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Subject: Medicine 2Topic: GI part 3
Lecturer: Dr. MappalaShifting /Date: 3rd /October 31, 2008Trans group: Eis, Candy, Isay, Jassie
“Diarrhea is the too rapid evacuation of too fluid stools”
The Amazing Intestines 10 liters of ingested fluid and secretions enter the intestine
daily 90% absorbed in small intestine 90% of remaining fluid (~800-1000 mL) absorbed in colon 80-100 mL fluid in stool daily Normal stool output: 200 grams/24hours Loose stool: increase of 50-60 mL
Diarrhea Acute diarrhea: diarrhea lasts less than 4 weeks Chronic diarrhea: diarrhea lasts longer than 4 weeks Excess water, electrolytes, fat, other substances in intestinal
lumen More than 200 grams stool in 24 hours
Is it Diarrhea? Pseudodiarrhea – more frequent bowel movements but <
200 g/24 hours Incontinence – involuntary loss of stool
o Anal sphincter dysfunctiono Neurologic impairment
Pathophysiology of Diarrhea Osmotic Malabsorption/Maldigestion/Fatty Inflammatory Secretory Altered motility
Certain causes of diarrhea have several pathophysiologic mechanisms
Osmotic Diarrhea Excess amounts of poorly absorbed substances that remain
in intestinal lumen Substances that exert osmotic effect Obligate water retention in intestinal lumen Lactose, lactulose, magnesium, polyethylene glycol (PEG)
MARY YVETTE ALLAIN TINA RALPH SHERYL BART HEINRICH PIPOY KC JAM CECILLE DENESSE VINCE HOOPS CES XTIAN LAINEY RIZ KIX EZRA GOLDIE BUFF MONA AM MAAN ADI KC PENG KARLA ALPHE AARON KYTH ANNE EISA KRING CANDY ISAY MARCO JOSHUA FARS RAIN JASSIE MIKA SHAR ERIKA MACKY VIKI JOAN PREI KATE BAM AMS HANNAH MEMAY PAU
RACHE ESTHER JOEL GLENN TONI
F is for Friends who do stuff together.
Subject: Medicine 2
Topic: GI part 3 (SI and LI)Page 2 of 18
Lactose Intolerance
Fecal Osmotic Gap290 mosm/kg H2O – 2 ([Na+] + [K+])Osmotic diarrhea: >125
Malabsorption Luminal phase
o Intraluminal maldigestion Mucosal phase
o Mucosal loss (i.e. surgical resection)o Mucosal disease
Transport phase
Fat Malabsorption Steatorrhea – “oily” stool Possible deficiencies of fat soluble vitamins: A, D, E, K Causes:
o Bacterial overgrowtho Pancreatic insufficiencyo Mucosal diseases
Diagnosis: Sudan stain stool; 72 hour stool collection and measurement of fecal fat
Bile Salt Inactivation: Small Intestinal Bacterial Overgrowth Syndrome
Normal concentration of bacteria in proximal small intestine: <104 organisms
Conditions that predispose to bacterial overgrowth cause:o Intestinal stasiso Abnormal connection between proximal and distal
bowel
Conditions Predisposing to Bacterial Overgrowth Intestinal Stasis
o Anatomic Intestinal Strictures Small intestinal diverticulosis Surgical procedures
o Motility disorders Scleroderma Diabetes mellitus
Abnormal connections between proximal and distal bowelo Resection of ileocecal valveo Fistulas
Pathophysiology of Malabsorption in Bacterial Overgrowth Reduced nutrient availability
o Bacteria consumes nutrients Bile salt inactivation
o Excess bacteria deconjugate bile saltso Unconjugated bile salts unable to solubilize
micelles → fat malabsorption
Diagnosis of Small Intestinal Bacterial Overgrowth Syndrome Direct aspiration of jejunal contents Breath tests
o 14C glycocholate Conjugated bile acid – deconjugated by
bacteria – 14C metabolized to 14CO2
Low sensitivity and specificity Not widely used in US
o 14C xylose – not widely availableo Glucose or Lactulose
Measure expired H2 (breakdown product of bacterial fermentation)
Treatment of Small Intestinal Bacterial Overgrowth Syndrome Correct predisposing condition Correct nutritional deficiencies Antibiotics
Increased Bile Salt Losses Mucosal disease in terminal ileum: Crohn’s disease Surgical resection or bypass of ileum Mechanism of diarrhea : (chlorrheic diarrhea, bile acid
diarrhea)o Bile acids that reach colon cause colonic secretion
of electrolytes and watero Fat malabsorption
Defective Nutrient Hydrolysis Lipase inactivation by excess HCl (Zollinger-Ellison syndrome) Pancreatic enzyme deficiency
o Chronic pancreatitiso Pancreatic cancer – obstruction of pancreatic duct
Improper mixing or rapid transit of nutrients
Test for Pancreatic Insufficiency Invasive
o Secretin stimulation test Inject secretin IV Aspirated pancreatic juice from
duodenum Bicarbonate and amylase levels Low levels consistent with pancreatic
exocrine insufficiency
Non-invasiveo Fecal Chymotrypsin level
Low with pancreatic exocrine insufficiency
o Fecal Elastase level Low in pancreatic exocrine insufficiency
Subject: Medicine 2
Topic: GI part 3 (SI and LI)Page 3 of 18
Most sensitive/specific fecal testo Serum trypsinogen level
Malabsorption: Mucosal Loss Extensive surgical resection
o Short bowel syndrome Extensive infarction
Malabsorption: Mucosal Disease Complication of radiation treatments Infections Vascular insufficiency (ischemia) Inflammatory conditions
o Crohn’s diseaseo Celiac sprue
Celiac Sprue Gluten sensitive enteropathy Reaction against gluten in diet Epidemiology: whites (highest in Northern European
descent) Pathogenesis
o Mostly Genetic & Environmental, sometimes Autoimmune
o Ingestion of gliadins, hordeins, and secalins: proteins found in wheat, barley, and rye → infiltration of intestinal mucosa with intraepithelial CD8+ lymphocytes and CD4+ lymphocytes in lamina propria → villous atrophy
o CD4+ T cells mediate disease processo Genetic: very close association with HLA-DQ2
(presents peptides to and binds CD4) Lesser association with HLA-DQS
Pathology o Villous atrophy: flattening of mucosa, loss of villio Increased lamina propria lymphocytes
Clinical Presentation o Varied – depends on extent of mucosal diseaseo Typical: crampy abdominal pain, chronic diarrhea,
bloating, weight loss, steatorrheao Iron deficiencyo Osteoporosis (vitamin D, Ca2+)o Easy bruising (vitamin K0o Peripheral neuropathy (Vitamin B12)
Associated Diseases o Dermatitis herpetiformis
IgA deposits in skin Pruritic, blistering
o Small intestinal lymphoma Risk may be less adherence to gluten
free diet
Diagnosis o Biopsy of small intestine during endoscopyo Blood tests
Anti-gliadin antibodies (IgA and IgG) Anti-endomysial antibodies (IgA) Tissue transglutaminase antibodies
Treatment o Gluten free dieto Nutritional supplementation
Iron Vitamin D, calcium Vitamin B12 (intramuscularly)
o The future: ingesting substances that will breakdown gluten
Drugs Causing Malabsorption Luminal effect
o Neomycino Cholestyramineo alcohol
Mucosal effecto Villous flattening
Colchicine Methotrexate
Strictureo NSAIDs
Enterocyte damageo Direct toxicity
alcohol Brush border enzyme effect
o Neomycino Alcohol
Intracellular effecto Laxatives
Subject: Medicine 2
Topic: GI part 3 (SI and LI)Page 4 of 18
o Colchicineo Biguanides
D-Xylose Test: General Test for Malabsorption Xylose
o Sugar absorbed in duodenum and jejunumo Not completely metabolizedo Excreted in urine intact form
Xylose administered orally and urine collected Abnormal: <4 g xylose in urine after 25 g dose Caveats
o Renal functiono Bacterial overgrowtho Vary rapid intestinal transit
Secretory Diarrhea Abnormal ion transport in intestinal epithelial cells Decreased abdorsption of electrolytes Electrolytes: major solutes in intestinal lumen Electrolytes account for most of luminal osmolality Congenital defects in ion absorption Intestinal resection Diffuse mucosal disease Abnormal mediators
o Fatty acids: stimulate colon secretiono Bile acids: stimulate fluid and electrolyte secretion
in colono Circulating agents released by neuroendocrine
tumors
Fecal Osmotic Gap290 mosm/kg H2O – ([Na+} + [K+]
Osmotoc diarrhea: >125Secretory diarrhea: <50
Altered Intestinal Motility Autonomic diabetic neuropathy – “diabetic diarrhea” Hyperthyroidism After vagotomy (peptic ulcer surgery) Irritable bowel syndrome (IBS)
Irritable Bowel Syndrome Chronic or recurrent Lower abdominal pain Disturbed defecation Bloating Not explained by structural or unknown biochemical
abnormalities
IBS: Symptoms Abdominal pain eith constipation or diarrhea Bloating, gas Abdominal distention
IBS: Epidemiology Prevalence in North America is 10%-20%
o Equally divided between IBS with diarrhea, IBS with constipation, and IBS alternating between diarrhea and constipation
o Prevalence of each subtype is ~ 5% 2:1 female predominance in North American population-
based studies
Extent and Impact of IBS
IBS in 10%-20% of US Population(approximately 35% of these patients seek medical care)
Increases Absenteeism andDecrease Work Productivity
IBS: Pathophysiology IBS is a condition associated with altered brain-gut
communication resulting in:o Distributed gut function and sensationo Disturbed CNS function
IBS patients displayo Altered CNS responsiveness to visceral stimulio Visceral hyper responsiveness to environmental
and luminal events (gut)
Role of Enteric Nervous System ENS contains many neurotransmitters, including 5-HT,
substance P, VIP and CGRP ENS controls motility and secretory functions of the intestine ENS functions autonomously, but may be modified by the
parasympathetic and sympathetic nervous systems
Selected Mediators of Motility and Visceral Hypersensitivity
Motility Visceral Hypersensitivityo Serotonino Acho ATPo Motilino Nitric Oxideo Somatostatino Substance Po Vasoactive intestinal
polypeptide (VIP)
o Serotonino Bradykinino Tachykininso Calcionin gene-related
peptide (CGRP)o Neurotropins
F is for Friends who do stuff together. F.U.N. Here with my best buddy.
Extent and Impact of IBS
Annual Cost of Disease is High (~$21 billion per annum)
Reduce Quality of Life
Subject: Medicine 2
Topic: GI part 3 (SI and LI)Page 5 of 18
Rome Criteria Atleast 12 weeks of continuous or recurrent symptoms:
o Abdominal pain and discomfort Relieved with defecation or Associated with a change in frequency of
stool or Associated with a change in consistency
of stool 2 or more of the following, a least on ¼ of accasions or days:
o Altered stool frequencyo Altered stool formo Altered stool passageo Passage of mucuso Bloating or feeling of abdominal distention
IBS: Diagnosis (RED FLAGS) Physical:
Abnormal exam Fever Positive occult stool
Historical: Weight loss Onset in elder patients Nocturnal awakening Family History of CA or IBD
Initial Labs: Hgb ↓ WBC↑ ESR ↑ Abnormal chemistry
Therapeutic Options for Patients with IBS Antispasmodics: hyoscyamine and dicyclomine Bulking agents Antidiarrheals Antidepressants Alosetron Tegaserod Behavioural therapy
Explanations for Diarrhea
Bile salt malabsorption- Cholerrheic diarrhea
Bacterial Overgrowth Syndrome Secretagogue Pancreatic insufficiency – chronic pancreatitis Alcohol Possible nutrient deficienies:
- Vitamin A, D, E, K- Vitamin B12
CASE PRESENTATION:
1) 62 year old woman complains of floating stool with oil droplets around stool. She has lost 10lbs. She also notices that she bruises very easily. She often feels bloated and distended. She had surgery 10 years ago to remove several areas of small intestine after an episode of ischemic bowel.
a. What is the most likely cause of her symptoms?b. What tests would you order to help confirm the
diagnosis?c. How would you treat her?
2) A 44 year-old man is admitted to the hospital with an acute upper GI bleed due to several gastric and duodenal ulcers seen on an urgent upper endoscopy of the duodenum. The patient also complains of a 1 year history of frequent non-bloody diarrhea. A fecal osmotic gap is very low.
a. What type of chronic diarrhea does this patient have?
b. What is the most likely cause?c. What is the mechanism to explain the diarrhea?d. What blood test can you check to make the
diagnosis?3) 55 year old male alcoholic referred to GI with persistent
(>4weeks) loose non-bloody stool. Diarrhea often wakes him from sleep. 6 months earlier: surgical resection of 50cm of ileum due to carcinod tumor of ileum. Reports no fever or abdominal pain. He has lost approximately 10 lbs.
4) 28 year old man complains of abdominal bloating and foul smelling gas. He has intermittent diarrhea after eating ice cream. He has always been able to eat ice cream before.
a. What is the most likely explanation for the patient’s symptoms?
b. How would you treat his symptoms?
ANSWERS:1) Short Bowel Syndrome (Malabsorption) confirmed by sudan
test. Bleeding due to ↓ in vitamin K dependent factors.2) Zollinger-Ellison hypergastrenemia3) Short Bowel Syndrome; if NO surgical resection + normal
laboratory findings IBS4) Lactose intolerance (Osmotic diarrhea) or Contaminated ice
cream
NON-MALIGNANT COLONIC DISEASES Constipation Diverticula Appendicitis Hemorrhoids Anorectal Disease
Hahahahaha… hahahahaha.. hahahahahaha…
Subject: Medicine 2
Topic: GI part 3 (SI and LI)Page 6 of 18
- fissures, fistulae, abscess
CONSTIPATION reported by 5-30% of the population women>men non-whites > whites Older age – but any age group possible 6.8% of >65 y.o. use laxatives weekly 2.5 million office visits yearly
Symptoms infrequent stools stools difficult to pass digitate sense of incomplete evacuation soiling clothes bloating
DefinitionTwo or more symptoms for at least 3 months: Training >25% of time Hard stools >25% of time Incomplete evacuation > 25% of time Less than 3 bowel movements per week
Functions of Colon absorb water and electrolytes slow feel of passage in right colon propulsion of feces to rectosigmoid by left colon storage of feces in rectum defecation
Mechanism of Defecation Holding
- Puborectalis plus external anal-sphincter contracting
Skeletal muscle responses- Puborectalis plus external anal-sphincter relax- Levator ani, rectus muscles and diaphragm
contract Smooth muscle responses
- Internal anal sphincter relaxes- Rectal contraction
Causes of Constipation mode of life drugs Metabolic Neurologic GIT abnormalities
- Mechnical obstruction Anorectal abnormalities Idiopathic
Drugs Associated With ConstipationClass ExamplesPrescription DrugsOpiates Morphine
Anticholinergic drugsTricyclic antidepressantsCalcium channel blockersAntiparkinsonian drugsSympathomimeticsAntipsychoticsDiureticsAntihistamines
Librax, belladonnaAmitryptiline>nortiptylineVerapamil hydrochlorideAmandatadine hydrochlorideEphedrine, terbutalineChlorpromazineFurosemideDiphenhydramine
Nonprescription drugsAntacids, especially calcium containingCalcium supplementsIron supplementsAntidiarrheal agentsNSAIDS
Loperamide, attapulgiteIbuprofen
Metabolic Causes of Constipation Hypothyroidism Diabetes mellitus Hypercalcemia
- Depressive effect on autonomic nervous system- Smooth muscle hypotonicity- Dehydration
Hypokalemia Uremia Heavy metal poisoning
Neurologic Causes of Constipation Spinal cord injury Multiple sclerosis Parkinson’s Diseae Autonomic neuropathy
GIT Abnormalities Colon cancer External compression on colon from malignant lesion
- Ovarian cancer Stricture
- Diverticular- Ischemia
Post-surgical (anastamotic stricture)
GIT Abnormalities: Hirschsprung Disease Ruysch 1691 HIrschprung 1886 Swenson 1948 Heterogenous genetic disorder
- Autosomal dominant and recessive forms Congenital absence of ganglion cells in distal colon
- Begins at anus and extend proximally (variable distance)
Myenteric (Auerbach’s) and submucosal (Meissner’s) plexus are absent
- Problem with migration and development of neural crest cells
- Loss of neural inhibition – colon remains contracted
Proximal colon is dilated (“megarectum”) Diagnosis: newborns/infants Treatment: surgery
Subject: Medicine 2
Topic: GI part 3 (SI and LI)Page 7 of 18
Anorectal Abnormalities Rectocoele (if very large)
- Protrusion of anterior rectal wall into vagina - Defect of recto-vaginal septum
Anal fissure Trauma
- Recent vaginal delivery
Idiopathic/Functional Constipation Irritable bowel syndrome Slow colonic transit (colonic inertia) Evacuatory failure
- Pelvic floor dysfunction
Idopathic Constipation: Slow Transit Constipation Slow Transit Constipation: slower than normal movement of
feces from right to left colon- Colonic inertia
Decreased numbers of high amplitude propagated contractions
- increased, coordinated motor activity in distal colon
functional barrier/resistance to normal transit
Idiopathic Constipation: Pelvic Floor Dysfunction “Evacuatory failure”: inability to adequately evacuate
content from rectum- Muscular hypertonicity
Faliure to relax Incomplete relaxation Paradoxical contraction of pelvic floor
and external anal sphincter during attempted defecation
- Muscular hypotonicity Excessive perineal descent
mechanism unclear; heterogenous disorders
Irritable Bowel Syndrome altered motility visceral hypersensitivity alterations in enteric nervous system and interaction with
central nervous system impact of neurotransmitters serotonin
Serotonin (5-HT) in the Human Gut5-HT1 5-HT2 5-HT4
Gastric accommodation ↑ ↑Transit ↓ ↑ ↑Colonic tone ↓ ↑Sensation ↑ ?Secretion ↑
Tests to Evaluate Cause of Constipation Barium x-ray, colonoscopy – exclude structural disease Measurement of colonic transit time
- Colonic markers studies Defecography Anorectal manometry
Treatment of Constipation diet life changes laxatives – avoid dependence enemas, suppositories Prokinetic drugs
DIVERTICULA may be located throughout intestinal tract (esophagus
colon) most common in colon rare in esophagus and stomach in SI may predispose to bacterial overgrowth syndrome
1. Meckel’s Diverticulum remnant of primitive yolk sac may be connected to umbilicus fibrous band: remnant of
vitello-intestinal tract mostly located in distal ileum on anti-mesenteric disorder walls have all layers of intestine
2. Colonic Diverticulosis associated with low fiber intake incidence increases with age higher incidence in western countries located most commonly on left side of colon 96% sigmoid 35% ascending, transverse, descending Herniations of mucosa and submucosal of colon through
muscularis Develop in rows between mesenteric and lateral taniae Penetrating vasa rectae – points of greatest weakness Hypersegmentation of colon - increased luminal pressure Clinical Manifestations:
- Most aysmptomatic- Intermittent abdominal pain or bloating- Altered stool caliber if colon is narrowed
Diagnosis: Colonoscopy
Diagnosis: Barium enema
Subject: Medicine 2
Topic: GI part 3 (SI and LI)Page 8 of 18
Treatment: - High fiber diet- Fiber supplements- Rarely: surgical resection
3. Diverticular Bleeding Painless rectal bleeding 15-40% of patients with diverticulosis Caused by chronic injury to vasa recta Diagnosis: Colonoscopy, nuclear medicine studies Treatmetn:
- Conservative- Angiography- Surgery (rarely)
4. Diverticulitis inflammation and perforation of diverticulum in 10-25% of patients with diverticulosis microperforation of diverticulum from impissiated stool
using abrasions of mucosal lining Symptoms: fever, left lower quadrant pain High WBC
Diverticulitis: Complications Abscess Luminal obstruction Peritonitis Fistula
- Colo-enteric- Colo-cutaneous- Colo-vesical- Colo-vaginal
Diverticulitis Evaluation Physical exam No endoscopic procedures No barium enemas Blood work: CBC CT scan
Diverticulitis: Treatment Uncomplicated
- Conservative measures- Antibiotics- Surgery in younger patients (<40 yo)
Complicated- Antibiotics
- Surgery – usually two stage
APPENDICITISMost common surgical emergency
5-10% of population Obstruction of appendiceal lumen by fecaliths In 1/3 of patients appendix has no obstruction –
pathogenesis unclear/ controversial
Variable locations of Appendix retrocecal subcecal postileal preileal pelvic
Appendicitis: Clinical Presentation History most importantClassic:
- pain at some site in abdomen (peri-umbilical)- anorexia, nausea, vomiting- pain over appendix (RLQ) – McBurney’s point- Fever
History may vary in retro-cecal appendix, elderly, pregnancy, immunosuppressed
Appendicitis: Evaluation and treatment Physical exam Blood tests: CBC Radiologic test not always necessary:
- CT Scan- Ultrasound
Treatment: Surgery- Open- Laparoscopic
HEMORRHOIDS Prevalence in USA: ≈ 50% adult population Symtpomatic in 10-25% Collection of vascular tissue, “cushion”, in anal canal Normal – maintains continence Internal hemorrhoids
- Dilatation of superior (internal ) hemorrhoids veins- Covered by mucosa
External hemorrhoids- Dilatation of inferior (external ) hemorrhoids veins- Covered by perianal skin
May have both as these veins may form anastomoses
Anorectal Anatomy
Subject: Medicine 2
Topic: GI part 3 (SI and LI)Page 9 of 18
Hemorrhoids Pathogenesis normal vascular cushions downward pressure during defecation muscle fiber anchor hemorrhoids loosen hemorrhoidal tissue slides, congested, bleeds prolapse
Hemorrhoids: Symptoms bright red bleeding prolapse ( may sense a protruding mass) mucoid discharge with prolapse itching if poor hygiene not painful unless external and thrombosed
Hemorrhoids: Diagnosis rectal exam anoscopy flexible sigmoidoscopy
Hemorrohids: TreatmentRationale TreatmentReduce Downward Pressure Diet, bulk agents(fiber)
Avoid prolonged sitting at defecation
Fix cushions to underlying sphincter
SclerosantsRubber band ligationCryotherapyPhotocoagulationElectrocoagulation
Reduce sphincter pressure Manual dilatationInternal sphincterectomy
Excise hemorrhoids hemorrhoidectomy
ANAL FISSURES longitudinal or elliptical defect in anal canal young – middle-aged 90-98% occur posteriorly in midline Due to trauma from stool or associated with Crohn’s
disease; carcinoma Chornic anal fissure:
- Fissure
- Hypertrophic anal papilla at proximal end- Sentinel at lower end
symptoms: extreme pain with defecation, bleeding treatment: fiber, bath, nitro, botox, surgery
1. Anorectal Abscess infections of tissue spaces adjacent to rectum and anal canal predisposing conditions: Crohn’s, hematological disorders,
immunodeficiency states pain, fever, mass surgical drainage antibiotics
Anorectal Abscess1. submucosal2. pelvirectal3. ischiorectal4. perianal5. marginal6. intersphincter
2. Anorectal Fistula hollow fibrous tract lined by granulomatous tissue opening inside anal canal or rectum and another orifice to
perianal skin drainage of pus, blood, mucus stool associated disorders: Crohn’s, cancer, prior radiation
treatments Treatment: antibiotic, surgery
Anorectal Fistulas Intersphincteric Suprasphincteric Trans-sphincteric Extrasphincteric
Subject: Medicine 2
Topic: GI part 3 (SI and LI)Page 10 of 18
Case Presentation52 year old woman with 25 year history of constipation. She often goes 1-2 weeks without a bowel movement. No trouble passing stool. She has bloating, cramping.
What disorders should be excluded as a cause of this patient’s constipation?
o Metabolic, mechanical obstruction, mediations, neurologic
What is the pathophysiology of idiopathic constipation?o Slow transito Pelvic floor dysfunction
How would you treat her?o Fibero Osmotic laxativeso Tegaserod
INFLAMMATORY BOWEL DISEASE
Inflammatory Bowel Disease
Ulcerative Colitis Crohn’s Disease
Mucosal Ulceration Transmural Inflammation in Colon
IleocolitisIleitis Colitis
The Spectrum of IBD
Epidemiology of IBD 1-2 million IBD patients in the U.S. Equal incidence of ulcerative colitis and Crohn’s disease Approximately 10,000 new cases diagnosed annually. Peak onset: 15 to 25 years of age Second peak incidence: 50 to 65 years of age Approximately equal between males and females Incidence increased in industrialized nations from 1970 to
1990
IBD – Interaction of Genetic Susceptibility, Immune Dysregulation, and Environmental Triggers
Environmental Triggers
Familial Patterns of IBD 10-15% occurrence of IBD in relatives Strong concordance by disease category Genetic vs. environmental influences still unresolved
Genetics of IBD Specific genes better understood NOD2/CARD15 gene on chromosome 16 – identified by
linkage studies NOD2/CARD 15 gene: encodes intracellular protein NOD2
o Innate immunity through NF-kB mechanismo Involved in apoptosiso Involved in recognition of microbes
Association of IBD with various MHC loci
Inflammatory Bowel Disease Process1. Antigen processing and presentation, activation of
macrophages Antibiotics Probiotics
2. Antigen recognition, activation of CD4+ T cells CyA Tacrolinase ?MTX
3. Generation of Tk1/Tk2 response IL-10
4. Production of proinflammatory cytokinase Anti TNF antibodies Thalidomide Corticosteroids IL-11
5. Recruitment, migration, and adhesion Antisense oligonucleotide to ICAM-1 Anti-α4 integrin antibody ?Heparin
6. Inflammation and injury
Subject: Medicine 2
Topic: GI part 3 (SI and LI)Page 11 of 18
Aminosalicylates Corticosteroids ?Local anesthetics
7. Repair and restoration ?Heparin ?IL-11 ?Nicotine
1. ULCERATIVE COLITIS
Symptoms Bloody diarrhea Urgency Abdominal pain (left-sided) Fever Nocturnal diarrhea Frequent small volume bowel movement
Location and Extent
30% - proctitis30% - Extensive/Pancolitis40% - Distal/Left-Sided Colitis
Diagnosis Clinical history Exclude infection Endoscopic appearance Pathology Serologic testing
ComplicationsToxic Megacolon
2. CROHN’S DISEASE
Clinical TypesInflammatory
Pain Tenderness Diarrhea
Obstructive Cramps Distention Vomiting
Fistualizing Diarrhea Damage to skin Air/feces in urine Types
o Enteroenterico Enterovesicularo Enterocutaneous
Gastroduodenal – 5%Small intestine alone – 5%Right Colon – 35%Distal Ileum – 35%Colon alone – 20%
Endoscopy
Subject: Medicine 2
Topic: GI part 3 (SI and LI)Page 12 of 18
Distinguishing Features Granuloma Focal lesions Perineal disease Asymmetric involvement Small bowel involvement Skip lesions Fistulizaton Strictures Rectal sparing 20-30% without bleeding
Natural Courses of CD – The Facts Nearly 80% of patients require surgery within 2 years of
onset Recurrence within 6 years of surgery: 90%
endoscopic/radiologic, 58% symptomatic 20% of patients treated with steroids fail to respond after 1
year 36% of patients are unable to discontinue due steroid to
rapid recrudescence
Diagnosis Clinical history
o Family history Physical exam Radiologic evaluation Colonoscopy with intubation of ileum Serologic testing
Antibody Testing in IBD pANCA – perinuclear antineutrophil cytoplasmic antibodies
o Targets histone 1, cross-reactive to bacteriao 65% sensitive, 85% specific for UC
ASCA – anti-Saccharomyces cerevisiae antibodieso 61% sensitive, 88% specific for CDo More common in small bowel CD
Extra-intestinal Complication of IBDEyes
Episcleritis Uveitis
Mouth Stomatitis Aphthous ulcers
Kidneys Stones (nephrolithiasis) Hydronephrosis Fistulae Urinary tract infection
Liver
SteatosisBiliary Tract
Gallstonses Sclerosing cholangitis
Joints Spondylitis Sacroiliitis Peripheral arthritis
Skin Eythema nodosum Pyoderma
o GangrenosumCirculation
Phlebitis
Extra-intestinal Complications of IBD: Relationship to Disease Activity Related to activity of bowel disease Peripheral arthritis
o Erythema nodosumo Episcleritiso Apthous oral ulceration
Usually relatedo Pyoderma gangrenosumo Uveitis
Unrelatedo Sacroileitiso Spondylitiso Primary sclerosing cholangitis
Systemic Complications of Ulcerative Colitis: Peripheral Arthritis Monoarticular Asymmetrical Large>small joint No synovial destruction No subcutaneous nodules Seronegative
Osteoporosis in IBD Incidence 20% to 30%
o Corticosteroid use, dose, and duration importanto May occur in absence of corticosteroid useo Pathophysiologic considerations (smoking,
amenorrhea, exercise status, etc) Corticosteroid-associated bone loss occurs early All IBD patients should have bone density scanning Prophylactic use of calcium, vitamin D, bisphosphonates,
nasal calcitonin
Pediatric Complications of IBD Growth Failure
IBD: Treatment
Subject: Medicine 2
Topic: GI part 3 (SI and LI)Page 13 of 18
Dose Response to Mesalamine in Active Ulcerative Colitis
*Significantly different from placebo
Corticosteroids in IBD Role
o Induction of Remission in CD and UC Toxicity
o Metabolico Musculoskeletal
Avascular necrosis Arthralgias Osteoporosis
o Gastrointestinalo Cutaneouso Neuropsychiatrico Ocularo Immunologico Growth failure
Remission Rates in Acute CDStudies with Budesonide CIR
Role of Immunosuppresive Agents6-Mercaptopurine, azathioprine, methotrexate, cyclosporine
Steroid-sparing Induction of remission Speed of onset variable Maintains remission Requires periodic monitoring Generally acceptable side-effect profile
Biologic TherapyAnti-TNFα Therapy
Infliximab Adalimunab
Infliximab Side Effects Infusion reaction Delayed type hypersensitivity reaction (human anti-chimeric
antibodies)o Less likely if on AZA/6-MP
15% had fistula-related abscess Headache Infections
o TB – all patients need pre-treatment PPD Malignancy Intestinal stenosis
Investigational Drugs Anti-sense oligonucleotides
o ICAM-1o NF-KB
Fish Oils Interleukin-10 Interleukin-11 Anti-integrin antibodies (natalizumab) – alpha-4 integrins
involved in leukocyte migration Thalidomide – anti-TNF Growth Hormone Anti-TB therapy G-CSF - ?Mucosal neutrophil deficiency in Crohn’s Parasitic therapy – induces Th2 response (IL-4)
IBD: Indications for SurgeryUlcerative Colitis:Panproctocolectomy
Failure of medical therapy Dysplasia or carcinoma Debility, poor QOL Intolerant of medications Massive hemorrhage, perforation Intractable pyoderma, hemolysis
Crohn’s Disease:Directed to specific complication
Symptomatic obstruction Symptomatic fistulae Perforation Hemorrhage Dysplasia or carcinoma Perianal disease
Nutritional Therapy in IBDFood: best nutrition source
Subject: Medicine 2
Topic: GI part 3 (SI and LI)Page 14 of 18
Parenteral: Ulcerative Colitis
o No role in primary therapyo Adjunct to surgery
Crohn’s Diseaseo “Bowel rest” as primary therapyo Fistula healingo Adjunct to surgeryo Short bowel syndromeo Growth failure
Enteral: Ulcerative Colitis:
o No role in primary therapy Crohn’s Disease
o Role in primary therapyo Fistula healingo Adjunct to surgeryo Short bowel syndromeo Growth failure
Case Presentation: Ulcerative Colitis 22 year old man complains of 5 weeks of small volume loose,
bloody stool. He has urgency to move his bowels. He occasionally has crampy left lower abdominal pain that diminishes after a bowel movement. He has occasional low grade fevers.
o What would you most likely see on colonoscopy? Erythema, punctuate ulcerations, loss of
vascular markings, friabilityo What is he at risk for in the long term?
Colon cancero If he had a fever, severe abdominal pain, and
distention, what would be your immediate concern?
Toxic megacolon
Case Presentation 36 yo white woman with right lower quadrant abdominal
pain, diarrhea and weight loss Has pain in perianal area with drainage No other past medical history PE: no fever, stable BP, HR
o One oral aphthous ulcero Mild fullness and tenderness in RLQo Fistula opening on labia and perineum
What is the most likely diagnosis?o Crohn’s disease
What is the most likely result of the anti-saccharomyces cerevisiae antibody test?
o Positive What is the most likely finding on small bowel barium x-ray?
o Narrowing, irregularity of ileum What is an important pro-inflammatory cytokine?
o TNF α, IFNy What is the effect of smoking on this disease?
o Worsens and reduces response to medical therapy
NOTES (Lecture from 3b)Part of the intestine where most absorption occurs:
Duodenum Jejunum
Absorption of bile salts and Vit. B12 occurs in the ileumIf you lack bile saltsfat malabsorption
SMALL INTESTINE
DIARRHEA predominant clinical manifestation of small intestine
disorder may be acute or chronic acute: < 4 weeks chronic: > 4 weeks Acute Diarrhea may be:
1. infectious2. non-infectious or parenteral diarrhea
Chronic diarrhea may be caused by:1. Luminal/mucosal disorder2. Pancreatic insufficiency3. Motility disorder4. Large resection of the bowel5. Short Bowel Syndrome6. Infectious: amoebiasis & TB
Psuedodiarrhea: fecal stool <200gTrue diarrhea: fecal stool of ≥200 g *these two are not clinically distinguishable
Diarrhea is described as having:1. liquid consistency2. increased frequency
Normal stools – liquid but once a day (balance between liquid and fiber; high fiber, increase liquid stool)
Defecation controlled by:o Skeletal: pudendal/puborectalis, external &
internal anal sphinctero Autonomic: sensation to defecate; if not regulated,
rectum will be filled with feces Effort:
o Abdominal muscles: involved in Valsalva maneuvero Pelvic muscles
Types of Diarrhea1. Osmotic2. Malabsorption/Maldigestion of Fat (Fatty Diarrhea/
Steatorrhea)3. Inflammatory Diarrhea4. Secretory5. Altered Motility*these types overlap
Altered motility o Causes
- seen usually in cerebrovascular accidents- neurological disorder (DM)- those who underwent surgery/resection- can be due to an infectious cause- those with mucosal abnormalities: celiac
sprue gluten (present in barley or wheat
products) sensitivity usually in Western countries
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Topic: GI part 3 (SI and LI)Page 15 of 18
Due to sensitivity to barley or wheat products
Dx:1. through biopsySee: atrophic
villi2. serologic markers: anti-gliadin
and anti-endomysialo transit is very slow --- strain bacterial
proliferate infectious
OSMOTIC DIARRHEA prototype: lactose intolerance Disaccharide induces osmotic pressure that will retain fluid
in stools Magnesium is part of antacids which induces diarrhea Aluminum: constipation Dx: take fecal osmolality gap
= 290 – 2 (Na+ + K+)if >125, osmotic diarrheaif <50, secretory diarrhea
most common cause of secretory diarrhea is cholera (infectious diarrhea din)
SECRETORY DIARRHEA Secretory tumors (gastrinomas, somatostatinomas,
Zollinger-Ellison syndrome, neuroendocrine tumors such as VIPoma)
Laxative abuse: Bisacodyl (Dulcolax) Drugs (antibiotics especially Macrolides, Erythromycin) Erythromycin is a prokinetic used for dysmotility disorder; it
is not corrosive in stomach but increase activity/motility that’s why people vomit because of relaxation of sphincters, increasing peristalsis
MALABSORPTION OF FAT it can mean pancreatic insufficiency (enzyme deficiency
involved in metabolism of fat, carbohydrate and protein) Fat malabsorption develops steatorrhea
o Oly way to test is through Sudan’s test or fecal fat (usually 10 grams, in books 7 grams)
Carbohydrate malabosorption overlaps with lactose intolerance which causes to 2 types of diarrhea:
1. osmotic diarrhea sec. to disaccharide2. malabsorption
o Dx: D-Xylose test - a general test used to detect
pancreatic insufficiency which works by stimulating pancreatic enzymes
Direct measurement of enzyme – such as chylose, trypsinogen, elastase, chymotrypsin
Can be categorized into defects of: luminal, mucosal and motility1. Mucosal
o involves SI mucosao due to nutrient deficiency, bowel resection,
infectious causes of bowel involving mucosa2. Altered motility delayed movement sec. to stasis or
short bowel syndrome which is due to resection
INFECTIOUS
common infectious disorder that affects terminal ileum are S. Typhi and TB
*if you have bile acid insufficiency and resection of ileum fat malabsorption*Test for carbohydrate malabsorption is D-Xylose test*General test together with pancreatic test: Secretin test*Evaluate deficiency in terminal ileum: lactose and B complex test for instrisic factor (Schilling’s test)
MOTILITY 3 Common Causes:
1. Post-surgical resections – also ____ bacterialluminal/mucosal diarrhea
2. Endocrine disorder – DM paresis & Neurological conditions
3. IBS predominantly diarrhea Treatment:: Remove offending agent
a. Infectious (bacterial): antibioticsb. Lactose intolerance: avoid dairy productsc. Tumors and IBD: surgery
CasesCASE 1: 44 y.o. male ate ice cream develops diarrhea. Hx shows he usually eats ice cream a lot. Dx: Secretory Diarrhea (based on the history)
CASE 2: 62 y.o. has chronic abdominal pain, intermittentdiarrhea more than 4 weeks duration. He had resection 10 years ago. Exams are normal.DDx: can be bacterial ruled out because he has no fever; Ask, why did he have a resection? Maybe she has a tumor.Dx: IBS if everything is normal, think about IBS
CASE 3: 45 y.o. male chronic alcoholic starts to have oily stoolDx: Alcohol-induced pancreatitisMx: confirm steatorrhea by Sudan’s test or fecal count
*In acute diarrhea, think whether it is infectious or non-infectious.*In chronic diarrhea, the possible causes can be due to osmosis, malabsorption, secretory, altered motility, or inflammatory
COLON For water absorption and fecal formation Major manifestation: constipation Major manifestation in SI is diarrhea.
CONSTIPATION Bowel movement should occur 3x/week It is also defined in terms of consistency and frequency. Clinically, the most common symptoms of constipation are:
a. Infrequent bowel movementb. Difficulty in defecation (straining)c. Incomplete evacuationd. Prolonged stay in the rest roome. Can manifest with bleddingf. Digital manipulationg. Common among children: pellet like stools, M&M’s
stools or goat like stools Major Criteria:
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Topic: GI part 3 (SI and LI)Page 16 of 18
1. Straining >25% of the time2. Hard stools 3. Incomplete evacuation4. Need to manipulateDX: 3 out of 4 Chronic constipation
3 Classification of Constipation1. Normal transit
o peristalsis is normal but the end result is constipation
o due to imbalance between fluid and fiber (↓fiber ↓fluid)
o Most common cause of constipation o Tx: Increase fiber in the diet or give fiber
supplements2. Slow Transit
o 2nd most common cause neurological or endocrine disorder especially DM
3. Outlet form or Obstructiveo 3rd most common is seen in conditions when
there is obstruction in outleto Most common cause
- Tumors in the rectum/anus- Tumors in pelvic organs
o Non-tumor cause: - Hemorrhoids- Proctitis,- Bolus of ascaris, polyps (occurs all over
the colon but more on the rectosigmoid and anus)
- Anismus (constriction is present at all times)
Dx of constipation: o Hx, personal/social, PMH, PEo Most impt. PE is DREo DRE:
1. Ask patient to be in left lateral decubitus2. Visually examine rectum first: if there is tumor,
you will see prolapse3. Lubricate gloved forefinger 4. If there is no tumor, start touching the anus5. Observe for:
a. anus starts to grin meaning it is contractingb. insert finger, feel for constriction at firstc. after which, sphincter starts to relaxd. palpate for internal wall (look for prostate or
hemorrhoids)e. ask patient to strain normally feels
proximal colon getting in your finger = means there is normal transit timeIf none, there is slow transit time.
Tx: o modify diet/give fiber supplementso For slow transit:
- Osmotic laxatives- Polyethylene glycol- Bulk-forming laxatives- Stimulating laxative: Bisacodyl- Lubricating laxative: Mineral oil
Worst scenario in constipation: when tumors cause obstruction
DIVERTICULAR DISEASE outpouching produced in the weakest part of colonic wall:
between vasa recta Types
1. Pseudodiverticularo Most commono Does not involve the whole wall: outpouching
reaches the submucosa, mucosa, and muscularis only
o Due to weakening of the mucosa2. True diverticular disease
o Common in children is Meckel’so Involves all layers of the wall
3 things that can happen in diverticulum:a. Fecalith stasis bacterial overgrowth = diverticulitisb. If eroded a vessel, it can lead to bleeding which is bright
red in color but spontaneously stop in most cases c. If diverticulitis becomes complicated, it can rupture and
get contained in the mesentery with an end result: Abscess
Most are located in the sigmoid (where defecation process starts)
Best way to dx diverticulitis: Barium enema Colonoscopy
o not diagnostic, can miss divertiular disease o can be done first if patients present with bleedingo if too much bleeding, visualization can be difficult:
Radionuclide imaging or RBC tagging becomes the next best imaging modality, used to identify the source of bleeding
o only limitation of RBC tagging: needs to time it because the requirement is for bleeding to persist 5 ml/min
o other alternative: angiography Diverticulitis/Abscess Formation is diagnosed by: CT Scan
which locate/visualize abscess formationo Clinically you can consider this if patient has abdominal
tenderness, fever & leukocytosis manifestation of bowel stasis or bacterial overgowrth
o Best initial management: supportive thru antibiotics; surgery can be done if vital signs are normalize
o If bleeding does not stop surgery
APPENDICITIS Most common theory: obstruction due to fecalith (which
happens in 2/3 of cases) 1/3 of acute appendicitis, negative for fecalith just
inflammation bec. Appendix is a lymphoid tissue autoimmune/immune responses
Classical manifestation of acute appendicits: classic ap gait “You are malicious!”
Classic sequence: Abdominal pain usually. Periumbilical (does not have to be epigastric pain usually vague abdominal pain) followed by nausea and vomiting or loss of appetite localization to McBurney’s Point (RLQ pain) manifest as AP walk and rebound tenderness fever
Most common differentials in females is: ectopic pregnancy
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Topic: GI part 3 (SI and LI)Page 17 of 18
Complications :a. Same picture as diverticular disease because
appendicitis is an outpouching and most common cause is fecalith
b. Like diverticular disease, if with rupture/perforation leads to peritonitis, adhesions (comes later)
c. If rupture/perforation is confined to the mesentery appendiceal abscess
Tx : surgery and antibiotics Dx : mostly clinical (HX, P.E.) If appendiceal abscess is considered: UTZ Rule out ectopic pregnanc by:
1. Pregnancy test2. Obtained by UTZ: either pelvic/transvaginal (more
accurate than pelvic but drawback is discomfort especially in very young patients)
Atypical manifestations may come because of variable location of appendix (retrocaecal, post caecal, inf. caecal, pelvic area)
HEMORRHOIDS Can be internal or external Internal: covered by mucosa thus not sensitive to pain; most
common manifestation is bleeding External: covered by anoderm and rectum (pain sensitive
areas, thus painful) Only instance when internal hemorrhoids become painful is
when there is prolapse to anoderm irritate anoderm Grading of Internal Hemorrhoids
When to do surgery?1. If hemorrhoids get thrombosed2. If there is repeated bleeding3. Has a grade of III or IV
TRAUMATIC ANAL DISORDER Anal tears/Anal fissures/Anal lacerations leads to infection
anal abscess Most common cause of anal tear:
1. Constipation (most common cause is hard stool)2. Self-induced/traumatic – usually seen in children
Management1. Drain2. Initiate antibiotics
Complications if infection is not addressed: development of fistulous tract anal fistula
In females, most common type is anal fistula because inadvertent suturing of colonic wall during perineal episiotomy
Same fistulas are also colo-vaginal but most get out to perianal
Management of fistulas: 2 or 3 stages of surgery is done- Depends on the length of the fistula
- Drawback: risk of recurrence if thorough cleansing of fistula is not done properly
Colorectal fistula: seen when patient starts to urinate feces
INFLAMMATORY BOWEL DISEASE Types
1. Ulcerative colitis2. Crohn’s Disease – manifests with Tuberculous colitis
Causes of IBD: genetic predisposition, environmental toxins and autoimmune
Commonality between the two is both have diarrhea and bleeding
Ulcerative Colitis Crohn’s DiseaseLocation Left Right
Proctitis or left side colitis
Ileocolitiis; right of colon and terminal ileum are affected; has rectal sparing bec. of its localization on the right side
Manifestation Diarrhea, bleeding Diarrhea, bleedingColonoscopy Diffuse lumps,
uniform length, perineal; signs of congestion all throughout mucosa
Skip lesions(normal intervening mucosa between lesions)
Both (+) ulcersDeeper ulcer that’s why TB ulcer is a ddx bec. TB ileitis is also seen in Crohn’s disease
Biopsy Crypt of abscess Granuloma Ba enema Demonstrate morbid
compication UC; toxic megacolon, whole colon is dilated
Visualize deep ulcers and fistulas
Tx: Same1. 5-ASA2. steroids3. biologic agents addressing inflammatory cells (TNF)4. Surgery
Surgery Very good recovery Very high recurrence rates
Predisposition to Malignancy
Yes (but has more chance)
Yes
Grade 1 Non-prolapsingGrade 2 Prolapsing but can be spontaneously reducedGrade 3 Prolapsing but needs to be digitally reducedGrade 4 Prolapsing but non-reducible (like prunes,
grapes)
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Topic: GI part 3 (SI and LI)Page 18 of 18