15 Flashcards
Inanition
State of advanced lack of adequate nutrition, food, and water or a physiological inability to utilise them
Cachexia
Weight loss or deterioration in physical condition e.g. muscle atrophy in someone not actively trying to lose weight
Effect of fat, calcitonin and insulin on appetite
Insulin decreases appetite
Calcitonin decreases appetite
Fat ingestion causes CCK release which slows gastric emptying and decreases appetite
How does opioids and GHRH effect appetite
Increase appetite
How does 5-HT, dopamine and GABA effect appetite
Decrease appetite
Common symptoms of bowel disease
- Pain, swelling, cramping in tummy
- Recurring or bloody diarrhoea
- Weight loss
- Extreme tiredness
Small intestine motility
Segmentation:
- Mixes digested food
- Oscillating movements resulting in contracted and relaxed areas
- Slow net movement towards anus
Peristalsis:
- Rapid propulsion of intestinal contents towards the anus
- Contraction of longitudinal muscles
- Reflex initiated by local distension
What causes gut motility in the fasting state?
Migrating motor complexes (MMC) which occur every 90-120mins
High frequency bursts of powerful contractions, beginning in the stomach and moving towards the terminal ileum
Pyloric sphincter open wide
Functions of migrating motor complexes?
Moves indigestible food e.g. tomato skins
Allows for removal of dead epithelial cells
Prevents bacterial overgrowth
Prevents colonic bacteria entering the small intestine
What is the gastro-ileal reflex?
Causes ileal segmentation in response to gastrin (from G cells) secreted due to presence of chyme
What is segmentation coordinated by?
Myenteric plexus and circular muscle
What is circular muscle contraction brought on by?
Acetylcholine and substance P
What is contraction of the small intestine mediated by?
Vagal excitatory contraction via substance P and acetylcholine
What is relaxation of the small intestine mediated by?
Vagal inhibitory contraction via NO and VIP
Motility of large intestine
Segmental (haustral) contractions:
- Brought about by contraction of teniae coli
- Distension of haustra stimulates contraction
- Contraction of adjacent haustra causes mixing effect
Peristalsis:
- Slower in large intestine than small intestine
- Slowly moves intestinal contents towards the anus
Mass movement:
- Describes intense contraction that begins halfway along the transverse colon and pushes intestinal contents towards the rectum
- Occurs shortly after meal and if faeces are present in the rectum, stimulates urge to defecate - gastrocolic reflex
- Partly hormonal via CCK
Bulk forming laxatives MOA
Increase the volume of non-absorbable solid residue in the gut, distending the colon and stimulating peristaltic activity
E.g. bran, methycellulose
Osmotic laxatives MOA
Poorly absorbed compounds that increase water content of the bowel by osmosis
E.g. movicol
Stimulant laxatives MOA
Increase peristalsis and water and electrolyte secretion possibly by stimulating enteric nerves
E.g. Senna
Faecal softeners (antispasmodics) MOA
Directly relax smooth muscle
E.g. mebeverine
Pathophysiology of Crohn’s disease
- Granulomatous inflammation from mouth anus
- Relapsing remitting
- NOD2/CARD15 gene
Macroscopic:
- Skip lesions
- Haemorrhagic ulcers/mesenteric lymph node hyperplasia
- Cobblestone pattern of bowel mucosa due to submucosal oedema and interconnected deep fissured ulcers
- Thickened bowel wall due to oedema and fibrosis
Microscopic:
- Transmural inflammation - all layers of bowel wall
- Non-caseating granuloma
Pathophysiology of ulcerative colitis
- Diffuse superficial inflammation
- Relapsing-remitting
Macroscopic appearance:
- May affect whole large bowel
- Bowel wall not thickened
- Shallow ulceration with pseudopolyps, hyperaemia and haemorrhage
- Diseased bowel is continuous
Microscopic appearance:
- Inflammation is limited to mucosa and submucosa with infiltration of both neutrophils and macrophages
- Crypt abscesses with ulceration, crypt atrophy and paneth cell metaplasia
Pathophysiology of malabsorption
Malabsorption is the decreased absorption of nutrients which may be caused by a number of conditions including biochemical disorders
Causes include:
- Reduced small intestine SA
- Infection
- Loss of digestive enzymes
- Drug induced mechanisms
- Lymphatic obstruction
- Rapid transit
- Failure of nutrient to reach small bowel (fistula)
- Surgical resection
Coeliac disease
- Abnormal reaction to gluten
- Damage to enterocytes
- Environmental factors allow gliadin to come into contact with transglutaminase in the lamina propria
- Gliadin is the modified by TTG and recognised as an antigen by CD4+ T cells
- Stem cells unable to keep up with rate of loss of enterocytes
- Results in villous atrophy
Consequences of malnutrition
- Frothy, greasy stools that are difficult to flush away
- Anaemia
- Diarrhoea
- Weight loss
- Abdominal distension
- Vit K deficiency
Describe intestinal epithelial cell barrier
- Lamina propria - where you find cells of immune system
- Tight junctions - make cells stick together
- Goblet cells secrete mucins
- Paneth cells
What do paneth cells (intestinal epithelial) secrete?
Anti-microbial peptides
What happens to concentration of bacteria as you move down gut?
And what changes about the bacteria?
- Conc. increases
- Becomes more anaerobic
How do innate immune system cells recognise pathogens?
Pattern recognition receptors e.g. Toll-like receptors/NODs/CARDs
They recognise patterns such as LPS, peptidoglycan and dsRNA
Cannot distinguish specifically
How do adaptive immune system cells recognise pathogens?
Use antigen specific receptors
B cell receptors is an antibody which can recognise 3D structures
T cell receptors recognise MHC complex
T-helper cell effector subsets
Th1 - IFN-gamma - effective against intracellular pathogens e.g. toxoplasmosis
Th2 - IL4 and IL-5 - effective against extracellular pathogens e.g. helminths
Th17 - IL-17 - effective against extracellular bacteria and fungi especially at mucosal sites e.g. Klebsiella and Candida
These help us fight pathogens
T-helper cell regulatory subsets
TR1 - IL-10
TR3 - TGF-beta
CD25+ - IL-10 and TGF-beta
These dampen the effectors - down-regulate
Pathology caused by Th1
Chronic inflammation
Autoimmunity
Type 1 diabetes
Pathology caused by Th2
Asthma
Allergy
Pathology caused by Th17
Chronic inflammation
Autoimmunity
RA, MS, psoriasis and IBD
What would you find at induction sites of GALT?
- Peyer’s patches
- Isolate lymphoid follicles
- Mesenteric lymph nodes
What cells would you find scattered around the GALT?
- Lamina propria leukocytes
- Intraepithelial lymphocytes
Which cells are peyer’s patches covered by?
M cells
How do M cells take up antigens?
- By endocytosis and phagocytosis
- They then transport antigens to basal site where immune cells are
- Dendritic cells pick up the antigen and are activated
- Dendritic cells then migrate to the T-cell areas of peyer’s patches
- Then travel via lymphatics to mesenteric lymph nodes - activate T cells here
Which pathogens specifically target M cells?
Poliovirus,
Reovirus,
Some retroviruses,
Salmonella,
Shigella
Yersinia
What do conditioned dendritic cells cause in healthy tissue?
Favour induction of Treg responses
Intestinal homeostasis
Either too many effectors (Th1, Th2, Th17) or regulatory cell defect (Tr1, Tr3, CD25)
In intestinal inflammation either too many effectors or not enough regulatory cells
Difference between IgA in blood and mucosal immune system
Monomeric in blood
Dimeric in mucosal immune system
Transcytosis of IgA and formation of secretory IgA
- Mediated by poly-Ig receptor
- J chain binds to receptor
- IgA then transported across lumen
- In the lumen, it is cleaved off with poly-Ig receptor still attached
- It is now known as secretory IgA
Functions of secretory IgA
- Binds to mucus layer, coating epithelium
- Prevents adherence of microorganisms
- Neutralises toxins and enzymes
- Little capacity to activate classical pathway of complement or act as a opsonin
What can replace IgA in IgA deficient people?
IgM - pentamer with J chain
Why is there normally no adverse response against food antigens and the commensal flora?
Food antigens:
- Default response to oral administration of protein antigen is oral tolerance
- Oral tolerance means effecter T cells - Th1, Th2 and Th17 are switched off
- Treg cells are generated which dampen immune response
Commensal flora:
- Induce IgA and Treg cells in intestine
- Ignored by systemic immune system - some antigens won’t get further than mesenteric lymph nodes
How can we mount effective immune response against pathogens?
- DCs fully activated in presence of pathogens
- Induce CD4+ cells to differentiate into effector cells
- Innate immune system activated through pattern-recognition receptors (toll-like receptors)
- TLR-2 - detects peptidoglycan
- TLR-4 - detects LPS
- TLR-5 - detects flagellin
- You get up-regulation of MHC and co-stimulatory molecules as well as cytokine production
How does immune system distinguish between harmless commensals and pathogenic bacteria?
Localisation of PRRs
- TLR-4 expression at crypt base
- Basolateral TLR5 expression inside epithelial cells so pathogens invading tissues can trigger TLR activation
Virulence factors in pathogens
- Salmonella has type III secretion system so they can inject material into host cel to trigger activation from inside
Commensals avoid PRR activation
Changes in flagellating sequences - TLR5 hyporesponsive so TLR5 cannot be triggered
Genetic predisposition of Crohn’s
- Mutation in NOD2 (a PRR) - usually stimulated by muramyl dipeptide
- IL-23 receptor - normally produced by innate cells following activation by PRR
Where can NOD2 be expressed?
Paneth cells (of SI)
Paneth cells produce large amounts of α-defensins and other antimicrobial peptides, such as lysozymes and secretory phospholipase A2 (sPLA2).
If you have mutation you therefore may not be able to mount immune response as they secrete antimicrobial peptides
Treatments for IBD that modulate immune system
- Helminth therapy
- Faecal microbiotia transplant
- Bacterial cocktails
Anti-inflammatory drugs for IBD
Aminosalicylates - dampen inflammatory response e.g. sulphasalazine
Corticosteroids
Immunosuppressants
Invasive GI infection syndrome
Mechanism - invasion of mucosa/production of cytokines
Location - colon
Organisms - shigella, salmonella, campylobacter and E. Coli
Non-inflammatory GI infection syndrome
Mechanism - enterotoxin/mucosal adhesion
Location - proximal small bowel
Organism - vibrio cholerae, enterotoxigenic E. Coli and bacillus cereus
Penetrating GI infection syndrome
Mechanism - induced phagocytosis
Location - distal small bowel
Organism - salmonella, listeria monocytogenes, yersinia enterocolitis
Use of antibiotics in gastroenteritis
Not advised
Can make E. Coli 0157 worse
Can cause diarrhoea
What is post-infectious syndrome of gastroenteritis?
Lactose intolerance
Intestinal hurry
What is the clearance time of gastroenteritis?
48hrs
Host defences against GI infection
- Sensory - taste and smell
- Behavioural - programmed to avoid GI infection
- Gastric acid pH 2
- Bile salts/acids
- Peristalsis
- Mucus - physical barrier and antimicrobial
Humeral immunity against GI infection
Secretory IgA production
Colonisation resistance
Where normal GI flora occupies space and produce antibiotic like substances
End products of metabolism may also be toxic
Microbiome
Sum of all species in the bowel
2-5kg
Antibiotics that can cause Clostridium Difficile?
Cephalosporin
Clindamycin
Co-amoxiclav
Ciprofloxacin
How to treat Clostridium Difficile?
Metronidazole
Diagnosis of bacterial overgrowth
Hydrogen breath test
Iron deficiency anaemia
Microcytic, hypochromic
B12 deficiency anaemia
Macrocytic, normochromic
Vitamin A deficiency
Visual acuity
Selenium deficiency
Dermatitis
Gut flora associated diseases
- Autism - clostridium boltiae
- Asthma/atopy - increased clostridia and decreased bifidobacteria
- Obesity - increased actinobacteria and decreased bacterioids
Cells you would find in the submucosa of the large intestine
- Cajal cells
- Cells of the enteric nervous system
- Adipose
- Collagen
Cells you would find in the mucosa of the large intestine
In the epithelium - goblet cells, absorptive colonocytes, endocrine and paneth cells (right colon only, metaplasia if found in the left)
Lamina propria
Basement membrane to support epithelium
Muscularis mucosae - thin layer of muscle
Type of epithelium in small intestine
Columnar - with goblet cells
Cells you would find in the small intestine
Paneth - base of crypts
Endocrine cells
Intraepithelial lymphocytes
Brunner’s gland - alkaline mucous secretions and also rich in epidermal growth factor which encourages mucosal regeneration (duodenum)
Lymphoid tissue
Where would you find peyer’s patches in the small intestine?
Ileum
What causes inflammation in appendicitis?
Obstruction by faecoliths
Food residues
Lymphoid hyperplasia
Diverticulitis
Neoplasia
Complications of appendicitis?
- Abscess formation
- Necrosis
- Spread of suppurative inflammation
- Perforation
- Septicaemia
Coeliac disease histology
- Blunting and atrophy of mucosa
- Increased intraepithelial lymphocytes
- Crypt hyperplasia
What is malabsorption in coeliac disease due to?
- Mucosal damage leads to less SA for absorption
- Immature enterocytes not capable of normal absorption
- Decreases hormone production
Deficiency in: iron, calcium, folate, and vitamin B1
Pseudomembranous colitis
- Caused by C. Difficile
- Volcano like eruptions of neutrophils, fibrin, mucus and epithelial cells on the surface which creates a pseudomembrane
- Causes infective diarrhoea and dehydration
Diverticulitis associated colitis
- Inflammation limited to segment affected by diverticulum
- Crypt architectural changes
- Can be transmural with lymphoid aggregates and fistula formation
Anatomy of portal circulation
Coeliac trunk –> hepatic artery proper –? R and L hepatic arteries
Right hepatic –> cystic artery (to gallbladder)
Hepatic portal vein carries products of digestion from the GI tract to liver (partially oxygenated)
Right and left hepatic ducts drain bile into the common hepatic duct which joins the cystic duct to form the bile duct
Phase I reaction in liver
- Oxidation carried out mainly by cytochrome P450 in the hepatocyte SER
- A number of drugs induce microsomal enzymes, affecting the metabolism of other drugs taken at the same time
Phase II reaction in liver
- Number of chemical products are conjugates with drugs or their metabolites in the liver inc. glucuronyl, acetyl, methyl
- Conjugation important with paracetamol
- Paracetamol is inactivated by conjugation to form a glucuronide or sulphate
Phase III reaction in liver
- Elimination of conjugated substances is via the blood, which then results in excretion through the kidneys or via bile through the intestines
- ATPase pumps required to actively transport the substance out of the hepatocyte
- The amount of active drug reaching the circulation is reduced and the drug is said to undergo significant first-pass metabolism
Alcoholic hepatitis
- Inflammation of the liver due to alcohol ingestion
- Mallory bodies appear in the hepatocytes
- Aggregation of neutrophils around damaged liver cells
- Focal necrosis in zone 3
- Ballooning of hepatocytes can occur due to retention of proteins and water after injury to organelles
- Alkaline phosphatase, alanine amino- transferase, aspartate aminotransferase, g-glutamyl transpeptidase, bilirubin and an increased prothrombin time
Acute pancreatitis
I GET SMASHED
Idiopathic Gallstones Ethanol (alcohol) Trauma Steroids Mumps Autoimmune Scorpion sting Hypothermia/hyperlipidaemia/hypercalcaemia ERCP Drugs
- Possible hyper stimulation of pancreas or pancreatic duct destruction leads to release of lytic enzymes which are then activated and cause damage
- Trypsin, lipase and phospholipase A2 particularly digest pancreatic tissue, causing fat necrosis
Chronic pancreatitis
Alcohol consumption main cause
4 key pathological features:
- Continuous chronic inflammation
- Fibrous scarring
- Loss of pancreatic tissue
- Duct strictures with formation of calculi
Hepatitis A
- ssRNA
- Picornavirus
- Does not cause chronic hepatitis
- Endemic in countered with poor hygiene and sanitation
- Faecal-oral transmission
Hepatitis C
- Contaminated blood products
- ssRNA with several immunogenic subtypes
- Fatigue and malaise common
- Clinical jaundice in less than 20% of patients
- 20% progress to cirrhosis
Hepatitis B
- partial dsDNA
- Transmission through contaminated blood products
- DNA virus that replicates i the liver where the core antigen incorporates itself into the host genome
- Host DNA polymerase then transcribes the virus
- Acute presentation - anorexia, abdominal discomfort
- Chronic presentation - asymptomatic, majority discovered by accident
Hepatitis D
- Deltavirus
- Incomplete RNA particle which is unable to replicate by itself
- Co-infection with hep B
- Activated in presence of hep B
Hepatits E
- ssRNA
- Faecal-oral transmission
- Developing countries
- No progression to chronic active hepatitis
Liver anatomy
- Covered by peritoneum except for bare area on the diaphragmatic surface
- 4 lobes
- Falciform ligament - remnant of the embryonic ventral mesentery
3 categories of patterns of injury that cause liver failure
- Acute liver failure with massive hepatic necrosis
- Chronic liver disease
- Hepatic dysfunction without overt necrosis - hepatocytes viable but unable to perform their normal metabolic function
Cirrhosis
- End stage of any progressive liver disease
- Caused by alcohol, viral hepatitis, drugs, autoimmune, cholestatic liver disease, metabolic liver disease etc.
- Necrosis, fibrosis and regeneration
2 types of cirrhosis
- Macronodular - regenerating nodules are generally large and of variable size
- Micronodular - contains nodules that are <3mm - more commonly seen with alcohol abuse
Complications of cirrhosis
- Portal hypertension
- This increases portal vascular resistance due to collagen deposition and fibrosis and hence the formation of varices in the gastro-oesophageal junction
Alcoholic liver disease
3 main types of liver damage:
- Fatty change - ethanol metabolised in the liver, which results in hepatic fatty acid synthesis and reduced fatty acid oxidation = accumulation and fatty destruction of hepatic cells
- Alcoholic hepatitis - infiltration with polymorphonuclear leucocytes and hyaline material (Mallory bodies)
- Fibrosis - fibrosis with nodular regeneration implies previous or continuing liver damage
Primary billiary cirrhosis
- Autoimmune disease
- Associated with other autoimmune phenomena such as hypothyroidism and sicca syndrome
- Antimitrochondrial antibodies
- Sensitised T cells may account for damage
Primary sclerosis cholangitis
- Inflammation of bile ducts both inside and outside the liver
- Impedes flow of bile to gut
- Causes cholestasis, leading to cirrhosis of the liver
- Fat soluble vitamin malabsorption and fat malabsorption
- Signs: hepatomegaly, jaundice, portal hypertension and dark urine
- Associated with ulcerative colitis
Wilson’s disease
- Error of copper metabolism
- Autosomal recessive gene on chromosome 13
- Faulty transporter protein ATP7B which excretes copper from liver via golgi complex
Liver cancer
- Hepatocellular carcinoma
- Hepatoblastoma - tumour formed by immature liver cells that primarily develops in children
- Cholangiocarcinoma - cancer of the bile duct
- Secondary metastasis
EBV effect on the liver
EBV
- May cause mild hepatitis during the acute phase of infectious mononucleosis
CMV effect on the liver
CMV
- Particularly in newborn or immunocompromised
- Can cause typical cytomegalic changes of that virus in almost any cell in the liver
Herpes simplex effect on liver
May infect hepatocytes in babies or immunocompromised and can lead to hepatic necrosis
Yellow fever effect on liver
Causes hepatocyte apoptosis
Pre-hepatic jaundice
Cause
- Increased haemolysis (e.g. haemolytic anaemia)
- Ineffective erythropoiesis
Signs
- Increased concentrations of unconjugated bilirubin
Hepatic jaundice
Cause
- Gilbert’s syndrome
- Viral infection
- Cirrhosis
- Drugs
- Autoimmune disease
- Weil’s disease
- Wilson’s disease
Signs
- Increased clotting time
- Increased ALT and AST
- Hepatocellular damage
What is Crigler-Najjar syndrome?
- Causes hepatic jaundice
- Due to deficit of UDP glucuronyl transferase
- Build up on unconjugated bilirubin in the blood
How can anorexia arise from malignancy?
Production of cytokines by malignant cells.
- May result from chemotherapy drugs.
- Impact upon appetite centres in brain and stomach.
Name 3 causes of anorexia.
Give examples.
1) Psychological, anorexia nervosa.
2) Malignancy, cytokines and chemotherapy drugs.
3) Infection/inflammation, AIDS, TB.
What demographics might be affected by nutritional neglect?
- Elderly (improper care or tea and toast diet).
- Hospitalised patients, can’t care for themselves.
- Neurological disease i.e. alzheimer’s/demetia.
What is dysphagia? What might cause it?
Difficulty swallowing.
- Oesophagitis, cancer (primary or secondary).
How might increased metabolic demands cause malnutrition? Give examples of conditions that may cause increased metabolic states.
Body requires more intake than usual and isn’t getting it.
- I.e. thyrotoxicosis, pregnancy.
What are MCV and MCH?
- Mean corpuscular volume, average size of a red blood cell.
- Mean corpuscular haemoglobin, average amount of haemoglobin per red blood cell.
What problems might vitamin B complex malnutrition cause?
Neuropathy, cardiopathy.
Chronic alcohol intake causes B vitamin deficiencies
What type of anaemia might folic acid deficiency result in?
What might cause it?
Megaloblastic anaemia
Through malabsorption i.e. coeliac disease or increased metabolic demand.
What might vitamin D malnutrition cause?
What demographics might it be seen in?
Osteomalacia (inadequate Ca2+ in bone)
- People of darker pigmented skin (especially in cold climates).
- Can’t make vitamin D as well.
- Indian sub-continent diet.
- Lack of UV light.
What type of anaemia would vitamin B12 deficiency result in? What might cause it?
Megaloblastic anaemia (pernicious). - Alcoholism.
Where are B12, intrinsic factor and bile reabsorbed?
Ileum
What problems might vitamin B12 deficiency cause?
- Pernicious (megaloblastic) anaemia.
- Ataxia.
- Peripheral neuropathy.
- Dementia.
- SACD (subacute combined degeneration of spinal cord).
What problems might vitamin C deficiency cause? Why do we not see it as much in the modern era?
Scurvy.
- A lot of vitamin C in fast foods now, not just fruit and veg.
What problems might vitamin K deficiency cause? Why is vitamin K important?
Coagulopathy (tendency to bleed).
- Used in the coagulation cascade (target of warfarin).
How is protein broken down? What are they broken down into?
Protein converted to peptides.
- Peptides to amino acids.
- Enzymes in inactive state then become active i.e. trypsinogen to trypsin.
What are lipids broken down into? How is this process different to the other 2 groups?
Lipids need to be emulsified by bile due to their phospholipid bilayer.
- Pancreatic enzymes used (lipases).
- Broken down into fatty acids and monoglycerides.
Give some examples of common fat soluble vitamins and water soluble vitamins.
- Water soluble: B complex, C
- Fat soluble: A, D, E, K.
Name some of the functions of the mouth in terms of digestion.
- Mastication, food broken down.
- Lubrication by saliva.
- Taste (more saliva produced).
- Digestion, breakdown of molecules (salivary amylases and lipases).
What are the 3 salivary glands of the mouth? Give examples of enzymes that they secrete.
1) Parotid.
2) Submandibular.
3) Submaxillary.
- Salivary amylases and lipases.
What is one of the risks of stomach surgery in terms of digestion?
Rapid gastric emptying time.
- Food isn’t being broken down properly.
What drives the digestive processes of the stomach?
Acid.
- pH 4 stomach acid activates enzymes.
What is the neuro-hormonal of the stomach in response to arrival of food?
Release of ACh and histamines.
- Increase acid production from parietal cells.
- Increase pepsinogen release from Chief cells.
What is the average gastric emptying time (time taken for food to be broken down)?
4hrs
When does a bolus of food become chyme?
When it is expelled from the stomach into the duodenum.
How is the acid chyme in the duodenum neutralised? Why?
Release of bicarbonate from the exocrine pancreas.
- Pancreatic enzymes would struggle to digest acidic chyme.
What is the role of the enzyme cholecystokinin (CCK)? Where is it secreted from?
- Contracts the gallbladder, bile released into duodenum for emulsification.
- Triggers pancreatic enzyme secretion.
Secreted from I-cells in the duodenum.
What 2 food groups does CCK help digest the most?
1) Lipids.
2) Proteins.
Role of bile
Emulsifies fat into micelles so that they can be easily digested by lipases
Where in the small intestine does the majority of absorption occur?
Jejunum
Give 2 ways that the SI is histologically adapted for absorption.
1) Large SA for absorption (including villi and microvilli).
2) Brush border enzymes i.e. lactase.
What might cause luminal disease of the SI?
- Infections (pain, diarrhoea, vomiting).
- Bacterial overgrowth.
What is mucosal disease of the SI? What might cause it?
Loss of the absorptive SA (Crohn’s, surgery).
Degradation of the absorptive SA (viili etc.) (Coeliac disease).
What is lymphangiectasia? What type of disease is this?
Disordered development of the lymphatic system.
- Post mucosal disease of the SI
What is Coeliac disease? What type of disease is it?
Gluten sensitivity (gliadin protein).
- Immune mediated attack of SI villi, SA reduced.
- Subtotal villous atrophy
- Mucosal disease.
What enzyme is tested for, and when found is highly indicative of Coeliac disease?
Anti-tissue transglutaminase.
What 3 deficiencies will Coeliac disease result in?
1) Fe deficiency.
2) Folate deficiency.
3) Vit D deficiency (osteomalacia).
What is post-mucosal disease of the SI?
Disorders of the lymphatic system.
Give some examples of luminal infections of the SI.
- Giardiasis (G. lamblia).
- TB.
- Whipple’s disease.
- Ancylostoma (iron deficiency, parasitic).
- AIDS associated OI’s such as cryptosporidium.
What is steatorrhoea?
What does it indicate?
What infection might cause it?
The presence of lots of fats in stool.
- Inability to flush stool away.
- Indicative of a malabsorptive state.
Giardiasis (G. lamblia).
How is vitamin B12 processed in the stomach?
Bound to intrinsic factor from parietal cells.
- Loss of intrinsic factor = pernicious anaemia (aka B12 deficiency).
Where is the largest amount of water reabsorbed?
Small intestine - it absorbed about 80-90%
At what point does chyme become faeces?
Large intestine
What happens if you have a SI dysfunction?
You do not get the water being reabsorbed so there is an increase in the liquidity and quantity of faeces
Histology of SI vs LI
SI - Brush border which increases SA = increased absorption capability
LI - No brush border but still have secretory glands such as crypt of Lieberkuhn
What is absorption by the colon drive by?
- Sodium transporters
- Sodium moved from the luminal side across the membrane of the LI creating a gradient
- Aldosterone
Where is secretion in the LI from?
Crypts of Lieberkuhn
What do the crypts of lieberkuhn mainly secrete and what is the purpose?
Mucous for protection
Types of wave movement
Peristalsis
Segmentation
Bristol stool chart
Constipation (1-2)
Normal (3-4)
Diarrhoea (5-7)
Ano-rectal angle
Position of rectum when it is storing faecal material
Which muscles are contracted when preventing faecal movement?
- Puborectalis
- External sphincter
What happens if you delay bowel movement?
- Reverse peristalsis
- Consistently doing this causes the material to become compacted
What happens when you decide to defecate?
- Puborectalis muscle and external sphincter relax
- Opens up anal canal, correcting the ano-rectal angle
- Allows the movement or contraction of muscle wall and gravity to work together to push faecal material out
Sulphasalazine
A sulphonamide antibiotic used to treat rheumatoid arthritis, ulcerative colitis, and Crohn’s disease.
It is often considered as a first line treatment in rheumatoid arthritis.
- Broken down in gut to release 5-ASA which is the active metabolite
- Contains sulphur which is not necessarily tolerated by patients
Kaolin
Aluminium silicate
Absorbs material and acts as binding agent in diarrhoea
Often sold with morphine as an anti-diarrhoeal
Where does portal vein carry nutrients from?
Stomach, spleen and intestines
Function of liver
- Protein synthesis - albumin and coagulation factors
- Lipoprotein synthesis
- Bile coagulation and excretion
- Storage of glycogen, release of glucose and gluconeogenesis
Hepatotropic viruses
CMV, EBV, HSV, varicella, mumps, yellow fever, rubella
How is ascites caused?
- Overproduction of lymph
- Hypoalbuminaemia
- Portal venous hypertension
Limitations of double contrast barium enema
- Less sensitive than colonoscopy
- Can’t biopsy
- Not tolerated by some patients
- Patient needs to be mobile
What shape is the right adrenal gland?
Pyramid
What shape is the left adrenal gland?
Crescent
Left gland is larger than the right.
What are the adrenal glands enclosed in?
Covered with perinephric fat and enclosed in renal fascia
What are the 3 layers of the adrenal cortex? What does each layer mainly secrete?
Zona glomerulosa - mainly mineralocorticoids (aldosterone)
Zona fasiculata - mainly glucocorticoids (cortisol)
Zona reticularis - mainly androgens and glucocorticoids
Lymphatic drainage of the adrenal glands
Para-aortic lymph nodes
Venous drainage of the adrenal glands
- Left - adrenal vein travels inferior to enter left renal vein
- Right - shorter –> straight into IVC
What stimulates the release of aldosterone?
- AngII
- High plasma K+
- ACTH
What does aldosterone do?
- Acts mainly on DCT and collecting ducts
- Causes reabsorption of Na+ and excretion of K+
Role of glucocorticoids
Regulate metabolism of carbohydrate, protein and fat
Actions of exogenous glucocorticoids
- Reduction in chronic inflammation
- Decreases uptake and utilisation of glucose
Example of an exogenous mineralcorticoid
Fludrocortisone
Conn’s syndrome
- Primary hyperaldosteronism
- Adenoma of the zona glomerulosa
- Triad of hypertension, hypokalaemia and alkalosis
Secondary hyperaldosteronism
- Excess renin stimulation of zona glomerulosa
- Common causes of secondary are accelerated hypertension and renal artery stenosis
Cushing’s syndrome
- Chronic excess of glucocorticoids
Symptoms of cushing’s syndrome
Centripetal obesity Facial plethora Glucose intolerance Weakness Hypertension
Why does ACTH cause pigmented skin?
Due to action melanocyte-stimulating action of ACTH on the receptors for the structurally similar melanocyte-stimulating hormone
Pheochromocytoma
Pain (headache), pallor, perspiration, palpitations, pressure, paroxysms
- Rare tumour in the adrenal medulla which secrete noradrenaline and adrenaline
Addison’s disease
- Deficiency of cortisol and possibly aldosterone
- Primary insufficiency of the adrenal cortex
- Can be caused by autoimmune adrenalitis, infection (TB) or tumour
- High levels of circulating ACTH can cause skin pigmentation too
Addison’s disease arises from problems with the adrenal gland - not enough cortisol and possibly aldosterone are produced
Adrenogenital syndrome - male
- Enlarged adrenal cortex secretes excess androgens
- Early pseudo puberty
- Early bone epiphyseal fusion
Adrenogenital syndrome - female
- Masculisation
- Masculine body shape
- Balding of temporal skull
- Increased muscle bulk
- Deepening of the voice
- Enlargement of the clitoris
What is shock?
Failure of the circulation that results in adequate perfusion of tissues and end organ
Hypovolaemic shock
Fall in circulating blood volume caused by either:
- External fluid loss e.g. vomiting, diarrhoea
- Internal fluid loss e.g. pancreatitis, internal bleeding
Cardiogenic shock
Caused by impairment of cardiac function such that the heart is unable to maintain adequate cardiac output
Obstructive shock
Direct obstruction to blood entering or leaving the heart or great vessels
Septic shock
- Caused by toxins e.g. endotoxin
- Systemic inflammatory response with production of cytokines
- Causes widespread vasodilation and increase in capillary permeability
- Total peripheral resistance falls and leakage of plasma proteins in interstitial fluid causes movement of fluid from vascular compartment into interstitial area, decreasing circulating volume
- Reduces venous return and stroke volume
Anaphylactic shock
- Severe type I hypersensitivity reaction
- IgE immune response consists of the activation of basophils and mast cells, leading to release of histamine and other factors
Neurogenic shock
- Sudden loss of sympathetic nervous system signals
- Results in hypotension and bradycardia
- Mechanism is that disruption of autonomic pathways leads to loss of sympathetic tone and vasodilation
3 things that can trigger renin secretion
- Decrease in BP detected by baroreceptors
- Decrease in Na+ levels in the nephron measured by macula densa cells of JGA
- Sympathetic nervous system
Major effects of Angiotensin II
- Adrenal cortex to produce aldosterone
- Hypothalamus to secrete ADH - increased water reabsorption in the CD and DCT which causes translocation of aquaporin water channels into CD plasma membrane and increases thirst
- Acts on arteries - SM to activate and constrict
3 components of juxtaglomerular apparatus
- Macula densa in DCT
- JG cells - smooth muscle cells of the afferent arteriole
- Extraglomerular mesangial cells found outside the glomerulus
What is the valsalva manoeuvre?
- Forcible expiration against closed glottis
- Increases intrathoracic pressure
- Venous return is reduced
- BP should drop
- Baroreceptors detect this and should decrease firing, causing inhibition of the vagus nerve
- Leads to increased HR and vasoconstriction
- This is corrected once the epiglottis is opened
Calculation for blood pressure
MAP = SVR x CO
Mean arterial pressure = systemic vascular resistance x cardiac output
What is Starling’s law of the heart
Force of contraction of the cardiac muscle is proportional to its initial length
Filling the heart makes it contract more, increasing preload
Hypovolaemia
PRIME - blood loss causes preload to be low and therefore CO is low
COMPENSATION - increased resistance, tachycardia, hypotension
CLINICALLY - cold/clammy, tachycardia, prolonged cap refill, empty veins
Pathological vasodilation
PRIME- reservoir increases
COMPENSATION - tachycardia, CO rises, auto regulation
CLINICALLY - warm/dry peripheries, tachycardia, short cap refill, bounding pulse
Clinical signs of shock
Poor tissue perfusion can result in oliguria,
Altered conscious levels due to lack of perfusion to the brain,
Tissues become acidotic due to lack of oxygen causing the production of lactic acid so lungs try to blow off more CO2
Causes of hypovolaemia
Intravascular - bleeding (revealed, concealed e.g. in femur or pelvic fracture)
Extravascular - evaporation, GI losses (diarrhoea), polyuria
Causes of pump failure
Intrinsic - muscle, conduction tissue, valves (aortic stenosis)
Extrinsic - obstruction (PE), compensation (tamponade), blood supply
What is SIRS?
Systemic inflammatory response syndrome
- Increased HR, RR, WCC
- Fever
What is sepsis?
SIRS and confirmed infection
What is septic shock?
SIRS with refractory hypotension
- Evidence of infection
- End organ failure
Effects of dobutamine
B1, B2 agonist
- Vasodilation (decrease BP)
- Increase HR,
- Increase SV
Dobutamine is a sympathomimetic drug used in the treatment of heart failure and cardiogenic shock. Its primary mechanism is direct stimulation of β1 receptors of the sympathetic nervous system.
Effects of adrenaline
Alpha, B1, B2 agonist
- Vasoconstriction (increase BP)
- Increase HR
- Increase SV
Pharmacological doses of epinephrine stimulateα1,α2,β1,β2, andβ3adrenoceptors of thesympathetic nervous system.
Effects of dopexamine
B2, D1, D2 agonist
- Splanchnic vasodilator
- Increase HR
Dopexamineis a synthetic analogue ofdopaminethat is administered intravenously in hospitals to reduce exacerbations ofheart failure.
It works by stimulatingbeta-2 adrenergic receptorsand peripheraldopamine receptor D1anddopamine receptor D2. It also inhibits of neuronal re-uptake ofnorepinephrine
What are drugs usually bound to in the blood?
What happens after this?
Albumin
- Absorbed into hepatocytes and made more water soluble (polar)
- Excreted into the bile duct or back into the blood
- Depends on size BIG = BLOOD
What is high intrinsic clearance also known as?
First pass metabolism
What is high intrinsic clearance?
- Most of the drug is taken up by the liver on the first pass
- Usually very lipid soluble
What do drugs with a low intrinsic clearance depend on?
Hepatic enzymes
What are the phases that make a lipophilic drug more soluble?
- Start with the lipophilic drug
- Phase 1 - P450 and mono-oxygenases in the SER makes drug more polar by hydrolysis, oxidation or reduction and adds a small active group onto drug, ready for phase 2
- Phase 2 - conjugation with small endogenous molecules such as transferases, sulphatases - resulting compounds are highly water soluble and can be excreted in bile or urine
How an drug interaction be affected in cytochrome P450 system?
- Multiple drugs bind to the same subtype of cytochrome P450
- Highest affinity one will out compete the lower affinity one
- Results in slowed metabolism of lower affinity drug
What is the cytochrome P450 system?
At least 50 different sub types of the enzyme - each with a unique binding site and some can metabolise several drugs
How might the cytochrome P450 system cause idiosyncratic drug reactions?
- This means individual features
- Happens through genetic variation
What is phase 3 reaction in drug metabolism?
Pathways of elimination
- Biliary excretion - directly into bile if highly polar after conjugation
- Can be actively transported into bile duct
- Biliary excretion important if molecular weight greater than 200
- As MW falls, urinary route more important
What can impair liver metabolism indirectly?
- Decreased albumin binding
- Malnutrition: reduced availability of micronutrients to create liver enzymes
- Decreased renal clearance
Consequences of drug biotransformation
- Liver can form a prodrug
- Drug could be turned into toxic metabolite
What is drug-induced hepatic necrosis?
- Electrophilic components added to drugs in liver
- If P450 doesn’t stop it, it can cause the development of free radicals which cause lipid peroxidation and cell death
What would differ between an alcoholic taking a paracetamol overdose and somebody taking an overdose with a bottle of vodka?
- Chronic alcohol use induces P450 and increases hepatotoxicity
- Acute use inhibits P450 and stops you producing toxic metabolites
How is paracetamol metabolised?
NAPQI is a metabolite of acetaminophen.
NAPQI (N-acetyl-p-benzoquinone imine) is a toxic byproduct produced during the xenobiotic metabolism of the analgesic paracetamol (acetaminophen).
It is normally produced only in small amounts, and then almost immediately detoxified in the liver.
What signs would be present in someone with paracetamol toxicity?
- Severe prolongation of prothrombin time
- Presence of acidosis
What is the early treatment for paracetamol toxicity?
- Administration of cysteine donors
- IV parvolex
Embryological origins of GI tract and their arterial supply
- Foregut - mouth to ampulla of vater in duodenum - coeliac
- Midgut - ampulla of vater to splenic flexure - sup. mesenteric
- Hindgut - splenic flexure - anus - inf. mesenteric
Where does occult bleeding stem from and what does it present with?
- Right sided cancer
- Iron deficiency anaemia
Common GI cancers
Oesophagus Stomach Pancreas Colon Rectum
Rare GI cancers
Anus
Small bowel
Gallbladder
Which GI cancers will be squamous?
- Anus
- Oesophagus (upper 2/3rds, lower 1/3rd is adenocarcinoma)
Why is paracetamol an issue in acute medicine?
- Used as suicidal agent
- 10g can produce hepatic necrosis
What cell marker indicates liver cell death?
High ALT
Which drug can cause fibrosis in the liver?
Methotrexate
Where are cancers of the GI system likely to metastasise to?
Liver and possibly lungs
Barrett’s oesophagus
Stratified squamous epithelium –> simple columnar due to long term acid reflux
Genetic aetiology of GI cancer
- FAP (autosomal dominant): development of lots of polyps in the colon
- HNPCC:mismatch repair defects
Symptoms of oesophageal cancer
- Dysphagia
- Associated with reflux
- Weight loss (due to dysphagia)
- Associated with elderly patients, smoking, alcohol and Barrett’s oesophagus
What type of cancer is very radiosensitive and shrinks with radiotherapy?
Squamous cell
Gastric cancer
- Associated with H. pylori bacterial infection
- Vague symptoms of weight loss, dyspepsia, abdominal pain
- Common in Japan
How is H. Pylori spread? Why is it falling now and what is this associated with?
Faecal-oral
- Can get it as a small child
- Better hygiene standard meaning this generation has less prevalence
Symptoms of pancreatic cancer
- If it presents very late it can be pain
- Typically painless jaundice - Courvoisier’s sign (palpable gallbladder)
- Poor survival rate
Symptoms of colorectal cancer
- Alteration in bowel habits
- Abdo pain
- Rectal bleeding with anaemia
- Rapid weight loss
- Begins as a benign polyps 3-5yrs before
Colorectal cancer mutations.
APC
- Which causes hyperproliferative epithelium
K-RAS
- Causes it to go from a small adenoma to a large adenoma
P53
Where is bile synthesised and stored?
What stimulates release of bile into the bowel?
Hepatocytes (synthesised)
Gallbladder (stored)
Eating stimulates CCK release from I cells of the small intestine
Where and how much bile reabsorbed?
95% in the terminal ileum
What does bile do?
- Helps body absorb necessary fat - emulsifies fat which increases SA for lipoprotein lipase to work on
- Helps eliminate waste products - e.g. bilirubin, excess cholesterol, non-water soluble xenobiotics
- Involved in signalling - activates the iv pathway and TGR5
What is bilirubin a product of?
And where is bilirubin conjugated?
Breakdown product of RBCs (haem + globin, then haem is broken down into iron + unconjugated bilirubin).
It’s conjugated in the liver
What is haemoglobin broken down into?
Haem and globin
Haem then broken down into iron + unconjugated bilirubin
How is unconjugated bilirubin transported in the blood?
Attached to albumin
When is bilirubin lipid soluble?
When it is in unconjugated.
Unconjugated bilirubin is attached to albumin which enables it to be transported in the blood.
When is bilirubin water soluble?
When it is conjugated
What is the conjugation process?
Unconjugated bilirubin + glucuronic acid –> conjugated bilirubin
What happens to conjugated bilirubin in the large intestine?
Glucuronic acid removed to form urobilinogen which then quickly becomes stercobilin
Some is reabsorbed and becomes urobilinogen then urobilin and is excreted by the kidneys
What is the cause of jaundice?
High levels of bilirubin in the blood
What are 3 types of jaundice and what causes them?
- Pre-hepatic - bilirubin unconjugated, producing lots of RBCs or breaking lots down e.g. haemolysis (haemolytic anaemia)
- Intrahepatic - enzyme defect, Gilbert’s, drugs, hepatocellular damage (hepatitis, alcohol, cirrhosis)
- Post-hepatic - duct obstruction outside the liver e.g. gallstones, fibrosis, extrahepatic biliary atresia
What type of jaundice causes pruritus?
Cholestatic pruritus!
- Conjugated bilirubin presents with pruritus.
- Unconjugated hyperbilirubinemia does not
Itch is present in 80%-100% of patients presenting with cholestasis and jaundice.
Cholestatic pruritus is the sensation of itch due to nearly any liver disease, but the most commonly associated entities are primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), obstructive choledocholithiasis, carcinoma of bile duct, cholestasis, and chronic hepatitis C viral infection and other forms of viral hepatitis.
What is extrahepatic biliary atresia?
Congenital condition, the common bile duct is blocked, narrowed or absent.
It causes post-hepatic jaundice
What are the different types of gallstones?
- Cholesterol
- Pigment
- Mixed
What is the cause of cholesterol stones?
- Cholesterol reaching levels beyond solubilising capacity of bile
- Hypersecretion of cholesterol
- Decreased secretion of bile salts
- Abnormal gallbladder function e.g. hypomobility
What are pigment stones?
- Bile pigment (calcium bilirubinate) is the main component
- Found in chronic haemolysis because of excess bilirubin
- Typically black
What is cholecystitis?
Inflammation of the gallbladder which is associated with gallstones 90% of the time
What causes acute calculous and chronic cholecystitis?
- Chemical effects concentrated, static bile
- Obstruction of outflow of gallbladder usually caused by gallstone
- Exacerbated by secondary infection
What is acalculous cholecystitis?
No gallstones form the inflammation
What happens in chronic cholecystitis?
- Wall of gallbladder is thickened and rigid from fibrosis
- Chronic inflammation of mucosa and submucosa
Complications of gallstones if it is in the gallbladder vs the common bile duct
In gallbladder:
- Acute/chronic cholecystitis
- Empyema
- Perforation
In common bile duct:
- Partial/total obstruction
- Cholangitis
- Gallstone ileus
What is cholangitis?
Inflammation of the common bile duct
Ascending cholangitis, also known as acute cholangitis or simply cholangitis, is an infection of the bile duct (cholangitis), usually caused by bacteria ascending from its junction with the duodenum. It tends to occur if the bile duct is already partially obstructed by gallstones.
What is glucagon and what secretes it?
Peptide hormone secreted by alpha cells of the pancreas
Pathophysiology of acute pancreatitis
- Duct obstruction - reflux of bile up the pancreatic duct - toxic injury/increased intraductal pressure releasing enzymes
- Direct acing injury e.g. trauma or viruses
- Zymogens (proenzymes) inappropriately activated i.e. trypsin and digest pancreatic tissue
How can alcohol cause acute pancreatitis?
Increased intraductal pressure due to production of protein-rich fluid
What is ERCP?
Endoscopic retrograde cholangiopancreatography
Symptoms of acute pancreatitis
- Acute abdominal pain - central, severe and radiates to the back, vomiting
- Signs - guarding and tenderness in upper abdomen
Causes of chronic pancreatitis
Chronic alcoholism (most common),
Biliary tract disease
Hypercalcaemia
Hyperlipidaemia
CF
Idiopathic
What is chronic pancreatitis?
Chronic inflammation and fibrosis of the pancreas
Relapsing-remitting pattern
Clinical features of chronic pancreatitis
- Recurrent bouts of severe abdominal pain
- Malabsorption due to reduced endocrine function
- Steatorrhea
- Jaundice
- Diabetes - due to destruction of endocrine pancreas
Exocrine pancreatic tumours
- Pseudocysts - contain fibrosis, organising blood clot, cholesterol crystals and debris
- Pancreatic abscess
- Cystic tumours
- Carcinoma of the pancreas
Risk factors for pancreatic adenocarcinoma
- Middle aged/elderly
- Smoking
- Obesity
Why is pancreatic adenocarcinoma so deadly?
Presents late
Most common form of GI bleeding?
Upper GI (70%)
- Oesophagus
- Stomach
- Duodenum
Rarest form of GI bleeding
- Small bowel GI bleeding
2nd most common form of GI bleeding:
- Large bowel (30%)
Causes of upper GIT bleeding
- Oesophagitis
- Oesophageal varices
- Mallory Weiss tear
- Oesophageal cancer
- Gastric cancer
- Peptic ulcer
- Gastritis/gastric erosions
- Duodenitis (rare)
- Angioectasia
- Aortoenteric fistula
- Angiodysplasia
- Haemobilia
- Pancreatitis
Causes of lower GIT bleeding
- Angiodysplasia (vascular malformation)
- Diverticular disease
- Crohn’s
- UC
- Carcinoma
- Haemorrhoids
- Fistula
- Fissure
Anal:
- Piles
- Fissure
- Carcinoma
Rectal:
- Carcinoma
- Inflammation
- Polyps
Colonic:
- Ischaemia (urgent)
- Carcinoma
- Diverticular disease
- Inflammation
- Polyps
- Angiodysplasia (fragile blood vessels, prone to bleeding)
What are faecal occult blood tests?
A fecal occult blood test (FOBT) checks for hidden (occult) blood in the stool.
The test does not directly detect colon cancer but is often used in clinical screening for that disease, but it can also be used to look for active occult blood loss in anemia or when there are gastrointestinal symptoms
What is haemoatochezia and what is it associated with?
- Passage of fresh blood out of the anus, usually with stools
- Lower GI bleeding
What is melaena and what is it associated with?
- Black, tarry faeces, foul smelling
- Upper GI bleeding
What is the Rockall scoring system?
A system used to predict patient mortality and assess severity of GI bleed
What are Mallory-Weiss tears and what causes them?
- Bleeding from tears in the mucosa at the junction between the stomach and the oesophagus
- Caused by alcoholism, retching, coughing, vomiting
Where is the largest amount of water absorbed in the GI tract?
Small intestine
What happens to H2O reabsorption with SI dysfunction?
- SI does not absorb enough H2O
- LI not designed to absorb large quantities
- Big increase in faecal quantity and liquidity
What is the tenia coli?
Longitudinal muscle that runs along entirety of colon
Main function of ascending colon and descending colon?
Absorption of water (ascending)
Storage of faeces (descending)
Why is the small intestine better than the large intestine at absorbing water?
- Small intestine has a brush border surface (villi and microvilli) which produces a huge SA
- Colon has no brush border but does have crypts of Lieberkuhn which are secretory glands (provides protection to LI from faeces)
How does the large intestine absorb water?
- Absorption of water driven by sodium transporters
- Sodium is moved from the luminal side across the membrane of the LI creating a gradient
- Water follows Na+ from the lumen
- Short chain fatty acid/Na symporter
- Sodium channel regulated by aldosterone
2 basic mechanisms of movement down the SI and LI
- Peristalsis - movement along the tract
2. Segmentation - mixing and churning
Composition of faeces
- 75% water
- 25% solids (dead bacteria, fat, inorganic matter, protein, undigested roughage)
What determines the colour of faeces?
- Stercobilin - brown
- Urobilin - yellow
How does the intestinal epithelial cell form a barrier to prevent pathogens from crossing epithelial + colonising tissues?
Tight junctions
Goblet cells secrete mucins – forms a layer on top of epithelial cells
Paneth cells secrete anti-microbial peptides
Name the different types of mucosa associated lymphoid tissue (MALT)
- Nasal-associated lymphoid tissue (NALT) – lining nose
- Bronchus-associated lymphoid tissue (BALT) – upper respiratory tract
- Gut-associated lymphoid tissue (GALT)
Name the largest part of the body’s immune tissues containing 3/4 of all lymphocytes.
Mucosa associated lymphoid tissue (MALT)
It produces the majority of immunoglobulin in healthy individuals
Important tasks of MALT?
o Ignore harmless antigens
o Mount protective immune responses to pathogens
Name 2 conditions where MALT goes wrong
Celiac disease - response to the wheat protein gluten
IBD - inappropriate response to intestinal bacteria
Which anti-inflammatory drugs are used in IBD?
- Aminosalicylates – dampening the inflammatory process
- Corticosteroids – block substances that trigger inflammation
- Immunosuppressants – suppress the immune system
- Biologicals – target a specific component of the immune system (e.g. anti-TNF-alpha monoclonal antibody)
Aside from antiinflammatory drugs, what other treatments are used for IBD?
- Helminth therapy (worms)
- Faecal microbiota transplantation
- Bacterial cocktails
- Small-molecule approaches – molecules that modulate host response to bac
Where is GALT found in organised tissues?
Peyer’s patches – mainly in the distal jejunum and the ileum
Isolated lymphoid follicles – in small intestine and large intestine
Mesenteric lymph nodes – largest lymph node in body, drain the intestinal tract
Where is GALT found in scattered lymphoid cells?
Lamina propria leukocytes
• Immune cells of lamina propria
• CD4,+ CD4+, DCs, plasma cells, macrophages, etc.
Intraepithelial lymphocytes
• Immune cells of the epithelial layer
• Specialised types of T cells mainly found in the gut
Peyer’s patches are covered by an epithelial layer containing specialised cells called?
M cells
M cells have characteristic membrane ruffles
M cells take up antigen by endocytosis and phagocytosis
Some pathogens target M cells to gain access to the subepithelial space
• e.g. poliovirus, reovirus, some retroviruses, salmonella, shigella, yersinia
Antigen is transported across the M cells in vesicles + released at the basal surface
Difference between serum + secretory IgA?
Serum IgA is monomeric
Secretory IgA is polymeric ( mainly bimeric); monomers are linked by 2 chains, one is J chain (joining chain)
Which immunoglobin is the dominant antibody class in the mucosal immune system?
IgA
o Dimeric secretory IgA is transported into the gut lumen through epithelial cells at the base of the crypts
o IgA in the gut neutralises pathogens and their toxins
Transcytosis of IgA across the epithelial is mediated by a specialised transport protein. Name it.
Poly-Ig receptor
It has a high affinity for the J-chain found in IgA
Describe the transcytosis of IgA across the epithelium into luminal surface of epithelium
IgA is transported to luminal surface of epithelium, where it is released by proteolytic cleavage of the poly-Ig receptor
Part of the cleaved receptor remains associated with the IgA and is known as the secretory component
The resulting antibody is referred to as secretory IgA
Functions of secretory IgA
Bind to mucus layer coating the epithelial surface via carbohydrate determinants in secretory component
Prevents the adherence of microorganisms
Neutralises toxins, enzymes, and bacterial LPS that has penetrated the epithelial cells
Has little capacity to activate the classical pathway of complement or to act as an opsonin (cannot induce inflammation)
Main function – limit access of pathogens to mucosal surfaces, without risking inflammatory damage to tissue
Have important role in the symbiotic relationship between an individual and their commensal bacteria, helping to restrict these organisms to the gut lumen
What can replace IgA as the predominant antibody in the mucosal secretions in IgA-deficient patients?
secretory IgM
IgM is pentameric, so it also contains a J-chain (which is the bit that the poly-Ig receptors bind)
Why is there normally no adverse response against food antigens?
o The default response to oral administration of a protein antigen is the development of specific peripheral unresponsiveness
o Antigen-specific effector T cells are turned off or deleted
o Antigen-specific Treg cells are generated
Why is there normally no adverse response against the commensal flora?
o Induce IgA and Treg cells in the intestine
o Ignored by the systemic immune system – antigens normally don’t reach the rest of the body
o Bacteria constitutes 60% of the cells in your body (weight 1-2 kg)
Innate immune response is activated through pattern-recognition receptors. What do these PRR target?
Peptidoglycan
LPS
dsRNA
List the cells of the innate immune response
Dendritic cells
Macrophages
Monocytes
Granulocytes (neutrophils, eosinophils, basophils)
List the effector subset of CD4+ T helper cells
Th1 – IFN-gamma
o Beneficial against intracellular pathogens
o Pathology: chronic inflammation, autoimmunity
Th2 – IL-4, IL-5
o Beneficial against extracellular pathogens
o Pathology: allergy, asthma
Th17 – IL-17
o Beneficial against extracellular bacteria + fungi
o Pathology: chronic inflammation, autoimmunity
List the regulatory subset of CD4+ T helper cells that dampen effectors?
- Tr1 – IL-10
- Tr3 – TGF-beta
- CD25+ - IL-10, TGF-beta
What are Th1 cells beneficial against?
o Beneficial against intracellular pathogens
Pathology of Th1 cells cause chronic inflammation and autoimmunity
What are Th2 cells beneficial against?
Extracellular pathogens
Pathology of these leads to allerrgy and asthma
What is Th17 cells beneficial against?
Extracellular bacteria + fungi
Name 2 biological agents that target a specific component of the immune system, used in IBD?
Infliximab – anti-TNF-a monoclonal antibody
Adalimumab – anti-TNF-a monoclonal antibod
SI histology
Columnar epithelium – goblet cells + enterocytes
Endocrine cells – amongst columnar epithelial cells (elaborate gut hormones and crypts – motility)
Paneth cells – base of crypts, contain eosinophilic lysozyme-rich granules, defensins, immunoglobulins (protection of stem cells + regulation of intestinal microbial levels)
Intraepithelial lymphocytes – less than 20 per 100 enterocytes; there are more at base than tip of villous
Brunner’s glands – duodenal submucosal glands producing alkaline mucous secretions, rich in epidermal growth factor, encouraging mucosal regeneration after injury
Lymphoid tissue (GALT) – dense aggregates in terminal ileum (Peyer’s patches), important in immunity, predominantly T suppressor cells maintaining tolerance to food antigens
Describe the epithelium of large intestines
Goblet cells – apical mucin for lubrication
Absorptive colonocytes – principles cells; they are responsible for:
o Ion + water transportation
o Eosinophilic cytoplasm with minimal mucin
o Striate border on apical surfaces
o Mucosal immunity
Endocrine cell – confined to crypts, inverse polarity, peptide hormones
Paneth cells – eosinophilic apical granules, innate immunity, physiological features of midgut, pathological manifestation of metaplasia
What is coeliac disease?
Coeliac disease is an immunologically mediated inflammatory disorder that is due to intolerance of gluten, in genetically susceptible individuals
Gliadin is thought to be toxic component – effects an immune response resulting in increased intraepithelial T-cells
What is coeliac disease strongly associated with?
Strong association with HLA-DQ2 in 90% (remainder HAL-DQ8)
Combination of genetic susceptibility and sensitivity to gliadin may be triggered by other factors – e.g. viral infection
How does coeliac disease present?
Malabsorption
Classical (children)
• Weight loss
• Chronic diarrhoea
• Failure to thrive (children)
Non-classical (adults) • IBS-type symptoms • Abdominal pain • Altered bowel habit • Anaemia (iron deficiency)
Where in the bowels can coeliac disease, Crohn’s disease and UC affect?
Coeliac disease - SI
Crohn’s disease - Most commonly occurs in SI + colon. Can affect any part of GIT.
UC - LI only
How does UC present?
Abdominal pain
Diarrhoea mixed with blood
Weight loss, fever, and anaemia may also occur.
Epidemiology of coeliac disease
Patients are at an increased risk with another autoimmune condition and FHx of coeliac disease
Affects females more than males (2:1)
Commonly presents in childhood, but minority diagnosed in adults and elderly
Affects 1/2000 individuals in UK (but 1 in 300 in Ireland)
But increasingly recognised in east, possibly due to introduction of wheat into diet, and increasing trend of autoimmune disease
What is the first line test used to test coeliac disease due to high sensitivity and negative predicative value (NPV)
• NPV: when the true negative is correctly predicted
Tissue transglutaminase (tTG) antibody
COX 1 functions
Constitutive (continuously stimulated by body)
Produces prostaglandin for basic house-keeping purposes, stimulate normal body functions such as stomach mucous production, regulation of gastric acid and kidney water excretion
Regulation of gastric acid and kidney water excretion
COX 2 functions
Induced (not normally presented in cells)
Produces prostaglandins for inflammatory response
Used for signalling pain and inflammation
Complications of NSAID usage
65% of LT use develop ulcers + erosions – usually distal ileum and duodenum, sometimes in colon
Perforation + bleeding
Focal active colitis
Chronic NSAID enteropathy (diaphragm disease) – subacute obstruction
• Thin diagram like projections that usually affects ileum that resembles perforated diaphragm
Suppositories – located proctitis, ulceration, strictures
What is C. difficile?
Spore-forming gram-positive anaerobe
2 toxins (A and B) detected in faeces
25% antibiotic associated diarrhoea
Primarily colonic, but may be accompanying ileitis, in immunosuppressed individuals
Histologically ‘volcano-like’ eruptions of mucus, epithelial cells, neutrophils, fibrin on surface (pseudomembrane)
Inflammation in appendicitis is due to obstruction by?
Fecalith, food residues, lymphoid hyperplasia, diverticulosis, neoplasia (carcinoid)
Other aetiology – specific infections (yersinia, tuberculosis), inflammatory bowel disease
What is diverticular disease?
Herniation of mucosa into/through muscle wall at entry/exit point of blood vessels
Common condition causing morbidity in western countries
Can occur anywhere in intestinal tract – sigmoid commonest site
How does diverticular disease present?
Abdominal pain, altered bowel habit, ulceration –> bleeding
Complications of diverticular disease?
Diverticulitis
Pericolic abscess
Perforation
Fistula – communication between 2 organs
Difference between diverticulitis and diverticular disease?
Diverticulitis - inflammation of a diverticulum, especially in the colon, causing pain and disturbance of bowel function.
Diverticular disease - a condition in which muscle spasm in the colon in the presence of diverticula causes abdominal pain and disturbance of bowel function without inflammation.
Diverticular colitis/diverticulosis-associated colitis
o Mucosal inflammation limited to segment affected by diverticulosis
o Mucosa proximal + distal (rectum) normal
o Histologically – inflammation confined to mucosa with crypt architectural changes, but can be transmural with lymphoid aggregates + fistula formation, mimicking IB
Infective enterocolitis
o Acute GI infection = major cause of morbidity
o Viruses play a leading role and small intestine is usually main site
- Endoscopically and histologically mimics Crohn’s disease
- Chronic granulomatous infection
- TB and Yersinia
- Terminal ileum and caecum
What is diverticular colitis?
Mucosal inflammation limited to segment affected by diverticulosis
Epidemiology of Crohn’s disease
- Higher incidence in northern Europe + US
- Proposed genetic defect that prevents a controlled and effective immune response to causative agent
- HLA-DR1 and DQw5 haplotypes
- Bimodal incidence – 20-30 years 60-70 years
- Can occur in children (usually with FHx)
- Becoming more prevalent that ulcerative colitis + incidence rising in Asia
Aetiology of Crohn’s disease
- Cigarette smoking increases risk in genetically susceptible individuals of developing Crohn’s disease
- Microvascular infarction – Oral contraceptive pill (procoagulant)
- Triggers appear to be infective agents – mycobacteria, measles virus
How does Crohn’s disease present?
SI is commonly affected, but any part of the intestinal tract may be affected:
o Colon alone 20%
o Small bowel alone 33%
o Ileocolic 45%
Presentation depends on disease location:
o Colon – bloody diarrhoea
o SI / Upper GI – severe abdo pain, vomiting, weight loss, strictures –> small intestinal obstruction
o Perianal – ulcers, fissures, perianal abscess, fistula
Macroscopic histology of Crohn’s disease
o Serosal fat wrapping
o Cobblestone – transverse ulcers intersecting oedematous mucosa seen on luminal surface
o Serpiginous ulcers – longitudinal
Microscopic histology of Crohn’s disease
o Flat surface
o Crypt architecture often preserved
o Ulcer, patchy activity – cryptitis + crypt abscess
o Plasma cell rich infiltrate
o Pyloric metaplasia – response to chronic inflammation/injury
o Granuloma – collection of macrophages; not specific to Crohn’s disease
Indications for surgery in Crohn’s disease
- Complications of disease process – fistula, strictures, intra-abdominal abscess, perforation, malabsorption
- Main principle of surgery – preserve bowel length to avoid short bowel syndrome + intestinal failure
Complications of Crohn’s disease
- Malabsorption – short loop/bowel syndrome due to repeated resection
- Fistula formation
- Anal lesions (60%) – fissures, fistula
- Perforation, haemorrhage, toxic dilation not as frequent as ulcerative colitis
- Increased risk of malignancy of SI but less frequent than ulcerative colitis
Epidemiology of UC
- 15–30 years or > 60 years
- Anglo-Saxon individuals ~1/1000
Abdominal pain, diarrhoea mixed with blood, weight loss, fever, anemia
Aetiology of UC
- Inappropriate immune response to an unknown environmental stimulus in the colon
- Unknown cause – infection, diet, environmental factors, primary immunological defects, abnormalities in mucin, genetic disorders, psychomotor disorder
- Appendicectomy may be protective – delay onset, producing a milder form
- Smoking appears to be preventative – could be linked to increased glycoprotein synthesis maintaining protective mucosal barrier
- NSAIDS known to reactivate CIBD
Progression of UC
- Always begins in rectum
- Can remain limited to rectum (ulcerative proctitis)
- Extend proximally to a variable length, or involve the entire LI (pancolitis) in a continuous manner
- Changes always most severe distally
- Primarily affects mucosa, but in severe disease, deeper layers can be involved – fulminant colitis (toxic megacolon)
Macroscopic histoloogy of UC
o Length may be shortened, reduction in transverse calibre – increase in sarcorectal distance radiologically
o Normal serosa except in toxin megacolon
o Granular/velvety friable surface
o Ulcers – flask-shaped or undermining
o Polyps – inflammatory – granulation tissue vs pseudopolyps (oedematous smucosal islands)
Microscopic histology of UC
o Irregular surface
o Diffuse crypt architectural distortion
o Diffuse chronic inflammatory cell infiltrate, rich in plasma cells
Indications for surgery in UC
- Resistance to medical therapy or dependence on unacceptable levels of therapy – immunosuppressants
- Severe disease
- Complications – dysplasia (unregulated cell proliferation and differentiation) and carcinoma
Extra-intestinal manifestations of IBD in the liver?
Incidence depends on severity + extent of colitis, but significant liver problems in 5-8%
Extra-intestinal manifestations of IBD in the skin?
Pyoderma gangrenosum – tissue becomes necrotic causing deep ulcers; usually occur on the legs
Erythema nodosum – swollen fat under the skin causing red bumps and patches
Extra-intestinal manifestations of IBD in biliary tract
Primary sclerosing cholangitis (PSC)
Disease of biliary tract
Most commonly seen with pancolitis (UC)
• 1-5% of patients with IBD have PSC
• 50-75% of patients with PSC have IBD
Extra-intestinal manifestations of IBD in the eyes
Iritis – inflammation of the iris
Uveitis – inflammation of the uvea
Episcleritis – benign, self-limiting inflammatory disease affecting part of the eye between conjunctiva and sclera
Extra-intestinal manifestations of IBD in the joints
Ankylosing spondylitis – form of arthritis that primarily affects the spine
Epidemiology of IBD
o Incidence and prevalence is increasing, particularly in developing countries
o This could be due to improved sanitation and health reducing exposure to enteric infections immature immune system
o There is an equal distribution between males and females
Which disease has a strong associated with HLA-DQ2 allele
Coeliac disease
List 4 complications of coeliac disease
- Small intestinal lymphoma/adenocarcinoma
- Osteopenia
- Dermatitis herpetiformis
- Hyposplenism
- Malabsorption
Where does carbohydrate + protein digestion begin?
Carbs: in mouth with salivary amylase
Protein: in stomach with pepsin
How is starch broken down?
o Begins in the mouth w/ salivary amylase
o Acidic pH of stomach destroys salivary amylase
o Starch not already broken down are cleaved by pancreatic amylase in pancreatic juice
Once starch has been cleaved by amylase, how is glucose clipped off one at a time?
o Brush-border enzymes (alpha-dextrinase) acts on resulting alpha-dextrin’s, clipping off one glucose at a time
o Sucrose, lactose, and maltose aren’t acted on until they reach the SI
How do monosaccharides pass from lumen of the SI through the apical membrane
Via facilitated diffusion (fructose) or active transport coupled with Na+ (glucose + galactose)
How do monosaccharides move from apical membrane out through basolateral surface into capillaries?
Move out trough basolateral surfaces via facilitated diffusion + enters capillaries
Protein digestion begins in the stomach with pepsin. Which enzymes in pancreatic juice continue to breakdown proteins into peptides?
Trypsin
Chymotrypsin
Carboxypeptidase
Elastase
Protein digestion is completed by 2 peptidases where?
In the brush border into aa
Where are amino acids absorbed? And how?
By active transport in the duodenum + jejunum
Summarise carbohydrate digestion + absorption
o Begins in the mouth w/ salivary amylase
o Acidic pH of stomach destroys salivary amylase
o Starch not already broken down are cleaved by pancreatic amylase in pancreatic juice
o Brush-border enzymes (a-dextrinase) acts on resulting a-dextrin’s, clipping off one glucose at a time
o Sucrose, lactose, and maltose aren’t acted on until they reach the SI
o Monosaccharides pass from the lumen of the SI through the apical membrane via facilitated diffusion (fructose) or active transport coupled with Na+ (glucose + galactose)
o Move out trough basolateral surfaces via facilitated diffusion + enters capillaries
Summaries protein digestion + absorption
o Begins in the stomach with pepsin
o Enzymes in pancreatic juice (trypsin, chymotrypsin, carboxypeptidase, elastase) continue to breakdown proteins into peptides
o Protein digestion is completed by 2 peptidases in the brush border into aa
o Amino acids are absorbed by active transport in the duodenum + jejunum
Summarise fat digestion + absorption
o Lipids combine w/ bile salts to form emulsification droplets
o These are digested by lipase to form free fatty acids (monoglycerides) + bile salts
o These combine to form micelles
o Micelles transport poorly soluble monoglycerides to the surface of the enterocytes to be absorbed
o Monoglycerides are absorbed once freely dissolved micelles are no absorbed
- Vitamins + minerals
List the cell types in the stomach glands
o Mucous neck cells – secrete mucous
o Parietal cells – produce intrinsic factor + HCl
o Chief cells – secrete pepsinogen + gastric lipase
o G cells – secrete gastrin (stimulate gastric acid secretion)
o Delta cell – secrete somatostatin
Examples of serous cells that secrete proteins (often enzymes)?
Gastric chief cells Paneth cells (SI)
List principal cells types of the SI
Paneth cells
Goblet cells
Enterocytes
Enteroendocrine cells
Examples of mucous cells that secrete mucus
Brunner’s glands
Oesophageal glands
Pyloric glands
Examples of mixed glands.
Examples include the salivary glands:
Parotid gland - is predominantly serous
Sublingual gland - mainly mucous glandcck
Submandibular gland - is a mixed, mainly serous gland
Gastrin is released by G cells in the pyloric antrum of the stomach, duodenum, and the pancreas.
What does it lead to?
Gastrin is a peptide hormone that stimulates secretion of gastric acid (HCl) by the parietal cells of the stomach and aids in gastric motility.
What do gastric parietal cells secrete?
HCl + IF
Intrinsic factor is a glycoprotein essential for the absorption of vitamin B12 (in the terminal ileum)
Where are Delta cells (r D cells) found? What do they secrete?
Somatostatin-producing cells.
They can be found in the stomach, intestine and the pancreatic islets.
Where are G cells found? What do they secrete?
Stomach, duodenum, pancreas.
Secretes gastrin
What do Enterochromaffin-like cells secrete?
Histamine when pH becomes too high
What do mucous neck cells secrete?
Mucous
Found in stomach
What do chief cells secrete?
Releases pepsinogen and gastric lipase and is the cell responsible for secretion of chymosin in ruminants.
What are foveolar cells?
Aka mucous neck cells in the stomach that produce mucous
What is cholecystokinin (CCK)?
A peptide hormone of the gastrointestinal system responsible for stimulating the digestion of fat and protein
Where is CCK made?
Synthesised and secreted by enteroendocrine cells in the duodenum.
Its presence causes the release of digestive enzymes and bile from the pancreas and gallbladder, respectively, and also acts as a hunger suppressant
What does CCK do to hunger?
Suppressant
Role of the peptide hormone Ghrelin.
When the stomach is empty, ghrelin is absorbed.
When the stomach is stretched, secretion of Ghrelin stops.
It acts on hypothalamic brain cells both to increase hunger, and to increase gastric acid secretion and gastrointestinal motility to prepare the body for food intake.
Where is secretin secreted from in the GIT?
S cells in glands of SI
It is a hormone released into the bloodstream by the duodenum (especially in response to acidity) to stimulate secretion by the liver and pancreas.
When do S cells of duodenum secrete secretin?
When gastric juice enters duodenum and it’s too acidic
Secretin stimulates flow of pancreatic juice rich in HCO3- to buffer acidic chyme
Role of jejunum?
Rapid digestion and absorption of macronutrients
Absorption of nutrients virtually complete in distal jejunum
What is the main function of the ileum?
Specialised transport systems for bile acids (90% reabsorbed) + vitamin B12 absorbed in distal ileum
List 2 causes of luminal disease of SI
Infections, bacterial overgrowth
List causes of mucosal disease of SI
Loss of absorptive surface area
• Crohn’s disease, surgery, lymphoma
Degradation of absorptive surface area
• Coeliac disease
Which pathogens cause luminal disease of the SI leading to malabsorption?
Giardiasis – bloating, steatorrhoea
TB
Ancylostoma (parasite) – can cause iron deficiency
Tropheryma whippelii – bacteria that causes subtotal villous atrophy
Cryptosporidium, microsporidium, isospora – opportunist infections in immunocompromised patients
List conditions in which bacterial overgrowth cause luminal disease of the SI and lead to malabsorption?
- High folate, low B12.
- Jejunal diverticulosis (structural abnormality).
- Blind loop syndrome.
- Motility disorder - autonomic neuropathy (diabetes), scleroderma (connective tissue disorder)
- Bowel obstruction.
- Fistulation.
- Hypochlorhydria in the elderly (low HCl secretion in stomach)
Does coeliac disease (gluten enteropathy) cause luminal, mucosal or post-mucosal disease of SI?
Mucosal
Complications of terminal ileal removal surgery?
Bile salt malabsorption
• Bile salt catharsis
B12 malabsorption • Megaloblastic anaemia • Peripheral neuropathy • Optic atrophy • Dementia • SACD – Subacute combined degeneration of spinal cord, aka Lichtheim's disease
Vitamin A deficiency leads to?
Night blindness,
Xerophthalmia (abnormal dryness of conjunctiva + cornea)
Vitamin D deficiency leads to?
Osteomalacia
Vitamin E deficiency leads to?
Ataxia
Dysarthria
Absent tendon reflexes
Vitamin K deficiency leads to?
Coagulopathy
What is Zollinger-Ellison syndrome?
Gastrin-secreting tumour or hyperplasia of the islet cells causes overproduction of gastric acid, resulting in recurrent peptic ulcers
Most common cause of chronic pancreatitis?
Alcohol
List the types of malnutrition
o Protein-energy malnutrition (PEM) - split into developing and developed world PEM
o Specific nutrient malnutrition – vitamin + mineral deficiency
In the developing work what are the causes of PEM?
Predominately lack of protein (Kwashiorkor)
Total caloric dietary lack (Marasmus)
In the developed work what are the causes of PEM?
Anorexia
Neglect
Dysphasia
Increased metabolic demands
What is Kwashiorkor?
Kwashiorkor is a form of severe protein malnutrition characterised by oedema, enlarged liver with fatty infiltrates
Sufficient calorie intake, but with insufficient protein consumption, distinguishes it from marasmus
What does Marasmus (total caloric dietary lack) cause?
Growth failure Apathy Diarrhoea Hepatomegaly Muscle wasting Oedema Anaemia Stomatitis – inflammation of mouth + lips
Causes of anorexia (suppression of appetite)?
Malignancy – cytokines suppress appetite
Infection/inflammation – TB, AIDS
Anorexia nervosa – self-induced
How many B vitamins are there?
8
GI infection exacerbates malnutrition. Malnutrition lowers resistance to GI infection.
List GI infection syndromes.
o Non-inflammatory
o Invasive
o Penetrating
Mechanism, location and examples of non-inflammatory GI infections.
Mechanism - Enterotoxins/Mucosal adherence
Location - Proximal small bowel
Examples:
- Vibrio cholerae
- Bacillus cereus
- Enterotoxigenic E. coli
Which pathogens cause invasion of mucosa and/or production of cytotoxins?
They act on colon
Shigella spp.
Salmonella spp.
Campylobacter jejuni
Enterohaemorrhagic/Enteroinvasive E. coli
Which pathogens induce phagocytosis in the distal SI?
Salmonella typhi
Yersinia enterocolitica
Listeria monocytogenes
List host defences against GI infection
o Behavioural/sensory
o Gastric pH
o Bile salts/acids
o Peristalsis
o Mucus – physical barrier, antimicrobials (lysozyme)
o Humoral immunity – secretory IgA, cellular
o GALT
o Regional (normal) flora of GIT excluding mouth
What is the role of the microbiome (sum of all species in the bowel)?
- Synergistic
- Synthetic (folate, biotin)
- Release of nutrients (Fe, Ca, aa)
- Remove toxins
- Compete w/ pathogens
- Release energy
Regional flora of GIT excluding mouth
SUMMARY
Colonisation resistance – occupy space, antibiotic-like substance production, metabolic end products may be toxic
Stimulate local immune system
Small numbers in stomach, duodenum, jejunum
Very large numbers in colon (>400 known species, possible 1500)
Regional GI can cause infection in extra-intestinal locations – peritonitis, UTI
The stomach, duodenum, jejunum have a light flora.
Overgrowth of bacteria can lead to?
Bloating Abdo pain Flatulence Steatorrhea Weight loss Diarrhoea
List the nutrient deficiencies diarrhoea can lead to
- Fe – microcytic anaemia
- B12/B9 – macrocytic anaemia
- Ca – tetany
- A – night blindness
- Selenium – dermatitis
- Protein – weight loss/cachexia
- Fats – haemorrhagic stroke
How is bacterial overgrowth treated?
Treatment of underlying condition
Rifaximin
Which diagnostic tests are used to diagnose bacterial overgrowth?
Hydrogen 14C-D-xylose breath test
105 bacteria/ml in proximal small bowel aspirate
What is bacterial overgrowth syndrome?
Bacterial overgrowth syndrome is a disorder in which poor movement of intestinal contents allows certain normal intestinal bacteria to grow excessively, causing diarrhea and poor absorption of nutrients (malabsorption). Some conditions and disorders slow or stop the movement of contents through the intestines.
Consequences:
- Malabsorption: steatorrhea + diarrhoea
- Deficiency of fat soluble vitamins
- Macrocytic anaemia
Compare prebiotics to probiotics
PREBIOTICS are a special form of dietary fiber that acts as a fertilizer for the good bacteria in your gut.
- Chemicals that alter the microbiome
PROBIOTICS are live bacteria that can be found in yogurt and other fermented foods.
- Microorganism such as lactobacillus or bifidobacterium
- That when consumed maintains or restores beneficial bacteria to the digestive tract
Gastroenteritis summary
A leading cause of death worldwide
Antibiotics rarely help, make E. coli 0157 worse, cause diarrhoea
Usually infectious
Comes from somewhere – travel/contact history
Can cause post infection syndromes e.g. lactose intolerance
Causes of gastroenteritis:
o Viral (70%) – rotavirus (most common in children), norovirus, adenovirus, astrovirus
o Bacterial – Campylobacter jejuni, E. Coli, salmonella, shigella
o Parasitic – Giardia lamblia, Entamoeba histolytica, Cryptosporidium spp.
Name 4 viruses that cause gastroenteritis
Rotavirus (most common in children)
Norovirus
Adenovirus
Astrovirus
Name 4 bacteria that cause gastroenteritis
Campylobacter (jejuni)
E. Coli
Salmonella
Shigella
Name 3 parasites that cause gastroenteritits
Giardia lamblia
Entamoeba histolytica
Cryptosporidium spp.
Most common cause of gastroenteritis?
70% Viral
What can clostridium difficile cause?
Mild symptoms to severe
Mild diarrhoea to perforation
Toxic megacolon
Malnutrition
Fever
No vomiting, not bloody
Which population does C difficile usually affect?
o Usually affects elderly/infirm patients
o Nearly all causes follow antibiotic therapy
Clostridium difficile is nearly always caused following antibiotic therapy (the 4 Cs) list them.
Clindamycin – 50s inhibitor
Cephalosporins – are a class of beta-lactam antibiotics
Ciprofloxacin – a quinolone antibiotic
Co-amoxiclav – amoxicillin/clavulanic acid (combination of beta-lactam antibiotic + beta-lactamase inhibitor)
Pathogenesis of antibiotic use on gut flora (leads to C difficile infection)
o Imbalance of regional flora caused by antibiotic
o Acquisition of C. difficile
o Increase in number of C. difficile in patients already colonised
o Production of mucosa-damaging toxins (A + B)
How is C. diff managed?
o Stop inciting antibiotics (if possible)
o Isolate patients
o Specific anti-C. difficile antimicrobials for 10-14 days
o Other measures – probiotics (e.g. Saccharomyces cerevisiae)
o Faecal flora transplant
o Relapsing infection
What can right iliac fossa pain be?
o Appendicitis o Ovarian ‘accident’ o Ectopic pregnancy o Renal colic o Inguinal/femoral hernia o Crohn’s disease o Diverticulitis o Perforated caecal cancer o Small bowel ischaemia
List all the causes of abdominal pain
GIT + digestive organs
Renal tract gynaecological sources
Vascular
Abdominal wall
Other – cardiac, hyperparathyroidism
Abdominal pain with an onset of minutes may be?
Infarct Ruptured aneurysm (AAA) Ruptured ectopic Perforated duodenal ulcer Stone disease Gonadal torsions
Causes of colic pain?
Obstructive as the hollow muscular structure contracts to unblock itself causing pain
Bowel colic, biliary colic, ureteric colic, labour
Late bowel obstructions may not have colicky pain due to over distension of bowels
Causes of non-colicky pain?
Usually inflammatory process
Acute cholecystitis, appendicitis, gastritis, pancreatitis, diverticulitis, colitis
May progress to infection and/or perforation
In which abdominal region would oesophagitis, peptic ulcer and perforated ulcer pain be?
Epigastric
In which abdominal region is pain from gallstone, cholangitis, hepatitis, live abscess, cardiac + lung problems felt?
Right hypochondriac
In which abdominal region is pain from spleen abscess, acute splenomegaly, spleen rupture felt?
Left hypochondriac
Where is pain from ureteric colic and pyelonephritis felt?
Right and left lumbar regions
In diverticulitis, UC, constipation, ovarian cyst and hernias where is pain felt?
Left iliac region
In testicular torsion, urinary retention, cystitis, placental abruption where is pain felt?
Hypogastric region
Where is the pain in late appendicitis, Crohn’s disease, caecum obstruction, ovarian cyst, ectopic pregnancy, hernias?
Right iliac
Is visceral or parietal pain poorly localised?
Visceral
Which fibres transmit visceral and parietal pain?
Visceral - C fibres
Parietal - myelinated A delta
Is visceral or somatic pain specific?
o Somatic – specific
o Visceral – general
Acute presentations of abdo pain
o 35% Non-specific abdominal pain (NSAP) o 17% Appendicitis o 15% Obstruction o 6% Urinary disease o 5% Biliary disease o 4% Diverticular disease o 3% Trauma o 3% Malignancy o 3% Perforated ulcer o 2% Pancreatitis
Inflammatory causes of abdominal pain
o Appendicitis o Pelvic inflammatory disease – from chlamydia o Cholecystitis o Pancreatitis o UTI o Ovarian cysts o Mesenteric ischaemia
List causes of perforation leading to abdo pain
o Peptic ulcer
o Colonic diverticulum
o Sterocoral perforation
o Aortic aneurysm
List causes of obstruction which lead to abdominal pain
o Pyloric stenosis
o Small bowel – adhesions, hernia, tumour, bolus (food/stone), Crohn’s
o Colonic – carcinoma, diverticular, volvulus, pseudo-obstruction
o Drugs
Non inflammatory, perforative and obstructive causes of abdo pain
o Sickle cell crisis o Acute leukaemia o Addisonian crisis o Lead toxicity o Tabes dorsalis o Parathyroid disease o Narcotic withdrawal
Abdo examination - inspection
Cachexic, bruising, posture, speech, gait
Asymmetry of abdomen
Liver signs: ascites, spider naevi, clubbing, jaundice, skin changes
Evidence of other autonomic effects: sweating, pale, nausea, restlessness
Abdo examination - palpation
Light palpation
• To elicit tenderness/guarding
• All quadrants
Deep palpation
• Go palpate for masses or organs or aortic aneurysm
• Elicit signs such as Murphy’s and rebound tenderness
Other sites
• Groin examination
• Digital rectal examination
Abdo examination - percussion
Tympanic = gaseous Dull = solid or fluid Percuss from resonant to dull preferably Define borders of organs such as liver Shifting dullness for ascites
Abdo examination - auscultation
Borborygumus or gurgling bowel sounds
Increased = increased bowel movement - e.g. gastroenteritis, bowel obstruction
Tinkling bowel sound = bowel obstruction
Absent bowel sound = no bowel activity - e.g. ileus, infarcted
Bruits
What can inflammation in the foregut be caused by?
Oesophagitis Gastritis Duodenitis Cholecystitis Pancreatitis Hepatitis
What can inflammation in the midgut be caused by?
Enteritis Meckel Appendicitis Colitis Diverticulitis
What can inflammation in the hindgut be caused by?
Colitis
Diverticulitis
Symptoms and signs of abdominal pain caused by obstruction
Symptoms:
- Rapid onset, colicky abdominal pain
- Vomiting
- Absolute constipation
- Abdominal distension
Signs:
- Abdominal distension
- Tympanic
- Visible peristalsis (thin patients only)
- Increased bowel sound
Symptoms of perforation
Initially – persistent or colicky pain initially
Later – localising severe pain progressing to generalised abdominal pain
Pain on movement / cough
Signs of perforation
Patient lying still Tender abdomen on light palpation Unable to tolerate deep palpation Rigid abdomen Rebound tenderness positive
What can perforation be caused by?
Ulcers Cancers Foreign bodies Stercoral Obstruction Infarcted bowel
What stimulates CCK?
Eating stimulates CCK
CCK stimulates bile release into bowel through ampulla of vater
What does the bile contain?
Bile acids:
Cholic acid
Chenodeoxycholic acid
Glycine and taurine conjugates
Secondary bile acids:
Deoxycholic acid
Lithocholic acid
Cholesterol
Phosphatidylcholine
Bilirubin
How is bile concentrated?
By water + ion absorption by the gallbladder mucosa (simple an epithelium with rugae)
Functions of bile?
Helps the body absorbs the necessary fats:
Emulsification of dietary fat (vital for absorption)
Helps eliminate waste products:
Excess cholesterol, bilirubin, non-water-soluble xenobiotics (conjugated by hepatocytes)
Signalling molecules:
Active MAPK pathway
Ligands for receptor TGF5
Active hormone receptor, e.g. FXR
Bile salts + reabsorbed by active transport + return by blood to the liver (enterohepatic circulation)
Name the waste products in bile which is eliminated
Excess cholesterol
Bilirubin
Non-water-soluble xenobiotics (conjugated by hepatocytes)
Bilirubin is secreted into the bile.
What happens then?
Bile (with bilirubin) passes into the SI and then the LI
In the LI, bacteria convert bilirubin into urobilinogen
Some urobilinogen is absorbed back into the blood, converted to urobilin, and excreted in urine
Most urobilinogen is excreted in the faeces in the form of stercobilin (given faeces its brown colous)
What is hyperbilirubinemia known as?
Jaundice
High bilirubin in the blood
Jaundice can be described as pre-hepatic, hepatic and pro-hepatic.
What is pre-hepatic jaundice?
Un-congugated
Causes include:
• Haemolysis
• Resorption from bleed – e.g. burst aortic aneurysm
• Gilbert syndrome – congenital condition where unconjugated bilirubin struggles to enter liver
• Ineffective erythropoiesis
What is Gilbert syndrome?
Congenital condition where unconjugated bilirubin struggles to enter liver
When stressed, patient can go jaundice
Causes of hepatic jaundice?
- Liver disease – cirrhosis, viral hepatitis, primary biliary cholangitis (PBC)
- Drugs
- Toxins
- Cancer
Causes of post-hepatic jaundice?
- Gallstones
- Pancreatic cancer
- Cholangiocarcinoma of biliary tree
- Strictures
- Biliary atresia
What is cholesterolosis?
Accumulation of cholesterol in macrophages within the lamina propria (from foam cells) of gallbladder
“Strawberry gallbladder” - stippled mucosa of gallbladder where you get cholesterol esters in foam cells
What is cholecystitis?
Inflammation of gallbladder
Difference between acalculous and calculous cholecystitis?
Calculous most common (obstruction of cystic duct usually by gallstones or biliary sludge)
Acalculous - much less common (inflammation of gallbladder without gallstones or cystic duct obstruction)
Risk factors (5Fs) for gallstones?
Female, fat, fertile, fair, fourty
Causes of gallstones?
Chronic haemolysis Lithogenic bile Inflammation/infection Rapid weight loss Stasis (e.g. pregnancy, spinal cord injuries)
o 80% are cholesterol stones
o 80% of stone have no identifiable risk factor
Complications of gallstones when the stone is in the gallbladder or cystic duct?
- More than 80% are silent
- Acute/chronic cholecystitis
- Mucocele – a swelling like a sac that is due to distension of a hollow organ or cavity with mucus
- Empyema – gallbladder fills with purulent material
- Perforation
- Gallstone ileus
Complications of gallstones when the stone is the common bile duct?
- Partial, total, intermittent obstruction
- Pain
- Cholangitis – infection of bile duct (cholangitis), usually caused by bacteria ascending from the duodenum
- Gallstone ileus – small bowel obstruction caused by an impaction of a gallstone within the lumen of SI
80% of acute pancreatitis is caused by which 2 things?
Gallstones + ethanol
Symptoms of acute pancreatitis?
- Acute abdominal pain
- Central, severe, and often radiates to back
- Vomiting
- History of alcohol excess gallstones, and certain drugs
Signs of acute pancreatitis?
- Guarding + tenderness in upper abdomen
* Can be complicated by: shock, DIC, renal failure, haemolysis, ARDS
Investigations for acute pancreatitis?
- Raised serum amylase
- Glucose intolerance
- Hypocalcaemia (fat sequestration)
- Raised CRP, WCC
- Haemorrhagic peritoneal effusion
Causes of chronic pancreatitis?
- ALCOHOL
- Biliary tract disease
- Hypercalcaemia
- Hyperlipidaemia
- Hemochromatosis
- Cystic fibrosis
- Idiopathic
Morphology of chronic pancreatitis?
- Irregular gland with fibrosis, fatty infiltration, calcification
- Appearance mimics carcinoma (difficult biopsy diagnosis)
- Endocrine pancreas relatively spare
Outcomes of chronic pancreatitis?
- Pain
- Weight loss
- Steatorrhea
- Diabetes
- Jaundice (fibrosis causes biliary obstruction)
- Hypalbuminaemia
- Pseudocysts
- Splenic vein thrombosis
List islet cell (endocrine) tumours?
o Insulinoma – tumor of pancreas that is derived from beta cells (secretes insulin)
o Gastrinoma (Zollinger-Ellison syndrome) – tumor in the pancreas or duodenum that secretes excess of gastrin leading to ulceration in duodenum, stomach, SI
o Glucagonoma – rare tumor of the alpha cells of pancreas
o Somatostatinoma – a malignant tumor of the delta cells of the endocrine pancreas
o VIPoma – watery diarrhoea, hypokalaemia, achlorhydria
Where are adenocarcinomas of the pancreas most likely to be anatomically?
60% head, 25% body, 15% tail
Symptoms of pancreatic carcinoma
- Frequently v. little
- Weight loss
- Back pain
- Painless jaundice (all painless jaundice is pancreatic cancer until proven otherwise)
What increases colorectal cancer risk?
Preserved + red meat
Alcohol (men)
Height
Obesity
What increases risk of breast cancer?
Alcohol
Maybe obesity and height as well
What decreases breast cancer risk?
Lactation
What increases risk of endometrial cancer?
Obesity
Glycaemic load
At the periphery of the hexagon which are 3 structures collectively known as the portal triad?
o Arteriole – a branch of the hepatic artery entering the liver
o Venule – a branch of the hepatic portal vein entering the liver
o Bile duct – branch of the bile duct leaving the liver
Hepatic venule is connected to surrounding veins and arteries by sinusoids.
Which cell types are in sinusoids?
Kupffer cells
Hepatocytes
Stellate cells (perisinusodial cells)
What are Kupffer cells?
Macrophages that capture + break down old, worn out RBCs
What are hepatocytes?
Cuboidal epithelial cells that line sinusoids, perform most of liver’s functions (e.g. detoxification)
What are stellate cells?
In normal liver they are the quiescent state, they store vitamin A, APC
When liver damaged they become activated + secrete collagen scar tissue leading to cirrhosis
The liver has a unique dual blood supply. What are these?
Hepatic artery proper (25%)
Hepatic portal vein (75%)
Hepatic artery proper
Supplies the non-parenchymal structures of the liver with arterial blood
It is derived from the coeliac trunk
Hepatic portal vein
Supplies the liver with partially deoxygenated blood, carrying nutrients absorbed from the SI
This is the dominant blood supply to the liver parenchyma
Allows the liver to perform its gut-related functions, such as detoxification
Describe venous drainage o.f the liver
Venous drainage of the liver is achieved through hepatic veins
o The central veins of the hepatic lobule form collecting veins which then combine to form multiple hepatic veins
o These hepatic veins then open into the inferior vena cava
List all the functinos of the liver
o Storage of glycogen, release of glucose, gluconeogenesis
o Protein synthesis – e.g. albumin, coagulation factors
Muscle wastage occurs in patients because the muscles are used as a reservoir for protein
o Catabolism of aa, urea production
o Detoxification of nitrogenous molecules form GIT
Toxins of ammonia metabolites in blood can cross BBB and patient presents with encephalopathy
o Drug + steroid metabolism
o Lipoprotein synthesis
o Conjugation + excretion of bilirubin
o Synthesis + secretion of bile salts
o Participation in immune processes
Which types of viral infection can cause chronic hepatitis?
Hep B – common, sometimes becomes chronic disease
Hep C – uncommon – 85% become chronic liver disease + occasionally cirrhosis
Which viruses other than hep A, B, C, D, E are hepatotropic?
- CMV, EBV, HSV, Varicella, Reovirus, Mumps, Yellow fever, Cocksackie B, Adenovirus, Rubella
- Lassa fever virus, Marbourg virus, Echovirus, Rift Valley Fever
Mode of transmission of hep A
Faeco-oral route (household, intimate, institutional)
How is hepatitis A (HAV) detected?
Increases in:
- ALT,
- Bilirubin,
- Faecal HAV IgA
- anti-HAV IgM
Mode of the transmission of Hep B?
Body fluids (blood, sex, vertical)
Needle, piercings, tattoos
Risk factors of Hep B
Heterosexual activity (40%) Unknown (27%) Homosexual activity (10%) IV drug use (20%) Healthcare workers Non-sexual household contact (3%)
Hep D can only propagate in the presence of what?
Hep B
The combo has the highest fatality rate of all the hepatitis infections (20%)
What is non-alcoholic steatohepatitis? (NASH)
Wide range of conditions caused by a build-up of fat in the liver – called NAFLD
• Non-alcoholic fatty liver disease!
• Ranges from fatty liver (steatosis) to cirrhosis to morbidity/mortality
NASH is the intermediate form of liver damage that sometimes progresses to cirrhosis
Some individuals who become cirrhotic from NAFLD develop hepatocellular carcinoma
Treatment/prevention of Hep B?
Vaccination (primary prevention)
Antivirals (when chronic hepatitis)
Transplant (liver failure)
How is Hep C transmitted?
Blood (IV drugs, transfusion) Unknown Household Sexual contact Vertical (maternal-neonatal)
Cirrhosis due to Hep C is more common in which ethnicity compared that caucasains?
Asians
Which virus is the commonest cause of acute viral hepatitis worldwide?
Hep E
It is more common than Hep A
Mortality
Standard (<1%)
Pregnant (25%)
Accompanied chronic liver disease (<70%)
Primary host of Hep E?
Pig is primary host – avoid undercooked pork
Pathogenesis of hepatic cirrhosis
o Development of fibrosis o Formation of nodules o Loss of hepatocyte microvilli o Activated stellate cells o Deposition of scar matrix o Loss of fenestrae o Kupffer cell activation
Aetiology of hepatic cirrosis
o Alcohol o Hepatitis B, B+D, C o Non-alcoholic steatohepatitis o Drugs o Autoimmune liver disease o Cholestatic liver disease o Metabolic liver disease
Complications of hepatic cirrhosis
o Portal hypertension – backup of blood down portal venous system leads to portal hypertension leads to anastomose
o Hepatorenal syndrome – rapid deterioration in kidney function in individuals with cirrhosis/liver failure
o Ascites + spontaneous bacterial peritonitis
o Hepatic encephalopathy – confused, altered consciousness level, coma due to ammonia accumulation
Describe hepatocellular cancer
Usually painless, until large
Diagnosis – AFP + USS/CT
Incidence is rising
Treatable with: Chemoembolisation RFA Excision Orthotopic liver transplantation (OLTx)
How is hepatocellular cancer treated?
Chemoembolisation
Radiofrequency ablation (RFA)
Excision
Orthotopic liver transplantation (OLTx)
Hepatic failure prevents normal functions of the liver. What are the clinical consequences of hepatic failure?
o Cerebral oedema o Bleeding + bleeding disorders o Infections o Kidney failure o Jaundice o Ascites o Melena o Hypotension + tachycardia – due to reduced systemic vascular resistance
Symptoms of GIT cancer?
Bleeding – overt, occult, anaemia
Pain – tubular blockage, tumour invasion
Alteration of flow – constipation, diarrhoea, dysphagia
Weight loss – at advanced stages
Pathology of cancer of GIT
Most of the GIT is lined with columnar epithelium
Most tumours are adenocarcinomas (glandular), except oesophagus + anus (squamous)
Spread via: Local Intramural Nodal Blood born (usually to liver/lungs)
Aetiology of GIT cancer
o Usually multifactorial o Genetic o Dietary o Environmental o Chemical (smoking, alcohol) o Inflammation – oesophagus (Barrett oesophagus), stomach (H. pylori) o Usually middle/older age o Slight male predominance (except familial conditions like APC + HNPCC)
Treatment of GIT cancer
o Surgery is the mainstay
o Increasingly other therapies such as radiotherapy, chemotherapy, biotherapy
o Decisions made by MDT
Name the types of oesphageal cancers
Squamous cell carcinomas (upper 2/3 of oesophagus)
Adenocarcinomas (lower 1/3 and into cardia)
Causes of squamous cell carcinomas of oesophagus
- Alcohol
- Tobacco
- Poverty
- Injury: very hot beverages, radiation to mediastinum
- Diet deficient in fruit + veg
Higher rates in Iran, China, Brazil, South Africa
Causes of oesophageal adenocarcinomas
- Less frequent (but on the rise), higher rates in Western countries
- Most arise from Barrett oesophagus
Clinical features of oesophageal cancer?
- Usually elderly patients (70+)
- Insidious onset with dysphagia, odynophagia
- Progressive weight loss
- Haematemesis –> anaemia
- Usually already spread when symptomatic
- Requires major surgery (high risks)
- RT + CT widely used
- Very poor 5-year survival (20% or less)
Types of stomach cancer
Intestinal type
Diffuse infiltrative type
Describe intestinal type stomach cancer
o Bulky or ulcerative with glandular structure
o Precursor lesions (adenoma)
o Pathogenesis – increased Wnt signalling (decrease APC, increase beta-catenin)
Describe diffuse infiltrative type stomach cancer
o Permeates stomach wall
o Causes desmoplastic reactions
o No precursor lesions
o Pathogenesis – key step is loss of E-cadherin (CDH1)
Epidemiology of stomach cancer
- Marked variation of incidence (eastern Europe > northern Europe), high frequency in Japan
- More common in lower socioeconomic groups
• Becoming less common in western countries due to:
o Decreased H. pylori prevalence
o Decreased salt + smoking for food conservation
Describe pancreatic cancer
- Infiltrating ductal adenocarcinoma
- 4th leading cause of cancer death (after lung, colon, breast)
- Primarily older adults (60-80)
- Smoking is the strongest risk factor
- Arises from precursor lesions (intraepithelial neoplasia)
- Oncogene KRAS altered in 90-95% cases
- Tumour suppressor CDKN2A inactivated in 95% cases
Which oncogene is altered in 90-95% of pancreatic cancer patients?
KRAS
Which tumour suppressor is inactivated in 95% of pancreatic cancer cases?
CDKN2A
What is the 4th leading cause of cancer death?
Pancreatic cancer (after lung, colon, breast)
5 year survival rate of of pancreatic cancer?
5%
When is a Whipple procedure used?
Surgical excision of pancreas
Only option for pancreatic cancer treatment but it’s only possible in >10% of cases
The clinical features of pancreatic cancer
- Silent until it invades adjacent structures
- Highly invasive
- Brief progressive clinical course
- Pain usually the first symptom
- Obstructive jaundice (Courvoisier’s sign) – painless jaundice is pancreatic cancer until proven otherwise
- Anorexia + weight loss when advanced
- Migratory thrombophlebitis (Trousseau’s sign of malignancy)
- Surgery (Whipple’s procedure) is the only option but only possible in >10% of cases
- Survival rates are dismal <5%
What is Courvoisier’s sign?
Courvoisier’s sign states that in the presence of a palpable enlarged gallbladder which is non-tender and accompanied with mild painless jaundice, the cause is unlikely to be gallstones.
Epidemiology of colorectal cancer
- 2nd commonest cause of cancer death in the UK
- Higher incidence in western countries – lifestyle, diet poor in vegetable fibre, high in refined carbs + fats)
- Usually starts as benign polyp 3-5 years earlier (suitable for screening, polyp-cancer sequence well characterised)
- Classic symptoms – alteration in bowel habit, pain, bleeding
Classic symptoms of colorectal cancer?
Alteration in bowel habit, pain, bleeding
Summary of colonic adenomas (neoplastic polyps)
- Sporadic
- Familial – FAP (familial adenomatous polyposis), less frequently DNA mismatch repair genes
- Present in 30% western adults >60 years
- Most clinically silent (unless large)
- Majority do not progress into adenocarcinoma
- Size correlates with risk malignancy
- Surveillance (colonoscopy) recommended >50 years, especially if there is a family history
Causes of adenocarcinomas of colon?
Sporadic – 80% Wnt pathway, 20% DNA mismatch repair genes
Familial – HNPC (hereditary non-polyposis colorectal cancer, Lynch syndrome):
o Associated to DNA mismatch repair genes
FAP and HNPC are rare autosomal dominant conditions and manifest at young age
What is FAP?
Familial adenomatous polyposis
Rare autosomal dominant conditions that manifest at young age
What is HNPC?
Hereditary non-polyposis colorectal cancer, Lynch syndrome
Associated to DNA mismatch repair genes
How does colorectal cancer present?
20% present as emergency intestinal obstruction o Colicky abdominal pain o Abdominal distension o Vomiting o Absolute constipation
Commonest with solid faeces passing through narrow bore lumen – sigmoid colon, ileocecal valve
Less common with liquid faeces or side lumen (unless advanced) – ascending colon and rectum
Symtpoms of colorectal cancer?
Alteration in bowel habits o More frequent than usual o Sometimes constipation o Feeling incompletely evacuation (tenesmus) o Main point is a change that persists o May have associated abdominal cramps
Bleeding
o Dark red, mixed with stool
o Persists over weeks/months
o May not be all the time
o May present as silent anaemia (classically from R sided cancer)
• Until proven otherwise underlying cause of Fe deficiency in older men or post-meno female is GI cancer
Rectal cancer summary
- Usually produces visible bleeding or mucous
- Often palpable on digital rectal examination
- Tenesmus is a classic symptoms
- Pain –> poor prognosis
- Reasons for no PR – no anus or no finger
Treatment and outcomes of colorectal cancer?
Surgery is the only curative option
RT + CT widely used – RT common in treating rectal cancer
Antibody therapy now use
Outcome Is totally stage dependent
o Stage A – >95% cure
o Stage D – <5% survival at 5-years
o Overall 50% 5-year survival
Main cause of death is tumour spread – liver is most common (liver secondaries can be treated)
Theoretical unrestricted maximum clearance of unbound drug by an eliminating organ, in absence of blood flow of plasma protein binding limitations
Oxidation Reduction Hydrolysis Conjugation Intrinsic clearance Metabolism
Intrinsic clearance
Gain of oxygen (loss of electrons) within a chemical reaction
Oxidation Reduction Hydrolysis Conjugation Intrinsic clearance Metabolism
Oxidation
All chemical reactions involved in maintaining the living state of the cell + organism?
Oxidation Reduction Hydrolysis Conjugation Intrinsic clearance Metabolism
Metabolism
Addition of chemical groups to drugs during metabolism?
Oxidation Reduction Hydrolysis Conjugation Intrinsic clearance Metabolism
Conjugation
The chemical breakdown of a compound due to reaction with water?
Oxidation Reduction Hydrolysis Conjugation Intrinsic clearance Metabolism
Hydrolysis
Loss of oxygen (gain of electrons) within a chemical reaction
Oxidation Reduction Hydrolysis Conjugation Intrinsic clearance Metabolism
Reduction
There is a differential oxygen gradient within the liver (high oxygen at the periportal end + low oxygen at the perivenous end)
Where is the periportal zone 1. What does it receives? What are the hepatocytes here specialised for?
Nearest to the entering vascular system
Receives the most oxygenated blood
Hepatocytes here are specialised for oxidative functions
Where are peripotal zone 3 hepatocytes found?
Poorest oxygenation because hepatocytes along the sinusoids have used up much of the available oxygen
This is exacerbated by excess alcohol consumption
Hepatocytes here are most important for glycolysis
In which zonea are hepatocytes most important for glycolysis found?
Zone 3
Summary of entry of drugs into hepatocytes
o Most drugs are fat soluble or lipophilic to a variable extent
o Fat solubility is important because an orally administered drug must generally diffuse across the lipid membrane of the enterocyte to reach systemic circulation
o A drug with little or no lipophilic property is poorly absorbed and is excreted in the stool
o A drug that is absorbed is then bound to protein, usually albumin, and distributes itself to various tissues, inc. fat
Unless rendered more polar or water soluble, such drugs tend to accumulate in the body over a prolonged period
o Whether give orally or parenterally, drugs eventually pass through the liver
o The degree of hepatic drug extraction depends on hepatic blood flow + activity of the drug metabolising enzymes
o In the hepatic sinusoids the drugs bound to protein pass through openings (fenestrae) in the endothelium + gain access to space of Disse, from which they enter the hepatocytes, where enzymes convert them into more polar compounds
o Some of these water-soluble molecules pass back to the sinusoids, whereas other enter the biliary canaliculi
Hepatic clearance of oral drugs is dependent upon?
Efficiency of metabolising enzymes
Liver blood flow
Intrinsic clearance
Protein binding
What is a high extraction ratio?
Drug rapidly cleared from the blood by the liver (e.g. in a single pass)
Clearance depends primarily on hepatic blood flow
Therefore, clearance is non-restrictive
E.g. verapamil, morphine, propanolol
What is a low extraction ratio?
Drugs not efficiently cleared by the liver and extracted incompletely from hepatic blood
Clearance is:
• Relatively independent of hepatic blood flow
• Determined by the intrinsic metabolising capacity of the liver + by the free drug fraction
Intermediate extraction ratio?
Hepatic clearance of these drugs depends on:
• Hepatic blood flow
• Intrinsic metabolising capacity
• Free drug fraction
E.g. aspirin, codeine
Summary of p450 isoenzymes
o Each human p450 isoenzyme appears to be expressed by a particular gene (distributed among different chromosomes)
o One p450 isoenzyme may be involved in the metabolism of one or more drugs, a single drug may be acted upon by multiple
o Many drugs, are largely metabolised by a single form of p450
o Drugs must bind to the p450 at the substrate binding site, which is located close the enzyme’s heme prosthetic group
o The binding affinity between certain drugs and p450 may vary so that a single p450 may be largely responsible for the metabolism of some drugs
Paracetamol
o Used as suicidal agent
o 10g produces hepatic necrosis
o Plasma levels affected by vomiting
o Alcohol – chronic use induces enzymes + increases hepatoxicity, acute use inhibits enzymes
o No signs of toxicity for 48 hours, then progressive liver failure
o Severe prolongation of PT and presence of acidosis predicts poor survival
o Liver transplantation
Drugs that interfere with bilirubin uptake, excretion, conjugation can induce liver disease.
What types?
Cytotoxic injury Cholestatic injury Mixed cytotoxic + cholestatic injury Fatty liver Cirrhosis
Drugs that interfere with phospholipioids can cause what types of liver disease?
Liver tumours
Vascular lesions
Chronic active hepatitis
Subacute hepatic necrosis
List examples of inducers that enhance the activity of p450 isozymes
CRAP GPS Carbamazepine Rifampicin Alcohol (chronic) Phenytoin Griseofulvin Phenobarbital Sulfonylureas
Tobacco
St. John’s wort
List examples of inhibitors that depress the activity of p450 isozymes
Cardiac:
- Amiodarone
- Verapamil
- Quinidine
Antibiotics:
- Chloramphenicol
- Ciprofloxacin
- Erythromycin
- Metronidazole
- Trimethoprim
- Isoniazid
Antifungals:
- Fluconazole
- Ketoconazole
Antacids:
- Cimetidine
- Omeprazole
Psychiatric:
- TCA
- Haloperidol
- SSRIs (fluoxetine)
- Sodium valproate
HIV antivirals
Grapefruit juice
---------------------------- SICKFACES.COM - Sodium valproate - Isoniazid - Cimetidine - Ketoconazole - Fluconazole - Alcohol..binge drinking - Chloramphenicol - Erythromycin - Sulfonamides - Ciprofloxacin - Omeprazole - Metronidazole
List 3 risk factors for impaired metabolism
Hepatocellular failure
- Decreased hepatic blood flow
- Decreased enzyme function
- Decreased plasma protein binding (which increases volume of drug distribution)
Reduced renal clearance
Malnutrition
- Reduced availability of micronutrients important in metabolism
How does blood loss present clinically?
Acute: Haematemesis Melaena Shock PR bleeding
Chronic:
Anaemia
Positive FOB (faecal occult blood)
Major causes of upper GI bleed?
o Oesophageal 10% o Peptic ulcer 50% o Gastroduodenal erosions 10% o Varices 10% o Idiopathic 20%
Major causes of lower GI bleed?
Small bowel:
Jejunal/ileal diverticulae
Large bowel: Angiodysplasia 40% Diverticular disease 40% Carcinoma/polyp <5% UC/Crohn’s <5% Haemorrhoids/fissures/fistula
Investigations to order if patient is chronically bleeding.
o History o Clinical examination o Abdominal examination o PR o Rigid sigmoidoscopy o Blood test including RBC, U+E, haematinics o Endoscopy, colonoscopy, CT colonography o Capsule, CT, or MR small bowel
Risk factors for death due to blood loss (GIT bleeding)
Age >65 Co-morbidities – IHD, chronic lung disease, cirrhosis Pulse >100bpm, bp <100 systolic Shock on admission Ascites Continued bleeding Re-bleeding HB <8% on admission
List risk factors that won’t increase the risk of death for GI bleeding
Alcoholism
Previous peptic ulcers
NSAID usage
Hepatomegaly
How to manage varices?
Monitor on ITU
Central line
Urine output
Regular FBC, clotting, creatinine, electrolytes, blood gases
Replace clotting factors – FFP, platelets, etc
Vasopressin, glypressin
Somatostatin, octreotide
Endoscopy – sclerotherapy or banding
What is gastroenteritis?
Food poisoning
It is charcterised by diarrhoea and vomitng plus or minus pain
Causes of gastroenteritis?
Microbial infection Bacterial – e.g. Salmonella, Staphylococcus aureus, E. coli, Campylobacter,!!!! Clostridium perfinges Viral – e.g. norovirus Fungal – e.g. aspergillus Protozoal – e.g. cryptosporidia
Toxins
Bacterial toxins – Clostridium perfringens, Staph aureus, Clostridium botulinum
Marine biotoxins – scombroid poisoning, shellfish, ciguatera
Chemicals
Heavy metals
Pesticides
Herbicides
- Campylobacter is the most common cause, norovirus is under represented
- If something comes on very rapidly it is unlikely to be bacterial/viral due to incubation period required
Which bacteria cause gastroenteritis?
Salmonella sp.
Staphylococcus aureus
E. coli
Campylobacter
Clostridium perfinges
Which bacterial toxins cause gastroenteritis?
Clostridium perfringens toxins
Staphylococcus aureus toxins
Clostridium botulinum toxins
Which bacteria is the most common cause of gastroenteritis?
Campylobacter
How is salmonella transmitted?
Infection of contaminated food, faecal contaminations, person-person, contact with infected animals
o Secondary cases are common in outbreaks
Clinical picture of salmonella? Different species cause different diseases - enteric fever + enterocolitis
Raw food or failure to achieve adequate cooking temperatures:
Enteric fever – S. typhi (causes typhoid fever) + S. paratyphi (causes paratyphoid fever)
Enterocolitis – S. enteritidis
Symptoms and treatment of salmonella
o Symptoms – diarrhoea, vomiting, fever, headache, chills
o Treatment – symptomatic
Explain the commensal to pathogenic transition of S. aureus
Previously cooked food gets contaminated with someone’s skin/nasal flora
Organism grows and produces toxin – 30-40% of S. aureus isolated produce enterotoxins
Toxin is heat + acid stable, therefore not affected by reheating food
Transmission, incubation period and symptoms of S. auerus infection
o Transmission – bacteria gets into food via contact
o Incubation period – 2-4 hours
o Symptoms – rapid onset + rapid resolution, projectile vomiting + diarrhoea
Transmission, incubation period, symptoms of cryptosporidium (a protozoa)
o Transmission – Animal-human, person-person, contaminated water or land, associated with foreign travel
o Incubation period – 2-5 days
o Symptoms – watery or mucoid diarrhoea, severe illness in immunocompromised patients
What is the winter vomiting disease aka?
Norovirus (RNA virus)
Named due to seasonality and symptoms
Most common cause of infectious gastroenteritis?
Norovirus
Where are norovirus outbreaks common?
Outbreaks common in semi-closed environments – e.g. hospitals, nursing homes
Extremely low infective dose hence quick spread + high rates
Incubation period and symptoms of norovirus?
Incubation period – 24-48 hrs
Symptoms – nausea, projective vomiting, low-grade fever, diarrhoea (usually lasts 1-2 days)
How is norovirus transmitted?
Transmission – person-person, food/water, environmental by faecal oral route
What is Clostridium perfinges
Widely distributed in the environment + foods
Part of normal gut flora
Slow cooling and unrefrigerated storage -> spores germinate to vegetative cells
Food poisoning follows ingestion of food containing large no. of vegetative cells
- C. perfringens enterotoxin is produced after ingestion, not in foods
Can also case gas gangrene
What is the incubation period of clostridium perfinges?
8-22 hrs
Symptoms and transmission of clostridium perfinges?
o Symptoms – Diarrhoea + abdo pain
o Transmission – contaminated cooked meat + poultry, inadequate temperature control during cooling + storage
Reservoir of Clostridium perfinges?
GIT of farm animals, soil, dust
What is Conn’s syndrome?
Conn’s syndrome is a disease of the adrenal glands involving excess production aldosterone.
Another name for the condition is primary hyperaldosteronism.
Conn’s syndrome is important because it is a potentially curable cause of high blood pressure (hypertension).
What is MEN 2 syndrome?
Multiple endocrine neoplasia type 2 (MEN2) (also known as “Pheochromocytoma and amyloid producing medullary thyroid carcinoma”.
It is a group of medical disorders associated with tumours of the endocrine system.
What is carcinoid syndrome?
Carcinoid syndrome is a paraneoplastic syndrome comprising the signs and symptoms that occur secondary to carcinoid tumours.
The syndrome includes flushing and diarrhoea, and less frequently, heart failure, emesis and bronchoconstriction.
It is caused by endogenous secretion of mainly serotonin and kallikrein.
What is a carcinoid tumour?
A slow growing type of neuroendocrine tumour in cells of neuroendocrine system.
Metastasis may occur in some cases.
Carcinoid tumours of the midgut (jejunum, ileum, appendix, and cecum) are associated with carcinoid syndrome.
Carcinoid tumours are the most common malignant tumour of the appendix, but they are most commonly associated with the small intestine, and they can also be found in the rectum and stomach.
Which imaging technique does the following describe?
Single contrast study
Patient drunks 250-500ml of dilute barium
Well tolerated
Answers most clinical questions
Can miss small lesions and low grade structures
Small bowel meal
Which imaging technique does the following describe?
A catheter passed to DJ flexure
Injection of 800 – 1200 ml of very dilute barium via syringe or pump
Images obtained as follow head of barium through small bowel
Double contrast technique
Sensitive for small lesions and low-grade strictures
Small bowel barium enema
Is a barium meal double or single contrast?
What about a barium swallow?
Barium meal is double contrast
Barium swallow is single contrast
What is a double contrast barium enema used to visualise?
Colon
Colon distended with air or CO2 then barium run into coon via rectal tube
Patient must be starved for 2 days and cleared out using a strong laxative (picomax)
What is proctoscopy?
Short, rigid endoscopy used to examine rectum only
No preparation needed
Gastroscopy can detect gastritis, gastric ulcers, duodenal ulcers and duodenal erosions.
What are the possible complications of gastroscopy?
- Sedation (cardiopulmonary problems)
- Perforation
- Haemorrhage
- Infection
- Slight mortality risk
Methotrexate
o Methotrexate is a widely used anticancer/antiarthritic drug
o Significant damage rare
o Associated with cumulative doses of >2g
o Excess alcohol, obesity, age, increase risk
o Monitoring – LFT, serum markers of fibrosis
o Liver biopsy
