Differential Diagnosis of Diarrhea in Patients With Neuroendocrine Tumors : Pancreas

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Differential Diagnosis of Diarrhea in Patients With Neuroendocrine Tumors

Eads, Jennifer R. MD; Reidy-Lagunes, Diane MD; Soares, Heloisa P. MD, PhD; Chan, Jennifer A. MD, MPH§; Anthony, Lowell B. MD; Halfdanarson, Thorvardur R. MD; Naraev, Boris G. MD, PhD#; Wolin, Edward M. MD∗∗; Halperin, Daniel M. MD††; Li, Daneng MD‡‡; Pommier, Rodney F. MD§§; Zacks, Jerome S. MD∥∥; Morse, Michael A. MD¶¶; Metz, David C. MD##;  from the Carcinoid Syndrome Control Collaborative

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Pancreas 49(9):p 1123-1130, October 2020. | DOI: 10.1097/MPA.0000000000001658
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Patients with neuroendocrine tumors (NETs) and carcinoid syndrome experience diarrhea that can have a debilitating effect on quality of life. Diarrhea also may develop in response to other hormonal syndromes associated with NETs, surgical complications, medical comorbidities, medications, or food sensitivities. Limited guidance on the practical approach to the differential diagnosis of diarrhea in these patients can lead to delays in appropriate treatment. This clinical review and commentary underscore the complexity in identifying the etiology of diarrhea in patients with NETs. Based on our collective experience and expertise, we offer a practical algorithm to guide medical oncologists and other care providers to expedite effective management of diarrhea and related symptoms in patients with NETs.

Neuroendocrine tumors (NETs) are a heterogeneous group of rare neoplasms that frequently oversecrete peptides, hormones, and neuroamines.1,2 In the United States (US), the incidence and prevalence of NETs are rising, currently at 5 to 7/100,000 per year and 48/100,000, respectively, owing to improvements in imaging techniques for detection of early-stage disease, more therapeutic options, and efforts to educate healthcare professionals about NETs.3 Given the indolent nature of NETs and the insidious onset of nonspecific symptoms, an accurate diagnosis may be delayed for many years, even when metastatic disease is present. In one seminal series in US patients (N = 758), a mean of 59 months from initial symptoms to confirmed diagnosis was reported, with an associated mean of 5.7 evaluations over a mean of 12.7 visits.4 Because only 9% of these 758 patients were diagnosed at a NET specialty center (ie, physicians with expertise in the diagnosis and management of patients with NETs), it is apparent that an accurate diagnosis can take a long time and requires persistence and patience on the part of patients.

Similar to delays in confirming a NET diagnosis, delays in determining the etiology of diarrhea in this patient population are common. Data from 2 large surveys of patients with NETs (N = 2231) revealed misdiagnoses of irritable bowel syndrome (IBS; 24%–49%); gastritis or dyspepsia (13%–46%); and anxiety, depression, or other psychiatric conditions (4%–26%) before receiving a NET diagnosis.4,5 Thus, tools supporting more timely and accurate identification of a specific hormonal syndrome or other cause of chronic diarrhea in a patient with NETs may expedite effective treatment and potentially optimize treatment outcomes.

Neuroendocrine tumors of the bowel hypersecrete serotonin and other vasoactive peptides such as histamine, prostaglandins, kallikrein, neurokinin, and tachykinins, manifesting as carcinoid syndrome (CS) and typically present in the setting of liver metastases.6,7 However, CS may also occur in the absence of liver metastases, particularly in the presence of lung, ovarian, or bone metastases.7 In one study, 19% of patients with small bowel NETs had CS, and its presence was associated with a shorter overall survival.8 Excess serotonin binds to 5-hydroxytryptamine receptors in the gut to increase motility and fluid/electrolyte secretion into the gut lumen, resulting in carcinoid syndrome diarrhea (CSD). Characteristics of CSD include frequent watery stools (up to 20–30 per day) accompanied by abdominal discomfort and fecal urgency that may awaken the patient during sleep and persist with fasting.6 The symptomatic burden of CSD has a debilitating effect on patient quality of life (QOL), such as emotional, social, physical, and occupational well-being, with anxiety, depression, and fatigue worsening with an increasing number of daily bowel movements (BMs).9–11

Determining the underlying cause of diarrhea can be challenging. Patients with NETs may experience uncontrolled diarrhea because of surgical complications or treatment with somatostatin analogs (SSAs). These SSAs suppress the release of hormones and other biologically active substances from tumors but also inhibit pancreatic enzyme secretion and gastrointestinal (GI) motility.6,12 In addition, patients may experience diarrhea that is neither syndromic nor related to therapy; thus, other conditions must be considered (eg, lactose intolerance, celiac disease).13

A review of the literature published over the last decade reveals a paucity of guidance on the differential diagnosis of diarrhea in patients with NETs. The purpose of this review and commentary is to raise awareness regarding the complexity of the diagnostic approach and to facilitate management in affected patients. To this end, we collaborated to develop a practical algorithm to assist clinicians in the complex investigation of chronic diarrhea in patients with a confirmed NET. Here, we aim to discuss the root causes for chronic diarrhea in an individual patient with NETs, using a process that combines a comprehensive medical history, physical examination, stool testing, and other laboratory assessments such that treatment may be adequately tailored to the patient's needs.


Chronic diarrhea is a common disorder, but patients do not typically seek medical attention until other symptoms, such as weight loss, abdominal pain, rectal bleeding, and fecal urgency/incontinence, have an impact on QOL.13 Chronic diarrhea is defined as stool weight of >240 g/d, with BMs occurring at least 3 times per day for more than 4 weeks.14 Although stool weight is utilized in some settings, this measure is not practical. Alternatively, chronic diarrhea may be defined by persistent alteration from the norm, with stool consistency between types 5 and 7 on the Bristol stool chart and increased frequency over a period of greater than 4 weeks.15

Figure 1 illustrates our algorithm for the differential diagnosis of chronic diarrhea in patients with NETs. Pertinent clinical characteristics of each condition in the differential diagnosis are summarized in Table 1.

Approach to the differential diagnosis and treatment of chronic diarrhea in patients with NETs. Note: this algorithm addresses chronic diarrhea only and excludes infection as an etiology. *Osmolar gap = 290 − 2(stool Na + stool K), a gap between 50 and 100 is nondiagnostic. Post cholecystectomy and/or terminal ileal resection, stool testing may not be consistent with secretory pathophysiology. 7aC4 testing may be used in some centers but is not widely available. §Especially if patient describes diarrhea with blood, mucous, or pus. Reference range is age dependent. Somatostatin analog treatment is associated with both malabsorptive (pancreatic insufficiency) and maldigestive (stasis and overgrowth) components. #Fructose or sucrose intolerance may also occur but is less common. ††A thorough discussion of treatment options is beyond the scope of this review. CEA indicates carcinoembryonic antigen; CVID, common variable immunodeficiency; GI, gastroenterologist; HLA, human leukocyte antigen; IgA, immunoglobulin A; IVIg, intravenous immunoglobulin; N/A, not applicable; tTG, tissue transglutaminase; VIP, vasoactive intestinal peptide; WNL, within normal limits; 7aC4, 7 α-hydroxy-4-cholesten-3-one.
TABLE 1 - Clinical Features of Disorders Associated With Chronic Diarrhea
Mechanism of Diarrhea Condition Clinical Features
Secretory CS6,7 Dry flushing; frequent, intermittent, watery diarrhea; urgency; diarrhea often nocturnal and unrelated to fasting; abdominal discomfort; right-sided cardiac valve disease; bronchospasm; hypotension; hypoproteinemia; niacin deficiency
ZES16 Abdominal discomfort, diarrhea, gastroesophageal reflux disease (heartburn), recurrent duodenal ulcers, steatorrhea
Systemic mastocytosis17 Clinical presentation and course are variable and may include abdominal pain, diarrhea, steatorrhea, nausea, vomiting, flushing, hypotension, dyspepsia, fever, weight loss, musculoskeletal pain, urticaria, pruritus, migraine
VIPoma syndrome18 Severe diarrhea, unaffected by fasting; carbohydrate intolerance; flushing; hypochlorhydria; hypokalemia; hypercalcemia; hyperchloremic acidosis; cramps; asthenia; arrhythmias
Medullary thyroid cancer19 Diarrhea; flushing; weight loss due to calcitonin hypersecretion; dysphagia, hoarseness, and/or difficulty breathing due to tumor invasion
Bile acid–induced diarrhea20,21 Frequent, watery stools; fecal urgency and leakage; steatorrhea may be observed when ileal involvement/resection >100 cm
Maldigestive Somatostatinoma22,23 Clinical syndrome (less common): diabetes, cholelithiasis, weight loss, steatorrhea/diarrhea, hypochlorhydria, abdominal pain/discomfort, weight loss, obstructive jaundice, duodenal or biliary obstruction
PEI24,25 Flatulence, diarrhea, abdominal bloating, abdominal pain, steatorrhea, weight loss, muscle wasting
Inflammatory IBD26,27 Bloody, mucoid diarrhea; urgency; abdominal cramps; nocturnal occurrence; weight loss; nausea; vomiting; fevers; chills; fatigue
NET therapy Small bowel resection12 Malabsorption, weight loss; with resection >100 cm, steatorrhea
SBBO28 Abdominal cramping, bloating; diarrhea/steatorrhea; weight loss; abdominal discomfort; fat-soluble vitamin deficiencies
Maldigestive and/or malabsorptive Lactose intolerance29 Abdominal pain, bloating; diarrhea; steatorrhea; indigestion; flatulence; stomach cramping; borborygmi; nausea; vomiting; systemic symptoms may include headache, lethargy, memory impairment, vertigo, muscle and joint pain, cardiac arrhythmia
Celiac disease14,30 Typical: diarrhea that is bulky, frothy, foul-smelling, and may float; vomiting, anorexia, abdominal pain and distention, weight loss
Atypical: GI symptoms minimal or absent; anemia (iron, B12, folate); reduced bone density; arthritis; peripheral neuropathy; hepatitis; failure to thrive
IBS31 Diarrhea, constipation, bloating, gas, and abdominal pain or discomfort; not associated with weight loss
Hyperthyroidism32 Diarrhea may be either secretory (severe, watery diarrhea without abdominal cramping or pain, weight loss, hypovolemia) or malabsorptive (steatorrhea, hyperphagia)
Common variable immune deficiency33 Chronic, watery diarrhea, abdominal pain, bloating, meteorism
Neuro/enteropathies34 Constipation, diarrhea, fecal incontinence
Protein-losing enteropathy35 Highly variable, owing to multiple underlying etiologies; edema is prominent because of hypoalbuminemia; fat malabsorption may be observed, but diarrhea and other GI symptoms may not be evident
Laxative abuse36 Watery diarrhea, abdominal cramping, weight loss, dehydration, volume depletion (orthostatic hypotension) and metabolic abnormalities (hypokalemia, hypochloremic metabolic alkalosis), lethargy, muscle weakness
VIPoma indicates vasoactive intestinal peptide secreting tumor.

Step 1: History and Physical Examination

Performing a detailed patient history and physical examination is an important first step to assist in determining the etiology of chronic diarrhea (Fig. 1). This includes a comprehensive understanding of the key features of diarrhea, as well as other presenting signs and symptoms (Table 1). Documenting dietary, medical, and surgical histories may also contribute valuable clues. A dietary history may identify specific food intolerances or bowel habits associated with particular etiologies. Comorbid conditions (eg, diabetes, hyperthyroidism) and current medications or supplements may be additional culprits.

Step 2: Does the Patient Have Secretory or Nonsecretory Diarrhea?

Once the history and physical are complete, stool testing to detect the presence of blood, pus, bacteria, or inflammatory markers should be considered. In our experience, spot stool testing is most convenient for patients with NETs to provide further information to aid diagnosis and treatment. The initial step is to determine the presence or absence of an osmolar gap by measuring stool electrolytes and osmolality in a fresh, liquid, spot stool specimen to categorize the diarrhea broadly into secretory and nonsecretory types. Except for the somatostatinoma syndrome, which is associated with steatorrhea, all other NET diarrheal syndromes (ie, gastrinoma, vasoactive intestinal peptide secreting tumors, medullary thyroid carcinoma [MTC]) are classified as secretory diarrheas which occur as a consequence of fluid and electrolyte secretion into the bowel that overwhelms its reabsorptive capacity. Based on the assumption that a purely secretory stool should be iso-osmolar with serum and that the osmolality of any liquid is exerted equally by cations and anions, the osmolality of normal serum is calculated to be approximately 290 mOsm (ie, twice the sum of the normal average sodium [140 mEq/L] and potassium concentrations [5 mEq/L]), suggesting that the osmolality of liquid diarrhea should be approximately 290 mOsm/kg as well.

In contrast to secretory diarrheas, osmotic diarrheas tend to occur following meals and decrease at night. Under such conditions, other osmotically active molecules draw fluid into the GI tract, overwhelming the fluid component of stool derived by electrolyte secretion to produce an “osmolar gap,” which can be calculated as follows.

Osmolar gap (mOsm/kg) = 290–2(stool [Na+] + [K+])

A stool osmolar gap of <50 mOsm/kg suggests secretory diarrhea, whereas values >100 mOsm/kg indicate nonsecretory, or osmotic, diarrhea.14 An osmolar gap between 50 and 100 mOsm/kg is considered nondiagnostic and requires repeat testing. In addition, it is important to confirm that the measured stool osmolality is within a range compatible with the clinical picture. If the measured osmolality is very high, the stool may have become desiccated before being tested or may have been contaminated with urine. On the other hand, a very low measured stool osmolality implies contamination with water (seen in patients with factitious diarrhea). Patients with secretory diarrhea typically report large-volume, watery stools that persist despite fasting. In patients with NETs, the differential diagnosis of diarrhea comprises multiple potential etiologies of a secretory or other nature (Fig. 1).

Causes of Secretory Diarrhea

Carcinoid Syndrome

In CS, tumor-secreted serotonin increases GI motility and fluid/electrolyte secretion, producing frequent watery BMs.12,37 Elevated serotonin is detected by measuring plasma or urine 5-hydroxyindoleacetic acid (5-HIAA), the major metabolite of serotonin. Measurement of 5-HIAA, the end product of serotonin breakdown, is preferred over serotonin, as the interpretation of serotonin levels may be challenging owing to fluctuation. Standards for measuring serotonin are lacking, and improper specimen handling may result in incorrect values. Positive test results for 5-HIAA, in the presence of symptoms suggestive of CS, should prompt consideration for treatment with an SSA. In patients with liver-dominant disease, resection or liver-directed therapy should be considered early on.38 Additional medical therapy with telotristat ethyl, liver-directed therapy, or debulking (cytoreductive) therapy may also be considered in refractory cases, even in patients who do not have liver-dominant disease. All patients who manifest CS, or with metastatic NETs associated with serotonin overproduction, should be screened with an echocardiogram for the presence of carcinoid heart disease.

Zollinger-Ellison Syndrome

Gastrinomas are gastrin-secreting duodenal or pancreatic NETs that result in the Zollinger-Ellison syndrome (ZES), a rare condition characterized by abdominal pain; severe peptic ulceration; heartburn; and high-volume, watery diarrhea.16 Diarrhea results from gastrin hypersecretion leading to excessive gastric acid production, mucosal trauma, digestive enzyme inactivation due to high luminal acidity, and volume overload within the small intestine. It should be noted that physiologically appropriate increases in gastrin production may also occur in patients who underproduce gastric acid, such as in atrophic gastritis (with or without pernicious anemia) or in patients who take antisecretory agents, such as proton pump inhibitors (PPIs). Therefore, inappropriate hypergastrinemia (ie, serum gastrin >1000 pg/mL and gastric pH <3) is necessary to diagnose ZES.14 Identification of ZES should prompt the initiation of a staging workup and PPI therapy to manage the gastric acid hypersecretion. Although SSA therapy is considered second line for controlling acid hypersecretion, it may be used concurrently with PPI therapy in ZES patients with metastases, to control tumor growth.

Systemic Mastocytosis

Systemic mastocytosis is a rare neoplastic disorder of clonal accumulation of mast cells in the skin, bone marrow, GI tract, and other organ systems; GI and other disease-related symptoms are attributed to release of vasoactive substances and inflammatory mediators (eg, histamine)39,40 (Table 1). Diagnosis is based on findings of an elevated serum tryptase, elevated urine histamine, or endoscopic biopsy showing mast cell infiltrates. Treatment is directed at the underlying cause and, for the secretory diarrhea associated with mastocytosis, also includes PPI, H1/H2 antagonists, and mast cell stabilizers such as cromolyn to reduce gastric acid secretion and block histamine-stimulated intestinal secretions, respectively.

Vasoactive Intestinal Peptide Secreting Tumors

Vasoactive intestinal peptide secreting tumors are rare pancreatic NETs that present with severe, intermittent or continuous secretory diarrhea unaffected by fasting, and involving substantial fluid (>3 L and up to 30 L per day) and electrolyte (potassium and bicarbonate) secretion that exceeds the absorptive capacity of the distal small intestine18,37 (Table 1). Diagnosis may be confirmed by an elevated fasting vasoactive intestinal peptide level (>200 pg/mL) in the presence of secretory diarrhea with a high stool sodium concentration (characteristic of secretory diarrhea), and radiologic evidence of a pancreatic lesion.14,18 Treatment includes aggressive fluid and electrolyte replacement, SSA therapy to manage hormone production and associated diarrhea, surgical resection of the primary tumor, and liver-targeted therapies or surgical debulking for metastases.

Medullary Thyroid Carcinoma

A non-GI syndromic NET to consider in a patient with secretory diarrhea is MTC. Typically, MTC originates in parafollicular C cells of the thyroid that secrete calcitonin, histaminases, carcinoembryonic antigen, serotonin, and prostaglandins.14 These substances increase GI motility and alter water absorption and electrolyte secretion. Patients with large primary tumors or metastatic disease may exhibit weight loss or hoarseness and/or respiratory difficulties (Table 1) related to elevated calcitonin and/or tumor invasion. Serum calcitonin levels of >100 pg/mL indicate the presence of residual disease or metastases.19 Diarrhea may be managed with antimotility drugs (eg, loperamide), SSAs, surgery, and/or local ablation therapy.41

Bile Acid–Induced Diarrhea

Bile acid–induced diarrhea is a secretory condition unassociated with NETs but commonly seen in patients with NETs because prior treatment may disrupt normal enterohepatic bile circulation. This includes impaired bile reabsorption related to ileal resection or disease (eg, Crohn disease), loss of bile storage during interprandial periods following cholecystectomy, altered bile metabolism due to small intestinal bacterial overgrowth, and enteric stasis.20 Celiac disease, chronic pancreatitis, or excessive hepatic bile acid synthesis are also potential contributors; in turn, an idiopathic form of the disorder may contribute to the clinical picture in IBS with diarrhea (Table 1). Bile acids promote diarrhea by enhancing mucosal permeability, stimulating secretion of water and electrolytes, and increasing colonic transit partly by inducing propulsive high-amplitude colonic contractions. Several diagnostic tests for bile acid malabsorption exist but are limited by the inconvenience of a 48-hour stool collection (fecal bile acids, 14C-glycocholate), inadequate sensitivity or specificity (serum fibroblast growth factor 19, FGF19), the need for further clinical validation (serum 7 α-hydroxy-4-cholesten-3-one, or 7aC4), or the lack of availability in the US (75SeHCAT). Therefore, an empiric trial of bile acid sequestrants, taken between meals and apart from other medications, may be indicated. In cases where there is uncertainty regarding the etiology of the diarrhea, a 48-hour stool collection can be considered.

Step 3: Does the Patient Show Evidence of Maldigestion?

If the osmolar gap is >100 mOsm/kg, diarrhea is classified as nonsecretory or osmotic and may be further categorized as maldigestive, malabsorptive, or inflammatory.13,14 Low elastase levels and/or elevated levels of fat in the spot stool sample indicate maldigestive diarrhea, which occurs when poorly absorbed solutes trap fluid in the intestinal lumen, accounting for osmotic activity of stool water. Unlike secretory diarrheas, maldigestive and other osmotic forms of diarrhea are substantially reduced in response to fasting.13 The differential diagnosis of maldigestion in a patient with NETs includes one hormone hypersecretory syndrome and one complication of therapy, as described in the following sections.


Somatostatinoma is a rare NET of the pancreas or duodenum that generally presents with nonspecific symptoms such as abdominal discomfort, weight loss, jaundice, and diarrhea22 (Table 1). Rarely, patients with functional tumors present with the “somatostatinoma syndrome,” which is easily predicted based upon the known pharmacological effects of SSAs (diabetes, gallstones, and steatorrhea) and due to the inhibitory effect of somatostatin on secretion of insulin and cholecystokinin, and pancreatic exocrine function, respectively. Somatostatinomas are usually identified incidentally during an endoscopic or imaging procedure and may be associated with hereditary syndromes such as neurofibromatosis type 1.

Pancreatic Exocrine Insufficiency

A second cause of maldigestive diarrhea is pancreatic exocrine insufficiency (PEI), a complication of chronic pancreatitis, pancreatectomy, and also commonly seen during SSA therapy.24,25 Signs and symptoms include flatulence, bloating, abdominal pain, and steatorrhea (Table 1). Fecal elastase-1 of <200 μg/g, measured by a spot stool evaluation, is indicative of PEI; in these patients, pancreatic enzyme replacement therapy should be initiated. Other conditions that present similarly to PEI but are nonresponsive to pancreatic enzyme replacement therapy include small-bowel bacterial overgrowth, celiac disease, inflammatory bowel disease (IBD), giardiasis, and Whipple disease.

Long-acting SSAs are considered the first-line treatment for secretory diarrhea associated with CS and act by inhibiting gastric motility and suppressing tumor secretion of serotonin and tachykinin.42 During SSA treatment, diarrhea may worsen, developing malabsorptive characteristics due to inhibition of pancreatic enzyme secretion and absorption of fluid and nutrients; symptoms are dose dependent but may subside with continued treatment and the addition of pancreatic enzyme supplements.43 In a prospective observational study of patients with well-differentiated NETs, PEI was noted in 12 of 50 SSA-treated patients, based on fecal elastase-1 and/or clinical presentation.25 Patients should be counseled to report worsening symptoms to facilitate appropriate treatment.

Step 4: Is There Evidence of Inflammation?

Inflammatory bowel disease, a chronic condition, is associated with potentially serious complications, such as strictures, fistulas, and an increased risk for colorectal cancer.44 Inflammatory mediators provoke colonic secretion and damage to the intestinal lumen, producing diarrhea often accompanied by blood and pus.14 This clinical feature distinguishes IBD from IBS, a common GI disorder that may impact QOL, but does not produce permanent bowel damage. Fecal calprotectin, a marker of migration of neutrophils to inflamed bowel, is helpful in detecting IBD.44 If elevated, endoscopic examination and/or cross-sectional imaging is generally advised.

Step 5: What Is the Evidence for Nonsecretory Maldigestive and/or Malabsorptive Diarrhea?

After ruling out secretory syndromes, maldigestive, and inflammatory causes for chronic diarrhea, we revisit presenting symptoms, diet, surgical and medical history, and the patient's current medication list to parse out clues that might point to other nonsecretory conditions.

Small Bowel Resection

Short bowel syndrome may develop after surgical resection because the capacity to preserve nutrient, fluid, and/or electrolyte homeostasis is lost.12,45 As a result, steatorrhea and weight loss may occur. It is important to document the extent and location of bowel resected: if a cholecystectomy was performed or if the terminal ileum in particular was resected, bile acid diarrhea and deficiencies in vitamin B12 and fat-soluble vitamins (A, D, E, and K) may ensue.14,45 Nutritional support is advised for all patients with extensive prior operations or those receiving long-standing SSA therapy.

Small Bowel Bacterial Overgrowth

Patients with short bowel syndrome may develop altered bowel transit and dilation of the GI tract, setting up conditions favorable to the development of small bowel bacterial overgrowth (SBBO),14 which is a commonly underdiagnosed condition associated with steatorrhea and fat-soluble vitamin deficiencies (Table 1).28,45 An abundance of bacteria residing in the small bowel produces high levels of toxic deconjugated bile acids, resulting in fat malabsorption, a relative increase in the osmotic load delivered to the small bowel, and damage to the mucosa, which manifest as steatorrhea.14,45 Patients at risk for SBBO may have underlying conditions associated with intestinal dysmotility, for example, diabetes, chronic pancreatitis, IBD, strictures, or a resected ileocecal valve.28,45 Patients who test positive for SBBO with a hydrogen breath test should receive antibiotics and may consider taking probiotics.

Several conditions exhibit features of a mixed clinical picture of maldigestive and/or malabsorptive diarrhea, as discussed in the following sections.

Lactose Intolerance

Maldigestion of lactose is a normal physiologic effect of growth and development because intestinal mucosal lactase levels decline from early childhood and throughout life.29 Although the mechanisms for this phenomenon are not entirely clear, it is believed to result from a reduction in a protein substrate key to lactate generation. Secondarily, lactase deficiency may develop in conjunction with a GI illness due to damage to the intestinal brush border or increased transit time, as in celiac disease or Crohn disease. As a result, undigested lactose osmotically draws fluid into the small intestine and is transmitted to the colon where osmotic pressure increases, and bacterial fermentation produces gases. Because symptoms of lactose intolerance may resemble those associated with IBS or celiac disease (Table 1), a lactose tolerance or hydrogen breath test is performed to make the distinction. Avoidance, but not complete elimination, of dairy products is an effective approach in symptom management. Other disaccharidase deficiencies (ie, sucrase or fructase) can lead to osmotic diarrhea after ingestion of excessive sucrose or fructose, and some sweeteners, such as sucralose, can also cause diarrhea on a similar basis.

Celiac Disease

Celiac disease is an autoimmune disorder with genetic and environmental components, triggered by gluten found in wheat, rye, and barley. Innate and adaptive immunities contribute to progressive inflammation and flattening of mucosa of the small intestine, leading to nutrient malabsorption.14,46 The typical clinical presentation is common in young children (Table 1); a delay in diagnosis may result in severe malnutrition and behavioral deterioration.46 Diarrhea is characterized as bulky, foul smelling, and occasionally frothy, and may float in the toilet water. In older children and adults, diarrhea tends to be watery and accompanied by abdominal discomfort, bloating, and weight loss, the latter sign differentiating celiac disease from IBS.14 An atypical presentation also may be observed in older adults, in which GI symptoms are less prominent and extraintestinal manifestations are more common (Table 1).14,30 A diagnosis may be confirmed with positive serology for tissue transglutaminase–immunoglobulin A antibodies, endoscopy with small bowel biopsy, and genetic testing. HLA-DQ2 or HLA-DQ8 is found in ≥95% of affected patients, but these genes also occur in about one quarter of individuals not afflicted with celiac, limiting their utility to confirm the disease but permitting exclusion if negative.46

Irritable Bowel Syndrome

Irritable bowel syndrome, a noninflammatory functional disorder, is often a diagnosis of exclusion.31 It is the most common cause of diarrhea encountered in clinical practice, with a reported US prevalence of 9% to 16%, depending on the criteria used.47 Females are more commonly affected. It is possible that a middle-aged woman with symptoms of CS (flushing, diarrhea, night sweats) might be misdiagnosed as perimenopausal with IBS. Symptoms of IBS (Table 1) can be debilitating, may be exacerbated with stress, do not occur during sleep, and typically resolve upon defecation.31 Although many factors may be involved, dysmotility likely contributes to the observed altered bowel habit patterns. Management is symptomatic, involving dietary changes, cognitive behavioral therapy, and traditional or alternative pharmacotherapies. Importantly, clues of nocturnal diarrhea, bleeding, and pain unrelieved by a BM should alert oncologists to the possibility of CS and the need to measure stool electrolytes and osmolality.


Patients with hyperthyroidism may develop diarrhea or steatorrhea, with bile acid malabsorption as a contributing factor; secretory diarrhea is associated with increased GI motility and accelerated intestinal transit results in malabsorption and steatorrhea.32,48 Reduced secretion of pancreatic enzymes may also contribute to fat maldigestion in patients with hyperthyroidism.32 A thyroid panel is recommended.

Common Variable Immunodeficiency

Common variable immunodeficiency is the second most common primary immune deficiency syndrome after immunoglobulin A deficiency.49 This heterogeneous condition may develop secondary to GI neoplasms and is characterized by chronic watery diarrhea. Other GI findings have been reported with common variable immunodeficiency, including villous abnormalities, sprue-like atrophy, chronic giardia, gastritis, gastric cancer, lymphocytic colitis, and IBD. Low levels of serum immunoglobulins are evidence of disease.50 Treatment includes administration of intravenous immunoglobulin.


Autonomic neuropathy may contribute to the development of diarrhea by disrupting fluid and electrolyte transport or by altering motility. In patients with diabetes, loss of α-adrenergic receptors that mediate fluid and electrolyte absorption in the small bowel may lead to increased net fluid and electrolyte secretion and manifest with diarrhea.14

Protein-Losing Enteropathy

Protein-losing enteropathy is caused by leaky mucosa, increased permeability, or obstruction of lymphatic drainage that results in diarrhea.14 Excessive loss of serum proteins or inflammatory, protein-rich exudates into the GI tract can result in systemic hypoproteinemia. Protein-losing enteropathy may also be associated with CS. Diagnosis is based on plasma and spot stool testing for α-1 antitrypsin.35

Laxative Abuse

Laxative abuse may occur in patients with a history of eating disorders, chronic constipation, or a factitious disorder.51 Patients may present with diarrhea alternating with constipation and other GI symptoms (Table 1). The diagnosis may be confounded by intermittent abuse. Although stool studies are suggested, the osmolar gap may vary depending on the laxative used. Patient education is key to reversal of this disorder.


This algorithm fills an important gap in the management of patients with NETs and uncontrolled diarrhea. As presented, this algorithm can only be effective in the context of a comprehensive history and physical examination, patient interview, medication review, and, importantly, a stool examination. In regard to the latter, it is imperative that the spot stool specimen be fresh, examined rapidly (before desiccation), and include a calculated and measured osmolality because a desiccated stool sample will yield a high osmolality, confounding subsequent evaluation. Similarly, patients who abuse laxatives or present with factitious diarrhea may contaminate stool samples with urine or water, yielding a falsely high or low osmolality, respectively.

After determination of the osmolar gap, a stepwise approach is recommended, but it does not obviate consideration of empiric treatment in the context of clear direction from initial data-gathering steps.


Writing and editorial support were provided by D. Michele Nikoloff, PhD, ScioScientific, LLC.


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neuroendocrine tumor; secretory diarrhea; carcinoid syndrome; osmolar gap; diagnostic algorithm

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