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
