Clinical Case: Diarrhea

Plan

Section (1): Importance, normal function, and defining the subject

Section (2): The subject and its various implication (pathophysiology, classification, differential, treatment… etc.)

Section (3): Case discussion on the subject, and attempting to answer the relevant questions

Importance, normal function, and defining the subject

1

Importance

• Very common• 1 billion suffer from an episode of acute

diarrhea worldwide each year• 250,000 require hospitalization• 5000 die (mostly elderly)• Economic burden may exceed $20 billion– Infectious and acute – most common– Mostly developing countries, contrary to

constipation, mostly developed counteries.

Importance - 2

• Can be a mere nuisance symptopms at one extreme

• On another, they can be life-threating.– Mild symptoms can signal serious underlying illness

• Colorectal cancer• Thyroid disease

• Imperative for clinicians to appreciate the pathyophysiology, etiologic classification, and diagnostic strategies, as well as principles of management

Normal Physiology

• Small intestines digest and assimilate food– Colon + Intestine do also:

• secretion + absorption of water & electrolyte• Storage & transport of intraluminal contents aborally• Salvage of nutrients after bacterial metabolism that are not

absorbed in small intestines.

– Alterations in fluid and electrolyte handling contribute significantly to diarrhea.

– Alterations in motor + sensory functions of colon result in highly prevalent syndromes such as IBS, chronic diarrhea, and chronic constipation.

Functional level at different sites

• Stomach and small bowel:– Synchronized MMC in fasting– Accommodation, trituration, mixing, transit

• Stomach ¬ 3h• Small Bowel 3 h

– Illeal Reservoir empties boluses• Colon: irregular mixing, fermentation, absorption,

transit– Ascending + transverse: resvervoirs– Descending: Conduit– Sigmoid/rectum: volitional reservoir

Neural control

• Intrinsic innervation (Enteric nervous system):– Myenteric, submucosal, and mucosal neuronal layers

• They modulate the action of neurostransmiters (eg., Ach, VIP, Opoids, NE, SE, ATP, and NO)

• Myenteric – smooth muscle• Submucosal plexus – absorption + secretion• Mucosal - blood flow

• Extrinsic: ANS: Vagus Small intestine+ proximal colon; pelvic parasympathetic (S2-4) distal colon; major substance: Ach, and Substance P.– Sympathetic = excite sphincter + inhibit nonsphinteric

muscles

Regulated by interneurons

Its normal function

• Visceral afferents convey sensation from the gut to CNS:– Course along sympathetic fibres– Go to cell bodies in DRG (in spinal cord)– Go to dorsal horn of spinal cord– Conveyed to brain along the lateral spinothalamic tract

+ nocireceptive dorsal column pathway– Projected after thalamus to insula + cerebral cortex to

be perceived.• Others are just afferent synapses in prevertebral ganglia and

reflexly modulate intestinal motility

Intestinal Fluid Absorbtion and Secretion

• Daily average 9 L of fluid in GI tract– 1 L reaches colon as residual

• Stool excretion of fluid is about 0.2 L/d• Colon has large capacitance and functional reserve• Can recover four times its usual volume of 0.8 L/d

– Very helpful in intestinal absorptive or secretory disorders

– Sodium absorption in colon, ‘’electrogenic’’ @ apical membrane.• Neural plus non neural mediators affect the colon, such as

cholinergic, adrenergic and serotonergic mediators• Can be affected by angiotensin + aldostrone secretion

– Due to Renal tubules have similar embryologic origin of distal colon

Motility of Small Intestine

• cyclical event migrating motor complex MMC – serves as a housekeeper to clear nondigestiable

residues– Occurs while fasting– On average 4 mins of propagation and contraction– Occurs every 60-90 minutes.

• If you eat: small intestine produce irregular mixing contraction of low amplitude– Except at distal illium where powerful intermittent

contraction occur to empty illeum by bolus transfers

Ileocolonic Storage and Salvage• Distal ileum acts as a reservoir and emptying place for bolus movements

intermittently– Allows time to salvage of fluid + nutritents + electorlytes

• Segmentation by haustra in colon– Compartmentalises food + facilitate mixing– Rentention of residue + forms stools

• Resident bacteria in colon– Digest unabsorbed carbohydrates

• Provides nutrients to mucosa

• Diarrhea happens due to alteration of – its reservoir function @ proximal site– Or Propulsive function @ left colon

• Contstipation happen as a result of disturbance of– Rectal or segmoidal resoirvoir– Dysfunction of pelvic floor– Coordination of defecation

Defining it: Diarrhea• Loosely defined as:

– Passage of abnormally liquid or unformed stools– @ increased frequency– For weight > 200 g/d– Acute < 2 weeks, persistant 2-4 weeks– Chronic > 4 weeks in duration

• < 200 g/d stool weight1) Pseudodiarrhea – frequent urgency of passage of small volumes of stool

( IBS or Proctits)2) Fecal incontinence, involuntary discharge of rectal contents – caused, often,

by neuromascular or antorectal problems– They should be always investigated in patients complaining of ‘’diarrhea’’

• Overflow Diarrhea due to fecal impaction happens in nursury homes mostly

Acute Diarrhea• 90% infectious agents

– Accompanied by:• Fever Vomitting Abdominal pain

• Remaining 10%:– Medication Toxins Ischemia Others

• Infectious agents: Fecal-oral transmission– Infected food or contaminated water– Disturbed flora by Antibiotics (C.dif.)– Bypassing immune + non-immune defense mechanism– Five high-risk group in US: Travelers, Food consumers, Immunodeficient,

daycare attendee and their family members, and institutionalised patients.– Clincial features: Profuse watery diarrhea secondary to intestinal secretion.– Treatment: Fluid and electrolyte replacement, ‘’ maybe’’ Antibiotics

The subject and its various implication (pathophysiology, classification, differential, treatment… etc.)

2

Chronic diarrhea

• Lasting > 4 weeks warrants evaluation• To exclude underlying pathology• Mostly, noninfectious

• Classified into 7 causes:1) Secretory2) Osmotic3) Steatorrheal4) Inflammatory5) Dysmotile6) Factitial causes7) Iatrogenic

Secretory causes• Exogenous Stimulant Laxatives• Chronic Ethanol Ingestions• Other drugs and toxins• Endogenous laxatives (dihydroxy bile acids)• Idiopathic secretory diarrhea• Certain bacterial infection• Bowel resection• Hormone producing tumors (VIPOMA, carcinoid, medullary cancer

of thyroid, mastocytosis, gastrinoma, colorectal villous adenoma)• Addison’s disease• Congenital Electolyte absorption defect

Secretory causes

• Due to derangements in fluid and electrolyte transport across the enterocolonic mucosa– Characterised clinically by:• Watery, large volume fecal utputs• Typically painless and persist with fasting• Thereis no malabsorbed solute

– Stool osmolality is accounted for by normal endogenous electrolite with no fecal osmotic gap.

Medication

• Side effects from ingestion of drugs and toxins– Most common secretory cause• Over the counter medications• Habitual use of stiumulant laxitives[e.g., senna, cascara]• Chronic Ethanol consumption Enterocyte injury

– Impaired sodium and water absorption

• Inadvertant ingestion of certain toxins (e.g., arsenic)• Bacterial infections occassionally persist and cause it

Bowel Resection, Mucosal Disease, or Entercolic Fistula

• Inadquate surface for reabsorption of secreted fluids + electrolyte– Unlike other subsets:

• They tend to be worse while eating• With disease states e.g., Chron’s ileitis or resection of <100 cm of terminal

illium– Dihydroxy bile acids may escape absorption and stimulate colonic secretion

(Cholorrheic diarrhea)» Called ‘’Idiopathic secretory diarrhea’’

• Idiopathic bile acid malabsorption 40% of unexplained chronic diarrhea• Fibroblast growth factor (FGF) 19 produced by eneterocyte results in

synthesis of excessive bile acids too much to be reabsorbed by ileal function.• It causes bile acids diarrhea

• Partial bowel obstruction, ostomy striction, or fecal impaction– Can lead to paradoxically increased fecal output due to fluid hyper secretion

Hormones• Uncommon, yet classic example for secretory.

– Metastatic Carcinoid tumors• Produce watery diarrhea alone or as part of carcinoid sx

– Episodic flushing, Wheezing, Dysnea, Rt sided vavular heart dx

– Intestinal secretagogues (SE, Hista., PGC)• Pellagra-like skin lesion, rarely happen due to serotonin with niacin depletion

– Gastrinoma (neuroendocrine tumor)• Refractory peptic ulcer and diarrhea due to fat mal-abs.

– Watery diarrhea hypokalemia achlorhydria syndrome (Pancreatic cholera)• Due to non-B cell pancreatic adenoma or VIPOMA

– Secretion of VIP and a host of other peptides.

• Often massive stool volume >3 L/d; daily, up to 20 L can be.• Life threatening complications: dehydration, neuromascular dysfunction from electrolyte imbalance. Flushing, and

hyperglycemia may accompany VIPOMA

– Medullary carcinoma of thyroid• Watery diarrhea due to calcitonin

– Systemic mastocytosis• Associated with skin lesion, urticaria pigementosa• Cause diarrhea that is secretory by histamine due to intestinal infiltration of mast cells

– Large colorectal villous adenoma• Rarely associated with secretory diarrhea• May cause hypokalemia, and can be inhibited by NSAID, and mediated by PGC

Congenital Defects in Ion Absorption

• Rarely, can cause diarrhea from birth.– Include: • Defective CL/HCO3 exchange (congenital chloridorrhea)

– With alkalosis (results from a mutated DRA [down regulated adenoma] gene)

• Defective Na/H exchange (congenital sodium diarrhea)– Results from a mutation in NHE3 (sodium hydrogen exchanger

gene» Results in acidosis

• Adrenocortical insufficiency (addison’s disease)– Can be accompanied with skin hyperpigmentation

Osmotic Cause

• Osmotic Diarrhea occurs when ingested, poorly absorbably, osmotically active solutes draw enough fluid into lumen to exceed the re-absorptive capacity of the colon. Fecal water output increases in propotion to such solute load. Ceases with fasting or with stopping causative agents

• Examples:– Osmotic laxatives (Mg, PO4, SO4)– Lactase and other disacchride defeciency– Nonabsorbable carbohydrates (sorbitol, lactulose,

polyethylene glycol)

Osmotic laxatives

• Ingestion of magnesium contaning antacid– Typified by as tool of osmotic gap >50 mosmol/L

Serum Osmolarity (typically, 290 mosmol/kg) – [2 x(fecal sodium + potassium concentration)]

Measurement of fecal somolarity is no longer recommended

cause even when measured immediately after evacuation

maybe erroneous because carbohydrates are metabolized by clonic bacteria causing increase in osmolarity

Carbohydrate malabsorption

• Acquired or congenital defects– @ Brush border disaccharides– Other enzymes• Leading to osmotic diarrhea with low pH

– Common cause: • Lactase deficiency

– Learn to avoid milk (3/4 of non-whites worldwide affected)

• Sugars: sorbitol, lactulose, or fructose Freq. mal-abs• Ingestion of medications, gum, or candies sweetened

Steatorrheal causes

• Fat malabsorption may lead to:– Greasy, foul smelling, difficult to flush diarrhea– Associated with: Weight loss + nutritional loss

• Increased fecal output due to osmotic effect of fatty acids. Quantitatively, steatorrhea is:– Stool fat exceeding the normal 7 g/d– Daily fecal fat averages 15-25 g with small intestine, and > 35 with

pancreatic exocrine dysfunction. Its types:1. Intraluminal maldigestion (pancreatic exocrine insufficiency, bacterial

overgrowth, bariatric surgery, liver disease)2. Mucosal malabsorption (celiac sprue, Whipple's disease, infections,

abetalipoproteinemia, ischemia)3. Postmucosal obstruction (1° or 2° lymphatic obstruction)

Intraluminal Maldigestion

• Pancreatic exocrine insufficiency >90% of pancreatic function is lost.– Chronic pancreatitis

• Sequel to ethanol abuse

– Cystic Fibrosis– Pancreatic duct obstruction– Rarely, somatostatinoma

• Bacterial overgrowth deconjucating bile aciss and alter micelle formation

• Cirhossis or billiary obstruction leading to mild steatorrhea due to deficient intraluminal bile acid concentration

Mucosal Malabsorption• Commonly, Coeliac Disease:

– Gluten sensitive enteropathy affects all ages• Characteristic: villous atropy + crypt hyperplasia in proximal small bower

– Can present with fatty diarrhea associated with nutritional deficiency of varying severity– Frequently without steatorrhea, can mimic IBS

• Tropical Sprue – similar histology + clinical– Occur in residents or travellers to tropical climates

• Whipple’s disease– Bacillus Tropheryma whipplei and histiocytic infiltration of small bowel mucosa

• Less common, and mostly young or middle aged men.• Arthalgia, fever, lympadenopathy, and extreme fatigue• Can affect CNS and endocardium

• Mycobacterium Avium intracellular infection in AIDS• Abetalipoproteinemia

– Rare defect of chylomicron formation and fat malabsorption in children– Association: acanthocytic erthrocyte, ataxia, and retinitis pigementosa

• Giardia: potozoal infection• Medications (e.g., colchicine, cholestryamine, neomycin• Amyloidosis• Chronic Ischemia

Postmucosal Lymphatic Obstruction

• Rare: congenital intestinal lymphangiectasia• Acquired: lymphatic obstruction– Secondary to trauma, tumor, cardiac disease, or

infection– Leads to unique constellation of fat malabsorption

with enteric losses of protein– Lymphocytopenia

Inflammatory causes

• Generally accompanied by pain, fever, bleeding or other inflammatory manifestation– Mechanism depends on the lesion site which can be:

• Fat malabsorption• Distrupted fluid/electrolyte absorption• Hypersecretion or hyper motility from cytokines release

– Unifying features on stool analysis• Presence of leukocytes or leukocyte derived proteins such as

‘’calprotectin’’• With severe inflammation: exudative protein loss can lead to

anasarca

Examples of Inflammatory causes

1. Idiopathic inflammatory bowel disease (Crohn's, chronic ulcerative colitis)

2. Lymphocytic and collagenous colitis3. Immune-related mucosal disease (1° or 2°

immunodeficiencies, food allergy, eosinophilic gastroenteritis, graft-vs-host disease)

4. Infections (invasive bacteria, viruses, and parasites, Brainerd diarrhea)

5. Radiation injury Gastrointestinal malignancies

Idiopathic Inflamatory bowel disease

• Include: Chron’s disaese + Ulcerative colitis– Range from mild to fulminant and life threatening– Associated: uveitis, polyarthralgias, cholestatic liver disease

(primary sclerosing cholangitis), and skin esions (erythema nodosum, pyoderma gangrenosum)

• Microscopic colitis: lymphocytic + collagenous collitis– Chronic cause of watery diarrhea, esp. middle aged women and

NSAID, statins, PPI, SSRI people– Biopsy of normal appearing colon is required for diagnosis

• Can exist with IBS or celiac sprue• Responds wel to anti-infallmatory drugs e.g., bismuth, to opoid

agonist loperamide, or to budesonide

Others• Primary or secondary Immunodeficiency

– Prolonged infectious diarrhea• Selective IgA deficency• Variable hypogammaglobulinemia

– Often prevalent and result of Giardiasis, bacterial overgrowth, or sprue

• Eosinophillic Gastroenteritis– Eosinophil infilteration of mucosa, muscularis, or serosa causing diarrhea, pain,

vomitting, or ascitis• Charcot leyden crystals due to extruded eosinophil contents on microscopic inspection of stool• Peripheral eosinophilia present 50-70% of patients

– Hypersensitivity to certain food can be present, but true allergy is rare• Chronic inflammatory diarrhea:

– Radiation entercolitis– Chrnic graft versus host disease– Becht syndrome– Cronkhite canada syndrome

Dysmotlity• Rapid transit may accompany many diarrheas as a secondary or

contributing phenmnon.– Primary dysmotility is unusual etiology of true diarrhea

• Stool features suggestion secretory diarrhea but mild steatorrhea of up to 14 g of fat per day

• Hyperthyroidism, carcinoid syndrome and certain drugs (PGC, prokinetic agents)– Can produce hypermotility with resultant diarrhea

– Diabetic diarrhea, accompanied by peropheral and generalised autonomic neuropathies.

– IBS is characterised by disturbed intestinal and colonic motor and sensory responses to various stimuli.• Smptomps of stool frequency typically cease at nigh• Alternate with periods of constipation• Accompanied by abdominal pain relieved by defecation• Rarely, result in weight loss

Factitial causes

• Accounts 15% of unexplained diarrhea referred to tertirary care centres, can be:– Munchausen syndrome– Eating disorders– Self-adminstration of laxitatives or combination of

other medication (e.g., diuretics)– Hypotension and hypokalemia are common co-

presenting features.– History of psychiatric illness– Disproportionately from careers in health care

Approach to The Patient: Chronic Diarrhea

• Extensive workup, can be costly and invasive• Direct it to History and physical examination first• Hx + Px + Blood tests should attempt to characterize the

mechanism of diarrhea– Through identifying diagnostically helpfful association– Assess patients fluid/electrolte and nutrtional status

• Questions to be asked: Onset; duration; pattern; aggrevating, and relieving factors; also, stool characterization of their diarrhea.

• Presence of fecal incontinence, fever, weight loss, pain, certain exposre (travel, medications, contacts with diarrhea), and common extraintestinal manifestional (skin changes, arthalgia, oral apthous ulcer)

• Therapeutic trial = appropriate + effective + definitive… if we suspect a specific diagnosis– Eg, chronic watery diarrhea that ceases with fasting in a young

adult• DO LACTOSE RESTRICTED DIET

– Bloating and diarrhea persisting since a mountain backpacking trip• GIVE THEM METRNIDAZOLE for GIARDIASIS

– Post prandial diarrhea persisting following resction of terminal ileum• Maybe due to bile acid malabsorption

– GIVE THEM CHOLESTYRAMINE OR COLESEVELAM

– Yet persistant symptomops mean addition investigations

Additional investigation

• Suspect IBS:– Evaluate with flexible sigmoidoscopy with colo-

rectal biopsy• Normal findings = reassurance and treat empirically

– Antispasmodics, antidiarrhea, bulk agents, anxiolytic and antidepressants.

• Chronic Diarrhea and hematochezia– Evaluate with stool microbiologic studies and

colonscopy

We still we do not know..• Quantitative stool collection

– Analayses yeild impottant objuctive data• If stool > 200 g/d

– Do electrolyte concentration, pH, occult blood testing– Leukocyte inspection (or leukocyte protein assay)– Fat quantitation– Laxative screens

• Secretory diarrhea (watery, normal osmotic gap)– Possible medication related side effects (lax?)– Microbiology for protozoas and parasites, Giardia antigen assay– Small bowel aspirates to exclude bacterial overgrowth# with

quantitative cultures, glucose, or lactulose breath test– Upper endoscopy and colonscopy with biopsies– Small bowel x-ray with barium swallow

• Further evaluation of osmotic diarrhea– Include tests for lactose intolerance + mg ingestion– Low fecal pH suggests carbohydrate malabsorption– Lactose malabsorption by lactose breath testing

• Fatty diarrhea– Endoscopy with small bowel biopsy (aspirate for Giradia)– Small bowel radiograph– Pancreatic direct tests (secretin cholecystokinin stimulation test)

• Indirect tests such as assay of fecal elastase or chymotrypsin• Bentiromide test because it has fallen out of favor because of sensitivity and specificity

• Chronic inflammatory-type diarrheas– Presence of blood or leukocyte in stool– Inspection for ova and parasites– C. Difficile toxin assay– Colonscopy with biopsy– Small bowel contrast studies

Treatment: Chronic Diarrhea

• Depends on specific etiology– Three modalities of treatment: Curative, suppressive or empiracal

• Eradicated cause = Curative treamt eg., resection of a colonrectal cancer or Antibiotics for Whipple’s disease

• Suppression of underlying condition eg., elimination of dietary lactose for lactase deficiency or gluten for celiarc sprue, or use steriods for idiopathic IBD; absorptive agens for illeal bile acid malabsorption (cholestryramine) PPI (omeprazole) for gastric hypersecretion of gastrinoma

• Empirical therapy beneficial for an evasive diagnosis– Mild opiates for moderate diarrhea diphenoxylate or lopermide– Codeine or tincture of opium for severe diarrhea

• Avoid antimotility in severe IBD to avoid toxic megacolon• Clonidine, a2 adrengic agonist allow control for diabetic diarrhea• Remember, it is always fluid and electrolyte replacement first.• Fatty diarrhea, also replace them with fat soluble vitamins.

Case discussion on the subject, and attempting to answer the relevant questions

3

Case• Abeer 23 year old female, Nurse • Watery diarrhea 5x a day for a year• Wake up at night – abdominal cramps• Feeling need to empty her bowel (Tenismus)• No relief or aggrevating symptomps ( Fasting =

less frequent)• Past 6 months, she noticed weight loss of 5 kg

despite eating more• No blood or mucos in stool• No nausea, vomiting or fever

Px

• Pale, mildly dehydrated, and underweight (46 kg), height 162 cm• BMI 17.5 • Blood Pressure = 110/58 mm Hg• Pulse = 98 bpm• RR = 18 bpm• No clubbing, thyromegally, or lymphadenopathy• Abdominal pain shows soft and non-tender abdomen with no

detectable ascites or organomegally• Breast cardiovascular, chest, and neurological exam =

unremarkable• There was mild lower limb edema

Labs

CBC with renal function tests + electrolyte & serum protein• HB 102 g/L *LOW*• MCV 68 *LOW*• Platelets 499,000 *high*• WBC 7200 *normal*• Hepatic profile is notable for: AST = 40 U/L (1-40)• ALT = 49 U/L (10-40)• Alkaline phosphatase = 125 U/L (40-100 U/L)• Albumin = 28 g/L (35-50 g/L)• Total bilirubin = 13 umol/L (5-20 umol/L)• Calcium 1.8 mmol/L (2.2-2.4)

Questions - 11. What are the active problems in this patient?

– The active problems are Chronic Diarrhea, abdominal pain, urgency, chronic weight loss

 

2. What other information in the history and physical examination you need to know to reach the correct diagnosis?

 

3. What is the definition of diarrhea? When you label patient to have acute vs chronic diarrhea?

 

4. How can you categorize chronic diarrhea?

 

Questions - 25. What laboratory tests you need to order (blood and stool) to reach the diagnosis?

 

6. What do you think this young patient has? (Our DDx)

IBS

IBD

Pancreatice insufficiency

 

7. What further test you need to do to confirm the diagnosis?

 

8. Name the complications of chronic diarrhea.

 

9. How to assess nutrition in patient with chronic diarrhea?