Digestion, GI Pathologies Flashcards
Where would you find enterokinase/ enteropeptidase, and what does it do?
- Duodenal brush border enzyme
- Converts trypsinogen - a proenzyme secreted by pancreas - to trypsin
What does trypsin do?
Cut down amino acids into smaller pieces
ie. proteolysis
What are apolipoproteins?
Proteins that bind lipids to form lipoproteins
They are amphipathic and when bound around lipids, allow them to be transported in the blood and other bodily fluids
Describe carbohydrate digestion:
Key enzymes, where they are, and steps of polysaccharides → monosaccharides and absorption
- Carbohydrates enter mouth - mechanical breakdown of food into a bolus
-
Salivary amylase breaks down α(1→4) glycosidic bonds → present in polysaccharides such as amylose & amylopectin
→ Creation of disaccharides (maltose, sucrose, lactose) & oligosaccharides (maltotriose)
→ 10-15% of polysaccharide breakdown - Bolus passes oesophagus → stomach (more mechanical digestion) → chyme secreted duodenum
-
Pancreatic amylase breaks down α(1→4) glycosidic bonds → present in polysaccharides such as amylose & amylopectin
→ Creation of disaccharides (maltose, sucrose, lactose) & oligosaccharides (maltotriose)
→ Remainder of polysaccharide breakdown - Throughout small intestines, “brush border enzymes” on enterocytes:
→ Lactase, Maltase, Sucrase α(1→4) glycosidic bonds & Isomaltase α(1→6) glycosidic bonds
break oligo/disaccharides down to monosaccharides (glucose, galactose, fructose) - Monosaccharides then transported from Lumen into Enterocyte
GLUT-5 → Fructose (FiveFructoseFacilitatedDiffusion)
SGLT → Glucose, Galactose (SodiumGlucoseLinkedTransporter) - uses low intracellular Na+ gradient to help drag in glucose - (banana islands!) - Monosaccharides then moved across Basolateral Membrane into portal bloodstream
GLUT-2 → Fructose, Glucose, Galactose (TwoTodos!)
Describe the steps of protein digestion and absorption
- Mechanical digestion in mouth - no chemical digestion here.
Food turned to bolus - Bolus reaches stomach
Chief cells excrete pepsinogen
Parietal cells secrete HCl
Pepsinogen → Pepsin 1.8HCl denatures proteins - unfolds
Pepsin cleaves peptide bonds (spec. carboxy side of aromatic amino acids)
Large polypeptides → small polypeptides
- Chyme secreted into duodenum.
- Presence of amino acids triggers CCK (CholyCystoKinin - a hormone) release
- CCK stimulates release of pancreatic proteases in inactive form - secreted via hepatopancreatic duct to descending duodenum
- Proteases include (inactive forms) - trypsinogen, chymotrypsinogen, procarboxypeptidease, proelastase
- Chyme secreted into duodenum.
- Brush border enzyme Enterokinase/Enteropeptidase converts trypsinogen → Trypsin
Trypsin then converts other proenzymes to active form
The active enzymes - trypsin, chymotrypsin, carboxypeptidase, elastase then break down polypeptides into either smaller - di/tri-peptides and individual amino acids
- Brush border enzymes - aminopeptideases (NH3+ end), tripeptidases, dipeptideases, → break down into individual amino acids
- Into enterocyte:
H+ co-transported - passive - tripeptides, dipeptides
Na+ co transported - passive - amino acids
(remember, enterocytes have 3Na+/2K+ (out/in) and H+/Na+ (out/in) ATPases making concentration gradients)
- Intracellular peptidases break tri/dipeptides into individual amino acids
- Moved from enterocyte to hepatic circulation - liver can then synthesise proteins
Describe the signs/symptoms of Coeliac disease
- Abdominal pain
- Abdominal discomfort
- Diarrhoea
- Steatorrhoea
- Weight loss/ failure to thrive in children
- Anaemia - B12 and/or iron deficiency
- Aphthous ulcers - mouth, gi tract
- Atrophic glossitis - shiny smooth red tongue, B12 deficiency
- Dermatitis herpetiformis - itchy rash, extensor surfaces commonly
- Can also be asymptomatic
How do you diagnose Coeliac disease?
Note - Remember “gluten challenge” for antibody and biopsy for accuracy
ie - 1st with no gluten, then with gluten consumption for confirmation
- Blood tests: → Don’t alone confirm
- Autoantibody tissue Transglutaminase (tTG)
- Autoantibody Gliadin
- Autoantibody Endomysin
- Endoscopic small bowel biopsy (Gold standard with “gluten challange”)
Looking for- Villous atrophy
- Crypt hyperplasia
- Lymphocyte infiltration
- Gene testing if still unclear - does not require “gluten challenge”
- HLA DQ2
- HLA DQ8
- Note - only 1 / 40 with these genes will develop coeliac disease
Define Coeliac disease
Auto immune disease.
Type 4 hypersensitivity - T cell mediated
Inflammatory process which occurs in susceptible individuals in response to ingestion of wheat protein - Gluten, specifically GLIADIN
Risk factors for Coeliac disease
- Family Hx
- Autoimmune Thyroid disease
- T1DM
- IBD
- IgA Deficiency
Describe current theory of Coeliac Disease
- Gluten broken down in lumen
- Gliadin absorbed into enterocyte
- Tissue Trans-Glutaminase (tTG) de-aminates gliadin peptides
- Antigen Presenting Cells absorb deaminated gliadin peptide
- APC presents de-amin-gliadin to HLA DQ2 / HLA DQ8 molecule
- Hell id Love All Da Quassaints <u>2</u>
- APC then presents to Naive T-Cell
- Activates it, becomes CD8+ (T-killer) or CD4+ (T-helper)
- T cells are now primed against De-aminated gliadin peptide
- CD8+ (T-Killer) cells now cause inflammation when gluten is present
- CD4+ (T-Helper) cells now help “B Cells” to become “Plasma Cells”
- Plasma cells produce antibodies → Anti-Gliadin, Anti-tTG, Anti-Endomysium
- Antibodies create inflammation now when Gliadin is present
What are some chronic clinical implications/complications of chronic inflammation in the small intestine in Coeliac disease?
The poor GI absorption and inflammation due to Coeliac disease can lead to:
- Anaemia
- Cancer of GI tract or T cell lymphoma
- Osteoporosis
- Anorexia
- Neuropathy
- Dermatitis Herpetiformus
What are the microscopic implications of coeliac disease
Coeliac Inflammation causes:
- Villous atrophy
- Crypt hyperplasia
- ↑ Lymphocyte infiltration of lamina propria
Some differential diagnoses for Coeliac disease are:
- Crohn’s Disease
- Ulcerative Colitis
- Giardia Lambia infection
- Food sensitive enteropathies
- Irritable Bowel Syndrome
What are the 3 longitudinal muscular bands of the large intestine called?
Where do they stop?
Taenia Coli
Rectum
Name the layers of GI tract (inner→outer)
- Columnar Epithelium
- Lamina Propria
- Muscularis Mucosae
- Submucosa
- Circular Muscle
- Myenteric Plexus
- Longitudinal Muscle
- Serosa
What is Zollinger Ellison Syndrome?
Rare pancreatic or duodenal tumour
Gastrinoma - ie tumour that produces too much gastrin
What are Paneth Cells?
Highly specialised small intestine epithelial cells
Live in the crypts of Lieberkühn
Secrete granules - antimicrobial peptides, immunomodulating proteins
Help regulate intestinal flora
Another word for Tumour
Neoplasia
“New Growth”
Steps of colon cancer development
- Healthy cell reproduction - cells born in crypts from stem cells, migrate along axis, shed into lumen several days later
- DNA mutation -
- Tumour suppressing gene APC (Adenomatous Polyposis Coli) turned off in stem cell → ~80% of CRCs
- Polyp - aka ADENOMA - forms
- Benign at this stage, non invasive
- Oncogene K-RAS turned on → Cell proliferation → ~50% cases
- Tumour suppressing p-53 turned off → cells become resistant to apoptosis → ~70%
- DCC - (Deleted in Colorectal Carcinoma) turned off → poor cell-cell adhesion, ie metastassis →~70%
- Tumour suppressing gene APC (Adenomatous Polyposis Coli) turned off in stem cell → ~80% of CRCs
Growth becomes malignant → Carcinoma
Local invasion, then spreads
In a healthy reproducing cell, there is a balance between histone:
Acetylation → Increase access to transcription factors
and
Methylation → Decrease access to transcription factors (repression)
Difference between oncogene and proto-oncogene
- Proto-oncogene → “PRE” oncogene - functioning well
- Oncogene → mutative or defective Proto-Oncogene - cell gains cancer functions
What are the 6 Hallmarks of Cancer?
- Self-sufficiency in growth signals
- Angiogenesis
- Limitless replicative potential
- Tissue invasion & metastasis
- Insensitivity to anti-growth signals
- Evading apoptosis
Describe the steps of Lipid digestion & absorption
- Food enters mouth, mechanical digestion of food into bolus
Salivary Lipase begins to break some Free Fatty Acids (FFAs) off Triglycerides - Bolus reaches stomach
Chief cells secrete Gastric Lipase, continues to break down ester bonds of triglycerides into more FFAs - Chyme reaches Duodenum
Bile is secreted into the duodenum from the gallbladder along hepato-pancreatic duct, through the sphincter of Oddi.
Phospholipids (Lecithin) and Bile Salts make bile Amphipathic.
Amphipathic nature of bile salts and phospholipids emulsify fats from:
Globules (big) → Droplets (smaller) → Micelles (smallest)
This allows Pancreatic Lipase to break down remaining triglycerides into FFAs
- FFAs, & MAG (mono-acetyl-glycerol - ie, triglycerides with only one FFA still attached) now cross cell wall into enterocyte.
Smooth ER then turns parts back into Triglycerides
Rough ER bundles up triglycerides, cholesterol, fat sol vitamins and others into lipoproteins - Chylomicrons (very, very low density lipoproteins) are exocytosed into interstitial fluid, and eventually move into Lacteal lymphatic circulation → thoracic duct → skm, adipose tissues
- Bile salts recycled back to liver - Enterohepatic circulation - mostly reabsorbed @ terminal Ileum
Describe the structure of a triglyceride
Glycerol bound to 3 free fatty acids by ester bonds
(Glycerol bound to 1 fatty acid is a Mono-Acetyl-Glycerol (MAG))
List the neurotransmitters of the GIT.
Include:
- Sensory Afferent
- Interneurons
- Secretory Efferent
- Inhibitory Efferent
- Excitatory Efferent
- Sensory Afferent - ACh & Substance P
- Interneurons - ACh & Serotonin
- Secretory Efferent - ACh & VIP
- Inhibitory Efferent - NO & VIP
- Excitatory Efferent - ACh & Serotonin
ACh - AcetylCholine
VIP - Vasoactive Intestinal Peptide
NO - Nitrous oxide
Name some long term complications of H-Pylori infection
- Chronic gastritis
- Gastric or Duodenal ulcer disease
- Neoplasia - Gastric adenocarcinoma / gastric lymphoma
Peyer’s patches are:
Lymphatic aggregates of small intestine specifically
What does Amylin do and where does it come from
Comes from pancreatic B cells along with insulin
Appears to work with insulin to:
- regulate blood glucose
- suppress glucagon release
- slow gastric emptying
- signal satiety
Causes of acute pancreatitis
I GET SMASHED
- Idiopathic
- Gallstones
- Ethanol
- Trauma
- Steroids
- Malignancy/Mumps
- Autoimmune
- Scorpion sting
- Hypertriglycerides or Hypercalcaemia
- ECRP - (Endoscopic Retrograde CholangioPancreatogram) - ie, a Scope
- Drugs
Secretin’s jobs are what?
Stimulates bicarb release from duodenal epithelial and pancreatic ductal cells in relation to acid in duodenum
Also downregulates acid production by parietal cells
Major apoproteins Chylomicrons
ApoB-48, ApoE
Major apoprotein for HDL
ApoA-I
High levels of triglycerides:
- increase significantly the risk of pancreatitis
- Lead to lower HDL’s
What is a tendon xanthoma?
Note: FH = Familial Hyperlipidemia
On a GIL exam, what are some key things we are looking for/ testing in the upper limbs?
“I am going to examine/palpate….”
- Nails
- Leuconychia - white opaque nails → hypoalbuminaemia
- Clubbing → assoc with long standing liver disease, also long standing nutritional depletion - coeliac, IBD
- Palms
- Palmar erythema - red thenar/hypothenar eminences - chronic liver disease
- Anaemia - palmar crease pallor - gi blood loss, malabsorption
- Dupuytren’s contracture - thickening palmar fascia, perm flexion, esp 4th digit → assoc w alcoholism, excessive xanthine cause?
- Hepatic flap (asterixis)
- Abd fingers, ext wrists and elbows. 15 sec, push hands into extension
- Early sign liver failure, but not diagnostic (can occ in cardiac, resp, renal failure, & hypoglycaemis, hypokalaemia, hypomagnesaemia, barbituate intoxification)
- Arms
- Pruritis - Scratch marks - cholestatic jaundice
- Ecchymoses - large bruises - ⇣ clotting factors
- Petechia - pinhead bruises - excessive alc consumption
- Spider naevi - usually arms, neck chest - blanch w pressure
On GIL exam, what are some key things we are looking for in the face?
“I am going to examine…”
- Eyes
- Jaundice - yellow sclera
- Anaemia - pale conjunctiva
- Bitot’s spots - yellow keratinised areas on sclera - vit A def, malabsorption/malnutrition
- Kayser-Fleischer rings - Wilson’s disease copper deposits periphery cornea
- Iritis - IBS
- Xanthelasma - Yellow lipid plaques in subcut → periorbital - can occur in cholestasis
- Salivary glands
- Parotid enlargement - indicates alcoholism vs FLD specifically. clench teeth as masseter covers when flexed in normal
- Submandibular gland - calculus
- Mouth
- Fetor hepaticus - sweet smell of breath - severe hepatocellular disease
- State of teeth
- Ulcers -
- Apthous (crohn’s)
- Angular stomatitis - cracks corner of mouth - deficiencies vit b6, b12, folate, iron
- HIV infection → many ulcers
- Tongue -
- Leukoplakia - white coloured mucosa
- Glossitis - smooth, can be erythematous → deficient iron, folate, B group (12 esp)
- Bacterial debris - smoking
- Candidiasis
- Candida albicans - (thrush)
- Moniliasis - assoc w immunosuppression →chemo, steroids, alcoholism
Causes of hepatosplenomegaly
- Chronic liver disease w portal hypertension
- Haematological disease - (lymphoma, leukaemia, pernicious anaemia, sickle cell anaemia)
- Infection - acute viral hepatitis, cytomegalovirus
- Infiltration - amyloid, sarcoid
- Connective tissue disease - systemic lupus erythematosus
- Acromegaly
- Thyrotoxicosis
2 examples of ketone bodies, and how they are created
- Acetoacetate
- β-hydroxybutyrate
- Created in beta oxidation of free fatty acids
- When this is done excessively, there is an excess of Acetyl-CoA
- This leads to Kreb cycle saturation → ketogenesis
6 I’s of DKA (diabetic ketoacidosis) and HHS (hyperglycaemic hyperosmolar syndrome)
How does an excess of NADH and Acetyl-CoA lead to down-regulation of glucose metabolism?
Excess of NADH and Acetyl-CoA inhibits pyruvate dehydrogenase
This is kind of referred to as the Randle Cycle
What are common GI commensals
Fancy pants name for gallstone formation
Cholelithiasis
Penicillin is an example of what type of antibiotic?
How does it work?
β-lactam
Works best on gram +ve bacteria
Inhibits peptidoglycan cross linking during cell wall synthesis → bacterial lysis and cell wall death
Vancomycin is an example of what type of antibiotic?
How does it work?
Glycopeptide
Inhibit cell wall synthesis of bacteria
What type of antibiotic is sulfurmethoxosol?
How does it work?
Sulfonamide
Interfere with folic acid synthesis, which is key for nucleic acid synthesis
What type of antibiotic is Chloramphenicol?
How does it work?
Amphenicol
Block enzyme peptidyl transferase, thus
Inhibiting the ribisome from forming peptide bonds between amino acids during the translation phase of protein biosynthesis
What is achalasia?
Specifically Oesophageal Achalasia in this case, but it can happen in other places along the GI tract like in “Hirschsprung’s Disease”
Failure of smooth muscle fibres of lower oesophageal sphincter to relax → regurgitation
Rx involves medications, botox injections or surgery
Most common cause is idiopathic failure of distal oesophageal inhibitory neurons
2nd less common cause is Chaga’s Disease
What is a Trypanosomal infection?
Aka
Chaga’s Disease
African trypanosomiasis, also known as African sleeping sickness
Insect born parasitic infection of humans and other animals
Carried by Tsetse Fly in subsaharan africa
Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense
Can cause Achalasia
Haemolytic anaemia due to antimalarial drug Chloroquinine is likely:
Due to glucose 6-phosphate dehydrogenase deficiency
Dispersed rash - dermatitis herpetiformis - around areas such as buttocks and wrists can be indicative of what type of GI pathology?
Coeliac Disease - autoimmune
How are amino acids absorbed?
Amino acids are absorbed via specific transporters (Na+ dependent)
How are lipids absorbed?
Micelles can be absorbed: free fatty acids (FFAs) and monoglycerides absorbed by diffusion across the cell’s plasma membrane
Describe the branches of the celiac trunk and where they supply
Describe Glycogen storage disease - Type V
AKA McArdle’s Disease
M for Muscle!
- Muscle glycogen storage disease
- Autosomal recessive deficiency of myophosporylase
- Accumulation of intramuscular glycogen - lack of glucose-1-phosphate for myocyte fuel
Symptoms:
- Exercise intolerance
- Muscle pain
- Early fatigue
- Inappropriate HR response to exercise
- Myoglobinuria (due to rhabdomyolysis post exercise)
Describe Glycogen Storage Disease type I -
AKA Von Gierke’s Disease
Von Gierke - the jerkie -Hepatic
- Hepatic glycogen storage disease
- Deficiency in glucose-6-phosphatase
- Inability to perform glycogenolysis of stored glycogen
- SEVERE HYPOGLYCAEMIA
- Typically present with hepatomegaly - due to excessive glycogen storage
- Chronic hypoglycaemia
- Neutropenia - increased infection risk
What is the pathogenesis of Acute Pancreatitis?
- Abnormal activation of digestive enzyme precursors within the pancreas
- Enzyme precursors are called “proenzymes” or “zymogens”
- Most notably - Trypsinogen -> Trypsin
- Active Trypsin activates more trypsinogen - leads to protein breakdown and inflammation, vascular injury and cell death
Describe pancreatico-duodenal circulation (arterial and venous)
Picture answer
