Week 3 Learning Objectives

Sunday, February 09, 2014 7:35 PM

5. Be able to list potential causes of constipation including functional, metabolic, dietary, pharmacological, neurological and hormonal.

Functional Causes Irritable Bowel Syndrome Idiopathic Slow Transit

Metabolic

Diabetes Melitus Hypercalcaemia Hypothyroidism Porphyria

Inadequate Fibre Intake

Dietary

Pharmacological

Opiates Antimuscarinics Calcium Channel blockers Antidepressants Iron Depression Anorexia Nervosa Repressed urge Spinal cord lesions Parkinson's disease
Diabetes etc

Neurological

Hormonal

6. Be able to list potential causes of diarrhoea including infective, disorder motility, inflammatory, malabsorptive, pharmaceutical, neurological and hormonal.

Infective

Bacterial: Campylobacter jejuni, Salmonella spp, Shjigella, Escherichia Coli, Sraph enterocolitis, Bacillus cereus, Clostridium, GI tuberculosis Viral: Rotavirus Fungal: Hystoplasmosis Parasitic: Amoebic dysentry, schisosomiasis, Giardia intestinalis
Diabetic, post-vagotomy and hyperthyroid diarrhoea are all due to abnormal motility in the upper gut

Disorder Motility

Inflammatory

Caused by things that cause damage to the intestinal mucosal cell so that there is a loss of fluid and blood as well as defective absorption of fluid and electrolytes Infective conditions (e.g. dysentry caused by Shigella) Inflammatory conditions: Ulcerative colitis, Crohn's Disease
Coeliac disease Lactose intolerance Stress? Anxiety? Purgative abuse

Malabsorptive

Pharmaceutical Laxatives, metformin, anticancer drugs, statins, PPIs

Neurological

Hormonal

Zollinger-Ellison syndrome, VIPoma, Samatostatinoma, Glucagonoma, Carcinoid syndrome, Thyrotoxicosis, Medullary carcinoma of the thyroid, diabetic autonomic neuropathy

9. Understand the nature of Irritable Bowel Syndrome (IBS) IBS is a multisystem disorder which co-exists with chronic fatigue, fibromyalgia and temporomandibular joint dysfunction.
Symptoms

Gynecological Dysmenorrhoea Dyspareunia Urinary Other Frequency, urgency, nocturia, incomplete emptying Joint hypermobility Back pain Headache Bad breath Poor Sleeping Fatigue

Diagnostic Criteria (Rome III 2006)

State that in the preceding 3 months there should be at least 3 days/month of recurrent abdominal pain or discomfort associated with two or more of the following: Improvement with defecation Onset associated with change in frequency of stool Onset associated with a change in form (appearance) of stool Other important clinical pointers:
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 Other important clinical pointers: Rome III symptoms in association with rectal bleeding, nocturnal pain, fever & weight loss. Raised stool calprotectin or lactoferrin would suggest inflammation needing investigation. Treatment Options
End-Organ Treatments Notes

High-fibre diet FODMAP diet for bloating

Alteration of microbiota Rifaximin

Anti-diarrhoeal drugs Constipation

Smooth muscle relaxants

Loperamide, Codeine phosphate, Co-phenotrope 5HT4 receptor agonist, e.g. prucalopride

Mebeverine hydrochloride, dicycloverine hydrochloride, peppermint oi; Pamphlets, diagrams etc

Central Treatments
Patient Education

Psychotherapy Hypnotherapy

Refer to clinical psychologist

Cognitive behavioural therapy Refer to psychiatrist

Antidepressants

Functional diarrhoea -clomipramine Predominant diarrhoea -TCAs Predominant constipation -SSRI

10. Understand the nature of inflammatory bowel diseases, their symptoms and how the two major forms are differentiated.

Crohn's Disease affects any part of the GI tract whereas Ulcerative Colitis only affects the colon Crohn's Disease
Genetics Crohn's disease is a relapsing inflammatory disease, mainly affecting the GI tract and frequently presents with abdominal pain, fever and clinical signs of bowel obstruction and diarrhoea with passage of blood, mucous or both. Confirmed familial aggregation with highest ethnic prevalence among Ashkenazi Jews. Genome-wide association studies have identified and confirmed 71 susceptibility loci on 17 chromosomes with an interrelation between loci related to Crohn's and the 47 loci identified for ulcerative colitis. Environmental Factors Systematic geographical analysis reports that rates are much the same over north-south, east-west and urban-rural gradients however lifestyle factors are suggested by increasing incidence rates in previously less affected ethnic groups, e.g. Asians and Hispanics. Some evidence for increased adverse life events, less breastfeeding, smaller families with less crowded living conditions, improved domestic hygiene and snitation, hot tap water, sedentary lifestyle, air pollution, western diet and increased tobacco use link. Strong link between early tobacco use and development of the disorder. Neither nicotine nor carbon monoxine are causative Frequently occurs are infectious gastroenteritis and has a distinct mucosal flora dysbiosis and increased numbers of intramucosal bacterial, often featuring adhesive species. Mycobacteria have been identified in tissues and blood of adults and paediatric patients with Crohn's and remain an important differential diagnosis in endemic areas although controlled trials with TB drugs have failed. Some animal research suggests that viral infection may convert genetic susceptibility to disease outbreak. Meta-analysis suggests a link to contraceptive use No link to MMR or BCG vaccines. Increased disk of development post-appendicectomy. Immunobiology Crohn's seems to result from an impaired interaction of intestinal commensal microbiota that is normally in a state of symbiotic mutualism with the human host immune system. Continuing challenges in understanding this relationship and distinction between inciting events and secondary occurences. Intestinal Barrier The first line of defense of the mucosal immune system is a polarised single layer of epithelial cells covered by mucous biofilm secreted from goblet cells. Decreased expression of the mucin gene MUC1 in the inflamed terminal ileum in patients with CD suggests mucin cover becomes insufficient Genome wide association studies link MUC1, MUC19 and PTGER4 to the disorder. Paracellular route of fluxes between neighboring cells are normally blocked by tight junctions Becomes leaky in CD possible due to changes in the expression of tight-junction proteins such as claudins (transmembrane protein) Results in increased permeability and access of luminal antigens to the lamina propria which is densly populated with immune cells. Link between permeability changes and activated T cells, TNF a, interferon gamma and intestinal microbiotica via NOD2. NOD2 gene encodes the NOD2 protein which acts as an intracellular pattern recognition receptor that specifically recognises muramyl dipeptide (MDP) in certain bacteria, activating NFKB Endoplasmic reticulum stress in the highly active secretory goblet and Paneth cells is mechanistically linked to autohagy and might disturb the unfolded protein response of these cells and induce inflammation. Microbial Sensing, Innate Immunity & Autophagy Microbial associated molecular patterns are recognized by different innate immune-cell populations of the intraepithelial and lamina propria mucosal spaces through receptors such as Toll-like receptors and nucleotide binding domain like receptors (NLR). Dendritic cells express the widest range of pattern recognition receptors and interpret microbial patterns to direct other immune cells toward immunity or tolerance. Form transepithelial dendrites that enable them to directly sample luminal antigens. Their distribution and phenotype correlate with disease activity in CD, e.g. Increased expression of TLR2 and TLR4 and exaggerated lipopolysaccharide response have been linked
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response have been linked Ability of dendritic cells to induce tolerogenic regulatory T cells might be lost in CD

Diagnosis techniques for patients with suspected Crohn's Disease Medical History

Endoscopy Gold standard for all patients with Crohn's disease is a full ileocolonoscopy with biopsies. Chromoendoscopy with methylene blue dye-spray targeted biopsies results in improved detection of dysplasia compared with conventional random and sequential biopsy methods. CT and MRI enterography or enteroclysis Very sensitive, can show inflammation missed by other techniques, can detect complications such as obstruction, fistulas and abscesses. Downside is that CTE requires a high radiation exposure MRE is a non-radiating, non-iodine contrast based alternative to CTE which can provides movies to assess motility and detailed imaging of bowel wall down to the mucosal level. Preferred choice for repeated imagine, long-term follow-up and work-up of perianal fistula and abscess complications. Ultrasound Native and contrast-enhanced abdominal ultrasound is a non-invasive imaging technique with an overall sensitivity and specificity that are much the same as MRI and CT. Studies show utility for initial diagnosis, assessment and detection of fistulas, stenoses and abscesses. Biomarkers Cost-effective, non-invasive and decreased need for ionising radiation exposure. Best studied are CRP and faecal granulocyte proteins lactoferrin and calprotectin. Good correlation with other lab tests, endoscopic and clinical disease activity indices and possible predictive potential. Medical Management Aims to achieve sustained clinical and endoscopic remission and to interrupt the naturally progressive destructive disease course that culminates in intestinal failure and associated complications. Age, corticosteroid use, perianal disease, colonic resection, repeated small bowel resection, stricturing phenotype, weight loss, endoscopic legions may predict a disabling disease course. Smoking promotes a fistulising and stricturing phenotype, aggrevated disease coursea nd suboptimal response to medical therapy. Drug Treatment
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Drug Treatment Directed by phenotype, disease activity, comorbidities and other individual characteristics of the drug and patient. In most cases, fast acting short-term agents such as steroids of anti-TNF agents achieve rapid symptom relief and disease control combined with thiopurines and methotrexate for long-term maintenance. Strong evidence from recent trials attest to the superiority of combination therapies with thiopurines and TNF blockers for improved symptom control and mucosal healing. Increased risk of infectious and malignant complications. Ulcerative Colitis
Ulcerative Colitis can affect the rectum alone (proctitis), extend proximally to involve the sigmoid and the descending colon (left-sided colitis) or may involve the whole colon (extensive colitis).

There is a reddening of the mucosa, inflammation and increased risk of bleeding (friability). In severe disease there is extensive ulceration with adjacent mucosa appearing as inflammatory pseudo polyps. Clinical Features Major symptoms are diarrhoea with blood and mucous, sometimes accompanied by lower abdominal discomfort General features include malaize, lethargy and anorexia with weight loss although these are lessened in CD Apthous ulceration in the mouth may be seen Proctitis is characterized by frequency passage of blood and mucous, urgency and tenesmus Acute attacks of left-sided or extensive UC cause bloody diarrhoea, passing up to 10-20 liquid stools per day, nocturnal diarrhoea with urgency and inconteinence that may be disabling for the patient. Toxic megacolon is a serious complication associated with severe colitis. Plain abdominal x-ray shows a dilated thin-walled colin with a diameter of >6cm, it is gas filled and contains mucosal islands Indicative of imprending perforation and high mortality (15-25%) Differential diagnosis includes infectious colitis Examination No specific signs in UC Abdomen may be slightly distended or tender to palpation Tachycardi and pyrexia are signs of severe colitis and mandate admission Anus is usually normal, rectal examination will show the presence of blood Rigid sigmoidoscopy is usually abnormal showing inflamed bleeding, friable mucosa. Very rare rectal sparing with normal sigmoidoscopy. Investigations Blood Tests Iron deficiency anaemia is common with raised WCC and platelet counts in moderate-severe attacks ESR and CRp are often raised, liver biochemitry may be abnormal with hypoalbuminaemia occuring in severe disease pANCA may be positive, this is contrary to CD where pANCA is usually negative Perinuclear Anti-Neutrophil Cytoplasmic Antibodies Weakly sensitive for UC itself but estimated at 97% specificity and 48% sensitivity when used alongside Anti-saccharomyces cerevisiae antibodies (ASCA) Stood Cultures Should always be used to exclude infective causes of colitis and to exclude amoebiasis in patients with relevant travel history. Faecal calprotectin and lactoferrin will be elevated. Colonoscopy Endoscopy with mucosal biopsy is the gold standard investigation for diagnosis of UC In patients with long-term colitis, chromoendoscopy is used to diagnose dysplasia Full colonoscopy should not be performed in severe attacks for fear of perforation. Imaging Plain abdominal X-ray can be used to exclude colonic dilatation Inflammation of the colonic wall is detected on ultrasound as is the presence of free fluid within the abdominal cavity but endoscopy is preferred

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 Inflammation of the colonic wall is detected on ultrasound as is the presence of free fluid within the abdominal cavity but endoscopy is preferred In patients in whom full colonoscopy is contraindicated, disease extent should be assessed by technetium-labelled white cell scan. 11. Understand acute and maintenance therapy for inflammatory bowel diseases and the need for long-term treatment of these chronic conditions. Crohn's Disease The aim of management is to induce and then maintain clinical remission and achieve mucosal healing to prevent complications. Alternative causes for symptoms such as extraintestinal sepsis and stricture formation must be excluded before commencing imunosupressive therapy. Diarrhoea can be controlled with loperamide, codeine phosphate or co-phenotrope Diarrhoea due to bile acid malabsorption should be treated with bile salt sequestrants. Anaemias should be treated with appropriate haematinics or intravenous iron infusion. Step One: Induction of Remission Glucocorticosteroids Moderate and severe attacks may be treated with oral prednisolone 30-60 mg/day. Mild to moderate ileocaecal disease should be treated with controlled release corticosteoids such as Budesonide which have high topical potency while also being extensively inactivated hepatically. Slow release lowers frequency and intensity of steroidal side-effects. Steroids should be avoided in patients with penetrating intestinal or perianal sepsis Aminosalicylates Have been used but there is little evidence to support their efficacy in CD Antibiotics Both ciprofloxacin (broad spectrum quinolone) and metronidazole (anaerobe targeting) are used to treating secondary complications of CD. Rifaximin has been shown to induce remission in moderately active CD Exclusive Enteral Nutrition Diets include low fat and low linoleic acid content show rates of induction of remission are similar to those obtained with steroids. Non-compliance biggest factor Refractory Disease In patients with disease limited to the terminal ileum, surgical resection is appropriate In patients with more extensive disease, remission should be induced with an anti-TNF agent either as monotherapy or preferably in combination with immunosuppressive such as azothioprine Step Two: Maintenance of Remission The main goal of maintenance therapy is to prevent disease progression to a stricturing or penetrating phenotype as well as to reduce the need for corticosteroids which are associated with a high burden of side-effects. Conventional Approaches Azathioprine 2.5 mg/kg/day Mercaptopurine 1.5 mg/kg/day Methotrexate 25mg one a week until remission then 15mg/week Anti-TNF agents Used in those with disease refractory to conventional immunosupressive therapy and in those with poor prognosis disease. Used to treat complex perianal/rectal disease once sepsis has been drained. Infliximab (chimeric anti-NA-a IgG1 monoclonal antibody) Adalimumab (humanized anti-TNG igG1 monoclonal antibody) Certolizumab pegol (PEGylated Fab' fragment of a humanized anti-TNF antibody). Major role of these Anti-TNF agents is to neutralize soluble TNF-a, bind to membrane bound TNF-a and induce immune cell apoptosis although the exact mechanism of action is not defined. Shown to exert a steroid sparing effect and result in complete mucosal healing in up to one-third of patients in the long-term. Association with significant complications including opportunistic infections (including TB), demyelination and malignancy such as lymphoma. Novel biological therapies Anti alpha 4 beta 7 integrin therapy vedolizumab, which acts to reduce leucocyte recruitment to the inflamed intestine. Therapies that target the IL12IL-23 pathways such as ursetkinumab are being used in the USA. Surgical Management Approximately 80% of patients will require an operation at some time during the course of their disease Indications are: Failure of medical therapy with acute or chronic symptoms producing ill-health Complications, e.g. toxic dilatation, obstruction, perforation, abscessed, enterocutaneous fistulae Failure to grow in children despite medical treatment Presence of perianal sepsis Stricturoplasty (widening of strictures) may be used in some patients with small bowel disease whereas other require resection and anastomosis. When colonic CD involves the entire colon and the rectum is spared or minimally involved, a subtotal colectomy and ileorectal anastomosis may be performed. If the whole colon and rectum are involved, a panproctocolectomy with an end ileostomy is the standard operation. The colon and rectum are removed and the ileum is brought out through an opening in the right iliac fossa and attached to the skin. Requires ileostomy bag Problems with ileostomies include: Mechanical problems, dehydration, psychosexual problems, erectile dysfunction, recurrence of CD. Ulcerative Colitis The mainstay of treatment for mild and moderate disease of any extend is an aminisalycylate which acts topically in the colonic lumen. The active moiety of these drugs is 5-aminosalicylid acid (5-ASA) which is absorbed in the small intestine. Delivered to the small colon through the binding of 5-ASA with an azo bond to sulfapyridine, coating with pH-sensitive polymer, packaging in microsphered or a combination of these. Azo bonds are broken down by colonic bacteria to release 5-ASA within the colon. Mode of action of 5-ASA in inflammatory bowel disease in unknown althought it may involve intracellular PPAR-y signalling pathway. Proctitis Rectal 5-ASA suppositories are the first-line treatment although Oral 5-ASA can be added to increase remission rates. Some cases may be resistant to 5-ASA treatment and require oral prednisolone. Left-sided Colitis

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Left-sided Colitis Topical 5-ASA enemas are the first-line treatment. Resistant treatment is the same as for proctitis. Extensive Colitis Oral 5-ASA with 5-ASA enema Resistant treatment with prednisolone Severe Colitis Those with severe colitis or those who do not respond to oral prednisolone should be admitted to hospital and treated initially with hydrocortisone 100mg i.v. 6hourly with s.c. low molecular weight heparin to prevent thromboembolism. Investigations to excuse enteric infection should be performed and full supportive therapy administered Non-response to i.v. steroids within 3 days is indicative of the need for salvage medical therapy or surgery. All patients admitted for severe colitis should commence long-term maintenance therapy with a thiopurine. Salvage Therapy Required in patients with a CRP >45 mg/L or more than eight bowel motions after 3 days of i.v. hydrocortisone Continuing steroid therapy alone in this situation will delay the inevitable colectomy and increase mortality Salvage therapies with clear evidence of benedit in controlled clinical trials are i.v. ciclosporin 2 mg/kg per day as a continuous infusion or infliximab 5 mg/kh as an infusion. Surgical Management Indications include failure of medical treatment, toxic dilatation, haemorrhage and imminent perforation post acute attack. Incomplete response to medical treatment and steroid dependance or dysplasia on surveillance colonoscopy are also indicative for surgical intervention. Acute disease treatment: Subtotal colectomy with end ileostomy and preservation of the rectum is the operation of choice Future options for proctectomy with permanent ileostomy or ileo-anal anastomosis

12. Have an overview of the microbiology of the gastrointestinal tract in health and its implications for disease.

More than 400 bacterial species have been identified in the faeces of a single person. Anaerobic bacteria predominate. The upper gastrointestinal tract (stomach, duodenum, jejunum and upper ileum) normally contains sparse microflora with a bacterial concentration of less than 104 organisms/ml of intestinal secretions. Most of these organisms are derived from the oropharynx and pass through the gut with each meal. Colinization of the upper intestine by soliform organisms is an abnormal event and is characteristic of certain infectious pathogens such as Vibrio cholerae and enterotoxigenic Escherichia coli. In contrast, the large intestine normally contains total concentrations of 10 11 bacteria/g of stood. Anaerobes such as Bacteroides, anaerobic streptococci and crostridia outnumber faculative anaerobes such as E coli by a factor of 1,000

The character of bacterial flora changes not only along the length of the GI tract but also cross-sectionally with regard to the mucosal surface. Bacteria occupy the lumen, overlie the epithelial cells and adhere to mucosa. Penetration of bacteria through the mucosal surface is an abnormal event (e.g. Shigella, Salmonella & Campylobacter). Controls of Bacterial Flora Gastric acid Bile Forward propulsive motility (peristalsis) Production of antibacterial substances (e.g. bacteriocins and fatty acids) by microflora itself stabilizes the normal population.

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