose or ill-fitting clothes and temporal or overall muscle wasting indicate that significant weight loss has occurred. Thyroid enlargement or nodules, exophthalmos, and tremor may be related to hyperthyroidism. Certain characteristic but uncommon rashes, such as necrolytic migratory erythema (glucagonoma), urticaria pigmentosa (mastocytosis), hyperpigmentation (Addison's disease), pyoderma gangrenosum or erythema nodosum (inflammatory bowel disease), and dermatitis herpetiformis (celiac disease, Figs 1 and 2Figs 1 and 2) may be present. Angular cheilitis suggests vitamin and mineral deficiency. Surgical scars suggest altered anatomy that can predispose to SIBO or bile acid malabsorption, and abdominal masses, organomegaly, distention, tenderness, and tympany may suggest malignancy or partial bowel obstruction.

During the rectal exam, the clinician should note if the patient is wearing a pad or diaper for fecal leakage, the presence of hemorrhoids, and the type of stool in the rectal vault (whether it is soft or hard and if any blood is noted). Furthermore, assessment of the anal sphincter tone at rest and with squeeze will characterize sphincter function. In those with a history of constipation, straining with bowel movements, a sense of incomplete evacuation and perhaps even a need for digital manipulation of the perianal region to facilitate a bowel movement, a detailed rectal examination can be helpful to include or exclude pelvic floor dysfunction, including palpation of the pelvic floor muscles for tenderness and spasticity, assessment of pelvic floor and sphincter relaxation, and assessment of perineal descent. However, physical exam findings are imperfect and a specific test of anorectal and pelvic floor function, such as an anorectal manometry with balloon expulsion, is recommended for confirmation.

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DIAGNOSTIC TESTING

The findings on history and physical exam discussed above should direct a common sense approach to diagnostic testing in patients with chronic diarrhea. When there is a clear relationship between the symptoms and intake of particular foods, such as sugar alcohols, lactose, or fructose, then a trial of food elimination and a symptom diary is recommended with no additional testing. Similarly, if a suspect medication or supplement can be stopped without the risk of adverse effects, this should be considered.

If celiac disease is suspected, prior to recommending a gluten-free diet, the diagnosis should be confirmed with celiac serologies and an esophagogastroduodenoscopy (EGD) with duodenal biopsies (Fig. 3). Empiric gluten restriction without histologic confirmation of celiac disease is not recommended. Self-directed gluten-free diets are seldom completely gluten free, and to avoid accidental ingestion through lesser known sources such as medications and spices, consultation with a knowledgeable dietitian is essential. Also, celiac disease can have serious clinical consequences, such as osteoporosis, infertility, anemia, and vitamin and mineral deficiencies, which must be screened for and treated if present.

Microscopic colitis has similar symptoms as IBS and the only way to distinguish these two is with colonic mucosal biopsies. However, IBS is much more common, and in patients with mild symptoms and a lack of alarm symptoms, such as fevers, bleeding, and significant weight loss, empiric treatment with antidiarrheals may be acceptable before pursuing colonoscopy. In others who have more severe symptoms, or if conservative therapy fails, further testing to rule out organic testing is indicated. In addition, an opportunity for age-appropriate colorectal cancer should not be missed even in the absence of alarm features. If a patient with chronic diarrhea undergoes colonoscopy, mucosal biopsies should be obtained to assess for microscopic colitis (Fig. 4) and other less common disorders such as eosinophilic colitis. If a patient has undergone appropriate colorectal screening with a recent colonoscopy, then a flexible sigmoidoscopy with biopsies from the left colon requires less preparation and is less costly while diagnosing up to 90% of microscopic colitis cases [5].

In most patients with chronic diarrhea, basic laboratory tests such as complete blood count and a comprehensive metabolic profile are reasonable first tests to exclude anemia, electrolyte disturbances, and a high leukocyte count. Additional blood tests can be considered depending on the differential diagnosis such as a thyroid stimulating hormone in a patient suspected to have hyperthyroidism.

If this initial workup is negative or when the clinical presentation fits a functional disorder such as IBS without alarm features, treatment can be initiated empirically before further testing. For example, in suspected functional diarrhea or diarrhea predominant IBS, an antidiarrheal such as loperamide can be helpful. In a patient suspected of having constipation with overflow diarrhea, a bowel regimen such as with regular use of polyethylene glycol can be considered, particularly after pelvic floor dysfunction has been excluded. In those who develop diarrhea after a cholecystectomy or ileal resection, an empiric trial with a bile acid binder is recommended. However, it is becoming increasingly recognized now that patients with other forms of chronic diarrhea may also have bile acid malabsorption. For example, bile acid diarrhea is thought to play a role in as many as one-third of patients with diarrhea predominant IBS [6▪]. If abdominal pain and diarrhea coexist, then neuromodulators such as tricyclic antidepressants can be used for their anticholinergic and thus constipating effects.

For patients with ongoing diarrhea without a diagnosis despite the above testing, particularly those with severe symptoms or diarrhea that does not respond to empiric antidiarrheal therapy, additional testing is necessary. At this point in the evaluation, it may be helpful to perform stool testing. In those with travel history to or recent immigration from endemic areas such as Asia and sub-Saharan Africa, a 3-day stool ova and parasite collection can help rule out pathology such as hookworm [7]. Evaluation with a 48–72 h stool collection while consuming a high-fat diet characterizes stool volume, is helpful in assessing for pseudodiarrhea, and for determining the presence of steatorrhea (pancreatic insufficiency, SIBO, and small bowel mucosal disease). Assessing stool electrolytes can broadly categorize the diarrhea into secretory (osmotic gap <50 mmol/kg) and osmotic (osmotic gap >75 mOsm/kg, e.g., osmotic laxatives, fructose, or lactose malabsorption) mechanisms. Assessing stool leukocytes and blood can determine the presence of inflammatory diarrhea, although clinical features, such as frank blood, significant abdominal pain, or fever are usually present and such testing is not always needed. Assessing stool pH can give an indication of carbohydrate malabsorption (pH < 5.5), as can specific breath testing (e.g., hydrogen breath testing for lactose intolerance), although a careful history is often sufficient in these cases.

Carcinoid tumor is an uncommon cause of chronic diarrhea and indiscriminant testing with urinary 5-hydroxyindoleacetic acid has a very low yield. However, this yield is higher in patients who have flushing, hepatomegaly and/or a cardiac murmur. Pancreatic function testing such as via secretin stimulation test, although specific, is not readily available. If steatorrhea is suspected and small bowel mucosal disease has been ruled out with a normal small bowel biopsy, then evaluation of the pancreas to exclude malignancy or chronic pancreatitis is indicated with dedicated pancreatic imaging such as a thin cut abdominal computed tomography scan with attention to the pancreas or endoscopic ultrasound. If steatorrhea is confirmed and serious pancreatic pathology is excluded, then a trial of pancreatic enzymes is reasonable, although this must be done properly to provide useful clinical information. Additionally, in those where Crohn's disease (inflammatory diarrhea, weight loss, and abdominal pain) is in the differential diagnosis, cross-sectional imaging to evaluate small bowel such as a computed tomography or MRI enterography is indicated.

Since currently, testing for bile acid malabsorption is not readily available in most centers in the United States, an empiric trial of bile acid binding resins such as cholestyramine is reasonable, particularly in patients whose diarrhea started after loss of ileal function via disease or surgery or after a cholecystectomy. In patients with a relevant history, such as scleroderma, strictures or surgically altered anatomy, hydrogen breath tests for SIBO may be helpful. However, the sensitivity and specificity of this test is highly variable [8–10][8–10][8–10], such that some practitioners use an empiric antibiotic trial based on strong suspicion and careful assessment of the risks and benefits involved. Alternatively, one can consider a duodenal aspirate for bacterial cultures to assess for SIBO, particularly if an upper gastrointestinal endoscopy will be performed to exclude other causes.

Visual clues on EGD that can be helpful, include furrowing and scalloping (celiac disease), ulcers (Crohn's disease or NSAID enteropathy), and white punctuate marks (lymphangiectasia). However, these findings are insensitive and nonspecific, and even if an EGD is endoscopically negative, duodenal biopsies should be obtained to rule out small bowel pathology such as celiac sprue, and less common entities, such as giardiasis, eosinophilic gastroenteritis, tropical sprue, and Whipple's disease. Particularly for celiac disease, multiple duodenal biopsies (>6) from the duodenum, including the duodenal bulb as well as the second and third parts of the duodenum, should be obtained [11]. Similarly, even a normal appearing colon should be biopsied in patients with chronic diarrhea to assess for microscopic colitis. A colonoscopy with biopsies can provide a histological diagnosis in approximately one-third of chronic diarrhea cases [12]. Obtaining biopsies from a normal appearing terminal ileum is not recommended since they are unlikely to be helpful [13,14][13,14].

Finally, hormone secreting tumors as a cause of chronic diarrhea are often considered but rarely found. There are a large number of potential tests that can be done to assess for these disorders, but the tests are expensive, and when performed indiscriminately will lead to unnecessary expense and an unacceptably high false positive rate.

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CONCLUSION

Chronic diarrhea can be quite distressing to patients, and achieving an early diagnosis and effective treatment plan is paramount. Clues are often provided in the symptomatology and physical examination which should not be overlooked. These features may promote a logical, efficient, and cost-effective approach to ordering tests and procedures, and ultimately to treatments that improve patient well-being and quality of life.

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Acknowledgements

We would like to thank Thomas C. Smryk, MD and Carilyn N. Wieland, MD for providing figures for this review.

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Financial support and sponsorship

None.

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Conflicts of interest

There are no conflicts of interest.

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REFERENCES AND RECOMMENDED READING

Papers of particular interest, published within the annual period of review, have been highlighted as:

▪ of special interest

▪▪ of outstanding interest

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REFERENCES

1. Thielman NM, Guerrant RL. Clinical practice. Acute infectious diarrhea. N Eng J Med 2004; 350:38–47.
2. Schiller LR. Chronic diarrhea. Gastroenterology 2004; 127:287–293.
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6▪. Camilleri M. Advances in understanding of bile acid diarrhea. Expert Rev Gastroenterol Hepatol 2014; 8:49–61.

Bile acids act as secretory irritants in the colon by multiple pathways, including by activating adenylate cyclase and increasing mucosal permeability. They can induce high-amplitude propagated contractions. Up to 1% of the western population may suffer from bile acid diarrhea. Although several tests for bile acid diarrhea exist, most are either laborious or invasive. Currently, stool testing for bile acids is available at only one tertiary referral center in the United States. Upcoming Serum C4 or FGF-19 testing is thought to be accurate and will likely emerge as a simpler way to diagnose bile acid malabsorption once validated.

7. Hotez PJ, Brooker S, Bethony JM, et al. Hookworm infection. N Engl J Med 2004; 351:799–807.
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11. Evans KE, Aziz I, Cross SS, et al. A prospective study of duodenal bulb biopsy in newly diagnosed and established adult celiac disease. Am J Gastroenterol 2011; 106:1837–1742.
12. Shah RJ, Fenoglio-Preiser C, Bleau BL, Giannella RA. Usefulness of colonoscopy with biopsy in the evaluation of patients with chronic diarrhea. Am J Gastroenterol 2001; 96:1091–1095.
13. McHugh JB, Appelman HD, McKenna BJ. The diagnostic value of endoscopic terminal ileum biopsies. Am J Gastroenterol 2007; 102:1084–1089.
14. Sayilir A, Kurt M, Kekilli M, et al. Diagnostic value of terminal ileum biopsy in chronic diarrhea with normal endoscopic appearance. J Dig Dis 2011; 12:188–192.
Keywords:

chronic diarrhea; evaluation; management

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