Evaluating the Patient

with Chronic Unexplained

Diarrhea: A Systematic
Approach to Diagnosis
and Treatment
Charles J. Kahi, MD
Assistant Professor of Clinical
Medicine
Indiana University School of Medicine
 Chronic Diarrhea: A Clinical
Challenge
Common complaint to primary care
physicians and gastroenterologists
Complex differential diagnosis
Wide variety of available tests
Accurate diagnosis may be elusive
Most recommendations for evaluation and
therapy based on expert opinion (referral
bias)
Systematic ,common-sense approach yields
answer in most cases ( > 90%)
 Is it Chronic? Is it Diarrhea?

No consensus definition
Four-week cutoff: Most acute (infectious)
diarrheas would have resolved; 6-8 weeks better
distinction
Increased frequency of stool ( > 3/day) is
hallmark
Most patients consider increased liquidity as
essential feature
Stool weight > 200 g/day: Not absolute criterion!
Fecal incontinence: Needs to be excluded and
managed as incontinence, not diarrhea
 Differential Diagnosis (1)
Watery Diarrhea
Osmotic diarrhea
- Osmotic laxatives
- Carbohydrate malabsorption - Endocrine diarrhea Hyperthyroidism
Secretory diarrhea Addisons disease
- Congenital syndromes (chloridorrhea) Gastrinoma
- Bacterial toxins VIPoma
- Ileal bile acid malabsorption Somatostatinoma
- Inflammatory bowel disease Carcinoid syndrome
Ulcerative colitis Medullary carcinoma thyroid
Crohns disease Mastocytosis
Microscopic colitis Pheochromocytoma
Lymphocytic colitis - Other tumors
Collagenous colitis Colon carcinoma
- Diverticulitis Lymphoma
- Drugs and poisons Villous adenoma
- Laxative abuse (stimulant laxatives) - Idiopathic secretory diarrhea
- Disordered motility/regulation Epidemic (Brainerd)
Postvagotomy diarrhea Sporadic Postsympathectomy diarrhea
Diabetic diarrhea
Irritable bowel syndrome
 Differential Diagnosis (2)
Inflammatory diarrhea Fatty diarrhea
- Inflammatory bowel disease - Malabsorption syndromes
Ulcerative colitis Mucosal diseases (celiac
Crohns disease disease, Whipples)
Diverticulitis Short-bowel syndrome
Ulcerative jejunoileitis Small bowel bacterial overgrowth
- Infectious diseases Mesenteric ischemia
Pseudomembranous colitis - Maldigestion
Invasive bacterial infections Pancreatic exocrine insufficiency
(TB, yersiniosis) Inadequate luminal bile acid
Ulcerating viral infections (CMV, HSV) concentration
Invasive parasitic infections
(amebiasis, strongyloidiasis)
- Ischemic colitis
- Radiation colitis
- Neoplasia
Colon carcinoma
Lymphoma
 Medications and toxins associated
with diarrhea
Antibiotics
Antiretroviral agents
Antineoplastic agents
Anti-inflammatory agents (NSAIDs, gold, 5-ASA)
Antiarrhythmics (quinidine)
Antihypertensives ( blockers)
Oral hypoglycemics (metformin, acarbose)
Antacids (magnesium-containing)
Acid-reducing agents (H2 blockers, PPIs)
Colchicine
Prostaglandin analogs (misoprostol)
Theophylline
Vitamin and mineral supplements
Herbal products
Heavy metals
Practical approach

Secretory
Osmotic
 History
Define patients complaint of diarrhea (change in
consistency, presence of urgency or incontinence)
Stool characteristics (blood, mucus, oil, pus, food
particles) and volume
Duration, pattern of onset
Relation to prandial state
Nocturnal diarrhea
Weight loss
Travel history
Risk factors for HIV infection
Dietary profile and medication review
Family history of IBD
Other systemic symptoms
 Epidemiological and Implication
historical features
Onset
Congenital Chloridorrhea
Abrupt Infections, idiopathic secretory diarrhea
Gradual All other etiologies
Travel history Infectious diarrhea
(exposure to contaminated water) Aeromonas, Plesiomonas
Giardiasis, Cryptosporidiosis
Brainerd diarrhea
Weight loss Malabsorption, pancreatic exocrine
insufficiency, neoplasm
Dietary history Sugar-free foods with sorbitol, mannitol ,
lactase deficiency, fructose intolerance
Previous treatments Medications, radiation enteropathy,
surgery (bowel, gallbladder),
pseudomembranous colitis
Systemic illness Hyperthyroidism, IBD, diabetes
Abdominal pain Mesenteric vascular insufficiency, IBD, IBS
Excessive flatus/bloating Carbohydrate malabsorption, small bowel
bacterial overgrowth
IV drug use, sexual promiscuity HIV infection
Secondary gain/Fixation on body image Laxative abuse
Institutionalized patients Medication, C. difficile colitis, tube feeding,
ischemia, fecal impaction with overflow
 Physical examination
More helpful to determine severity rather than etiology
Hemodynamics, temperature, signs of toxicity
Helpful clues:

Physical finding Diagnosis

Skin changes Celiac sprue (dermatitis herpetiformis)
Mastocytosis (urticaria pigmentosa)
Amyloidosis (macroglossia, purpura)
Addisons disease (hyperpigmentation)
Glucagonoma (migratory necrolytic
erythema)
Carcinoid syndrome (flushing)
Degos disease (malignant atrophic
papulosis)
Peripheral neuropathy, orthostatic Amyloidosis
hypotension
Thyroid nodule Medullary carcinoma of the thyroid
Right-sided cardiac murmur, Carcinoid syndrome
hepatomegaly
Arthritis IBD, Whipples, infections
 Stool Analysis

Directed testing for confirmation based on clinical

suspicion, or broad net cast in difficult cases
Categorize diarrhea into watery, inflammatory,
fatty
Timed collection is best, spot tests on random
stool sample more practical
- Occult blood
- White blood cells
- pH
- Sudan stain for fat
- Cultures
- Laxative screen
- Electrolytes, osmolality
 Stool Analysis

Occult blood and white blood cells:

- Primarily define inflammatory diarrhea
- Wright stain: Sensitivity 70%, specificity 50% for leukocytes
- Fecal calprotectin and lactoferrin less operator dependent, but
test characteristics in chronic diarrhea not well defined

pH:
- Low pH (< 6) generally indicative of carbohydrate
malabsorption

Sudan stain:
- Fatty diarrhea (steatorrhea)
- Gold standard: Quantitative estimation of stool fat on collected
specimen
- Qualitative estimation feasible on random sample,
- Semiquantitative methods (number and size of fat globules)
correlate well with quantitative collection
 Stool Analysis

Stool cultures:
- Infection: Usually inflammatory diarrhea
- Bacterial infection rarely cause of chronic diarrhea in
immunocompetent host - Routine cultures are low yield and not
recommended (but done anyway!)
- Special techniques for Aeromonas and Plesiomonas
- Ova and Parasites
- Always consider giardiasis (stool ELISA for Giardia antigen)

Laxative screen:
- High index of suspicion
- Stool for bisacodyl and phenolphtalein, urine for anthraquinones
- Confirm on another sample before confronting patient
 Stool Analysis

Stool electrolytes:
Stool osmotic gap: 290 2([Na+] + [K+])
- Gap < 50 mOsm/Kg: Pure secretory diarrhea
- Gap > 125 mOsm/Kg: Pure osmotic diarrhea
- Gap 50-125 mOsm/kg: Mixed or mild carbohydrate
malabsorption

Measured stool osmolality:

- Not used to calculate gap
- Useful in cases of unexplained diarrhea
- Low measured stool osmolality (< 290 mOsm/Kg)
suggestive of contamination with water or dilute urine
Chronic Watery Secretory Diarrhea
Chronic Watery Secretory Diarrhea

Exclude giardiasis
All patients who undergo sigmoidoscopy or colonoscopy should have
biopsies obtained to exclude microscopic colitis
Colonoscopy preferred: Intubation of terminal ileum, screening for
neoplasia, right-sided disease (collagenous colitis)
Sigmoidoscopy reasonable first test otherwise
Upper endoscopy with small bowel biopsies to exclude celiac sprue
Small bowel radiographs, WCE: IBD, tumors, fistula, short-bowel
syndrome
CT scan to assess small and large bowel, and pancreas
Endocrine diarrhea: RARE, even among patients with chronic
diarrhea
Screening with peptide panels unhelpful due to high false-positive
rate
Bile acid malabsorption: Controversial
Trial of bile acid sequestrant reasonable diagnostic/therapeutic step
 Chronic Watery Osmotic Diarrhea

Magnesium ingestion:
- Stool concentration > 90 meq/L
- Intentional (laxative abuse) or accidental (antacids,
mineral supplements)

Carbohydrate malabsorption:
- Lactase deficiency
- Fructose intolerance (high fructose corn syrup)
- Sugar alcohols used as artificial sweeteners (sorbitol,
mannitol)
 Chronic Inflammatory Diarrhea

Important considerations:
- IBD
- Infection (C. difficile, CMV, TB, amebiasis)
- Ischemia
- Radiation enteritis
- Neoplasia

Conditions may produce watery secretory diarrhea

Diagnosis: Radiographic and endoscopic
techniques
 Chronic Fatty Diarrhea
Steatorrhea usually defined as loss of fat of > 7 g per 24 hours;
however 7-14 g range has poor specificity
Test may be compromised by orlistat and olestra
Three major causes:
1. Pancreatic exocrine insufficiency (chronic pancreatitis)
2. Mucosal diseases (celiac sprue, small bowel bacterial overgrowth)
3. Lack of bile (advanced primary biliary cirrhosis)
Clue: Fecal fat concentration
- Concentration > 9.5 g per 100 g suggestive of pancreatic or biliary
cause
Exclude mucosal disease first, then evaluate pancreas (CT, MRCP,
EUS)
Elderly, B12 deficiency, low albumin, previous partial gastrectomy,
small bowel diverticula: Suspect Small bowel bacterial overgrowth
Pancreatic function tests not commonly used
Empiric trial of pancreatic enzyme supplementation
 Empiric Therapy of Chronic
Diarrhea
Drug Class Agent Dose
Opiates Diphenoxylate 2.5-5 mg QID
Loperamide 2-4 mg QID
Codeine 15-60 mg QID
Morphine 2-20 mg QID
Tincture of opium 2-20 drops QID
Adrenergic agonist Clonidine 0.1-0.3 mg TID
Somatostatin analog Octreotide 50-250 g SQ TID
Bile acid-binding resin Cholestyramine 4 g once daily to QID
Fiber supplements Psyllium 10-20 g daily
Calcium polycarbophil 5-10 g daily
Others Probiotics
Herbals (berberine,
arrowroot)
 Irritable Bowel Syndrome

Rome Criteria:
Recurrent abdominal pain or discomfort at least 3 days per month
for the past 3 months, associated with 2 or more of:
- Improvement wih defecation
- Onset associated with a change in frequency of stool
- Onset associated with a change in form (appearance) of stool
Periods of constipation common
Long history, passage of mucus, exacerbation by stress
Diarrhea during waking hours, urgency
Coexistence with other functional disorders
Against IBS: Recent onset, nocturnal diarrhea, bleeding,
weight loss, voluminous or greasy stool, abnormal blood
tests
Rule out celiac sprue!
Functional diarrhea: Recurrent loose stools without pain.
 Additional reading

Fine KD and Schiller LR. AGA technical review: Evaluation and

management of chronic diarrhea. Gastroenterology 1999; 116:1464.

Mayer EA. Irritable Bowel Syndrome. NEJM 2008; 358:1692.

Singh VV, Toskes PP. Small bowel bacterial overgrowth: presentation,

diagnosis, and treatment. Curr Treat Options Gastroenterol 2004;
7:19.

Gibson PR et al. Fructose malabsorption and the bigger picture.

Aliment Pharmacol Ther 2007; 25:349.

Stroehlein JR. Microscopic colitis. Curr Opin Gastroenterol 1004;

20:27.