Valerie murphy GI Flashcards
Describe the absorption of carbohydrates across the enterocyte.
- Duodenum + Jejunum
- Carbohydrates are broken down in the lumen by pancreatic amylases and brush border enzymes e.g. maltase, sucrase and lactase –> Glucose, Galactose and Fructose are formed.
- Glucose and galactose are transported across the apical surface by SGLT-1 transporter using the sodium gradient created by the Na/K ATPase pump on the basolateral side. They are then transported across the basolateral side into the interstitial fluid by GLUT-2 transporter.
- Fructose is transported into the enterocyte by GLUT-5 and then GLUT-2 transports it into interstitial fluid.
The absorption of sodium via SGLT is accompanied by water reabsorption which aids in nutrient absorption.
Malabsorption = watery diarrhoea due to osmotic effects of luminal sugars and sodium
Describe central tolerance
- T cell education in the thymus
- Positive selection: Self-MHC molecules are presented to immature T cells on thymic epithelial cells or dendritic cells. Those that respond with moderate affinity are allowed to survive and mature. Those which don’t recognise self-MHC at all undergo apoptosis.
-Negative selection: immature T cells that respond to self-antigens with strong affinity undergo apoptosis through activation of FAS/FAS-L pathway.
- B cells (bone marrow)
- Negative selection: developing B cells that strongly recognize self-antigens undergo clonal deletion or receptor editing
- Receptor editing involves re-arrangement of receptor genes to produce a new receptor that is not auto-reactive.
Describe peripheral tolerance
Governed by 3 main mechanisms:
- Anergy (inactivation of autoreactive T or B cells)
-T cells: if a self-reactive T cell encounters its antigen in the absence of the necessary co-stimulatory signals (e.g. CD28 not interacting with CD80/86), it becomes anergic.
-B cells: self-reactive B cells that encounter self-antigens without the necessary T cell help (CD40 with CD40L) are rendered anergic.
-Anergic cells are metabolically/immunologically inactivated - T-regulatory cells
- Tregs suppress self-reactive T cells through secretion of anti-inflammatory cytokines such as IL-10 and TGF-beta or by engaging inhibitory receptors e.g. CTLA-4. - Clonal deletion: similar to anergy but instead of being metabolically inactive, the T/ B cells undergo apoptosis, particularly via activation of the FAS/FAS-L pathway.
Describe the absorption of proteins by the enterocyte
Duodenum and jejunum
- Dietary proteins are broken down by pancreatic and brush border peptidases in the lumen.
- Short peptides are absorbed via proton-coupled symporter, using the H+ concentration gradient to enter the enterocyte -> H+ diffuses into the enterocyte down its concentration gradient. Within the enterocyte these peptides are broken down to amino acids by intracellular peptidases.
- Amino acids enter the enterocyte via a sodium-amino acid co-transporter using the Na gradient created by the Na/K ATPase pump.
- Amino acids are then transported across basolateral side by various amino-acid transporters –> portal system –> liver for processing/ storage.
Malabsorption = oedema due to low albumin
Describe the absorption of fats by the enterocytes
- Fats are emulsified by bile salts to increase surface area for pancreatic lipase action.
- Pancreatic lipases break down triglycerides into monoglycerides and free fatty acids.
- Micelles are formed and include monoglycerides, FFA, cholesterol and fat soluble vitamins.
- The lipid component of micelles passively diffuses across enterocyte apical membrane.
- FFA + monoglycerides are reassembled into triglycerides which are then assembled with cholesterol, apolipoproteins and phospholipids to form chylomicrons.
- Chylomicrons are released across the basolateral membrane into lacteal and eventually enter blood stream via thoracic duct where they are brought to adipose or muscle tissue for use of fat for energy or storage.
Describe the absorption of vitamin B12 by the enterocyte
terminal ileum
- In the stomach, vitamin B12 binds to haptocorrin (R-protein) secreted by salivary glands and the stomach to protect it from acidic degradation.
- In the duodenum, pancreatic enzymes degrade haptocorrin, releasing B12, which then binds to intrinsic factor (IF), a glycoprotein secreted by gastric parietal cells.
- In the ileum, the B12-IF complex binds to cubilin receptors on the apical membrane of enterocytes in the terminal ileum, triggering endocytosis of the complex.
- Inside the enterocyte, B12 is released from intrinsic factor in lysosomes and binds to transcobalamin II (TCII) for transport out of the cell.
- In the bloodstream, the B12-TCII complex delivers B12 to tissues for use or storage in the liver.
Describe the absorption of fat soluble vitamins
Fat-soluble vitamins (A, D, E, and K) are incorporated into micelles in the small intestine with the help of bile salts and phospholipids, which emulsify dietary fats.
The micelles deliver these vitamins to the brush border of enterocytes, where they are absorbed by passive diffusion or specific transporters.
Inside the enterocytes, fat-soluble vitamins are incorporated into chylomicrons along with triglycerides, cholesterol, and phospholipids.
Chylomicrons are secreted into the lymphatic system via lacteals and eventually enter the bloodstream through the thoracic duct.
Once in circulation, fat-soluble vitamins are delivered to tissues or stored in the liver and adipose tissue.
Describe absorption of folic acid
Folic acid, in its dietary form (as pteroylglutamic acid), is absorbed primarily in the proximal small intestine, mainly in the duodenum and jejunum.
It is first converted to its active form, tetrahydrofolate (THF), by the action of folate conjugases in the brush border of enterocytes
The active form of folate is absorbed into enterocytes through specific folate transporters
From the enterocyte, folate enters the bloodstream via passive diffusion or through folate transporters
Once in the blood, folate is transported bound to plasma proteins (primarily albumin) and delivered to tissues for use in DNA synthesis, methylation, and other metabolic processes.
Name 3 causes of steatorrhea/ malabsorption
- Pancreatic causes
–> Cystic fibrosis; mucous obstruction of pancreatic duct
–> Chronic pancreatitis; destruction of lipase producing acinar cells of pancreas - Biliary causes
–> Primary biliary cholangitis
–> Primary biliary sclerosis
–> Bile acid deficiency - Intestinal causes
–> Crohn’s disease
–> Celiac disease
–> Small intestinal bacterial overgrowth (SIBO)
–> Tropical sprue
–> HIV enteropathy
Clinical features of malabsorption
- Unintentional weight loss
- Growth retardation in children
- Abdominal bloating, cramping, diarrhea, steatorrhea
- Vitamin deficiencies
–> Vit A: Night blindness
–> Vit D: Bone pain, fractures, osteomalacia
–> Vit E: Peripheral neuropathy and muscle weakness
–> Vit K: Easy bruising/ bleeding
–> Vit B12: Megaloblastic anemia, neuropathy, cognitive disturbance
–> Calcium: Osteoporosis, Osteopenia, Muscle cramps, tetany
–> Folate: anemia, fatigue - Iron deficiency or megaloblastic anemia
- Edema –> protein malabsorption causing hypoalbuminemia
- Dermatological signs
–> Dermatitis
–> Dry skin
–> Hair loss - Hypoglycemia.
outline causes of watery and bloody diarrhea
- Watery
-Infectious : Viral (rotavirus, norovirus), bacterial (E.coli, cholera), Parasitic (giardia intestinalis)
-Non infectious : pelvic radiotherapy, lactose intolerance, stress, carbohydrate malabsorption, antibiotics
- Bloody
-Infectious : Shigella, Salmonella, E.coli
-Non infectious: IBD
Name extra-intestinal manifestations of IBD
General to IBD
- Uveitis
- Ankylosing spondylitis
- Erythema nodosum
- Pyoderma gangrenosum
Crohn’s
- Kidney stones (calcium oxolate)
- Aphthous mouth ulcers
- Hidradenitis suppurativa
UC
- Primary sclerosing cholangitis
- Migratory polyarthritis
Name 4 possible causes of IBD
- Dysbiosis and reaction against microbes
-> Dysbiosis occurs due to imbalance or loss of diversity within the flora of the intestine. This can trigger an inflammatory reaction.
–> Inflammation caused by microbial agents (virus, bacteria, fungus) may play a role although no specific causative microbe has been identified. - Reduced mucosal integrity
–> Dysfunctional epithelium can allow for influx of antigens into the lamina propria and subsequently cause a heightened immune response causing inflammation - Aberrant immune response to normal/ harmless microbes
–> The immune system in the gut plays a critical role in distinguishing between harmful and harmless substances (e.g., food, beneficial microbes).
–> In IBD, this balance is disrupted, and the immune system overreacts to normal gut contents or harmless microbes
–> made worse by reduced mucosal integrity - Genetic predisposition
–> Mutations in genes such as NOD2 or having certain HLA-DR1 alleles increase risk of IBD
–> These genes are involved in immune regulation, microbial recognition, and maintaining the epithelial barrier
outline 5 endoscopic findings in ulcerative colitis
- Continuous mucosal erythema (no skip lesions) that starts in the rectum and extends proximally. In severe cases, this inflammation can be pancolitis (involvement of the entire colon).
- Pseudopolyps: These are formed by regenerating mucosal tissue, which bulges into the lumen of the colon. They occur due to healing of the mucosa after ulceration and inflammation.
- Ulcerations of the mucosa: Ulcers can be seen along the long axis of the colon and are typically shallow. These lesions often run along the length of the colon and can cause bleeding.
- Friability and granularity of the mucosa: The mucosa may appear granular, and tissue can be friable, meaning it bleeds easily when disturbed. This is a hallmark of active inflammation.
- Loss of vascular markings: Inflammation can cause the vascular pattern (which is normally visible through the mucosa) to be obscured or lost due to swelling and erythema of the mucosa.
5 endoscopic findings of crohn’s disease
Cobblestone appearance due to deep mucosal ulceration and fissuring.
Discontinuous mucosal inflammation i.e. skip lesions
Luminal stenosis due to stricture formation caused by transmural inflammation.
Apthoid ulcers or deeper serpentine ulcers
Bowel perforation/ fistulae
describe the absorption of iron
-Ingested iron exists as heme (Fe2+) or non-heme (Fe3+).
-Non-heme Fe3+ is reduced to Fe2+ by gastric HCl, duodenal cytochrome b, or vitamin C.
-Fe2+ is absorbed into enterocytes via DMT1 or HCP1
-Inside enterocytes, heme oxygenase releases Fe2+ from the porphyrin ring and it can be stored as ferritin or exported into the blood via ferroportin.
-Exported iron is oxidized by hephaestin and binds to transferrin in the blood in the Fe3+ form.
-Transferrin delivers iron to the liver or bone marrow.
-Hepcidin, produced by the liver in response to high iron levels, inhibits ferroportin, limiting iron absorption and release into the blood.
-Iron absorption is regulated by hepcidin, which inhibits ferroportin when iron levels are high, and promotes absorption when iron levels are low.
Describe the pathogenesis of coeliac disease
- The gliadin component of gluten is resistant to digestion within the gut lumen.
- Gliadin induces stress in enterocytes, leading to the release of IL-15 and the expression of MIC-A on their surface.
- IL-15 activates CD8+ intraepithelial lymphocytes (IELs) and natural killer (NK) cells, which express the NKG2D receptor.
- The interaction between NKG2D and MIC-A leads to enterocyte cytotoxicity, causing disruption of the epithelial barrier and tight junctions, which allows gliadin to enter the lamina propria.
- In the lamina propria, gliadin is deamidated by tissue transglutaminase (tTG), enhancing its binding affinity for HLA-DQ2 and HLA-DQ8 molecules on antigen-presenting cells.
- This deamidated gliadin is presented to CD4+ T cells, which release inflammatory cytokines and further amplify the immune response and activate B cells against the gliadin.
- Activated B cells produce antibodies, including anti-tTG, anti-endomysium, and anti-gliadin.
- Chronic inflammation, villous atrophy, and malabsorption result from this immune-mediated damage to the small intestine.
Give 3 uses of anti-tTG antibodies in coeliac disease
- Used in diagnostic work-up –> highly sensitive and specific to coeliac disease, the degree to which they are elevated can give an idea of the degree of intestinal damage, very high levels e.g. >10x normal may allow for diagnosis without biopsy (for example in pediatrics)
- Monitoring adherence to gluten free diet
- Monitor for refractory or complicated disease –> persistently elevated levels despite adherence to GF diet may indicate refractory disease or enteropathy associated T cell lymphoma.
What are the classic histological findings at jejunal biopsy in coeliac disease
- Villous atrophy
- Crypt hyperplasia
- Increased intraepithelial lymphocytes
Name 5 complications of coeliac disease
- Osteopenia or osteoporosis due to malabsorption of vitamin D/ Calcium
- Anemia - most commonly iron deficiency anemia or vitamin B12 deficiency anemia
- Chronic non-specific ulcerative enteritis - chronic inflammation of all parts of the small bowel
- Carcinoma - particularly adenocarcinoma of the small bowel
- Enteropathy-associated T cell lymphoma (EATL)
Explain why kidney stones can occur in IBD
In Crohn’s disease, significant small bowel inflammation can cause malabsorption.
Unabsorbed fat in the intestinal lumen binds to calcium, preventing calcium from binding to oxalate. This increases oxalate absorption, which is then excreted by the kidneys, where it can crystallize into kidney stones.
Additionally, chronic diarrhea contributes to dehydration, reducing renal clearance of oxalate and further increasing the risk of stone formation.
Describe the pathogenesis of Crohn’s disease
Crohn’s disease is a chronic inflammatory disorder caused by an abnormal immune response to gut microbiota, leading to a dysregulated autoinflammatory reaction.
CD4+ T cells, predominantly Th1 and Th17, drive inflammation by producing cytokines such as IFN-γ, TNF-α, IL-12, IL-17, and IL-23. This leads to macrophage activation and non-caseating granulomatous inflammation, where immune cells attempt to contain persistent antigens.
The result is transmural inflammation, often presenting as skip lesions and leading to complications such as strictures, fistulas, and malabsorption
Briefly describe the role of NOD2 gene mutation in the pathogenesis of crohn’s disease
NOD2 mutations can lead to problems in recognizing bacteria in the gut. Normally, NOD2 protein recognizes the bacterial peptidoglycan layer and helps initiate the process of autophagy. NOD2 is typically highly expressed in macrophages, dendritic cells and Paneth cells of the ileum. When NOD2 doesn’t work properly, harmful bacteria can persist, leading to gut dysbiosis and a subsequent overactive immune response in the GALT. This causes chronic inflammation in the gut and increased activation of CD4+ T cells, contributing to Crohn’s disease.
List 4 possible causes of anemia in IBD
Chronic inflammation
Chronic blood loss
Iron malabsorption
Malabsorption of vitamin B12 or folic acid
Describe the neural control of peristalsis in the small bowel
- The arrival of a food bolus stretches the gut wall, activating mechanoreceptors (stretch receptors) in the intestinal wall.
- Afferent signals from these receptors synapse with interneurons in the myenteric plexus, which is located between the circular and longitudinal muscle layers of the muscularis externa.
- These interneurons coordinate both excitatory and inhibitory pathways by synapsing with motor neurons:
a. Excitatory motor neurons behind the bolus release acetylcholine (ACh) and substance P, stimulating circular muscle contraction to push the bolus forward.
b. Inhibitory motor neurons ahead of the bolus release nitric oxide (NO) and vasoactive intestinal peptide (VIP), causing circular muscle relaxation to reduce resistance.
- This coordinated contraction and relaxation propels the bolus forward, and the process repeats to sustain peristalsis along the bowel.
Name 4 serological tests that can be done in the workup of coeliac disease
- Anti-tTG igA antibody
- Total IgA levels (to check for IgA deficiency)
- Anti-endomysial IgA
- Anti-gliadin IgA
- Anti-deamidated gliadin peptide IgA antibody
if total IgA levels show deficiency, then the IgG class of these antibodies can be checked
