week 3 learning objectives

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

Functional Causes Irritable Bowel Syndrome

Idiopathic Slow Transit

Metabolic Diabetes Melitus

Hypercalcaemia

Hypothyroidism

Porphyria

Dietary Inadequate Fibre Intake

Pharmacological Opiates

Antimuscarinics

Calcium Channel blockers

Antidepressants

Iron

Neurological Depression

Anorexia Nervosa

Repressed urge

Spinal cord lesions

Parkinson's disease

Hormonal Diabetes etc

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

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

Disorder

Motility

Diabetic, post-vagotomy and hyperthyroid diarrhoea are all due to abnormal motility in the upper gut

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

electrolytes

Infective conditions (e.g. dysentry caused by Shigella)

Inflammatory conditions: Ulcerative colitis, Crohn's Disease

Malabsorptive Coeliac disease

Lactose intolerance

Pharmaceutical Laxatives, metformin, anticancer drugs, statins, PPIs

Neurological Stress? Anxiety? Purgative abuse

Hormonal Zollinger-Ellison syndrome, VIPoma, Samatostatinoma, Glucagonoma, Carcinoid syndrome, Thyrotoxicosis, Medullary carcinoma of the thyro

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 Frequency, urgency, nocturia, incomplete emptying

Other Joint hypermobility

Back pain

Headache

Bad breath

Poor Sleeping

Fatigue

Diagnostic Criteria (Rome III 2006)

Improvement with defecation

Onset associated with change in frequency of stool

Onset associated with a change in form (appearance) of stool

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:

Week 3 Learning ObjectivesSunday, February 09, 2014 7:35 PM

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Rome III symptoms in association with rectal bleeding, nocturnal pain, fever & weight loss.

Raised stool calprotectin or lactoferrin would suggest inflammation needing investigation.

Other important clinical pointers:

Treatment Options

End-Organ Treatments Notes

High-fibre diet

FODMAP diet for bloating

Alteration of microbiota Rifaximin

Anti-diarrhoeal drugs Loperamide, Codeine phosphate, Co-phenotrope

Constipation 5HT4 receptor agonist, e.g. prucalopride

Smooth muscle relaxants Mebeverine hydrochloride, dicycloverine hydrochloride, peppermint oi;

Central Treatments

Patient Education Pamphlets, diagrams etc

Psychotherapy Refer to clinical psychologist

Hypnotherapy

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

Crohn's disease is a relapsing inflammatory disease, mainly affecting the GI tract and frequently presents with abdominal pain, fever and clinical signs of b

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 Cr

the 47 loci identified for ulcerative colitis.

Genetics

Systematic geographical analysis reports that rates are much the same over north-south, east-west and urban-rural gradients however lifestyle factors ar

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

hot tap water, sedentary lifestyle, air pollution, western diet and increased tobacco use link.

Neither nicotine nor carbon monoxine are causative

Strong link between early tobacco use and development of the disorder.

Frequently occurs are infectious gastroenteritis and has a distinct mucosal flora dysbiosis and increased numbers of intramucosal bacterial, often featurin

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 en

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.

Environmental Factors

Crohn's seems to result from an impaired interaction of intestinal commensal microbiota that is normally in a state of symbio tic mutualism with the huma

immune system.

Continuing challenges in understanding this relationship and distinction between inciting events and secondary occurences.

Immunobiology

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.

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.

NOD2 gene encodes the NOD2 protein which acts as an intracellular pattern recognition receptor that specifically recognises muramyl dipepti

in certain bacteria, activating NFKB

Link between permeability changes and activated T cells, TNF a, interferon gamma and intestinal microbiotica via NOD2.

Endoplasmic reticulum stress in the highly active secretory goblet and Paneth cells is mechanistically linked to autohagy andmight disturb the unfo

protein response of these cells and induce inflammation.

Paracellular route of fluxes between neighboring cells are normally blocked by tight junctions

Microbial Sensing, Innate Immunity & Autophagy

Microbial associated molecular patterns are recognized by different innate immune-cell populations of the intraepithelial and lamina propria mucosal spa

through receptors such as Toll-like receptors and nucleotide binding domain like receptors (NLR).

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 lipopolysacchar

Dendritic cells express the widest range of pattern recognition receptors and interpret microbial patterns to direct other immune cells toward immunity o

tolerance.

Intestinal Barrier

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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

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.

Endoscopy

Downside is that CTE requires a high radiation exposure

Very sensitive, can show inflammation missed by other techniques, can detect complications such as obstruction, fistulas and abscesses.

Preferred choice for repeated imagine, long-term follow-up and work-up of perianal fistula and abscess complications.

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 dow

mucosal level.

CT and MRI enterography or enteroclysis

Studies show utility for initial diagnosis, assessment and detection of fistulas, stenoses and abscesses.

Native and contrast-enhanced abdominal ultrasound is a non-invasive imaging technique with an overall sensitivity and specificity that are much the sam

and CT.

Ultrasound

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.

Biomarkers

Aims to achieve sustained clinical and endoscopic remission and to interrupt the naturally progressive destructive disease course that culminates in intest

failure and associated complications.

Smoking promotes a fistulising and stricturing phenotype, aggrevated disease coursea nd suboptimal response to medical therapy.

Age, corticosteroid use, perianal disease, colonic resection, repeated small bowel resection, stricturing phenotype, weight loss, endoscopic legions may pr

disabling disease course.

Medical Management

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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 thiopurin

methotrexate for long-term maintenance.

Increased risk of infectious and malignant complications.

Strong evidence from recent trials attest to the superiority of combination therapies with thiopurines and TNF blockers for improved symptom control and

mucosal healing.

Drug Treatment

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 th

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 m

appearing as inflammatory pseudo polyps.

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 incont

that may be disabling for the patient.

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

Toxic megacolon is a serious complication associated with severe colitis.

Clinical Features

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.

Examination

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

Perinuclear Anti-Neutrophil Cytoplasmic Antibodies

Weakly sensitive for UC itself but estimated at 97% specificity and 48% sensitivity when used alongside Anti-saccharomyces cerevisiae antibo

(ASCA)

pANCA may be positive, this is contrary to CD where pANCA is usually negative

Blood Tests

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.

Stood Cultures

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.

Colonoscopy

Plain abdominal X-ray can be used to exclude colonic dilatation

Imaging

Investigations

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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.

Understand acute and maintenance therapy for inflammatory bowel diseases and the need for long-term treatment of these chronic conditions.11.

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.

Crohn's Disease

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 w

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

Glucocorticosteroids

Have been used but there is little evidence to support their efficacy in CD

Aminosalicylates

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

Antibiotics

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

Exclusive Enteral Nutrition

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 w

immunosuppressive such as azothioprine

Refractory Disease

Step One: Induction 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 cortico

which are associated with a high burden of side-effects.

Azathioprine 2.5 mg/kg/day

Mercaptopurine 1.5 mg/kg/day

Methotrexate 25mg one a week until remission then 15mg/week

Conventional Approaches

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)

Major role of these Anti-TNF agents is to neutralize soluble TNF-a, bind to membrane bound TNF-a and induce immune cell apoptosis althoug

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

Certolizumab pegol (PEGylated Fab' fragment of a humanized anti-TNF antibody).

Anti-TNF agents

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.

Novel biological therapies

Approximately 80% of patients will require an operation at some time during the course of their disease

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

Indications are:

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 ileorectalanastomosis may be

performed.

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

If the whole colon and rectum are involved, a panproctocolectomy with an end ileostomy is the standard operation.

Mechanical problems, dehydration, psychosexual problems, erectile dysfunction, recurrence of CD.

Problems with ileostomies include:

Surgical Management

Step Two: Maintenance of Remission

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

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.

Ulcerative Colitis

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.

Proctitis

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Topical 5-ASA enemas are the first-line treatment.

Resistant treatment is the same as for proctitis.

Left-sided Colitis

Oral 5-ASA with 5-ASA enema

Resistant treatment with prednisolone

Extensive 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

hourly 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.

Severe Colitis

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/

infusion.

Salvage Therapy

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.

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

Acute disease treatment:

Surgical Management

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 les

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

enterotoxigenicEscherichia coli.

Anaerobes such as Bacteroides, anaerobic streptococci and crostridia outnumber faculative anaerobes such as E coliby a factor of 1,000

In contrast, the large intestine normally contains total concentrations of 1011 bacteria/g of stood.

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).

Gastric acid

Bile

Forward propulsive motility (peristalsis)

Production of antibacterial substances (e.g. bacteriocins and fatty acids) by microflora itself stabilizes the normal population.

Controls of Bacterial Flora

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