Chronic diarrhea

Chronic diarrheaDefinitionIts definition has traditionally been based upon the frequency, volume, and consistency of stools.BUTthe relationship between these features and patients' perception of diarrhea is variable.DefinitionChronic diarrhea should be defined as a decrease in fecal consistency lasting for four or more weeks.

The American Gastroenterological Association (AGA) technical review for the evaluation andmanagement of chronic diarrhea: www.gastro.org/practice/medical-position-statementsEpidemiologyBased upon a commonly used definition (ie, the presence of excessive stool frequency) a reasonable approximation is that chronic diarrhea affects approximately 5 percent of the population.

Chronic diarrhea can decrease quality of life.EtiologyIn developing countries, chronic diarrhea is frequently caused by chronic bacterial, mycobacterial, and parasitic infections, although functional disorders, malabsorption, and inflammatory bowel disease are also common.

In developed countries, common causes are irritable bowel syndrome (IBS), inflammatory bowel disease, malabsorption syndromes, and chronic infections (particularly in patients who are immunocompromised).Irritable bowel syndromeThe symptom complex of chronic lower abdominal pain and altered bowel habits;

Symptoms of IBS often correlate with episodes of psychologic stress.Irritable bowel syndromePatients with IBS complain of crampy lower quadrant pain with diarrhea, alternating diarrhea and constipation, or normal bowel habits alternating with either diarrhea and/or constipation.

Diarrhea is usually characterized as frequent loose stools of small to moderate volume.Irritable bowel syndromeStools generally occur during waking hours, most often in the morning or after meals.

Most bowel movements are preceded by extreme urgency and may be followed by a feeling of incomplete evacuation.Irritable bowel syndromeApproximately one-half of all patients with IBS complain of mucus discharge with stools.

Incontinence of liquid stool may occur during periods of disease activity.

Pain may be relieved with defecation.Post-infectious IBS Following recovery from C. difficile and other bacterial infections.May mimic the symptoms of the original infection with diarrhea and crampy pain.

Patients who develop this condition are more likely to have had mild symptoms of IBS prior to the inciting infection.Irritable bowel syndromelarge volume diarrheabloody stoolsnocturnal diarrheagreasy stools

are notassociated with IBS and suggest an organic disease.

Functional diarrheaContinuous or recurrent passage of loose or watery stools without abdominal pain or discomfort Inflammatory bowel diseasePrimarily refers to ulcerative colitis and Crohn's disease.Most cases have their onset between ages 15 and 40.Crohn's disease May involve the entire gastrointestinal tract from mouth to perianal area.

Diarrhea, abdominal pain, weight loss, and fever are the typical clinical manifestations for most patients with ileitis, ileocolitis, or Crohn's colitis.Crohn's disease Patients can have symptoms for many years prior to diagnosis.

Although Hemoccult positive stools are common in Crohn's disease, gross bleeding is much less frequent than in ulcerative colitis.Ulcerative colitisMild disease Patients present insidiously with intermittent rectal bleeding associated with the passage of mucus, and the development of mild diarrhea with fewer than four small loose stools per day.Mild crampy pain, tenesmus, and periods of constipation are also common.Ulcerative colitisModerate disease Involvement of more than the distal colon, with the inflammatory process extending to at least the splenic flexure (left-sided colitis).Frequent loose, bloody stools (up to 10 per day), mild anemia not requiring blood transfusions, abdominal pain that is not severe, and low grade fever.Ulcerative colitisSevere disease Usually extensive colonic involvement, often but not always extending to the cecum (pancolitis). Typically have frequent loose stools (greater than 10 per day) with severe cramps, fever up to 39.5C, and bleeding often necessitating blood transfusion. Patients may suffer rapid weight loss, leading to a poor nutritional state.Microscopic colitisCharacterized by chronic watery (secretory) diarrhea of up to two liters daily without bleeding, with a mainly intermittent clinical course. Usually occurs in middle-aged patients.

Lymphocytic colitisCollagenous colitis (the diagnosis is made by histology, and biopsies obtained from the right colon are optimal)Malabsorption syndromesMalabsorption refers to impaired absorption of nutrients.

The clinical and laboratory features of malabsorption depend upon the cause and severity of the diseaseMalabsorption syndromesThe CLASSIC MANIFESTATIONS of malabsorption are pale, greasy, voluminous, foul-smelling stools and weight loss despite adequate food intake.

However, this spectrum of findings is relatively uncommon, even in generalized mucosal disease. Malabsorption syndromesThe majority of patients with malabsorption have relatively mild gastrointestinal symptoms, which often mimic more common disorders such as irritable bowel syndrome.Malabsorption syndromesIn some cases, anorexia, flatulence, abdominal distension, and borborygmi may be the only complaints suggesting malabsorption; other patients may be asymptomatic.

CholecystectomyDiarrhea following cholecystectomy has been reported in 5 to 12 percent of patients.In many cases resolves or significantly improves with time (weeks to months).

The diarrhea is related to excessive bile acids overcoming the terminal ileums reabsorptive capacity and entering the colon (cholerheic diarrhea).Chronic infectionsSome persisting infectionsC. DifficileAeromonasPlesiomonasCampylobacterGiardiaAmebaeCryptosporidiumWhipple's diseaseCyclosporacan be associated with chronic diarrhea25Chronic infectionsThese diagnoses should be considered in patients with specific risk factors such as travel, HIV infection, use of antibiotics, and consumption of potentially contaminated drinking water.

All patients should be asked about use of antibiotics within the last three months!Chronic infectionsChronic diarrhea due to Candida albicans infection has been described in case reports.Most patients immunosuppressed (in some cases received antibiotics) and malnourished.Diagnosis established by detection of large numbers of Candida in small bowel aspirates and stool specimens and response to antifungal therapy. EVALUATIONOptimal strategies for the evaluation of patients with chronic diarrhea have not been established.

Recommendations have been derived mostly from expert opinion and from experience in individual clinical centers.EVALUATIONHowever, it is generally agreed upon that a specific diagnosis can be achieved in more than 90 percent of patients.The selection of specific tests, timing of referral, and the extent to which testing should be performed depend upon an appraisal of the likelihood of a specific diagnosis, the availability of treatment, the severity of symptoms, patient preference, and comorbidities.Timing of referralThe timing of referral to a subspecialist depends upon the severity of symptoms, the diagnoses being considered and the need for endoscopic procedures.

(referral may be unnecessary in a young patient with typical symptoms of IBS while it may be considered early in a patient in whom Crohn's disease is suspected)

30HistoryA thorough medical history can guide appropriate evaluation. HistoryA clear understanding of what led the patient to complain of diarrhea;

Stool characteristics;

Duration of symptoms, nature of onset (sudden or gradual)

Travel history

Risk factors for HIV infection1. (eg, consistency or frequency of stools, the presence of urgency or fecal soiling)2. (eg, greasy stools that float and are malodorous may suggest fat malabsorption while the presence of visible blood may suggest inflammatory bowel disease)32HistoryWeight loss;

Occurrence of diarrhea during fasting or at night (suggesting a secretory diarrhea);

Family history of IBD;

The volume of the diarrhea (SB vs. colon);2. (which may be confused with diarrhea)4. (eg, voluminous watery diarrhea is more likely to be due to a disorder in the small bowel while small-volume frequent diarrhea is more likely to be due to disorders of the colon)

33HistoryThe presence of systemic symptoms;

All medications;

Association of symptoms with specific food ingestion;

A sexual history;

A history of recurrent bacterial infections (eg, sinusitis, pneumonia).which may indicate inflammatory bowel disease3. (such as dairy products or potential food allergens)4. (anal intercourse is a risk factor for infectious proctitis and promiscuous sexual activity is a risk factor associated with HIV infection)5. which may indicate a primary immunoglobulin deficiency.34Physical examinationThe physical examination rarely provides a specific diagnosis.Physical examinationCLUES:findings suggestive of IBD (eg, mouth ulcers, a skin rash, episcleritis, an anal fissure or fistula, the presence of visible blood on digital examination, abdominal masses or abdominal pain);

evidence of malabsorption (such as wasting, physical signs of anemia, scars indicating prior abdominal surgery);

Physical examinationCLUES:lymphadenopathy (possibly suggesting HIV infection);

abnormal anal sphincter pressure or reflexes (possibly suggesting fecal incontinence);

palpation of the thyroid and examination for exophthalmos and lid retraction may provide support for a diagnosis of hyperthyroidism.

Specific testingA large number of tests are available for diagnosing specific causes of diarrhea.There is no firm rule as to what testing should be done. The history and physical examination may point toward a specific diagnosis for which testing may be indicated.Minimum evaluationComplete blood count and differential;Erythrocyte sedimentation rate;Thyroid function tests;Serum electrolytes;Total protein and albumin;Stool occult blood.Minimum evaluationIn addition, most patients require some form of endoscopic evaluation and mucosal biopsy, depending upon the clinical setting (either sigmoidoscopy, colonoscopy, or sometimes upper endoscopy)40CATEGORIZE THE SYMPTOMSBecause irritable bowel syndrome is one of the most common causes of chronic diarrhea, it is frequently useful to begin evaluation by attempting to categorize the symptoms and signs of the diarrhea as more likely to be eitherfunctional (related to IBS)or organic (related to an identifiable bowel pathology).CATEGORIZE THE SYMPTOMSThe presence of:significant weight loss,anemia, occult or overt gastrointestinal bleeding, nocturnal awakening with pain or diarrhea

are inconsistent with IBS and should alert to other diagnoses.CATEGORIZE THE SYMPTOMSAnother useful way to guide specific testing is to attempt to categorize diarrhea as:Watery (secretory/osmotic);Inflammatory;orFatty.Those with watery diarrhea can be subcategorized further as having secretory or osmotic diarrhea 43Secretory/osmotic diarrheaIn contrast to osmotic diarrhea, secretory diarrhea characteristically:continues despite fasting;is associated with stool volumes >1 liter/dayoccurs day and night.

.

44Secretory/osmotic diarrheaAlthough usually unnecessary, the distinction between an osmotic and a secretory diarrhea can also be established by measuring stool electrolytes and calculating an osmotic gap: 290 - 2 ({Na+} + {K+})

>125 mOsm/kg suggests an osmotic diarrhea ;6 grams of fecal fat in a 24-hour collection indicates fat malabsorption.on a diet containing 100 grams of fat per day, 62FAT ABSORPTIONCentral to the mechanism of fat absorption is the problem of solubilizing lipids in an aqueous environment.Lipids must be emulsified to expose a large surface area to lipolytic enzymesmasticationgastric mixingbile salts63FAT ABSORPTIONEnzymessalivary lipasepancreatic lipase and colipase

2-monoglycerides and fatty acids are then absorbed across the apical membrane of the enterocyte.intraluminal pH to approximately 6.5, which is optimal for fat digestion. Diseases that substantially decrease duodenal pH, such as Zollinger-Ellison syndrome, can selectively inhibit fat absorption.64FAT ABSORPTIONDisease, or resection, of greater than 100 cm of terminal ileum commonly results in severe impairment of the enterohepatic circulation of bile salts resulting in fat malabsorption.

Similarly, deconjugation of bile acids by florid small bowel bacterial overgrowth defunctionalizes the bile acids, and can also result in fat malabsorption.such that the liver's ability to upregulate de novo bile acid synthesis is inadequate to meet normal physiological needs for bile production, 65CARBOHYDRATE ABSORPTIONDietary starch and disaccharides must be broken down into their constituent monosaccarides prior to absorption.

Enzymessalivary and pancreatic amylasebrush border enzymes (disaccharidases)

Starch, sucrose, and lactose are the most abundant digestible carbohydrates in the human diet.

Impaired absorption of carbohydrates may result from a deficiency in pancreatic amylase, reduced disaccharidase activity in the small intestinal epithelium, or decreased absorptive intestinal surface area. In primary carbohydrate malabsorption, single functional elements of carbohydrate digestion or absorption are missing, such as in congenital lactasedeficiency and sucrase-isomaltase deficiency. Secondary carbohydrate malabsorption can occur from diseases leading to a reduced intestinal absorptive area, such as celiac disease.

66CARBOHYDRATE ABSORPTIONCarbohydrates that are not digested and absorbed in the small intestine undergo bacterial degradation in the colon.

Excessive bacterial fermentation is the reason for acidic stools, abdominal distension, and flatulence in patients with carbohydrate malabsorption.

67PROTEIN ABSORPTIONProtein digestion begins in the stomach by the action of gastric pepsins, which are released as proenzymes (pepsinogen 1 and 2), and undergo autoactivation at low pH.The observation that patients who are achlorhydric or have lost control of gastric emptying can still digest proteins suggests that proteolysis within the stomach is not essential for protein digestion. 68PROTEIN ABSORPTIONIn the duodenum, several proteases act together to digest proteins into amino acids, or dipeptides and tripeptides.

Central to this process is enterokinase, which converts trypsinogen to trypsin, which then catalyzes the conversion of all other pancreatic proteases to their active forms.which is released from the microvillus membrane of duodenal absorptive cells by the action of bile salts. 69PROTEIN ABSORPTIONFollowing pancreatic enzyme digestion, amino acids, dipeptides, and tripeptides can be absorbed through highly efficient sodium-dependent amino acid co-transporters at the brush border membrane.; this step is passive 70PROTEIN ABSORPTIONImpaired digestion and absorption of dietary protein occurs when pancreatic protease secretion and/or activity is impaired, as in chronic pancreatitis or cystic fibrosis.

Protein malabsorption can also occur in diseases associated with a generalized reduction of the intestinal absorptive surface. 71VITAMIN, MINERAL, AND TRACE ELEMENT ABSORPTIONThe fat-soluble vitamins (A, D, E, and K) require solubilization in a mixed micellar phase in order to be absorbed.

The proximal half of the small intestine is the predominant site for the absorption of most vitamins and minerals;Exception: vitamin B12.Vitamins and minerals represent a wide array of compounds, possessing an equally wide array of biochemical properties. It is therefore not surprising that the intestine has many types of transport mechanisms to facilitate assimilation of these nutrients across the intestinal barrier. Some nutrients, such as the carotenoids, appear to be absorbed solely by passive diffusion while many others are absorbed by carrier-mediated, non-energy requiring processes or active transport systems (ie, energy-requiring transporters that can work against a chemical gradient) such as folate and calcium. The type of transport varies in different portions of the small intestine for many micronutrients.As a result, factors that adversely impact on fat absorption will usually affect absorption of these vitamins in a parallel manner.A notable exception is vitamin B12, ileal disease or resection exceeding 100 cm is associated with a high risk of B12 deficiency.72VITAMIN, MINERAL, AND TRACE ELEMENT ABSORPTIONThe excess fatty acids present in the intestinal lumen of patients with untreated fat malabsorption bind divalent cations, such as calcium and magnesium, creating soaps and causing undue losses of these minerals.

Clinically significant deficiencies of these minerals are common in untreated fat malabsorption and create a substantial risk for metabolic bone disease. The problem of calcium depletion in this setting will be further magnified if vitamin Ddeficiency is also present.73MALABSORPTIONRefers to impaired absorption of nutrients.

Results from:congenital defects in the membrane transport systems;acquired defects in the epithelial absorptive surface.Maldigestion (due to impaired digestion of nutrients).It can result from congenital defects in the membrane transport systems of the small intestinal epithelium or from acquired defects in the epithelial absorptive surface.Another factor that can interfere with nutrient absorption is maldigestion, which is due to impaired digestion of nutrients within the intestinal lumen or at the terminal digestive site of the brush border membrane of mucosal epithelial cells.Although malabsorption and maldigestion are pathophysiologically different, the processes underlying digestion and absorption are interdependent. As a result, in clinical practice the term malabsorption has come to denote derangements in both processes.

74CLINICAL FEATURESThe clinical features of malabsorption depend upon the cause and severity of the disease.

Malabsorption may either be global or partial (isolated).

Global malabsorption results from diseases associated with either diffuse mucosal involvement or a reduced absorptive surface. An example is celiac disease in which diffuse mucosal disease can lead to impaired absorption of almost all nutrients.

75CLINICAL FEATURESThe classic manifestations of global malabsorption are diarrhea with pale, greasy, voluminous, foul-smelling stools and weight loss despite adequate food intake.

However, this spectrum of findings is relatively uncommon, even with generalized mucosal disease. The majority of patients have relatively mild gastrointestinal symptoms, which often mimic more common disorders such as irritable bowel syndrome.In some cases, anorexia, flatulence, abdominal distension and borborygmi may be the only complaints suggesting malabsorption; other patients may be asymptomatic.

76CLINICAL FEATURESClinical manifestations related to a specific micronutrient deficiency can predominate in some patients.. As an example, iron deficiency anemia or osteopenia may be the only clue to the presence of celiac disease in some patients 77CLINICAL FEATURESPartial or isolated malabsorption results from diseases that interfere with the absorption of specific nutrients. Defective cobalamin absorption, for example, can be seen in patients with pernicious anemia or those with disease (or resection) of the terminal ileum such as patients with Crohn's disease.

78Signs and symptoms of malabsorption

TESTSBecause symptoms may be absent or mimic other diseases, a routine battery of blood tests is often helpful as an initial step when malabsorption is suspected. Blood tests alone cannot establish a diagnosis of malabsorption but can provide supportive evidence. Furthermore, deficiencies of specific nutrients and vitamins may point towards the underlying cause and its duration.81TESTSThe malabsorption of fat is the most commonly used indicator of global malabsorption for two reasons:(1) among the macronutrients (fat, carbohydrates, and protein), the process by which fat is absorbed is the most complex and, therefore, it tends to be the most sensitive to interference from disease processes; (2) it is the most calorically dense macronutrient and, therefore, its malabsorption is a critical factor in the weight loss that often accompanies malabsorptive disorders. TESTS for fat malabsorptionQualitative assessment of fecal fat on a single specimen, since it is easier to perform.

Quantitative assessment of a 72 hour stool collection on a 100 gram fat/day diet if the qualitative is negative and clinical suspicion remains high.Sudan III stainon a spot sample of stool can detect more than 90 percent of patients with clinically significant steatorrheaMore than 6 g/day of fat in stool is pathologic, although patients with steatorrhea usually have more than 20 g/day.

83TESTS for carbohydrate malabsorptionD-xylose test - measures the absorptive capacity of the proximal small intestine;Low blood levels and urinary excretion suggests mucosal disease such as celiac sprue. Absorption is usually normal in pancreatic insufficiency since pancreatic enzymes are not required for xylose absorption.

The D-xylose test is used to determine whether defects in the intestinal epithelium are responsible for malabsorption. D-xylose is a pentose monosaccharide that can be absorbed both by an active sodium transporter and by passive diffusion. Following an overnight fast, the patient ingests a 25 g dose of D-xylose, and urine is collected for the next five hours. A venous blood sample is also collected after one hour. Normal excretion of D-xylose is 6.0 +/- 1.5 g (the lower limit of normal in individuals >65 is 3.5 g). Excretion of lesser amounts of D-xylose or a serum D-xylose concentration less than 20 mg/dL suggests abnormal absorption. 84TESTS for carbohydrate malabsorptionLactose tolerance testFollowing oral administration of a 50 g test dose, blood glucose levels are monitored at 0, 60, and 120 minutes. An increase in blood glucose by less than 20 mg/dL plus the development of symptoms is diagnostic. orAn increase in breath hydrogen by more than 20 ppm is diagnostic.85TESTS for carbohydrate malabsorptionBreath tests using H2 or (13)CO2 can be used to diagnose specific forms of carbohydrate malabsorptionBUTRely on bacterial fermentation of nonabsorbed carbohydrate (antibiotic administration often alters the results)13CO2 lactose86TESTS for protein malabsorptionTechnically difficult

Enteral protein loss should be directly demonstrable by measurement of the alpha-1 antitrypsin clearance.Plasma citrulline and arginine concentrations are highly correlated to small bowel length In patients with short bowel syndrome, postabsorptive plasma citrulline determination can be used to estimate functional absorptive bowel length and help determine the likelihood of permanent intestinal failure.

87ADDITIONAL TESTSSchilling test- can also be used to determine the restoration of the functional integrity of the ileal mucosa after treatment of ileal Crohn's diseaseHowever, it is rarely performed given the availability of serum B12 and methylmalonic acid to diagnose B12 deficiency and the easy use of oral crystalline or parenteral injection of B12. Nevertheless, there may be occasional patients in whom it can be informative.Abnormal absorption after the addition of intrinsic factor (and after the exclusion of small intestinal bacterial overgrowth), suggests terminal ileal disease. Small intestinal bacterial overgrowth is suggested if an abnormal test is normalized after a therapeutic trial with antibiotics. 88ADDITIONAL TESTS75SeHCAT (selenium-homotaurocholic acid) testserum test for 7 alpha-hydroxy-4-cholesten-3-one BUTquantitative measurement of bile acids in stool in patients who did not respond to cholestyraminemay be the method of choice to diagnose cholerheic enteropathy.Bile acid malabsorption most often occurs when more than 100 cm of terminal ileum has been removed but can also result from disease of the terminal ileum (usually Crohn's disease).Patients with diarrhea in association with terminal ileal resection are often treated with a bile acid binding resin such as cholestyramine. If this is ineffective, or in patients with terminal ileal disease in whom the diarrhea does not respond to conventional antidiarrheal or anti-Crohn's therapy, objective evidence of cholerheic enteropathy can be established by the seleniumhomocholic acid taurine(75SeHCAT) test.The SeHCAT test involves the administration of a selenium75 labeled synthetic bile acid (selen-homotaurocholic acid) orally, followed by measurement of retention of the bile acid by whole body scan or gamma camera at seven days (abnormal is less than 5 percent).89Tests for bacterial overgrowthThe gold standard for diagnosis of bacterial overgrowth is the direct quantitative measurement of bacterial counts from aspirated intestinal fluid.BUTHydrogen breath tests carbohydrate substrates have replaced bacterial cultures for the diagnosis of small bowel bacterial overgrowth.Normal counts rarely exceed 10(4)/mL in the jejunum and 10(5)/mL in the ileum. However, direct estimation of bacterial counts in the gut requires intubation of the intestine and careful technique to avoid contamination from oral or nasal sources Dyzaccharydes90Tests for pancreatic insufficiencyDIRECT (duodenal fluid is collected and analyzed to quantify normal pancreatic secretory content (ie, enzymes, and bicarbonate)INDIRECT (measure the consequences of pancreatic insufficiency )Several invasive and noninvasive tests are available for the diagnosis of pancreatic insufficiency, which can be classified as direct or indirect. Direct tests involve the stimulation of the pancreas through the administration of a meal or hormonal secretagogues after which duodenal fluid is collected and analyzed to quantify normal pancreatic secretory content (ie, enzymes, and bicarbonate). Only a few specialized centers perform these tests.Indirect tests measure the consequences of pancreatic insufficiency and are more widely available. However, they depend upon the consequences of pancreatic maldigestion, which are generally not apparent until normal enzyme secretory output has declined by more than 90 percent. Thus, they are insensitive to early pancreatic insufficiency.

91Endoscopy and pancreatic imagingA cobblestone appearance of the duodenal mucosa is seen in Crohn's disease, while reduced duodenal folds and scalloping of the mucosa may be evident in celiac disease. The unusual finding of multiple jejunal ulcers may indicate the presence of jejunoileitis or lymphoma Endoscopy and pancreatic imagingSmall bowel biopsy is safe and can help establish the diagnosis.Tissue should be obtained distal to the ampulla of Vater using biopsy forceps passed through a gastroduodenoscope or enteroscope.Obtaining four biopsies at different sites optimizes the likelihood of obtaining a diagnosis Endoscopy and pancreatic imagingImaging of the pancreas by CT, ERCP, MRCP, or ultrasonography may be helpful in the diagnosis of chronic pancreatitis and may be critical for distinguishing benign from malignant causes.

Direct pancreatic intubation tests, such as the secretinstimulation test, still constitute the most sensitive means of diagnosing pancreatic insufficiency in centers in which it is performed accurately (sensitivity and specificity of approximately 80 to 90 percent)The test involves intubation of the duodenum and the collection of pancreatic juices after intravenous secretin injection94Barium studiesAn upper gastrointestinal series with small bowel follow-through or enteroclysis (a double contrast study performed by passing a tube into the proximal small bowel and injecting bariumand methylcellulose) can provide important information about the gross morphology of the small intestine. As an example, identification of small bowel diverticula and other anatomic abnormalities associated with bacterial overgrowth is best achieved with barium studies.

95Wireless capsule endoscopyWireless capsule endoscopy allows for visualization of the entire small bowel and allows for much more detailed evaluation of small bowel mucosal disease than bariumstudies. Thus, it may have a role in evaluating suspected small bowel disease (such as Crohn's disease) associated with malabsorption.Because of the risk of retention, wireless capsule endoscopy should generally be avoided in patients with known or suspected small bowel strictures. 96Celiac disease gluten-sensitive enteropathy/nontropical sprue

frequent intrafamilial occurrence;remarkably close association with the HLA-DQ2 and/or DQ8 gene loci;

immune disorder that is triggered by an environmental agent (the gliadin component of gluten) in genetically predisposed individuals EpidemiologyCeliac disease occurs primarily in whites of northern European ancestry.

Prevalences of 1:300 to 1:500 in most countries.

Although classically a disease of infants, celiac disease now often presents later, between the ages of 10 and 40 years.98CLASSIFICATIONClassic disease:villous atrophysymptoms of malabsorption such as steatorrhea, weight loss, or other signs of nutrient or vitamin deficiencyresolution of the mucosal lesions and symptoms upon withdrawal of gluten-containing foods.Patients with classic disease present with diarrhea, weight loss, or malabsorption, and possess antibodies against gliadin and especially tissue transglutaminase.

99CLASSIFICATIONAtypical celiac disease - patients exhibit only minor gastrointestinal complaints:anemia, dental enamel defects,osteoporosis, arthritis, increased transaminases, neurological symptoms, or infertility.However, most of these patients show severe mucosal damage and possess the celiac specific antibody pattern.

100CLASSIFICATIONAsymptomatic (silent) celiac diseaserecognized incidentally based upon screenings for antibodies against gliadin or tissue transglutaminaseAlthough these patients very often display the characteristic architectural remodelling of the intestinal mucosa seen in celiac disease (ie, crypt hyperplasia and villous atrophy), they do not show clinical symptoms. Often minor symptoms (eg, fatigue) are only realized after introduction of a gluten free diet.

101CLASSIFICATIONLatent celiac diseasepatients who have normal jejunal mucosa and minor symptoms or no symptoms at one or more time points while on a normal, gluten-containing diet Celiac disease was present before, usually in childhood; the patient recovered completely with a gluten-free diet, remaining "silent" even when a normal diet was reintroduced. About 20 percent of such patients continue to have latent disease (asymptomatic with normal villous architecture) into adulthood, while the others re-develop variable degrees of villous atrophy102Clinical manifestationsdiarrhea with bulky, foul-smelling, floating stools due to steatorrhea and flatulence

the consequences of malabsorption:growth failure in children, weight loss, severe anemia, neurologic disorders from deficiencies of B vitamins, osteopenia from deficiency of vitamin Dand calcium.celiac disease may represent a continuum with variable degrees of severityOligosymptomatic patients with celiac disease may have significant nutritional deficiencies.103Nongastrointestinal manifestationsNeuropsychiatric disease(peripheral neuropathy, ataxia, depression, anxiety, or epilepsy)ArthritisIron deficiencyMetabolic bone diseaseHyposplenismKidney disease-glomerular IgA depositionIdiopathic pulmonary hemosiderosisASSOCIATED CONDITIONSDermatitis herpetiformis(up to 24%)

ASSOCIATED CONDITIONSDiabetes mellitus- type 1Down syndromeLiver diseaseAutoimmune thyroid disease InfertilityMyocarditis and cardiomyopathyAtrophic glossitisPancreatitisDIAGNOSTIC APPROACHAll testing should be performed while patients are on a gluten-rich diet.

Serologic evaluation(IgA anti tissue transglutaminase and IgA endomysial antibody)The duodenal mucosa may appear atrophic with loss of folds, contain visible fissures, have a nodular appearance or the folds may be scalloped, but such findings are not universally present and may be seen with other disorders 107DIAGNOSTIC APPROACHSmall bowel biopsy

The duodenal mucosa may appear atrophic with loss of folds, contain visible fissures, have a nodular appearance or the folds may be scalloped (picture 1), but such findings are not universally present and may be seen with other disorders 108DIAGNOSTIC APPROACH

109

DIAGNOSTIC APPROACHSymptoms resolve subsequently on a gluten-free diet111Principles of a gluten-free dietWheat, rye, and barley avoided.

Soybean or tapioca flours, rice, corn, buckwheat, and potatoes are safe.112Nutritional considerationsSpecific dietary deficiency such as iron, folic acid, calcium, vitamin Dand, rarely, vitamin B12 deficiency should be corrected.Monitoring the response to a gluten-free dietThe rapidity of the response to a gluten-free diet is variable. Approximately 70 percent of patients have noticeable clinical improvement within two weeks;

Symptoms improve faster than histology;

Decline in the titer of antiendomysial antibodies.We suggest that a repeat small intestinal biopsy be obtained three to four months after beginning a gluten-free diet to demonstrate histologic improvement. 114NonrespondersThe most common reasons for a lack of response are poor compliance or inadvertent gluten ingestion

Other disorders Refractory sprue (type 1 and 2)Ulcerative jejunitis or intestinal lymphomagluten-free labeled productsType 1 in which there is a normal population of intraepithelial lymphocytes.Type 2 in which there is an aberrant or premalignant population of intraepithelial lymphocytes based upon clonality analysis of T-cell receptors and immunophenotyping. Type 2 can progress to enteropathy-associated T-cell lymphoma, which may present clinically as ulcerative jejunitis 115Refractory sprueCan be severe and associated with progressive malabsorption and death. A subset of patients develops subepithelial collagen deposition, a condition referred to as "collagenous sprue.

The dose of glucocorticoids required varies among patients, and not all patients respond. The dose of glucocorticoids required varies among patients, and not all patients respond. In severely ill patients, we usually begin with hydrocortisone(100 mg IV Q6H). Oral dosing (such as 40 to 60 mg of prednisolonedaily) can be used in patients who are tolerating an oral diet. After a few weeks, the dose can be reduced by 5 to 10 mg per day in responding patients and subsequently tapered to the lowest dose that keeps the patient in remission.However, azathioprineand 6-mercaptopurine appear to be effective steroid-sparing agents

116Ulcerative jejunitis and intestinal lymphomaConsidered in patients with refractory sprue unresponsive to corticosteroids;

Aberrant T-cell monoclonality;

Clinical manifestations are similar to severe celiac disease; lassitude, anorexia, weight loss, abdominal pain, diarrhea, and fever.Intestinal stricturing can develop with resulting small bowel obstruction.Ulcerative jejunitisUlcerative jejunitis responds poorly to a gluten-free diet

Associated with an unfavorable prognosis. Up to one-third of patients die from complications.

The prognosis can be improved if the ulcerated or strictured segment can be resected.118Enteropathy-associated T-cell lymphomaLymphomas are almost always of high-grade histology and the prognosis is poor. Five-year survival is approximately 10%.

Other complicationsEsophageal cancerAdenocarcinoma of the small bowelSHORT BOWEL SYNDROMEMalabsorption due to insufficient intestinal surface area, such that the affected person is unable to absorb sufficient fluid, energy or nutrients to sustain life in the absence of specific nutritional supportLess than 200 cm of SB presentEtiologyCrohns diseaseMesenteric infarctionMassive enterectomies after trauma, etc.

Intestinal atresia, necrotisig enterocolitis (pedriatic)ConsequencesThe degree of malabsorption is determined by:The length of the remaining intestine;The adequacy of the adaptive process in the residual intestine (up to 2 years to fully develop)The presence of the ileo-cecal valve (brake to slow the intestinal transit) and prevents bacterial overgrowthThe presence of the colon (up to 1000 kcal/day)

Most patients with a jejunal length of less than 100 cm and no colon will require long-term parenteral nutritionConsequencesThe ileum is able to compensate for the jejunal lossThe jejunum is unable to compensate for the ileal absorption of bile salts and vitamin B12ConsequencesThe proximal small bowel receives 7-9 L daily of water and electrolytes, of which 6-8 L is reabsorbed in the small bowel

HypovolemiaHyponatremiaHypokalemia

Medical managemetAppropriate fluid and electrolyte managementTotal parenteral nutrition

Wait for ADAPTATION

Medical managemetAntidiarrheal drugs (loperamide, codeine, octerotide)Special diets (hypercaloric, in small meals)Vitamin supplementationMedication malabsorbtion also!!!

Home parenteral nutrition (overnight; tunneled catheter)

ComplicationsBile stones (altered composition of bile)Liver disease (after 5 y of TPN, frequent grade 2 fibrosis or more, including liver failure) due to malabsorbtion of nutrients and shortcut of the portal routeCalcium oxalate kidney stones (fat malabsorbtion)Lactic acidosis (colon present)Metabolic bone diseaseNeurologic abnormalities

Bacteria in the colon metabolize carbohydrates128SurvivalTPN dependence:86% at 2 years;75% at 5 years.

Quality of life!In U.S. most of them can work full-time!!Surgical managementAnastomosis with the remaining colonIntestinal lengthening proceduresCreation of intestinal valves

Intestinal transplantation (intestinal/liver transplant!)

Whipple's disease

etiologic agent was identified in 1991

Tropheryma whippleigram-positive, non-acid-fast, periodic acid-Schiff (PAS) positive bacillusEPIDEMIOLOGYThe spectrum of infections due to T. whipplei is wide.

In Europe, the prevalence of the bacterium in fecal samples from the healthy adult population is estimated to be 1 to 11 percent.EPIDEMIOLOGYThe disorder has a predilection for white males of European ancestry, suggesting an underlying genetic predisposition that leads to colonization of T. whipplei throughout the intestinal tract, lymphoreticular system, and central nervous system upon exposure to soil microbesthe annual incidence since 1980 has been approximately 30 cases per yearPATHOGENESISInvasion or uptake of the bacillus is widespread throughout the body.

All of these sites show a remarkable lack of inflammatory response to the bacillus. In addition, the organism exerts no visible cytotoxic effects upon host cells, thereby allowing massive accumulation of T. whipplei at sites of infection.

CLINICAL MANIFESTATIONSArthralgiasWeight lossDiarrheaAbdominal pain

progress to a severe wasting syndrome

migratory arthralgias of the large joints or, less often, a chronic, migratory nondeforming oligoarthritis or polyarthritis which may precede other symptoms by many yearsLater in the course, diarrhea and weight loss progress to a severe wasting syndrome, with late findings including abdominal distention due to ascites or massive adenopathy. Dementia and other central nervous system findings (such as supranuclear ophthalmoplegia, nystagmus, and myoclonus) occur more frequently (21 percent in one series) in the later stages of the disease 135CLINICAL MANIFESTATIONSThere may also be symptoms or signs related to cardiac disease (dyspnea, pericarditis, culture-negative endocarditis), pleuropulmonary (pleural effusion), or mucocutaneous disease;

CNS disease(cognitive dysfunction, oculomasticatory or oculofacial myorhythmia , cerebellar ataxia, dementia, myoclonus, hemiparesis, peripheral neuropathy, seizures, upper motor neuron disorders)migratory arthralgias of the large joints or, less often, a chronic, migratory nondeforming oligoarthritis or polyarthritis which may precede other symptoms by many yearsLater in the course, diarrhea and weight loss progress to a severe wasting syndrome, with late findings including abdominal distention due to ascites or massive adenopathy. Dementia and other central nervous system findings (such as supranuclear ophthalmoplegia, nystagmus, and myoclonus) occur more frequently (21 percent in one series) in the later stages of the disease 136EVALUATIONEndoscopy with small bowel biopsy(extensive PAS-positive material in the lamina propria and villous atrophy )

EVALUATIONConfirmatory electron microscopy to demonstrate T. whipplei should be performed if the diagnosis is in doubt PCR techniques

TREATMENTparenteral ceftriaxonefollowed by oral trimethoprim-sulfamethoxazole(TMP-SMX, one double-strength tablet twice daily) maintenance therapy for one yearTreatment regimens in more severely ill patients consist of an initial phase of intravenously administered antibiotics known to penetrate the blood-brain barrier, followed by 12 months of oral maintenance treatment (table 1). We suggest initial therapy with ceftriaxone(2 g IV once daily) or penicillin (2 MU IV every 4 hours) for two weeks, followed by TMP-SMX (one double-strength tablet twice a day) for one year [85]. For sulfa allergic patients, an alternative maintenance therapy is doxycycline(100 mg PO twice daily) in combination with hydroxychloroquine(200 mg PO thrice daily) [19]. For ceftriaxone and penicillin allergic patients, we suggest TMP-SMX (one double-strength tablet three times daily) plus streptomycin(1 g IM daily) for two to four weeks, followed by TMP-SMX (one double-strength tablet twice a day) for one year.For patients with endocarditis, we suggest penicillin G(2 MU IV every 4 hours) or ceftriaxone(2 g IV once daily) for four weeks, followed by TMP-SMX (one double-strength tablet twice a day) for one year. Surgical resection of the infected valve is usually also needed.For patients with CNS disease we suggest ceftriaxone(2 g IV once daily) or penicillin G(4 MU IV every 4 hours) for four weeks, followed by TMP-SMX (one double-strength tablet twice a day) for one year.For patients who relapse, we suggest penicillin G(4 MU IV every 4 hours) or ceftriaxone(2 g IV twice daily) for four weeks followed byoral doxycycline(100 mg twice daily) in combination with hydroxychloroquine(200 mg PO thrice daily) [18]ORTMP-SMX (one double-strength tablet twice a day) for one year.

139TREATMENTSeveral reported cases of Jarisch-Herxheimer reactions one to two hours after initial therapy of Whipple's disease with intravenous antibiotics, especially penicillin. The reaction consists of fever of 39 to 40C, chills, headache, hypotension, and severe abdominal pain or pleuritic chest painRelapseRelapses have been reported in as many as 17 to 35 percent of patients.

Relapses should be treated with initial ceftriaxone(2 g IV twice daily for four weeks) followed by one year or more of oral doxycycline(100 mg twice daily) plus hydroxychloroquine (200 mg PO thrice daily).Lactose intolerance

Intolerance to lactose-containing foods (primarily dairy products) is a common problem:the prevalence is 7 to 20 percent in Caucasian adults;65 to 75 percent among Africans and African Americans;50 percent in Hispanics.

Clinical symptoms diarrhea, abdominal pain, and flatulence after ingestion of milk or milk-containing productsETIOLOGY OF LACTOSE MALABSORPTIONprimary lactasedeficiencylactase deficiency induced by underlying intestinal diseasePrimary lactose malabsorptionRacial or ethnic lactose malabsorption(lactase nonpersistence)

Developmental lactase deficiency(a consequence of prematurity)Congenital lactase deficiency(rare autosomal recessive disorder)This disorder was usually fatal prior to the development of lactose-free infant formulas.145Secondary lactose malabsorptionBacterial overgrowth or stasis syndromes Any form of mucosal injury of the gastrointestinal tract that causes villus flattening or damage to the intestinal epithelium

Lactaseis usually the first affected disaccharidase in these disorders, presumably because of its distal location on the villus. Treatment of the primary disorder can lead to restoration of lactase activity, which often lags behind the return of normal intestinal morphology. Lactose intolerance may persist for months after healing starts; this effect is unique to this enzyme and its biochemical basis is unexplained.

146DIAGNOSISLactose tolerance test(sensitivity of 75 percent and a specificity of 96 percent )

Has largely been replaced by the lactose breath hydrogen test - measures lactose nonabsorption.Values of breath hydrogen over 20 ppm are considered diagnostic of lactose malabsorptionFollowing oral administration of a 50 g test dose in adults (or 2 g/kg in children), blood glucose levels are monitored at 0, 60, and 120 minutes. An increase in blood glucose by less than 20 mg/dL (1.1 mmol/L) plus the development of symptoms is diagnostic. False negative results may occur in patients with diabetes or bacterial overgrowth. Abnormal gastric emptying also can lead to spurious results; the blood glucose may be relatively higher with rapid emptying and depressed with delayed gastric emptying.

147TREATMENTfocuses on eliminating symptoms, while helping the patient adapt to a gradual increase in lactose intake.

correctable underlying disease?TREATMENTReduced dietary lactose intakeSubstitution of alternative nutrient sources to maintain energy and protein intakeAdministration of a commercially available enzyme substitute (beta-galactosidases)Maintenance of calcium and vitamin DintakeComplete restriction of lactose-containing foods should only be necessary for a limited period to ascertain the specificity of the diagnosis. Some patients can tolerate graded increases in lactose intake, small quantities of lactose may subsequently be reintroduced into the diet.

Commercially available "lactase" preparations are actually bacterial or yeast beta-galactosidases.Lactaid (tablets or liquid), Lactrase, LactAce, DairyEase, and Lactrol

Live culture yogurt, which contains endogenous beta-galactosidase, is an alternative source of calories and calcium, and may be well-tolerated by many lactose-intolerant patients. However, yogurts that contain milk or milk products added back after fermentation (such as many of the commercially available yogurt products in the United States) may produce symptoms.

Avoidance of milk and other dairy products can lead to reduced calcium intake, which may increase the risk for osteoporosis and fracture .149