Implementation Of A National Colorectal Cancer Screening Programme: The West Experience

30.10.06

Wilson-Junger criteria for population screening
• Important health problem? YES.
• Early/latent stage? YES.
• Is natural history known? YES.
• Suitable screening test? YES.
• Agreed criteria for who should be treated? YES.
• Diagnostic and treatment facilities available? YES.
• Is programme economically viable? YES.

Is colorectal cancer important health problem? YES!

5-year survival [conditions completely curable]
• Stage 0: 100%.
• Stage I: 90%.
• Stage II: 65%.
• Stage III: 25%.
• Stage IV: 15%.

Proportion diagnosed so that can be cured [condition asymptomatic if confined to gut wall]
• Stage I: 11%.
• Stage II: 33%.
• Stage III: 33%.
• Stage IV: 23%.

If lucky, become anaemic: through investigation of anaemia, cancer becomes obvious.

Screening has two meanings
Opportunistic e.g. Europe, USA Population-based e.g. UK
Recruitment At patient-doctor consultation Systematic invitation of all eligible in population
Participation Low High
Objective Prevention of death in participants Reduction in population mortality
Total cost Low High

Performance of potential screening tests
Screening test Sensitivity Specificity
Faecal occult blood - guaiac 30-50% ~50%
Faecal occult blood - immune 54-89% >94%
Flexible sigmoidoscopy ~50% >95%
Colonoscopy ~95% >95%
CT colography 55-92% -
Faecal DNA test 41% 94%

Flexible sigmoidoscopy - MRC/CRUK "Flexisig" study
• One examination at age 55-60.
• Detects all distal adenomas.
• Detects 50% proximal adenomas.
• Recruiting closed 1999.
• Reports in 3-5 years' time.
• 4.7% normal 55-year-olds have high-risk lesions.
• In 40,000 55-year-olds, 140 cancers were found.
• ~ 55% patients with advanced proximal lesions do not have distal lesions.

CT virtual colonoscopy
>6mm >8mm >1cm
Sensitivity of virtual colonoscopy 86% 93% 92%
Sensitivity of optical colonoscopy 90% 90% 88%

DNA stool testing
• Panel of 21 mutations:
-3 x K-ras, 10 x APC, 8 x p53, Bat-26.
-Long DNA - indicative of apoptosis.
-APC and p53 most frequent mutations.
• Sensitivity for TNM I, II and III cancers 52% compared to 13% for haemoccult II.

What is screening protocol in England?
• Guaiac-based FOBT every 2 years.
• Age 60-69.
• Positive FOBT will have colonoscopy.
• Intermediate-/high-risk polyps: 3-year surveillance.
• Invitations for screening by letter.
• Patients identified by national database.
• Public education and advertising programmes.
• National quality assurance standards.

Detailed mathematical model of colorectal cancer screening constructed - each transition represented by range of probabilities.

Survival advantage: flex sig and FOBT decrease mortality - main advantage at age 70.

Preventing Colon Cancer

30.10.06
Screening versus prevention.

Prolongation of life by colon cancer prevention in normal-risk individuals: statistical problem for organ-targeted screening
• 3% all deaths due to colorectal cancer.
• Median age >65.
• Life lost by death ~10 years.
• 15% reduction by acute blood screening prolongs life for average-risk individual by average of 10 days.
• Abolishing all deaths from colorectal cancer prolongs life on average by 3% of 10 years i.e. 4 months per person.

False positives present in screening - benefits of screening should be debated with individual.
Risk of death from colorectal cancer reduced by ~15% if screening carried out.

Colorectal cancer: questions to be answered
• Why do Westernised countries have more colorectal cancer?
• Why does the colon get cancer more often that the small intestine?
• What dietary factors are important?
• What are the mechanisms for interactions between diet and colon cancer?

Epidemiology of colon cancer
Correlated with increased risk: ↑ red meat
↑ calories
↑ body mass index
↓ exercise
↓ vegetables, cereals??
↓ calcium
↓ faecal pH
↓ selenium

Colon cancer and diet
• What dietary components are important?
• What are the mechanisms for their effects?
• What is important about the food?

Questions needing answers before reliable dietary advice can be given
• What foods should you eat? [E.g. which vegetables?]
• Where should they be grown? [Cf. selenium.]
• How should they be harvested? [Young sprouts.]
• How should they be cooked? [Burnt meat.]
• How quickly should they be eaten? [Is slowly, better?]
• Which foods are good for which genes? [Can slow acetylators eat roast beef?]
• Does it matter what food you eat if you take an aspirin a day?

Potential mechanisms for interactions between food and colon cancer risk
• Carcinogens.
↑ clearance of carcinogens.
• Pro-proliferative.
Anti-proliferative.
• Pro-apoptotic.
Anti-apoptotic.
• Anti-oxidant.
• ?Inhibition of interaction between bacteria and colonic epithelium.

Eating 1 pack peanuts per day for 1 week increases mitotic rate in rectal mucosa.

Risk for colon cancer determined at cellular level by:
(i) Mutation rate;
(ii) Mitosis rate;
(iii) Apoptosis.
Do we know which of these is most important? Increasingly, evidence pointing towards apoptosis.

Inflammation decreases arachidonic acid decreases apoptosis.

Two main types of genomic instability in colon cancer:
1. Chromosomal instability.
2. Microsatellite instability.

Conclusions so far:
BAD: High energy intake.
High intake red meat.
GOOD: Regular exercise.
Aspirin.
Non-legume green vegetables.
NEUTRAL: Cereal fibre.

Prevent 50% premature deaths from IHD, stroke and diabetes = 253 days saved.
Prevent 50% premature deaths from colorectal cancer = 42 days saved.

Conclusions
• Prevention in normal-risk population more likely to be taken up if also decreased risk for other common diseases.
• Colon-specific screening gives greatest benefit in high-risk groups: FAP and HNPSS relatives, high-risk family history, longstanding ulcerative colitis/Crohn's disease.

Module 2.05

Rectal Bleeding.
23.10.06 - 3.11.06.

Abdominal Pain - 4

Intestinal Obstruction
16.10.06

Causes of obstruction
SMALL INTESTINE
• Adhesions.
• Hernias.
• Neoplasms.
• Miscellaneous.

COLON
• Neoplasms.
• Volvulus.
• Diverticular stricture.
• Miscellaneous.

Intra-abdominal adhesions
• Common cause of small bowel obstruction: 66-75% cases.
• Exacerbated by intra-abdominal infection, ischaemia, foreign bodies.
• Any abdominal/pelvic surgery.
• 1 year post colectomy risk 11%, 10 years 30%.
• Variable interval between surgery and adhesive obstruction (7 months-65 years, average 6 years).

Hernias
• 2nd most common cause of small bowel obstruction (25%).
• Complete obstruction and strangulation related to rigid fascial defect through which hernia passes.

Neoplasms
• Unusual cause of small bowel obstruction (<10%).
• Usually extrinsic compression on local invasion by advanced GI (pancreatic, colonic, gastric)/gynaecological (ovarian) malignancies.

Pathophysiology
• Outcome depends on duration/degree of obstruction.
• Severity of ischaemia determines local and systemic pathophysiological consequences.
• Profound accumulation of fluid and swallowed air within intestinal lumen proximal to obstruction.
• Impaired water and electrolyte absorption and enhanced secretion → movement of isotonic fluid from intravascular space into intestinal lumen.
• Distension due to swallowed air, gases from bacteria and fluid.
• Failure of normal intestinal motility → bacterial overgrowth → translocation of bacteria to lymph nodes and systemic organs → systemic infection.

Presentation
• Acute onset of cramping mid-abdominal pain, vomiting, constipation, abdominal distension.
• Degree depends on degree of obstruction, site and duration.
• Paroxysms of pain every 4-5 minutes for proximal obstruction.
• Proximal obstruction: profuse vomiting, pain, minor abdominal distension.
• Distal obstruction: less frequent vomiting (but faeculent) and greater abdominal distension.

Examination
• Bowel sounds usually described as high-pitched/musical.

Abdominal x-ray
• If suspect obstruction, need AXR.
• Upright AXR: multiple air-fluid levels with loops of distended bowel resembling "U."

Contrast studies and CT
• Definite diagnosis, no obstruction, high-grade/complete obstruction in 50-80% patients studied.

Complete small intestine obstruction
• Complete - urgent laparotomy and broad-spectrum antibiotics.

Adenocarcinoma of colon
• >20% patients with colorectal cancer present with obstructive symptoms.
• Poor prognosis if need emergency surgery.

Volvulus
• Abnormal twisting of segment of bowel on itself along longitudinal axis.
• Results in occlusion of intestinal lumen, often closed loop obstruction → strangulation.

Diverticulitis
• Benign colonic strictures occur as consequence of diverticulitis, ischaemia and post-operative anastomotic strictures.

Pathophysiology
• Competency of ileocaecal valve important in Pathophysiology of colonic obstruction.
• If ileocaecal valve competent → caecum cannot decompress fluid and gas into small bowel → closed loop obstruction, fluid and gas accumulate → intraluminal pressure increased → colonic wall becomes ischaemic.

Presentation
• Periumbilical or hypochondriac pain and abdominal distension.

Benign and malignant colonic strictures
• Change in stool calibre/frequency.
• Malaena (or iron-deficiency anaemia).

Colonic volvulus
• Sigmoid volvulus usually 70-80 years.
• Caecal volvulus - younger sufferers.

Treatment and outcome
• Resuscitate as for small bowel obstruction.
• Obstructions proximal to Splenic flexure usually adenocarcinomas → right hemicolectomy and primary ileocolic anastomosis.
• If unfit → loop ileostomy.
• Obstruction distal to Splenic flexure either adenocarcinomas/Diverticular strictures.

Colonic pseudo obstructions
• Clinical picture suggestive of mechanical obstruction.
• Acute/chronic.
• Acute: symptoms as mechanical.
• Pathophysiology: imbalance in ANS (increased sympathetic and decreased parasympathetic tone).

Treatment
• Treat underlying cause.
• Correct electrolyte abnormalities.
• Drip and suck.
• Neostigmie.

Incidentally, this is the 100th post on this blog. Would you believe it?

Abdominal Pain - 3

Upper Abdominal Pain
16.10.06

Peptic ulcer disease
• Defects in mucosa as result of acid-peptic juices.
• Causes:
-H. pylori (80%).
-NSAIDs.
-Pancreatic duct blockage.
-Zollinger-Ellison syndrome.
• Males 4X>females.
• Duodenal ulcers 2-3X>gastric ulcers.

Causes
• Early 20th Century - stress and diet.
• 1950s - acid.
• 1970s - H2 receptor antagonists - ulcers chronic incurable.
• 1980s - PPIs; H. pylori.

Symptoms
DUODENAL ULCER
• Burning/gnawing in epigastrium.
• Occurs 2-3 hours after meal.
• Relieved by ingestion of food/antacids.
• 2/3 pain wakes in middle of night.
• Anorexia and weight loss unusual - can put on weight.

GASTRIC ULCER
• Burning/gnawing in epigastrium.
• Sooner after meals than duodenal ulcer.
• Not relieved/worsened by food and antacids.
• 1/3 wake from sleep with pain.

Complications
• Haemorrhage.
• Perforation, leading to peritonitis.
• Scar tissue build-up, leading to obstruction.

All gastric ulcers must be biopsied to exclude gastric cancer.
Duodenal ulcers are never malignant.

Treatment
• If H. pylori positive: H. pylori eradication triple therapy - PPI + 2 antibiotics.
• If H. pylori negative: PPI.
• Perforation needs urgent surgery.
• Haemorrhage: endoscopic therapy.

Acute cholecystitis
• Usually caused by gallstones.
• Gallstone affect 10% in West.
• 80% asymptomatic.
• Helminthic infection (ascariasis) major cause of biliary disease in developing countries.
• Obstruction of cystic duct → inflammation → acute cholecystitis.

Risk factors for gallstones
• Age >40 years.
• Bile salt loss (ileal disease/resection).
• Female sex (twice risk than men).
• DM.
• Genetic/ethnic variation.
• CF.
• High fat, low fibre diet.
• Obesity.
• Gall bladder dysmotility.
• Pregnancy.
• Etc.

Pathophysiology of cholecystitis
• 90% acute cholecystitis caused by obstruction of cystic duct by gallstones/sludge.
• Increase in intraluminal pressure and cholesterol supersaturates bile.

Clinical presentation
• Sudden onset pain in epigastrium.
• Can radiate round to back in intrascapular region.
• Pain often does not fluctuate, but persists 15 minutes - 24 hours.
• Nausea or vomiting common.
• Peritonitis localised to RUQ.

Investigations
• USS investigation of choice.
• Pericholecystic fluid.
• Distended gall bladder.

Management
• Fasting, IV fluids and analgesia.
• 20% need emergency surgery.
• Cholecystectomy.

Complications
• Gangrenous cholecystitis.
• Gall bladder perforation.
• Cholecystoenteric fistulas.

Jaundice and gall stones
• Most commonly occurs when stone migrates from gall bladder into common bile duct.
• LFT cholestatin pattern.

Acute pancreatitis
• >80% with alcohol/gallstones.
• Proteolytic enzymes activated → local and systemic inflammatory cell response.
• Often self-limiting.
• 5-20% fulminating course - pancreatic necrosis and cytokine activation → multiple organ dysfunction syndrome.

Symptoms
• Presentation variable.
• Alcohol-induced - symptoms 6-12 hours after binge drinking.
• Pain in epigastrium radiates to back.
• Associated with nausea and vomiting.
• Severe attacks mimic perforation/ischaemic bowel and "ruptured" aortic aneurysm.
• Abdominal distension.

Diagnosis
• Appropriate clinical features.
• Serum amylase activity over 3X normal.

Clinical course
• Self-limiting in 80% cases.
• Severe cases have 3 phases.

Assessing severity - initial predictors
• 1st attack alcohol induced.
• Obesity.
• Haemodynamic instability.
• Severe signs.

Severe pancreatitis
• Adequate resuscitation of hypovalaemic shock.
• Monitor urine output.
• Antibiotics - minor benefit.
• May need ventilation/dialysis.

Prognosis
• Overall mortality 10-15%.
• Not changed in past 20 years.

Abdominal aortic aneurysm
• True arterial aneurysms >50% increase in normal diameter of vessel.
• 90% mortality from ruptured abdominal aortic aneurysm, 80% die before reaching hospital and 50% die during surgery.
• Complications: rupture, thrombosis.

Presentation
• ¾ asymptomatic.
• Symptoms usually result from embolisation/rupture of aneurysm.
• Triad of hypovolaemic shock, pulsatile abdominal mass and abdominal/back pain in minority.

Factors predisposing to ruptured abdominal aortic aneurysm
• Diameter of aneurysm.
• Diastolic BP.
• COPD.
• Smoking.
• FH of ruptured aneurysm.
• Expansion rate.
• Etc.

Diagnosis
• Can usually palpate pulsatile mass.
• CT best test.

Treatment
• All should be considered for emergency surgical repair.
• Patients with symptomatic aneurysms need urgent aneurysm repair.

Non-abdominal causes of abdominal pain
• MI.
• Pneumonia, PE.
• New-onset DM.
• Addison's disease.
• Porphyria.
• Lead poisoning.

Conclusions
• Symptoms and signs often lead to correct diagnosis of acute upper abdominal pain.
• Remember non-abdominal causes of upper and mid-abdominal pain.
• USS early if atypical pain and aortic aneurysm suspected.

Abdominal Pain - 2

Lower Abdominal Pain
13.10.06

Irritable bowel syndrome
Epidemiology
• IBS affects 9-20% of population.
• Very dependent on criteria.
• In 1year, 38% will resolve and 8% develop new IBS.
• Female: male ratio = 1.1 to 2.6.
• Age and race have no consistent effect on incidence of symptoms.

Presentation
• Only small fraction seen by gastroenterologists.
• 50% do not seek medical advice.
• Large spectrum of severity.
• Often referred to other specialties.

Abdominal symptoms
• Almost universal symptoms.
• Colicky abdominal pain.
• Bloating.
• Sensation of increased flatus production.
• Rectal dissatisfaction.
• Often upper GI symptoms of heartburn, early satiety.

Associated symptoms
• Increased urinary frequency.
• Urinary dissatisfaction.
• Headaches.
• Atypical chest pain.
• Fibromyalgia.
• Chronic fatigue.
• Menorrhagia, dyspareunia.

Rome II criteria
At least 12 weeks in last 12 months of abdominal discomfort/pain that has 2 out 3 of following features:
• Relieved by defaecation.
• Onset associated with change in frequency of stool.
• Onset associated with change in form of stool.
Supportive symptoms
• <3 bowel movements per week.
• >3 bowel movements per day.
• Straining during bowel movement.
• Hard/lumpy stools.
• Urgency.
• Etc.

Approach to diagnosis
• Positive diagnosis and minimise investigation.
• Typical symptoms without alarm symptoms - weight loss, nocturnal symptoms.
• Normal UEC, LFT, FBC, CRP, TFT.
• Screen for coeliac disease.
• Search for depression.

Pathogenesis
• Abnormal bowel motility.
• Visceral hypersensitivity.
• Psychological factors.
• Post-infective.
• Post-surgical.
• Abnormal colonic fermentation and gas production.
• Food intolerances.

Treatment
• Careful explanation - benign nature.
• Normal diet.
• ?Increase fibre.
• Antispasmodics helpful - mebeverine, alverine.
• Tricyclic antidepressants.
• Relaxation therapy.
• Hypnotherapy.

Problems with trials in IBS
• High placebo response.
• High drop out rate.
• Safety issues.

Appendicitis
• Appendectomy most common abdominal operation.
• Diagnosis difficult at extremes of life.
• 20% normal and up to 40% misdiagnosis especially in women.
• No such thing as grumbling appendix.

Signs
• Fever.
• Guarding.
• Rebound tenderness.
• Indirect tenderness.
• Psoas sign.

Symptoms
• RLQ pain.
• Nausea.
• Vomiting.
• Onset of pain before vomiting.
• Anorexia.

3 most predictive signs
• Pain in RIF.
• Abdomen rigidity.
• Migration of pain from periumbilical region to RIF.
Other factors
• Short duration of pain than with other disorders.
• Atypically presents with back pain, LIF pain.

RIF pain in women
• Most common misdiagnoses in women with:
Pelvic inflammatory disease.
-Gastroenteritis.
-UTI.
-Ruptured ovarian follicle, ectopic pregnancy.

PID more likely if:
• History of PID.
• Vaginal discharge.
• Urinary symptoms.
• Tenderness outside RIF.

Laboratory tests
• b-HCG level.
• 70-90% increased WCC, but not specific.
• MSSU.
• 40% of acute appendicitis have pyuria, haemuturia or bacteriuria.
• CT more accurate and better at identifying other diagnoses and complications that ultrasound scan.

Crohn's disease
• Idiopathic inflammatory bowel disease.
• Occurs anywhere from mouth to rectum.

Signs/symptoms
• Young Caucasian.
• Diarrhoea (80%).
• Abdominal pain (70%) - usually colicky lower abdomen.
• Occasionally obstructive symptoms.
• Weight loss (50%).
• Extra-GI symptoms.
• Examination - usually normal.
• RIF mass/fullness.

Smoking
• Probably most important intervention: stopping smoking.
• Smokers with CD have:
-More relapses.
-More pain.
-More operations.

Extra-GI manifestation
• Arthralgia.
• Mouth ulcers.
• Iritis.
• Etc.

Diagnosis
• Clinical.
• Raised inflammatory markers.
• Endoscopy.

PID
• Usually caused by invasion of either gonorrhoea/chlamydia from cervix up to uterus and tubes.
• Bacteria and neutrophils fill tubes.

Risk factors
• Low socioeconomic status.
• Multiple/high-risk sexual partners.
• Intrauterine contraceptive device.
• Previous episode.

Symptoms/signs
• Lower abdominal/pelvic pain.
• Dyspareunia.
• Dysuria.
• Abnormal uterine bleeding.
• Nausea and vomiting.
• Fever.
• Etc.

Investigation
• Increased WCC, ESR and CRP - non-specific.
• USS and CT.
• Laparoscopy.

Management
• Oral/IV antibiotic regimes.
• Ofloxacin.
• Ceftriaxone and doxycycline.

Ectopic pregnancy
• Most common location: Fallopian tubes.
• Pregnancy outgrows tube, tube wall ruptures.
• Haemorrhage into pelvic cavity occurs.

• Suspect in females of child-bearing age with:
-Abdominal pain.
-Unexplained shock.
• When was LNMP?
-Does not necessarily cause missed period.

Conclusions
• Pattern of pain and associated symptoms vital in making diagnosis.
• Functional pain most likely cause in younger adults.
• Important to think of PID, but difficult to diagnose.
• RIF pain in females most difficult.

CPC: Causes Of Abdominal Pain

13.10.06

Acute abdomen: principles
• Intestinal obstruction - causes:
-Ileus.
§Vascular event.
-Obstruction.
§Intussusception.
§Volvulus.
§Hernial entrapment/incarceration.
§Due to tumours.

Complication of acute abdomen
• Peritonitis.
• Septicaemia.
• Shock:
-Definition.
-Types.
-Systemic inflammatory response syndrome.
Appendix
• Acute appendicitis.
• Threadworms.
• Carcinoma.
• Faecoliths.

Diverticular disease
• Pressure in large bowel.
• Effect of diet.
• Commonest in sigmoid colon.
• Weak points in wall.
• Diverticulosis and diverticulitis.

Chronic idiopathic inflammatory bowel disease
• Crohn's disease.
• Ulcerative colitis.
• Differences:
-Age/sex of index patients.
-Distribution.
-Wall involvement.
-Activity, granulomas.
-Complications.

Ovarian cancer
• 7000 new cases every year.
• Often presents insidiously i.e. later.
• Therefore, poor prognosis.
• Treatment difficult.
-Surgical clearance often not possible.
-Chemotherapy ~50%/year survival.
• Screening programme under discussion.

Neoplasia - 1

13.10.06

Terminology
• Cancer: all malignant disease.
• Neoplasm: any autonomous growth.
-Benign or malignant.
• Malignant: shows invasion and/or metastasis.
• Benign: local growing only.
• Tumour: a swelling.
-[But colloquially = cancer.]
• Non-neoplastic "tumours."
-Choristoma, hamartoma.
• Dysplasia: cellular and architectural changes of neoplasia.
• Anaplasia: lack of differentiation, marked pleomorphism.
• Differentiation: degree to which neoplastic tissue resembles normal equivalent.
• Carcinoma: epithelial malignancy.
• Adenocarcinoma: malignancy of glandular tissue.
• Sarcoma: mesenchymal/connective tissue malignancy.
• Lymphoma: solid malignancy of immune system.
• Leukaemia: malignant blood cells in blood.

Definition of neoplasm:
• Abnormal mass of tissue, growth of which exceeds and is uncoordinated with that of normal tissues and persists in same excessive manner after cessation of stimulus that evoked change.

Cancer - the size of the problem
• 1 in 3 people will get it.
• 1 in 4 will die from it.
• England and Wales deaths from cancer: ~150,000/year.
• Mainly in older age groups but important, rarer types in children and young people.
• "Genetic" types occur at younger ages.

Theory of neoplasia
• Stem cell defect, often with chromosomal abnormality, resulting in expression of oncogenes or deletion of anti-oncogenes.
• Clonal theory, clonigenic cells.
• Versus field change.

Histogenic classification
• Clonal theory results in:
• Histogenic classification:
-Differentiation may vary in subclones.
-Other components: stroma, blood vessels, inflammatory cells.

Expansion
• Doubling times.
• Cell loss from tumour.
• Submutation and clonal evolution.
• Tumour angiogenesis.
• Mechanisms of invasion and metastasis.
-Detachment, invasion, spread to planes and vessels, embolisation, implantation.

E.g. colorectal tumour

Normal

APC loss/mutation

Metaplasic polyp

Loss of DNA methylation

Adenoma

Ras mutation (12p)

Adenoma

Loss of DCC (18q)

Late adenoma

Loss of p53

Carcinoma



Epithelial neoplasms
• Spectrum of benign, dysplasia, carcinoma in situ, invasive carcinoma.
• Concept of intra-epithelial neoplasia.
• Cytogenic and flow of cytometric abnormalities.

Features of dysplasia
• Loss of polarity (maturation towards surface).
• Basal cells above bottom layer.
• Mitoses above basal layer.
• Heaping up of layers.
• Individual cells show features of atypia.

Carcinogenesis
• Initiation and promotion.
• Multistep transformation.
• Mutations:
-Balanced translocations.
-Deletions.
-Gene amplification.
-Amplification.
-Extra/deleted chromosomes.

Mechanisms
• Initiation.
-Permanent change to DNA, mutations.
-Requires replication to stabilise it.
• Promotion.
-Reversible change, not capble alone of producing tumour.
-Allows changes of initiation to become effective.
• Mainly apply to chemical carcinogenesis.

Principal agents
• Radiation:
-Ionising.
-Non-ionising.
• Chemicals.
• Micro-organisms:
-Viruses.
-Bacteria.

Radiation carcinogenesis
• UV:
-A: 320-400nm.
-B: 280-320nm.
-C: 200-280nm.
• Damage pyrimidine dimers.
• Ras and p53 mutations.
• Cell mediated immunity reduced.
• Ionising:
-X-rays, γ-rays.
-Particles.
• Sources:
-Radiology.
-Radiotherapy.
-Miners.
-Bomb survivors.
-Chernobyl.
-Radiation workers.

Viral carcinogenesis
• Animal viruses (historical/experimental).
• HUMAN VIRUSES.
• HPV (especially 16, 18, 33 35, 51).
• EBV (Burkitt's, NPC, AIDS-lyphoma).
• Hepatitis B (and C).
• HTLV-1 (T-ALL and NHL).

Bacterial carcinogenesis
• H. pylori.
-Gastritis.
-Gastric ulcers etc.

Chemical carcinogenesis
• Initiators.
• Direct acting (electrophilic).
-Alkylating and acylating agents.
• Indirect (cytochrome p450 dependent).
-Polycyclic hydrocarbons.
-Aromatic amines.
-Plant and bacterial/fungal.
-Man-made.

Abdominal Pain - 1 or MORRISSEY HAS BINGO WINGS

Structure And Function/Approach To Diagnosis
9.10.06

Abdominal pain
• Common, often trivial.
• But can be acute and severe pain.
• Gangrene/perforation of gut occur rapidly after interruption of blood supply.

3 types of abdominal pain:
• Visceral pain.
• Parietal pain.
• Referred pain.

Nerve fibres
• 2 types:
-Myelinated A-δ fibres (skin and muscle).
-Unmyelinated C fibres (mesentery, peritoneum and viscera).
• Nociception from abdominal viscera conveyed by C fibres - dull pain.

Visceral pain
• Noxious stimuli trigger visceral nociceptors.
• Pain dull and poorly localised in midline epigastrium, periumbilical region or lower midabdomen.
• Pain cramping/burning/gnawing.

Position of pain and anatomy
• Foregut:
-Stomach.
-Duodenum.
-Hepatobiliary system.
-Pancreas.
• Midgut:
-Small bowel.
-Ascending colon.
-Appendix.
• Hindgut:
-Hepatic flexure → rectum.
-Reproductive organs.

Parietal pain
• Noxious stimulation of parietal peritoneum.
• More intense and localised e.g. course of appendicitis.
• Aggravated by movement/coughing.
• Patient lies still with knees up.

Referred pain
• Pain felt in areas remote to diseased organ.
• Convergence of visceral afferent neurones with somatic afferent neurones from different anatomic region on second-order neurones in spinal cord at same spinal segment.
• Usually well-localised.

History
• 70% diagnoses can be made based on history.
• 90% diagnoses can be made based on history and physical examination.
• Expensive tests often confirm what is found during history and examination.

Age important in diagnosis.

Key points
• Chronology (time course).
• Location/quality.
• Radiation.
• Associated symptoms.

Location of abdominal pain clue to cause.
Can get combination of visceral, somatoparietal and referred pain.

Pain intensity
• Difficult to measure.
• Depends on individual, setting, past experience, personality and cultural differences.
• Not particularly reliable diagnostic clues.

Aggravating/alleviating factors e.g.
• Peritonitis - lie motionless.
• Renal colic - writhe to try and get comfortable.
• Duodenal ulcer - often helped by meals.
• Gastric ulcer/chronic mesenteric ischaemia - worse with eating.

Associated symptoms and review of systems
• Fever/night sweats.
• Weight loss, myalgias, arthralgias.
• Anorexia, nausea, vomiting, diarrhoea, constipation.
• Jaundice.
• Urinary frequency, urgency, discomfort.
• Sexual activity, contraception, LNMP and pregnancy.

PMH and SH
• ?Previous episodes e.g. renal stones, inflammatory bowel disease.
• Generalised diseases e.g. scleroderma, lupus, nephritic syndrome.
• Family history.
• Social history.

Examination - general points
• History much more important.
• Elderly less likely to show signs of peritoneal irritation.
• Systemic examination as important as abdominal examination.

Systemic examination
• Appearance.
• Breathing pattern.
• Position in bed and posture.
• Degree of discomfort.
• Pulse - tachycardia important sign.
• Blood pressure.
• Chest examination.
• Cardiovascular examination.
• Features of shock.
• Features of underlying systemic disease.

Inspection
• Distension.
• Scars.
• Hernias.
• Bruises.
• Visible hyperperistalsis.

Palpation
• Degree of tenderness, guarding, rigidity.
• Palpable mass.
• Hernia orifices should be examined.

Auscultation
• Bowel sounds:
-Absent = possible peritonitis.
-Tinkly sounds = possible bowel obstruction.

Investigations - laboratory
• U+Es.
• Hb, WCC.
• LFTs.
• Amylase.
• Urinalysis.
• Pregnancy test.

Radiology
• Chest X-ray and plain abdomen X-ray.
• Ultrasound.
• CT.
• MRI.

Learning points
• 3 main types of abdominal pain.
• Knowledge of basic neuroanatomy.
• Patterns of common causes of abdominal pain.
• Important points in history of abdominal pain.

Module 2.04

The Civil Servant's Examinations.
9.10.06 - 20.10.06.

Drugs For GI Problems

6.10.06

Nausea and vomiting
Antiemetics
• Anticholinergics* e.g. hyoscine - side effects: dry eyes, dry mouth, can affect urinary retention in old men.
• Antihistamines* e.g. promethazine - causes drowsiness.
• Phenothiazines+ e.g. prochloperazine - work on chemoreceptor trigger zone and vomiting centre - very effective.
• Dopamine receptor antagonists+ e.g. metoclopramide - work on chemoreceptor trigger zone and vagal afferent.
• 5-HT3 antagonists e.g. ondansetron - used for cancer-induced nausea.
• Others e.g. dexamethasone.

*Work on vomiting centre.
+Drugs of choice.

Dyspepsia
Symptoms
• Epigastric discomfort.
• Anorexia.
• Retrosternal pain.
• Nausea.
• Vomiting.
• Fullness.
• Early satiety.
• Heartburn.

Aetiology
• GORD - 15-25%.
• Ulcers - 15-25%.
• Stomach cancer - 2%.
• NUD - 60%.

Causes
• Acid reflux.
• Abnormalities of gastric acid secretion e.g. gastrin-secreting tumour i.e. Zollinger-Ellison syndrome.
• H. pylori - produces inflammation - hypersecretion of HCl.
• Stress - vagus nerve stimulates over-production of gastrin and histamine.
• NSAIDS, steroids, alcohol and other drugs.

Age-related management
Dyspepsia


<45>45 years


Nil alarming Alarm signs



Endoscopy

Alarm signs
Anorexia.
Loss of weight.
Anaemia.
Rapid progression.
Malaena.
Dysphagia/odynophagia.

Treatment
• Bismuth - coats mucosa - rarely used any more.
• Antacids - neutralise acid - remove symptoms at low doses - curative at high doses.
• PPIs - at apex of cell - more potent than H2A.
• H2 antagonists - at base of cell.
• Antibiotics - eradicate H. pylori.
• Anticholinergics.

Antacids
• Weak alkali.
• Relieve symptoms.
• Increase gastric emptying.

GORD
• Incompetent gastro-oesophageal sphincter.
• Hiatus hernia.
• May results in strictures.

Treatment
• Antacids and alginate.
• High-dose PPI - anti-secretory.

Diarrhoea
• Common complaint.
• Often settles spontaneously.
• Treat CAUSE rather than symptom.

To treat symptom:
• Stimulate opioids receptors - disrupt peristalsis - more time to digest.
-Loperamide/diphenoxylate/codeine phosphate.
• Absorbents:
-Kaolin.
• Anti-spasmodics (antincholinergics):
-Mebeverine/propantheline.

Constipation
• Bulking agents.
• Osmotic agents.
• Stimulants.
• Faecal softeners.

Inflammatory bowel disease
• Ulcerative colitis/Crohn's disease.

Anti-inflammatory drugs
• Steroids (oral, enema).
• Azathioprine.
• Sulphalazine (=sulphapyridine + 5-ASA).
• 5-ASA:
-Mesalazine (sustained release).
-Osalazine (2 x 5-ASA).

Acute Pancreatitis

2.10.06

Definition:
• Acute inflammatory process of pancreas, with variable involvement of other regional tissues or remote organ systems.

Why is it important?
• Common abdominal disease:
-Always a differential in abdominal pain.
-Common admission on acute surgical take.
• Spectrum of clinical presentations:
-Mild, self-limiting disease.
-Apocalyptic destruction of pancreas, multi-organ failure and death.
• Therapy essentially limited to supportive care.

Pancreas - a little history
• "Discovered" by Herophilos (335-280 BC).
-Alexandrian physician and anatomist.
-"Father of anatomy."
• Named by Ruphos.
• Galen:
-Claimed pancreas was cushion - to protect vessels behind.
-Word was "law" - not questioned for ~1500 years.
• Wirsung:
-Discovered pancreatic duct named after him.
• Langerhans.
• Banting and Best:
-Discovered insulin (in dog).
-6 months later, 14-year-old boy with diabetes treated with insulin.
-18 months later, mass-marketed.
-Nobel prize in 1923 (Best omitted).
• Digestive enzymes.
-Discovered throughout mid-late 19th Century.
• Wohlgemuth:
-Discovered amylase.
-Introduction to potential to diagnose pancreatitis.

Embryology
• Ventral bud - close to bile duct.
• Dorsal bud - in dorsal mesentery.
• Both have own duct.
• Duodenum rotates to right.
• Ventral and dorsal portions fuse.
• Ventral portion form uncinate process and inferior head.
• Dorsal portion forms rest of head, neck and tail.
• Ventral and dorsal ducts fuse to form main pancreatic duct (Wirsung's).

Anatomy
• Retroperitoneal.
• Immediately posterior to stomach.
• Space between stomach and pancreas form anterior and posterior borders of lesser sac.

Physiology
• Endocrine:
-Mainly body and tail.
-Islets of Langerhans.
-Insulin - β cells.
-Glucagon - α cells.
-Somatostatin - δ cells.
• Diabetes mellitus.
• Exocrine secretion:
-1500ml per day.
-Digestive proenzymes (zymogens):
§Carbohydrates (amylase).
§Proteins (pro-trypsin, pro-chymotrypsin, pro-carboxypeptidase, pro-elastase).
§Fats (pro-lipase, pro-phospholipase).
-HCO3- - alkalinises duodenal contents.
-Stimulated by CCK, secretin, vagal tone (ACh).

Pathogenesis
Idiopathic.
Gallstones.
Ethanol.
Trauma.
Steroids.
Mumps (and other viruses).
Autoimmune disease.
Scorpion sting (tityus trinitatis).
Hyper- Ca2+/lipids (and hypothermia).
ERCP.
Drugs (SAND - steroids/sulphonamides, azathioprine, NSAIDS, and something beginning with 'D' that I didn't get because he was started to panic about the time.)

• Gallstones:
-Impacting at ampulla.
-Flow of bile up pancreatic duct.
-?Increased pressure up duct.
• Most passed by time of admission.
• Other complications of obstructed bile duct.
• ERCP.
• Scorpion:
-South American scorpion.
-Venom causes haemorrhagic pancreatitis.

• Most common in Western world.
• Rising alcohol consumption in young.
• Leads to chronic pancreatitis.

• Premature enzyme activation within acinar cell.
• Normally trypsin activated in duodenum by enterokinase.
• Mechanisms in acute pancreatitis unknown.
-Disordered Ca2+ signalling shown to be crucial.
-Bile salts and alcohol metabolites shown to lead to enzyme activation in experimental pancreatitis.
• Exact site controversial - many theories e.g.
-Activation within zymogen granules.
-Disordered manufacture, storage or packing of zymogen etc.

Events in acinar cell
• Premature enzyme activation.
• Disruption of cell structure.
• Loss of apical enzyme secretion.
• Formation of apical vacuoles.
• Lysosomes fuse with granules.
• Inflammatory signals released.
• Cell death ensues at later stage.

Local
• Destruction of pancreas:
-Malabsorption.
-Diabetes mellitus.

Regional
• Pseudocyst (after 4 weeks):
-Obstruction.
-Haemorrhage.
• Splenic artery thrombosis.

Systemic
• Cytokines response.
• Multi-organ failure.
• Cardio-respiratory/coagulopathy/renal failure etc.

Incidence
• 3% of all cases of abdominal pain admitted in UK.
• Incidence ~15-420 cases per million per year.
• Overall mortality has dropped:
-From 30% to 6-10%.
-No further drop over decade.
-80% have mild, self-limiting attack/20% have severe disease.
-Up to 40% mortality in severe group.

Presentation
• Symptoms:
-Severe abdominal pain.
-Radiation through to back.
-Nausea +/- vomiting.
• Signs:
-Biliary pancreatitis.
-Alcoholic pancreatitis.
-Ecchymosis to abdominal wall.
§Cullen's sign.

Clinical assessment
• Majority: increased temperature, increased respiratory rate, increased pulse, decreased blood pressure.
• Shock - inadequate tissue perfusion leading to cellular hypoxia.
• SIRS:
-Temperature >380C (or <360C).
-Heart rate >90 bpm.
-Respiratory rate >20 per minute.
-White cell count >12 x 103.
• Sepsis.

Bloods
• Diagnostic.
• Amylase (4X upper limit of normal) - rises 2-12 hours/normalises <7 days, ~10% normal in acute-onset pancreatitis.
• Lipase (2X upper limit of normal) - rises 4-8 hours/normalises 8-14 days - more acute than amylase, but less available.
• FBC.
• U + Es/LFTs/serum Ca2+.
• Arterial blood gas:
-Pa O2, acidosis.

Investigations
• Plain radiographs.
-Erect chest and plain supine abdomen.
-Exclude other pathology.
-Baseline films (especially with later events).
• USS.
-Detects free fluid, gallstones, dilatation of CBD.
• CT.
-Not in first 48 hours.
-Intrapancreatic.
-Shows necrosis/acute fluid collections/abscesses.

Scoring
• Ransom criteria.
• Glasgow score modified from Ransom criteria for all patients.
• APACHE-II.
• APACHE-0.

Management
• General measures.
• Specific measures:
-ITU.
-Antibiotic therapy.
-Nutrition:
§"Drip and suck" - old thinking.
§Early nutrition.
§Use enteral route if possible (oral/NG/NJ feeding).
§"More physiological" - protective "gut barrier."

Interventions
• ERCP.
• Surgery:
-Infected necrosis.
-Pseudocyst:
§Collection of inflammatory fluid > weeks.
§Enzymes, blood, necrotic tissue.
§Symptomatic - obstruction/infection.
§Endoscopic.

Surgery
• Open versus closed.
• Open necrosectomy:
-Conventional procedure.
-Laparotomy.
-Pancreatic necrosectomy.
• Closed necrosectomy.

A Burning Question: Inflammation - Acute And Chronic

29.9.06

Inflammation
• Results from injury.
• Organised set of defence responses.

Cellular injury - causes
• Physical.
• Radiation.
• Chemical.
• Ischaemic.
• Free radicals.
• Infection - has elements of several of these.

Inflammation
• Acute - stimulus involved.
• Chronic - stimulus persists.

Acute inflammation
• Cardinal signs:
-swelling (tumor);
-heat (callor);
-redness (rubor);
-pain (dolor);
-loss of use.
• Vascular change:
-permeability;
-pressure.

Inflammatory mediators (chemotactic, chemokinetic)
• Plasma protein cascades:
-complement;
-kinins;
-blood clotting;
-fibrinolytic.
• Intracellular, sorted, released on demand:
-histamine (vasoactive) from mast cells;
-serotonin: platelets and enterochromaffin cells (not mast cells);
-lysosomal enzymes (proteases).
• Synthesised and released from cells:
-prostaglandins (peroxidation of arachidonic acid) - pain and fever in inflammation;
-leukotrienes (lipo-oxygenase pathway) - activate Neutrophils (adhesion, free-radicals, enzymes);
-platelet activating factor;
-cytokines:
§interleukins (IL1-IL15) - IL1 and IL6: systemic acute phase responses;
§interferons (α, β, γ);
§cytotoxins (TNF-α and lymphotoxin).

Complement
• Opsonisation.
• Membrane attack complex (cell lysis).
• Proteolysis.
• Mediators for vascular and cellular pathways (anaphylatoxins C3a and C5a - cause histamine release).
• Classical pathway: antibody-mediated.
• Alternative pathway: LPS-mediated.

Kinins
• Hageman factor (factor XII) activates:
-factor XI to initiate clotting;
-plasminogen proactivator (fibrinolytic);
-prekallikein cleaved → kallikrein;
-kininogen → bradykinin;
-short-lived, but:
§increased vascular permeability;
§and something else, but nobody got it because he moved onto the next slide far too quickly.

Phagocytosis
• Neutrophils adapted for bacterial ingestion.
• Opsonisation by complement/specific immunoglobulin.
• Oxidation of organism by superoxide anion, H2O2, OH• radical and HOCl. Presence of myeloperoxidase required.
• Macrophages attack larger particles (but also some bacteria).

Defence against invasion
• Complement system.
• Non-specific defences.
• Immune system.
• Phagocytosis - opsonisation.

Chronic inflammation
• The immune system - lymphocytes, plasma cells.

Prescribing In The Community

25.9.06

Thanks to Marion for these.

Elderly are biggest consumer of drugs on prescription
• Less therapeutic variation (dose standard).
• Better evidence of effect - more obvious.
• Increasing elderly population.
• Defensive behaviour by doctor - in case they miss something.

Don't pay for prescriptions over 60/65?

40% take inappropriate drugs.
50% of hospital admissions due to adverse drug events are due to inappropriate prescribing.
Huge increase in prescribed drugs in over-65s since 1977.

Who prescribes?
• Doctors, mostly.
• Dentists - mostly antibiotics.
• Nurses - new act - antibiotics and fluids.
• Pharmacist.
• Patients/carers eg. paracetemol etc. - self-medication.

Process is flawed
• Prescriptions often written based purely on clinical acumen - presumptive diagnosis.
• Patient/carer often takes it to chemist - can be lost.
• Processed by hand - writing often hard to read.
• Renewal of prescription often without adequate counselling.
• Generation:
-not much else to think about;
-health is most crucial thing to them - drugs are exciting point of day.

Prescribing
• How to chose? Cost/industry reps/scientific evidence/efficacy/SE.
• Increasing availability of drugs - increasing complexity.
• Demand from patients - now well-informed.
• Increased volume of prescriptions - increasing risk of errors, less time for patient counselling.

Challenges
• Increased prescriptions and OTC meds - more mortality and morbidity associated.
• High financial costs due to morbidity (drug-related).
• Poorly-written prescription - pharmacists have to call prescriber, leading to another cost.

Patient safety
• Medication errors and adverse drug effects - result of interactions between prescribers, patients and medications.
• Need full picture of what's going on.
• High costs - financial and human - due to ADEs.
• Lack of access to patient information contributes to ADEs eg. in hospital and on discharge.
• Move to standardise NHS practices so information can be shared.

Barriers
• Lack of integration - this is changing slowly.
• Politics based on industry competition.
• Dave likes boys.
• Can the prescriber afford it? Economics - cost-effectiveness.
• There are fundamental changes to way prescribers operate - have to protect business interests.

Forward
• Promote access to accurate and complete patient information.
• Apply knowledge regarding drug therapy.
• Monitor drug therapy:
-effective?
-continuing indication? Has complaint been dealt with already?
-ADEs/SE (side-effects).
• Confirming tests before prescribing when possible.
• Standardise products for treating conditions - national guidelines from NICE, but remember: individual variation.
• Prescription not based on industry incentives.
• Improving patient education - explain medication changes - what to expect, written information.

Community pharmacists
• Review inappropriate drugs - check with prescriber.
• Check duplicate prescription eg. if they've been in hospital.
• Check drug/drug and drug/disease interactions.
• Advice on SEs/adverse effects.

Module 2.03

The New Open-Access Endoscopy Clinic.
25.9.06 - 6.10.06.

Examination Of The Chest

22.9.06

General principles
• Careful and detailed clinical history basis of chest diagnosis (many physical signs picked up during history).
• Methodical and structured chest examination only way to identify important clinical signs.
• Idea that investigations alone can give you diagnosis is false.

Examination
• Look - general inspection.
• Face and neck.
• Hands - clubbed fingers.
• Chest inspection.
• Listening to breathing sounds at mouth.
• Palpation.
• Percussion.
• Auscultation.

Respiratory system as acoustic organ
Pulmonary acoustics
• Percussion of chest.
• Sound of breathing (mouth and at chest wall).

Percussion
• Chest divided into 2 acoustic chambers separated by mediastinum.
• Impulse contains wide spread of frequencies.
• Resonant frequency of chest cavities excited.
• Most useful when there is an effusion.

Breath sounds heard at chest
Laennec's classification
• Breath sounds bronchial and vesicular.
• Added sounds:
-rales;
-rattles;
-rhonchi.

General principles
• Sound and its analysis.
• Sound sources.
• Transmission of sound.

Sound sources
• Airflow through bronchial tree (higher frequency sound).
• Muscles, joints, heart, lung tissue etc. (lower frequency sounds).

Sounds heard at mouth
• Pants.
• Gasps.
• Sighs and yawns.
• Hisses.
• Sniffles.
• Snores.
• Whistles and grunts.
• Stridor.
• Wheezes.
• Rattles.
• Crackles.

Normal lung sounds (originally called vesicular)
• Low frequency.
• Rustling quality.
• Louder on inspiration.
• Vary according to site.
• Some correlation with airflow.

Tracheal sounds
• Higher intensity.
• Inspiration and expiration separated.
• Wider spread of frequencies.

Bronchial breathing
• Occurs when lunch parenchyma airless and supplying lobar airway patent.
• Sounds like tracheal sounds (high frequency).
• Loud, easily heard sounds.

Voiced sounds
• Measuring transmission characteristics of lung.
• "99."
• Muffled in normal lung.
• Easily heard over consolidated lung.
• Whispering pectoriloquy in consolidation.

Lung classification - additional sounds
• Continuous sounds - high-/low-pitched wheezes.
• Interrupted sounds - coarse/medium/fine crackles.

Wheeze
• Sudden onset.
• Frequency does not change with low-density gases.
• Dynamic phenomena.
• Models associated with airflow limitation.
• Continuous musical sound.
• Lasts >250ms.

Types of wheeze
• Random polyphonic wheezes.
• Expiratory polyphonic wheezes.
• Fixed monophonic wheeze.

Crackles
• Very short discontinuous sounds <20ms.
• Usually inspiratory, but also heard in expiration.
• Thought to be due to airways opening.
• Sound is pressure equalisation or sudden.
• Heard from airways close to stethoscope.

Types of crackles
• Fine end inspiratory (<10ms) associated with restrictive lung disease.
• Coarse early inspiratory associated with severe airflow obstruction (COPD) and bronchiectasis.
• Expiratory crackles - severe disease.

Pleural friction rub
• Occurs with friction between 2 inflamed surfaces of pleura.
• Sounds like creaking leather.