Colon, IBD, etc

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


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


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


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


- 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


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


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


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


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


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


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


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


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

Subject: Medicine 2


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:

Subject: Medicine 2


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

Subject: Medicine 2


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)

Subject: Medicine 2


Documents

Colon, IBD, etc