CLINICAL SCENARIOA 50-year-old woman reported multiple loose bowelmovements associated with mild, cramping abdominalpain. She had been well until 2 months earlier, when herbowel habits changed from one formed stool per day tofrequent loose stools (soft) of moderate volume.The abdominal pain was variable in intensity and wasslightly relieved with defecation.She had no recent dietary changes and no family historyof intestinal problems, and she had not traveled outsidethe United States. She didnot have anorexia, weight loss, hematochezia, episodes ofconstipation or abdominal bloating, fever, dyspnea,nausea, vomiting, pruritus, or flushing.
DEFINITIONMore than 200 gms ?Increased volume ? Hard to quantifyIncreased frequency ? Some individuals have increased fecalweight due to fiber ingestion but do not complain of diarrheabecause their stool consistency is normal. Conversely, otherpatients have normal stool weights but complain of diarrheabecause their stools are loose or wateryconceptuallyratio= water-holding capacity of insoluble solids/total water presentConsensus statement by AGA= decrease in fecal consistency lasting for four ormore wks
ORGANIC VS FUNCTIONAL DIARRHEAshorter duration of diarrhea (less than 3 months),nocturnal diarrhea,an abrupt onset of diarrhea,weight loss of more than 11 lb (5.0 kg), andstool weight of more than 400 g per day.70 % SPECIFIC FOR FUNCTIONAL ETIOLOGY
CASE…The patient had a history of Graves disease, which had beentreated 8 years earlier with radioiodine, and she was receivingoral levothyroxine at a dose of 88 µg per day.She said that she did not used alcohol, tobacco, or illicitdrugs.She appeared well. Her weight was 131 lb (59.4 kg), herheight was 5 ft (1.5 m), and her body-mass index (theweight in kilograms divided by the square of the heightin meters) was 26.4.She was afebrile, with a blood pressure of 102/67 mm Hgand a heart rate of 89 beats per minute.She had no lymphadenopathy.The lung and cardiac examinations were normal.Her abdomen was soft, with normal bowel sounds and notenderness or hepatosplenomegaly.There were no rectal masses;A stool specimen was negative for occult blood.Skin and neurologic examinations were normal.
CLUES ?Hypothyroidism ? Underlying graves diseaseLevothyroxine ? How long and any change in doses?Think about celiac dx. ? Why ?
CASE CONTD:The patient received a diagnosis of the irritable bowelsyndrome, and diphenoxylate–atropine and belladonna–phenobarbital were prescribed.She noted some improvement with this regimen (e.g.,the number of stools per day decreased from 10 to 7), butshe reported tenesmus, and her diarrhea became watery.At a follow-up visit 1 month later, she was advised tocontinue these medications.One month later, the patients gynecologist referredher to a gastroenterologist for further recommendationson management of the irritable bowel syndrome.The patients stool was again negative for occultblood.
PAINFULL FUNCTIONAL DIARRHEA-IRRITABLE BOWEL SYNDROMEThe irritable bowel syndrome is characterized by recurrent abdominal pain ordiscomfort that occurs at least 3 days per month for at least 3 months, withtwo or more of the following:improvement with defecation,an onset associated with a change in the frequency ofbowel movements, oran onset associated with a change in the form (appearance)of stool.ABSENCE of alarm characteristics such as weight loss,nocturnal symptoms, a family history of colorectalcancer, rectal bleeding, or anemia; these would warrant furtherevaluation.When measured, daily stool output is low, typically less than 400 g per 24 hours.Consistency varies from loose to soft and rarely is waterDiarrhea does not wake patients from sleep.Long Hx, extending back to adolescenceLabs are usually nl (hg, esr, albumin)The irritable bowel syndrome should be a diagnosis of exclusion
CLUESThe new symptom of tenesmus is consistent with rectal inflammation and pointsaway from the diagnosis of the irritable bowel syndrome. A more likely cause ofher chronic diarrhea would be celiac disease, microscopic or collagenous colitis,or IBD.Also there is change in consistency: watery
CLASSIFICATIONBy volume (large vs. small),By pathophysiology (secretory vs. osmotic),By epidemiology,By stool characteristicswatery vs. fatty vs. inflammatory.For the clinician, these classification schemes are only usefulif they serve to focus the diagnostic and managementapproaches toward patients. In this regard, no singlescheme is perfect; the experienced physician uses all ofthese classifications to expedite patient care
HISTORYQUESTIONING CLINICALIMPLICATIONIntravenous drug abuse, sexualpromiscuityAIDSImmune problems AIDS, immunoglobulin deficienciesAbdominal painMesenteric vascular insufficiency, obstruction,irritable bowel syndromeExcessive flatus Carbohydrate malabsorptionLeakage of stool Fecal incontinenceStool characteristicsBlood Malignancy, inflammatory bowel diseaseOil/food particles Malabsorption, maldigestionWhite/tan color Celiac disease, absence of bileNocturnal diarrhea Organic etiology
Large-Volume Versus Small-Volume StoolsRATIONALE: that the normal rectosigmoid colon functions as a storagereservoir.When that reservoir capacity is compromised by inflammatory ormotility disorders involving the left colon, frequent small-volume bowelmovements ensue. (< 350 ml)If the source of the diarrhea is upstream in the right colon orsmall bowel and if the rectosigmoid reservoir is intact, bowel movements arefewer, but larger.( 750 ml or more)Thus, frequent, small, painful stools may point to a distal site of pathology,whereas painless large-volume stools suggest a right colon or small bowelsource.PROBLEM: it is difficult for patients to quantify volume
Watery diarrhea - adefect primarily in water absorption due to increased electrolytesecretion or reduced electrolyte absorption-secretory diarrhea- ingestion of a poorly absorbed substance-osmotic diarrhea).The essential characteristic of osmotic diarrhea is that it disappears withfasting or cessation of ingestion of the offending substance. Thischaracteristic has been used clinically to differentiate osmotic diarrheafrom secretory diarrhea that typically continues with fastingInflammatory: diarrhea implies the presence of one of a limited number ofinflammatory or neoplastic diseases involving the gut.Fatty diarrhea: implies defective absorption of fat in the small intestine.Fatty diarrhea (steatorrhea) should be suspected in patients who reportgreasy, floating, and malodorous stools and those who are at risk for fatmalabsorption, such as patients with chronic pancreatitis
Peripheral neuropathy and orthostatic hypotensionmay be the only clues to a diagnosis of amyloidosis.A thyroid nodule with cervical lymphadenopathy maybe the only lead to the presence of medullarycarcinoma of the thyroid.Tremor and other systemic signs should lead toconsideration of hyperthyroidismThe perineal, anal, and rectal examinations areimportant. Signs of incontinence include skinchanges from chronic irritation, gaping anus, andweak sphincter tone.Crohns disease is associated with perianal skin tags,ulcers, fissures, abscesses, fistulas, and stenoses.Fecal impaction or masses might be noted.Other associated physical findings includeexophthalmos (hyperthyroidism),aphthous ulcers (IBD and celiac disease),lymphadenopathy (malignancy, infection orWhipples disease),enlarged or tender thyroid (thyroiditis, medullarycarcinoma of the thyroid),arthritis (IBD, Whipples disease),wheezing and right-sided heart murmurs(carcinoid syndrome), andclubbing (liver disease, IBD, laxative abuse,malignancy).PHYSICAL EXAMINATION
CASE:Six months after the first visit to her physician, the patient consulted a general internistwhile she awaited her appointment with a gastroenterologist.Her diarrhea persisted, and occasional nausea, vomiting, fever, and chills had developed.She had no weight loss but now reported that she was awakened during the night severaltimes each week by fecal incontinence or the need to defecate.Tests of stool samples for ova and parasites, salmonella, shigella, andcampylobacter were negative.Stool smears had no white cells or red cells.Blood tests showed a white-cell count of 4100 per cubic millimeter, withno leftward shift. The hematocrit was 35%, with a normal meancorpuscular volume, and the platelet count was 310,000 per cubicmillimeter.Liver-function tests were normal, including the serum albumin level(4.3 g per deciliter).A referral for an urgent evaluation by a gastroenterologist was made, and an appointmentwas scheduled for the next month.A few days later, the patient visited her endocrinologist for a regular follow-up of Gravesdisease. The free thyroxine level was normal, at 1.0 ng per deciliter, and the thyrotropinlevel was low, at 0.12 µU per milliliter (normal range, 0.20 to 5.39). Her dose oflevothyroxine was reduced to 75 µg per day.
CLUES:Absence of fecal leukocytes makes inflammatory diarrhea less likely,although the sensitivity of this test is only 70% and specificity is 50%The test for fecal lactoferrin has higher sensitivity.Bacterial infections are rarely a cause of chronic diarrhea.The sensitivity of tests of three fixed, concentrated stool specimens for ovaand parasites is up to 85%, although giardiasis, amebiasis, andpersistent infection with microsporidia, coccidia, or cryptosporidiaremain possibilities.The low level of thyrotropin warrants a reduction in the dose oflevothyroxine, although the patients increasingly severe symptomsshould not be attributed to overreplacement with levothyroxine.
CASEThe patient returned to her internist 1 month later. She noted a decrease in stoolfrequency to six bowel movements per day and a 3-lb (1.4-kg) weight loss.The serum sodium level was 139 mmol per liter; chloride, 103 mmol per liter;potassium, 2.8 mmol per liter; bicarbonate, 21 mmol per liter; blood urea nitrogen,10 mg per deciliter (3.6 mmol per liter); creatinine, 0.7 mg per deciliter (62 µmol perliter); and glucose, 89 mg per deciliter (4.9 mmol per liter).Oral potassium chloride at a dose of 40 mmol per day, pantoprazole at a dose of 40 mgtwice a day, and promethazine at a daily dose of 12.5 mg every 4 to 6 hours asneeded for symptom relief were prescribed, with reported benefit.Several days later, she was evaluated by a gastroenterologist and an upper endoscopyand colonoscopy were scheduledA repeat measurement of potassium showed a level of 3.6 mmol per liter; the vitaminB12 level was 463 pg per milliliter (342 pmol per liter) (normal range, 180 to 900 pgper milliliter [133 to 665 pmol per liter]); free thyroxine, 1.1 ng per deciliter; andthyrotropin, 0.35 µU per milliliter. Stool samples were negative for giardia.
CLUES AND DIFFERENTIALDXHypokalemia and acidosisany chronic diarrheaVIPomarectal villous adenoma inflammatorybowel disease celiacdiseaseneoplasmmicroscopic colitisNext step ??
CASE:The patient returned 2 months later (9 months after her initial presentation)for endoscopy and colonoscopy. She reported an additional 15-lb (6.8-kg)weight loss, anorexia, increased nausea, and approximately eight bowelmovements per day.Her colonoscopic examination was normal to the cecum; biopsies were notperformed.The upper endoscopic examination was normal to the fourth portion of theduodenum, with no evidence of pale, yellow, or shaggy mucosa, findings thatwould be suggestive of Whipples disease.Two small-bowel biopsy specimens obtained from the fourth portion of theduodenum showed mild chronic inflammation, with no evidence of giardiaand no villous flattening.The serum gastrin level was normal, at 15 pg per milliliter, andstool samples were negative for Clostridium difficile.Repeat blood chemical tests were normal except for a potassium level of 2.5mmol per liter. The dose of potassium chloride was increased to 80 mmolper day; a follow-up potassium measurement 1 week later was 3.4 mmol perliter.A skin test for tuberculosis was positive.
CLUESUlcerative colitis, Celiac disease and colonic neoplasmappear to be ruled out.Positive PPD ? Intestinal TBHx. of drinking unpasteurized milk? anunlikely diagnosis in the United States, especially inan immunocompetent patient, and it would notappear to account for this patients persistenthypokalemia.increases concern regarding secretory diarrhea; stoolelectrolyte levels should be evaluated
CASEchest radiograph was normal.One month later, the patient returned for a flexiblesigmoidoscopic examination to investigate the possibilityof collagenous colitis; biopsy specimens obtained duringthis examination were normal.The patient had now lost a total of 27 lb (12.2 kg).A repeat potassium measurement showed a level of 2.9 mmolper liter; the dose of potassium chloride was increased to120 mmol per day.The stool sodium level was 70 mmol per liter, and the stoolpotassium level was 82 mmol per liter
CLUESfecal osmotic gap290–[(stool sodium level+stool potassium level)x2], is less than 50 mOsm,a finding that is consistent with secretory diarrhea.secretory diarrhea+ profound hypokalemia+weight loss = Highly suspicious forneuroendocrine tumorTesting VIPoma andfor medullary carcinoma of the thyroid, which may also cause chronicsecretory diarrhea.Acarcinoid tumor and mastocytosis are other potential causes of thispresentation, but the patient does not report other typical symptoms such asflushing.Abuse of nonosmotic laxatives remains a possibility to be testedby means of urine and stool screening, if the results of gastrointestinal peptidehormone screening are unrevealing.
CASEThe serum calcitonin level was less than 1 pg per milliliter (normal range, 0 to 4).The 5-hydroxyindoleacetic acid (5-HIAA) level in a 24-hour urine specimen was 4.4mg (normal range, 0 to 6.0).The VIP level was more than 400 pg per milliliter (normal value, <50).
elevated VIP level should be confirmed with repeattesting, this result strongly supports a diagnosis of theVIPoma syndrome.VIPomas are rare VIP-secreting tumors that arise mostoften in the tail of the pancreas and classically resultin watery diarrhea and hypokalemia, as well ashypochlorhydria or achlorhydria.Abdominal computed tomography (CT) or magneticresonance imaging should be performed to localizethe tumor and look for metastases.Treatment with a long-acting somatostatin analogueshould be initiated to control the patients diarrhea.
COMPLEX DIARRHEAMost clinically significant diarrheas are complex;rather than being produced by a singlepathophysiologic mechanism, they are due toseveral. These may include the effects ofsubstances released by enteric endocrine cells,cytokines released by local and remoteimmunologically reactive cells, by the activity ofthe enteric nervous system, and by peripherallyreleased peptides and hormones (paracrine,immune, neural, and endocrine systems)
PINESFurther complicating the understanding of diarrhea is that certain mediators not onlyaffect epithelial or muscle function, but also each other.For example, enteric nerves may stimulate mast cells and products so released from mastcells (particularly histamine) may alter enteric neuron functions A single agonist—suchas prostaglandin—may have multiple, simultaneous effects on epithelial function,muscle contraction, and the paracellular pathway, leading to effects on ion transport,motility, and mucosal permeabilityThus, multiple modulators and multiple effectors contribute to the final clinical picture. Afull appreciation of the pathophysiology of diarrhea requires consideration ofparacrine, immune, neural, and endocrine modulators, a regulatory system that can beabbreviated by the acronym “PINES”