What is the clinical definition of diarrhea? Physiological definition?
- CLINICAL (symptoms): INC in frequency, volume, or urgency of defecation +/- change in consistency
1. “Normal” stool frequency = 3 BM per week up to 3 BM per day
- PHYSIOLOGIC: >200 gm stool output per day
- NOTE: do NOT have to have watery diarrhea to have diarrhea; even an INC in frequency counts
What is the approximate daily input into the gut? Sources (image)?
- Majority of stuff in our gut from the body itself, and not what we eat
Where is fluid absorbed in the gut (image)? How much is lost each day?
- Only 0.1 liters lost (of the 8.5L input)
What is the basis of normal fluid absorption in the gut?
- Na+ uptake
- Small intestinal villi:
1. Na+/glu transporter
2. Na+/H+ exchanger
- Large intestinal crypts:
1. Epithelial Na+ channels (ENaC)
What are the 2 pathophysiologic mechanisms of diarrhea?
- INC intraluminal fluid = INC workload for the gut
1. Decreased absorption,
2. Increased secretion, or
- More rapid transit through GI tract: we don't know too much about this, except that various mediators INC motility
1. More rapid transit = less time to absorb
What are the 3 mechs of INC intraluminal fluid in the GI tract?
- DEC absorption (OSMOTIC): ingestion of unabsorbable solutes, and osmotic draw of fluid into the gut lumen
1. Osmoles in gut that can’t be absorbed will lead to osmotic draw/retention of fluid in the gut
- INC secretion (SECRETORY): active secretion of electrolytes and fluid into the lumen; electrolytes comprise most of stool osmolality
1. Wherever NaCl goes, fluid goes
- INFLAMMATION (INC secretion + DEC absorption): inflammatory mediators stimulate secretion, and epi barrier compromised by cell death, affecting absorption
How is fluid transit in the gut changed via the 3 mechs of INC intraluminal fluid diarrhea?
- OSMOTIC: non-absorbable osmoles will retain fluid and electrolytes in lumen of small bowel, and they will then move into the colon, which will absorb most, but not all of these (0.5 instead of typical 0.1 output)
- SECRETORY: normal 8.5 + secretory mechanism pouring fluid into small intestine = markedly INC workload of small intestine, and exceeding it and colon’s capacity -> large volumes come out
- INFLAMMATORY: most inflammation involves colon, so small bowel process relatively normal, but due to inflam and cell death, both secretion and challenges in absorbing nutrients in colon, leading to INC stool
What are some of the causes of osmotic diarrhea?
- NON-ABSORBABLE CARBOHYDRATES:
1. Lactose: milk, yogurt, cheese, etc. (more common in AA, and most common in Asians)
2. Sorbitol, mannitol: diet soda, gum, candy
3. Lactulose: Rx for hepatic encephalopathy -> intention is to create osmotic diarrhea and acidic stool to cleans the gut
- NON-ABSORBABLE ELECTROLYTES (laxatives):
1. Mg2+ compounds: MOM (milk of magnesia), Maalox, Epsom salts
2. Golytely (PEG: polyethylene glycol) prep for colonoscopy: to cleanse bowel
3. Fleets phosphosoda prep: can be used for colonoscopy prep too
- MISCELLANEOUS MALABSORPTION SYNDROMES
What is the key to all secretory diarrheas?
- Excessive Cl- secretion into the gut
How does cholera cause secretory diarrhea?
- CFTR the main player in cholera, which is the prototype of secretory diarrhea
- V. cholera produces toxin that enters apical membrane and activates adenylate cyclase, INC cAMP
- As Cl- enters lumen, Na+ travels paracellularly with it -> COD = dehydration (self-limited disease if you can get through vast amount of fluid losses)
How does the WHO oral rehydration formula work in the tx of cholera?
- Based on exploitation of Na/glucose co-transporter
- By including glucose in this high salt drink, Na+ absorption can continue despite cAMP inhibition of Na+ absorption by NHE
- Critically important in underdeveloped countries where IV fluid replacement is not readily available
What are the mediators of secretory diarrhea (3 categories)?
- Bacterial enterotoxins
- Neurohormonal agents
- Immune mediators
What are the causes of secretory diarrhea (5)?
- BACTERIAL TOXINS: cholera, heat stable enterotoxin (E. coli), yersinia
- LAXATIVES: discourage people from using these b/c “mess up” cells
1. Senna, phenolphthalein (ExLax), bisacodyl (Dulcolax), ricinoleic acid (castor oil)
- OTHER MEDS: cholinergics, prostaglandins
- CHEMICAL IRRITANTS: bile, arsenic, caffeine, ETOH
- NEUROENDOCRINE TUMORS: VIPoma, carcinoid, medullary carcinoma of thyroid
How do osmotic and secretory diarrhea differ clinically?
- Flatulence: sugars that are not being absorbed are metabolized by bacteria, producing CO2 gas
1. This is the 1st question Dr. Marino always asks when someone comes in complaining of diarrhea
- Lower pH: bacteria making short-chain FA’s
How do stool electrolytes differ for osmotic vs. secretory diarrhea?
- Can send stool sample to test for electrolytes: if osmolality approximates serum osmolality, then most likely secretory diarrhea
- Mostly unmeasured osmoles in osmotic diarrhea; low amount of electrolytes in the diarrhea
What is the pathophysiology of inflammatory diarrhea (image)?
- GVH: graft-vs.-host
- Mast cells release histamine -> secretory-type diarrhea via cAMP
- Secretion and cell death caused by all of these
- Shigella and rotavirus can cause cell death directly
What are the mechs of cell death in inflammatory diarrhea? Provide some examples.
- IMMUNE-MEDIATED: complement, cytokines, cytotoxic T-cells, mast cells, neutros, etc.
1. Crohn's, UC, Whipple's, Salmonella, Campylobacter
- DIRECT CELL DEATH: enterocyte penetration, toxins
1. Ameba, Shigella, Rotavirus, Giardia, Cryptosporidium
What is Whipple's disease?
- Rare, systemic infectious disease caused by Tropheryma whipplei
- Weight loss, diarrhea, joint pain, and arthritis are the presenting symptoms
- Highly variable; more common in M
What are the clinical features of acute diarrhea?
- <3 weeks duration
- Etiology: infectious
- Pathophysiology: secretory or inflammatory
- Prognosis: self-limited
- Management: mostly supportive
What are the MCC's of infectious diarrhea in the US and the 3rd world?
- In order of DEC frequency
- Note that viral is the MCC worldwide
- Campylobacter, salmonella, shigella: affect colon
- Giardia: drinking water from streams, wells
- C. diff: extremely important nosocomial infection
- Not much cholera and ameba in US
What is going on here?
- Infectious enteritis: Giardia lamblia -> present in the luminal space over normal-appearing villi
- This is the duodenum (common site for giardia)
- Likes to hang out on outside/luminal area: often described as falling leaves
- Close-up view attached here: protozoa with flagella
- If history is appropriate, usually just treat this: don’t need to biopsy
What is this?
- Amebic colitis: classic, flask-shaped ulcer -> this is an extreme case
- Infectious enteritis (entamoeba histolytica): invasive and necrotizing
- About the size of a macrophage: invades through mucosa into submucosa
1. Ingest red cells
What do you see here? What else might be on your differential?
- Cryptosporidiosis: small, round organisms typically visible
- Protrude from apical surface of enterocytes
- Immunocompromised patients
- Start looking at these on the outside
- Also microsporidiosis on differential, but these usually live further down the enterocyte
What are the major causes of traveler's diarrhea (image)?
- Affects 20-60% of visitors to the 3rd world
- Enterotoxigenic E. coli
What are the prophylaxis recommendations for traveler's diarrhea? Tx?
- PROPHYLAXIS: eat only cooked foods
1. Drink only bottled beverages, and avoid ice
2. Wash hands before meals
3. Consider peptobismol QID (4x/d)
- TX: PO fluids, anti-diarrheals for symptom control
1. If severe, ciprofloxacin 500mg BIDx3d (RARE)
How is acute diarrhea managed medically?
- Most acute diarrhea goes away on its own as long as you are able to maintain hydration
- NO DEHYDRATION:
1. Non-bloody: likely viral or toxin-mediated, and self-limited
a. PO fluids, +/- Peptobismol
2. Bloody (dysentery): likely bacterial, and often self limited
a. Stool for culture (in case things get worse), ova and parasites (O&P)
b. PO fluids, Peptobismol
1. +/- Blood: obtain stool for culture, O&P
a. IV fluids vs. oral WHO rehydration solution (esp. if cholera)
b. Anti-diarrheal agent
2. Bloody, “septic”: febrile, lethargic
a. Obtain stool for culture and O&P
b. HOSPITALIZATION, IV fluids
c. IV fluoroquinolone (cipro); avoid w/EHEC
- NOTE: bleeding is not uncommon, esp. in bacterial causes
C. diff: risk factors, cause, tx, dx
- RISK FACTORS: AB use (alteration in colon flora), extremes of age, hospitalization or institutionalization
- CAUSE: cytotoxins A and B -> mucosal cell injury; toxin is what is causing the injury, not bacteria itself
- DX: pseudomembranous colitis on colonoscopy
1. Stool assay for toxin A (+/- B)
- TX: stop offending AB, if possible
1. Metronidazole or PO Vanc
2. Cholestyramine (binding agent) to bind toxins
- NOTE: people can die from this -> not going to think about it in an outpt setting, but more in an elderly pt in the hospital
What is this? Cause?
- Pseudomembranous colitis: classic appearance from C. diff (can diagnose without a biopsy)
- Can also dx C. diff with a stool sample
What is going on here?
- Pseudomembranous colitis (C. diff): denuded surface epithelium and neutros in the lamina propria
1. Plasma cells and lymphos in lamina propria too (damage deep down)
- Superficially damaged crypts are distended by a mucopurulent exudate that forms an eruption reminiscent of a volcano -> exudates coalesce to form pseudomembranes
- Note the normal-appearing surface on the far right
- Differential ischemic colitis, but with exploding volcanoes, think C. diff -> hard when all of this begins to coalesce (clinical history will help, in this case)
What are the clinical characteristics of chronic diarrhea?
- > 3 weeks duration
- ETIOLOGIES: infectious, immune-mediated, malabsorption
- PATHOPHYS: osmotic, secretory (no mucosal injury) vs. inflammatory (mucosal injury)
- PROGNOSIS: variable
- MGMT: specific interventions required (depends on cause)
What causes of chronic diarrhea do NOT involve mucosal injury?
- MALDIGESTION/MALABSORPTION SYN: bacterial overgrowth
1. Disaccharidase deficiencies
2. Pancreatic insufficiency
3. Short bowel syndrome: not enough to absorb all the nutrients you are inputting
- HYPER-MOTILITY: hyperthyroidism
2. Diabetic neuropathy
3. Alcoholism: secretory-type mechanism
- NE MALIGNANCIES: VIPoma, carcinoid
- FACTITIOUS: laxative abuse -> may not tell you they are taking these (PSYCH)
What are the clinical features of lactase deficiency?
- Osmotic diarrhea
- Acidic stool pH (due to SCFA)
How can bacterial overgrowth cause chronic diarrhea? TX?
- Small bowel not supposed to have bacteria in it, but can grow here with motility issues
- Can unconjugate bile acids so they are not able to be picked up in terminal ileum
- Can also eat the carbs in the small intestine -> SCFA
- TX: give AB’s to kill bacteria in the small bowel
What is IBS? Dx? Tx?
- Abdominal pain assoc w/bowel functions, i.e., with diarrhea, or intermittent pain if pt is having a diarrheal or constipative episode
1. Common cause of chronic diarrhea in U.S.
2. A disorder of motility and pain perception
- DX: abdominal pain and bloating + symptoms assoc with bowel functions
1. No weight loss, bleeding, malnutrition, or anemia -> just very uncomfortable
- TX: anti-cholinergic medications (diarrhea)
1. 5-HT receptor antagonists (constipation)
What are the causes of chronic diarrhea that involve mucosal damage?
- CHRONIC INFECTION: HIV
1. Parasites/worms: strongyloides, etc.
2. Tropical sprue and Whipple’s disease
- ALLERGIC/IMMUNE-MEDIATED: food allergy, e.g., milk, soy, etc.
1. Celiac sprue
2. Inflammatory bowel disease: Crohn’s or UC
3. Eosinophilic gastroenteritis
4. Microscopic (lymphocytic, collagenous) colitis
- MALIGNANCIES: colon cancer or lymphoma
What is going on here?
- Infectious enteritis (strongyloides): diffuse eosinophilic infiltrates in parasitic infection
- Skin of foot -> lungs -> cough up and re-swallow -> GI tract
- Can cause chronic diarrhea with mucosal damage
What do you see here?
- IBD (immune-mediated): UC on left, Crohn's on right
- UC: confined to colon and looks a little like C. diff, but immune-mediated destruction of enterocytes, so bloody
- Crohn’s: colon, small bowel, or both -> flat, apthous ulcers (bloody, or not)
- Can be difficult to distinguish pathologically
What is microscopic colitis? Types? Tx?
- Chronic, watery, non-bloody diarrhea in adults
- TYPES: 1) lymphocytic, 2) collagenous
- TX: bismuth, aminosalicylates, steroids
What do you see here?
- Microscopic colitis (collagenous type)
- Characterized by presence of:
1. Dense, subepithelial collagen layer
2. INC #'s of intraepithelial lymphocytes (T)
3. Mixed inflam infiltrate in lamina propria
- Surface epi can slough off (attached image); may be fragile from subepi collagen
What is this?
- Microscopic colitis (lymphocytic type): subepithelial collagen layer is of normal thickness
- > INC in intraepithelial lymphocytes, frequently exceeding one T- lymphocyte per five enterocytes
What is the initial approach to the pt with chronic diarrhea?
- ASSESS for RED FLAGS: unintentional weight loss
1. Nocturnal diarrhea
2. Signs of malnutrition: muscle wasting
3. Rectal bleeding
- INITIAL WORK-UP:
1. Stool studies: leukocytes, blood, culture, O&P
2. Labs: CBC, albumin, electrolytes, thyroid
What might you think about in pt presenting with chronic diarrhea and absent red flags + normal initial labs?
- Lactose intolerance: flatulence
- Bacterial overgrowth: flatulence
- Irritable bowel syndrome (IBS): pain related to BM's
What might you think about in pt presenting with chronic diarrhea and red flags, or abnormal initial labs?
- IBD: rectal bleeding, pain, weight loss
- Hyperthyroidism: weight loss
- Infection: bleeding, cramps
- Malabsorption: anemia, weight loss
- Malignancy: weight loss, bleeding
What might be included in the additional work-up for chronic diarrhea?
- Colonoscopy with biopsies
- Abdominal CT Scan
- Fecal Fat
- Small bowel biopsy
- Capsule endoscopy
- ERCP: endoscopic retrograde cholangiopancreato-graphy -> specialized technique used to study the bile ducts, pancreatic duct and gallbladder