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–Dietary habits

–Current medications

–Family history

Determine aggravating or alleviating factors; changes with oral intake or improvement with selective food avoidance (e.g., dairy products)

Unintentional weight loss

Review of systems including skin changes (rashes, hives), arthritis, ocular problems, heat intolerance, polyuria/polydipsia, headache, fever, flushing, alcohol intake

Food allergies are rare, occurring in only 1–2% of adults. Consider in patients with hives (2).

Flatus and bloating are predominant features of carbohydrate malabsorption (2).

IBS or functional diarrhea by Rome IV criteria (5):

–IBS: recurrent abdominal pain at least 1 day/week for past 3 months (symptoms >6 months); ≥2 of:

Related to defecation

Associated with change in frequency of stool

Associated with change in form of stool

–Functional diarrhea: ≥25% loose or watery stools without prominent abdominal pain or bloating for >3 months (symptoms >6 months)

PHYSICALEXAM

General: Assess for volume depletion, nutritional status, recent weight loss (2).

Skin: flushing (carcinoid), erythema nodosum (IBD), pyoderma gangrenosum (IBD), ecchymoses (vitamin K deficiency), dermatitis herpetiformis (celiac disease) (1,2)

HEENT: iritis/uveitis (IBD)

Neck: goiter (hyperthyroid), lymphadenopathy (Whipple disease)

Cardiovascular: tachycardia (hyperthyroid)

Pulmonary: wheezing (carcinoid)

Abdomen: hyperactive bowel sounds (IBD), abdominal distension (IBD/IBS), diffuse tenderness (IBD/IBS)

Anorectal: anorectal fistulas (IBD), anal fissures (IBD)

Extremities: arthritis (IBD)

Neurologic: tremor (hyperthyroid)

DIFFERENTIALDIAGNOSIS

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See “Etiology and Pathophysiology,” “Commonly Associated Conditions,” and

“Risk Factors.”

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

Generally, testing is indicated in patients with alarm symptoms (bleeding, weight loss) or with persistent symptoms persist and no identifiable

Blood: CBC with differential, electrolytes (Mg, P, Ca), total protein, albumin, thyroid-stimulating hormone (TSH), free T4, erythrocyte sedimentation rate,

iron studies (2)

Stool: WBCs (fecal calprotectin or lactoferrin are potential surrogates), culture, ova and parasites, Giardia stool antigen, C. difficile toxin, stool electrolytes (fecal osmotic gap), fecal occult blood, qualitative fecal fat (Sudan stain) (2)

Abdominal plain film to evaluate for obstruction, toxic megacolon, bowel ischemia (1)

CT to evaluate for chronic pancreatitis or malignancy if abnormal pancreatic enzymes or evidence of malabsorption (1,2)

CT or MR enterography for small bowel imaging when Crohn disease is suspected (2)

Follow-Up Tests & Special Considerations

Celiac disease: antiendomysial antibody IgA, anti-tissue transglutaminase (TTG) IgA, antigliadin (AGA) IgA, serum IgA(10% of celiac patients have IgAdeficiency—may cause false-negative results) (3)[A]

Chronic pancreatic insufficiency: fecal elastase and chymotrypsin (2)[C]

Protein-losing enteropathy: fecal α1 antitrypsin (2)[C]

Carbohydrate malabsorption: fecal pH (<7.0) and hydrogen breath test

Small bowel overgrowth: hydrogen breath test

Prior history of hospitalization or antibiotics: C. difficile toxin

HIV ELISA, special stains for Isospora and Cryptosporidium (2)[C]

Consider testing for protozoa, atypical infections, Strongyloides, and tropical sprue in travelers and migrants of endemic areas (2)[C].

Allergy testing (2)[C] Neuroendocrine tumor

–Serum: chromogranin A, VIP, gastrin (1)

–Urine: 5-HIAA, histamine (1)

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Diagnostic Procedures/Other

Ileocolonoscopy with biopsies: IBD, microscopic colitis, CMV colitis, and colorectal neoplasia (6)[A]

Flexible sigmoidoscopy: especially if pregnant, with comorbidities, or if leftsided symptoms predominate (tenesmus and urgency) (6)[A] Esophagogastroduodenoscopy (EGD) with small bowel biopsies if malabsorption is suspected:

–Celiac, Giardia infection, Crohn disease, eosinophilic gastroenteropathy, Whipple disease, intestinal amyloid, pancreatic insufficiency (6)[A]

Capsule endoscopy if further evaluation of small bowel is needed (6)[C]

Upper GI series with small bowel follow-through

CT or magnetic resonance (MR) enterography (1,2)

Test Interpretation

Celiac disease: Marsh classification:

– Intraepithelial lymphocytosis, crypt hyperplasia, villous atrophy (3)

Crohn disease: cobblestoning, linear ulcerations, skip lesions, noncaseating granulomas

Ulcerative colitis: crypt abscesses, superficial inflammation (6)

Lymphocytic colitis: increased intraepithelial lymphocytes, increased inflammatory cells within the lamina propria, normal mucosal architecture (6) Melanosis coli suggests laxative abuse (2).

TREATMENT

GENERALMEASURES

Volume resuscitation if necessary

Electrolyte replacement if indicated

If stable, treatment is generally outpatient (2)[C].

MEDICATION

First Line

Based on underlying cause:

–Lactose intolerance: lactose-free diet

–Cholecystectomy or ileal resection: cholestyramine or colestipol 2 to 16 g/day PO divided BID

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–Diabetes: glucose control

–Hyperthyroidism: methimazole 5 to 20 mg/day PO, propylthiouracil (PTU) 100 to 150 mg/day PO divided; thyroid ablation

–C. difficile: vancomycin 125 mg PO q6h or metronidazole (Flagyl) 500 mg PO q8h or fidaxomicin 200 mg PO BID

–G. lamblia: metronidazole 250 mg PO q8h, nitazoxanide 500 mg PO q12h (2)[A]

–Whipple disease: ceftriaxone 2 g IV for 14 days then Bactrim DS 160/800 mg PO BID for 1 to 2 years

–Small intestinal bacterial overgrowth: rifaximin 550 mg PO BID, fluoroquinolones 250 to 750 mg PO BID, metronidazole 500 mg PO q6–8h, penicillins

–Pancreatic insufficiency: enzyme replacement (1)[A]

–HIV/AIDS: antiretroviral therapy

–Microscopic colitis: budesonide 9 mg/day PO, mesalamine 800 mg PO TID, Pepto-Bismol 786 mg PO TID

–IBD: 5-aminosalicylic acid (5-ASA), corticosteroids (short-term only), antibiotics (short-term only), immunomodulators (6-mercaptopurine [6- MP], azathioprine, methotrexate), anti-TNF therapy (infliximab, adalimumab, certolizumab) (4)[A]

–Neuroendocrine tumor: octreotide 100 to 600 g/day SC (2)[C]

–Celiac disease: gluten-free diet (wheat/barley/rye avoidance) (3)[A]

–IBS diarrhea predominant: rifaximin 550 mg PO BID, alosetron 0.5 to 1 mg PO BID, peppermint oil, eluxadoline 100 mg PO BID (2)[C]

Symptom relief (2)[C]:

–Loperamide 4 to 8 mg/day PO divided

–Diphenoxylate-atropine 1 to 2 tabs PO BID–QID

–Fiber supplementation

–Bismuth subsalicylate 525 to 1,050 mg every 0.5 to 1 hour; max dose 4,200 mg/day (2)[C]

SURGERY/OTHER PROCEDURES

Resection of neuroendocrine tumors

Intestinal resection for medically refractory IBD

Fecal transplant for recurrent C. difficile infection

COMPLEMENTARY& ALTERNATIVE MEDICINE

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Many homeopathic and naturopathic formulations are available; most have not been evaluated by the FDA.

ONGOING CARE

DIET

Abstain from gluten-containing foods, nonabsorbable carbohydrates, lactosecontaining products, and food allergens depending on etiology of diarrhea.

Low FODMAP(fermentable oligosaccharides, disaccharides, monosaccharides, and polyols) diet helps relieve symptoms in up to 75% of IBS patients (2).

PATIENT EDUCATION

Reassure patient of wide variation of “normal” bowel habits.

Restrict colon stimulants.

Specific education and dietary changes based on underlying etiology.

PROGNOSIS

Depends on etiology

COMPLICATIONS

Fluid and electrolyte abnormalities (1)

Malnutrition (1); anemia (1)

Malignancy (colon cancer in IBD, small bowel cancer in celiac disease and Crohn disease, lymphoma with IBD therapies) (4)

Infection with immunomodulator, biologic, and corticosteroid therapies for IBD (4)

REFERENCES

1.Schiller LR. Definitions, pathophysiology, and evaluation of chronic diarrhoea. Best Pract Res Clin Gastroenterol. 2012;26(5):551–562.

2.Schiller LR, Pardi DS, Sellin JH. Chronic diarrhea: diagnosis and management. Clin Gastroenterol Hepatol. 2017;15(2):182–193.e3.

3.Rubio-Tapia A, Hill ID, Kelly CP, et al. ACG clinical guidelines: diagnosis and management of celiac disease. Am J Gastroenterol. 2013;108(5):656– 677.

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4.Talley NJ, Abreu MT, Achkar JP, et al; for American College of

Gastroenterology IBD Task Force. An evidence-based systematic review on medical therapies for inflammatory bowel disease. Am J Gastroenterol. 2011;106(Suppl 1):S2–S26.

5.Lacy BE, Mearin F, Chang L, et al. Bowel disorders. Gastroenterology. 2016;150(6):1393–1407.e5.

6.Shen B, Khan K, Ikenberry SO, et al; and ASGE Standards of Practice Committee. The role of endoscopy in the management of patients with diarrhea. Gastrointest Endosc. 2010;71(6):887–892.

ADDITIONALREADING

Camilleri M, Sellin JH, Barrett KE. Pathophysiology, evaluation, and management of chronic watery diarrhea. Gastroenterology. 2017;152(3)515– 532.e2.

Ford AC, Lacy BE, Talley NJ. Irritable bowel syndrome. N Engl J Med. 2017;376(26)2566–2578.

SEE ALSO

Algorithm: Diarrhea, Chronic

CODES

ICD10

K52.9 Noninfective gastroenteritis and colitis, unspecified

CLINICALPEARLS

Acomprehensive medical history guides the appropriate workup and avoids unnecessary testing.

Consider IBS, IBD, malabsorption syndromes (e.g., lactose intolerance), celiac disease, over-the-counter medications, herbal products and chronic infections (immunocompromised) in differential diagnosis.

Treatment is based on the underlying cause.

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DIFFUSE INTERSTITIALLUNG DISEASE

J. Andrew Woods, PharmD, BCPS Jacqueline L. Olin,

MS, PharmD, BCPS, CDE, FASHP, FCCP Brian Hertz,

MD

BASICS

DESCRIPTION

Interstitial lung diseases (ILDs) represent a diverse group of chronic progressive lung diseases associated with alveolar inflammation and/or potentially irreversible pulmonary fibrosis.

>200 individual diseases may present with similar characteristics, making ILD difficult to classify.

Aclassification scheme proposed by the American Thoracic Society and European Respiratory Society includes these subtypes:

–Known causes (environmental, occupational, or drug-associated disease)

–Systemic disorders (e.g., sarcoidosis, Wegener granulomatosis, collagen vascular disease)

–Rare lung diseases (e.g., pulmonary histiocytosis, lymphangioleiomyomatosis)

–Idiopathic interstitial pneumonias (IIPs)

Based on clinical, radiologic, and histologic features, IIPs are further subclassified into the following diagnoses (1):

–Major IIPs, including idiopathic pulmonary fibrosis (IPF), nonspecific interstitial pneumonia (NSIP), respiratory bronchiolitis-associated ILD (cryptogenic organizing pneumonia [COP], etc.)

–Rare IIPs

–Unclassifiable IIPs

Classification of IIPs and relationships between the subtypes are difficult to classify due to mixed patterns of injury.

Pediatric Considerations

ILD in infants and children represents a heterogeneous group of respiratory disorders. Diseases result from a variety of processes involving genetic factors and inflammatory or fibrotic responses, and processes are distinct from those

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that cause ILD in adults (2). Some diseases result from developmental disorders and growth abnormalities in infancy (2). After common causes are excluded, referral of infants to a subspecialist is recommended (2).

EPIDEMIOLOGY

Incidence

Exact incidence and prevalence are difficult to determine because of differences in case definitions and procedures used in diagnosis.

Cited incidence of IPF in the United States: 16.3 to 17.4/100,000 and pediatric ILD 1.32/1 million

Prevalence

Cited prevalence of IPF in the United States: 42.7 to 63 cases/100,000 in the general population and pediatric ILD of 3.6/1 million

ETIOLOGYAND PATHOPHYSIOLOGY

Alveolar inflammation may progress into irreversible fibrosis.

Varying degrees of ventilatory dysfunction occur among the ILD subtypes.

ILD associated with collagen vascular disease and systemic connective disorders can manifest involvement of skin, joints, muscular, and ocular systems.

Some types of ILD are associated with specific exposures:

–Medications (amiodarone, antibiotics [especially nitrofurantoin], chemotherapy agents, gold, illicit drugs)

–Inorganic dusts (silicates, asbestos, talc, mica, coal dust, graphite)

–Organic dusts (moldy hay, inhalation of fungi, bacteria, animal proteins)

–Metals (tin, aluminum, cobalt, iron, barium)

–Gases, fumes, vapors, aerosols

Genetics

Some subtypes of ILD may be associated with specific predisposing genes and environmental exposures; however, the role of genetic factors is unknown.

RISK FACTORS

Environmental or occupational exposure to inorganic or organic dusts

66–75% of patients with ILD have a history of smoking.

Due to diversity of diseases, age is not a reliable predictor of pathology:

– Most patients with connective tissue disease-related pathology and inherited

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subtypes present between ages 20 and 40 years.

–Median age of patients with IPF is 66 years. Studies of clinical predictors of survival including age, ethnicity, and smoking status have been inconsistent.

COMMONLYASSOCIATED CONDITIONS

Many systemic disorders and primary diseases are associated with ILD. Apartial list includes the following:

Collagen vascular disease

Sarcoidosis

Amyloidosis

Goodpasture syndrome

Churg-Strauss syndrome Wegener granulomatosis

DIAGNOSIS

Accurate diagnosis is imperative, as treatment choices and prognosis can vary with pathogenesis.

Diagnosis of IPF requires exclusion of other known ILD causes, the presence of a UIPpattern on high-resolution computed tomography (HRCT), and/or surgical lung biopsy pattern (2).

HISTORY

Symptoms may include progressive exertional dyspnea and nonproductive cough.

Patients may also present with hemoptysis or fatigue.

Obtaining a history of illness duration (acute vs. chronic), potential environmental/occupational exposures, travel, medical conditions (including systemic diseases), and medication reconciliation is important in assessing the cause of the ILD.

Some cases of lung disease may occur weeks to years after discontinuation of an offending agent.

PHYSICALEXAM

Physical findings are usually nonspecific. Some common features includes the following:

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Crackles (typically present on auscultation of lung bases on posterior axillary line)

Rales

Inspiratory “squeaks”

Clubbing of the digits and cyanosis in advanced disease

DIFFERENTIALDIAGNOSIS

Acute pulmonary edema

Diffuse hemorrhage

Atypical pneumonia

Diffuse bronchoalveolar cell carcinoma or lymphatic spread of tumor

DIAGNOSTIC TESTS & INTERPRETATION

Initial Tests (lab, imaging)

O2 saturation

Peak expiratory flow rate

CBC with differential, comprehensive metabolic profile

CRPor sedimentation rate

Chest x-ray (CXR): most commonly reticular pattern, less commonly nodular or mixed patterns

Follow-Up Tests & Special Considerations

HRCT of the chest is the most useful tool for distinguishing among ILD subclasses, especially if normal CXRs:

If indicated, arterial blood gas (ABG), hypersensitivity pneumonitis panel, plasma ACE inhibitor concentration (sarcoidosis)

If a systemic disorder is suspected, consider antinuclear antibody (ANA), rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), and antineutrophil cytoplasmic antibodies (ANCA).

Diagnostic Procedures/Other

Pulmonary function testing (PFT; spirometry, lung volumes, carbon monoxide diffusing capacity)

–Commonly demonstrates a restrictive defect (decreased vital capacity and total lung capacity)

–Forced vital capacity (FVC) has been shown to decline 100 to 200 mL/year in the placebo arm of IPF patients in clinical trials.

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