Term
A patient presents to you office with gingival redness and swelling, complaining that his gums have been bleeding during brushing.
When you get close to look at his teeth you detect a noxious smell on his breath.
What could be going on pathophysiologically and how can you tell between the 2 possible diagnoses? |
|
Definition
Gingivitis (reversible gingival inflammation without loss of epithelial attachment or Periodontitis (irreversible damage WITH loss of attachment).
This patient has halitosis, which is a bit more severe and suggests periodontitis.
1) Bacterial biofilm of gram (+) cocci builds up, causing inflammation, which leads to "gram-negative shift" (P. gingivalis, gram (-) rod)
2) Innate and adaptive inflammation/MMPs lead to disruption of epithelial barrier and systemic dissemination.
3) Damage to periodontium and in certain cases autoimmunity (GroEL and hsp60) |
|
|
Term
| How do you treat a patient who presents with gingival redness, swelling, halitosis and increased tooth mobility? |
|
Definition
Periodontitis (P. gingivalis)
1) Brush/floss
2) Scaling (scrape enamel) and root planning (scrape cementum)
3) Doxicycline in mouth rinse (also an MMP-inhibitor) |
|
|
Term
| How is periodontal disease related to CVD, Diabetes and Pregnancy complications? |
|
Definition
1) CVD
- TLR up-regulation on phages and endothelial cells, leading to innate immune response and arterial compromise.
2) Diabetes
- Treat periodontal disease to improve glycemic control in Pima indians
3) Pregnancy
- TLR-activation increases IL-1 and PGE2, causing pre-mature contractions and premature birth. |
|
|
Term
Which of the following provides a source of osteoblasts and fibroblasts to teeth?
1) Cementum
2) Periodontal ligament
3) Dentin
4) Pulp |
|
Definition
| 2) Anchors cemuntum (in root) to alveolar bone. |
|
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Term
| What is the distribution of serious and mucous glands in each of the 3 primary oral glands? |
|
Definition
The closer you are to swallowing (esophagus), the more serous (digestive enzymes)
1) Parotid (all serous)
2) Submandibular (80% serous, 20% mucous)
3) Sublingual (20% serous and 80% mucous) |
|
|
Term
| What are the 2 major nerve plexuses that regulate secretions and peristalsis in the GI tract? |
|
Definition
1) Meisner's secretory plexus in submucosa
2) Aurbach's (myenteric) plexus in muscular externa with ICC cells. |
|
|
Term
| What GI structures are involved in mixing/segmentation and which are critical for peristalsis? |
|
Definition
1) Segmentation
- Small intestine (haustra and tanea coli)/colon
2) Peristalsis
- Esophagus, stomach and small intestine. |
|
|
Term
| What are the defining characteristics of the 3 portions of the esophagus? |
|
Definition
UES (CN IX and X) and LES (DMN-myenteric NO) have high resting tone
UES consists of cricopharyngeal muscle (inferior pharyngeal constrictor)
1) Upper is skeletal muscle
2) Middle is mixture
3) Lower is smooth muscle
LES- thickening of circular layer of muscularis externa |
|
|
Term
| What are the important cell types/enzymes found in each of the 5 anatomical compartments of the stomach? |
|
Definition
1) Cardia (stratified squamous to folded simple columnar transition)
- Pit to gland 1:1
- Parietal cells (IF and HCl)
- Mucous cells (HCO3- and H2O)
2) Fundus/Body (Oxyntic glands)
- Pit to gland 1:4
- Parietal cells (IF and HCl)
- Chief cells (pepsinogen, rennin, lipase)
- Mucous neck cells (HCO3- in mucous depressed by NSAIDs)
3) Antrum (Pyloric glands)
- Pit to gland 1:2
- No parietal cells, but many APUD cells (G, ECL, D, D1, Fundic)
4) Pyloric region
- Pit to gland 1:1
- No chief/parietal, but mucous/APUD |
|
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Term
What factors are produced by each of the following APUD cells found in the gastric antrum?
1) G cell
2) ECL cell
3) D cell
4) D1 cell
5) Fundic cell |
|
Definition
1) Gastrin (stimulates parietal cells on basolateral surface via Gq)
2) Histamine (binds H2 receptors of parietal cells on basolateral surface via cAMP)
3) Somatostatin (when pH is low, inhibits gastrin and acid release, as well as chief cell secretions)
4) VIP (increases pancreatic HCO3- and water secretion and relaxes LES)
5) Ghrelin (stimulates hunger) |
|
|
Term
| What factors activate/inhibit acid secretion from parietal cells? |
|
Definition
1) ACh, histamine and gastrin bind basolateral membrane and activate HCl release
2) Somatostatin inhibits parietal, chief and G cells. |
|
|
Term
| How might giving atropine influence gut motility? |
|
Definition
| Efferent motor neurons of the ENS are cholinergic, so you would have decreased peristalsis, since VIP/NO drive would take over. |
|
|
Term
| Describe the 2 basic afferent archs of the ENS. |
|
Definition
Use 5-HT in response to stretch
1) Extrinsic primary with bodies in nodose ganglia, projection to vagal centers in medulla
2) Intrinsic primary that have bodies in submucosal plexus and synapsewith ENS interneurons and anglia in myenteric and submucosal plexus. |
|
|
Term
| How does Ondansetron (Zofran) treat nausea? |
|
Definition
| Inhibits 5-HT3 receptors in CTZ and nucleus solitarius (dorsal motor nucleus) |
|
|
Term
| Why might someone on an L-type calcium channel inhibitor be constipated? |
|
Definition
Contractions depend on efferent motor neurons that release ACh, which binds to L-type calcium channels and generates an AP on top of ICC slow waves.
This also happens with opioids, which suppress inhibitory motor neurons and cause chronic contraction. |
|
|
Term
| How is peristalsis generated? |
|
Definition
Contractions depend on frequency of slow waves generated by ICC (greater in small intestine than in stomach or colon-most digestion).
Excitatory neurons release ACh and substance P moving rostrally, leading to Ca2+ influx, MLCK activation and contraction. These signals block inhibitory dilation near bolus.
Inhibitory neurons release VIP/NO caudally, inhibiting MLCK and causing dilation. |
|
|
Term
| What is the function of the migrating motor complex (MMC)? |
|
Definition
Main intestinal motility pattern during fasting
- large amplitude, 3/minute contractions in antrum through duodenum that clean out the gut.
- MMCs are released by STRETCH from food (cannot be given IV) |
|
|
Term
| What is the basic 3 neuron arch of visceral pain sensation? |
|
Definition
1) Primary DRG afferent
2) Dorsal Horn neuron
3) Brainstem/thalamus (GI) |
|
|
Term
| What 2 factors can account for why the "adequate stimulus" theory of pain sensation does not apply in the GI tract? |
|
Definition
Neurons are multimodal
1) Frequency Coding
2) Silent Afferent |
|
|
Term
| What is the difference between hyperalgesia and allodynia in the context of visceral hypersensitivity? |
|
Definition
1) Pain gets worse
2) Pain for non-noxious substance |
|
|
Term
| What are the 2 systems of visceral sensation? |
|
Definition
Sensory fibers run with autonomic tracts, but are NOT PART OF THEM
1) Vagal afferants (runs with parasympathetic pelvic nerve, but 85% sensory) synapse in nodose ganglia- "affective" pain from esophagus to transverse colon
2) Spinal visceral afferents (runs with sympathetic) and synapse in pre-vertebral ganglia, causing cramping, sharp pain. |
|
|
Term
| What is pain from the gallbladder sometimes felt in the shoulder? |
|
Definition
|
|
Term
Which of the following is the best solution for chronic pain from pancreatitis?
1) PPi like Prilosec
2) Octerotide (somatostatin analouge)
3) Oral pancreatic enzymes
4) Whipple procedure |
|
Definition
Whipple is the only strategy that addresses the UNDERLYING PROBLEM (next best is CBT and non-pharmacological)
Removes head of pancreas, gall bladder and cystic duct (attach bile duct and tail of pancreas to duodenum) |
|
|
Term
| Why might an NO-inhibitor cause achalasia? |
|
Definition
| Can't swallow because inhibitory (dilating) motor neurons are inhibited. |
|
|
Term
| How does neuromuscular regulation of peristalsis differ in the UES and the LES? |
|
Definition
1) UES is striated muscle, and peristalsis is initiated by sequential cranio-to-caudal stimulation of motor units by nerve fibers arising from nuclei in CN IX and X of brainstem.
2) LES peristalsis is NOT programmed by brainstem
- it is tonically contracted at rest by "myogenic tone," and the first action in peristalsis is swallow-induced NO-mediated relaxation
contraction occurs by "reversal of inhibition" |
|
|
Term
Patient presents with "burning" sensation in mid-epigastrium, near the xyphoid process. He reports feeling this pain intermittently, especially after large, fatty meals.
What is the mechanism underlying this sensation |
|
Definition
Heartburn (often associated with dysphagia)
- NOT sharp, crampy or squeezy pain
1) Over-eating increases pressure gradient from stomach to esophagus
2) Fats entering duodenum decrease force of closure on LES and decrease rate of gastric emptying
3) Gastric distention causes spontaneous relaxations of LES, which leads to reflux. |
|
|
Term
What are the common mechanisms generating heartburn in with mucosal inflammation in the distal esophagus?
How do you diagnose/treat? |
|
Definition
1) GERD (without inflammation, it is NERD)
- Transient relaxation of LES
- Decreased LES resting pressure, causing impaired barrier function.
**WATCH out for hiatal hernia**
2) Give PPi for diagnostic reversal AND treatment
- If complicated (dysphagia, odynophagia, chest pain) GERD, do an endoscopy, or a barium swallow if endoscopy is contraindicated.
Maintenance with PPi is required. |
|
|
Term
| What are the 3 most common/significant complications of GERD |
|
Definition
1) Stricture from scar formation
2) Barrett's (intestinal metaplasia)
- Adenocarcinoma risk
3) Dysphagia
- Oropharyngeal (neuromuscular or structural)- "difficulty swallowing, cough, choking"
- Esophageal (GERD pain)- "fullness, foreign object sensation" |
|
|
Term
A child presents with heartburn and difficulty swallowing, explaining that it feels like he has something in his throat." He is having particular trouble consuming solids.
He explains that the feeling is intermittent (comes and goes).
What is going on and how do you manage? |
|
Definition
Foreign body sensation and solid bias suggests Esophageal Dysphagia due to mechanical obstruction, a common consequence of GERD.
- Intermittent chronology suggests either an Eosinophillic issue, leading to GERD stricture, or a Schatzki's mucus ring.
- You need to order an esophageal biopsy to look for eosinophillic infiltration of epithelium and trachealization of the esophagus.
- Treat with topical "swallowed" steroids. |
|
|
Term
What might you be worried about in a patient with progressive, esophageal dysphagia for solids and liquids?
You order a biopsy, which reveals inflammation of the myenteric plexus in the esophagus.
How do you treat? |
|
Definition
Achalasia, Scleroderma and Cancer and present as progressive dysphagia for solids and liquids, but the biopsy is classic Achalasia.
You need to lower sphincter forces with nitrates or calcium-channel blockers
Sudden dysphagia for solids/liquids is infection, and intermittent is a motility disorder. |
|
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Term
Patient presents with dysphagia, heartburn and intermittent regurgitation of sour fluid.
What are the major histological features of this condition? |
|
Definition
Reflux esophagitis
1) Inflammation, with IELs, eosinophils and PMNs
2) Intercellular edema
3) Basal zone hyperplasia
4) Elongation of LP |
|
|
Term
What kind of esophageal disease is described in each of the following histological pictures?
1) Esophageal ulcerations with viral inclusions in the nuclei of squamous epithelial cells, as well as multi-nucleated squamous cells adjacent to the lesions.
2) Ulceration of esophageal mucosa with viral inclusions in the cytoplasm and nuclei of infected stromal, inflammatory and endothelial cells at the base of the ulcer.
3) Diffuse, oozing white plaques in the esophagus with ulceration and oral thrush.
4) Esophageal dysmotility and failure of LES relaxation with absent ganglion cells in the myenteric plexus
5) Trachealized, "corrugated" esophagus with small, discete white nodules |
|
Definition
All are infectious esophagitis which may present with dysphagia and odynophagia.
1) HSV
2) CMV
3) Candida or other fungal
4) Achalasia from Chagas (T. cruzi) in south/central america (autoimmune)
5) Eosinophillic esophagitis (treat with Monelukast, diet and steroids) |
|
|
Term
Patient presents with dysphagia that will not improve with H+ pump inhibitors.
You notice esophageal ulcerations, with proximal stenosis and "corrugation" (trachealized) of the esophagus. You also note a intraepithelial eosinophilic infiltrate.
What is going on and what do you do? |
|
Definition
Since PPi does not work, it is not simple GERD. Proximal stenosis with corrugation suggests eosinophillic esophagitis.
Treat with Monelukast (LCT inhibitor), diet and steroids |
|
|
Term
What is the most common type of esophageal neoplasm in the US?
In the world? |
|
Definition
Adenocarcinoma (Barrett's and smoking are risk)
Squamous cell carcinoma (Smoking and alcohol risk) |
|
|
Term
Patient present with progressive dysphagia for solid food along with weight loss and signs of heartburn.
You order an endoscopy and biopsy, which reveal metaplastic changes in the distal esophagus and intestinal metaplasia.
What are you worried about and what is the prognosis if you are correct? |
|
Definition
Remember, adenocarcinoma occurs in distal esophagus in the context of Barrett's esophagus.
Prognosis strongly depends on stage at time of treatment (If there is metastasis (<10% with mets). However, since barrett's is so often silent, adenocarcinoma progresses without treatment many times!!! |
|
|
Term
| How might an endoscopy help you distinguish between squamous cell and adenoncarcinoma of the esophagus? |
|
Definition
1) Adenocarcinoma is in distal esophagus where Barrett's esophagus takes place.
- Looks glandular
2) SCC takes place in middle 1/3 of esophagus (50% of time)
- Look like squamous epithelium with kerratin, desmosomes and intracellular bridges. |
|
|
Term
| How can you tell easily between GERD and eosinophillic esophagitis? |
|
Definition
| Eosinophils in GERD will only be in distal esophagus, while they will be up and down in Eosinophillic |
|
|
Term
| Why is the stomach relatively resistant to infarction? |
|
Definition
Overlapping anastamosing arterial supply (ultimately drained by portal vein)
1) Less curvature (left and right gastric arteries)
2) Great curvature (left and right gastroepiploic arteries)
3) Fundus (short gastric arteries from splenic) |
|
|
Term
| What are the 3 mechanisms that stimulate HCl release from the parietal cells of the stomach? |
|
Definition
1) Neurocrine- ACh from vagus binds M3 receptors on basolateral parietal cell membrane (smell alone)
2) Endocrine- Gastrin from antrum G cells binds CCK receptor on basolateral parietal cell membrane and ECL cells, leading to acid secretion directly and indirectly.
**also inhibits somatostatin release by D cells**
**Gastrin and ACh act through PIP2, increasing Ca2+/kinase activity and H+/K+ ATPase
3) Paracrine- Histamine released by ECL enteroendocrine cells binds to H2 receptors on parietal cells
- acts through increased cAMP (via Ga) and H+/K+ ATPase |
|
|
Term
Which of the following does not control gastrin release from antrum G cells?
1) ACh
2) Gastrin-releasing peptide
3) Histamine
4) Somatostatin
5) Luminal acid concentration |
|
Definition
3) Histamine is released IN RESPONSE to gastrin binding to CCK receptors on ECL APUD cells.
- ACh and GRP act to stimulate gastrin secretion via CNX
- Somatostatin inhibits gastrin secretion via paracrine diffusion
- Luminal acid causes feedback inhibition of G cell |
|
|
Term
How is HCl secretion from parietal cells inhibited?
(hint: 2 ways) |
|
Definition
1) Somatostatin (D cells)
- Directly binds receptor and inhibits GPCR/PKA activity (H+/K+ ATPase)
- Indirectly binds somatostatin receptor on G cells and inhibits gastrin release.
2) Prostaglandins
- bind PG receptor on parietal cell, inducing inhibitory GPCR activity, down-regulated kinase activity and decreased H+/K+ ATPase activity |
|
|
Term
| Why might you suspect a carcinoid tumor in a patient with Pernicious Anemia? |
|
Definition
Issue of IF loss due to parietal cell loss
1) Carcinoid is endocrine tumor that arises because of hypertrophy of G cells under conditions oh high gastric pH, when parietal cells have been lost.
2) Without parietal cells, you don't have IF, so you can't reabsorb B12 in terminal illeum (this is the original cause for G cell hypertrophy). |
|
|
Term
Which of the following is the most effective therapeutic method of lowering acid levels in the stomach?
1) Vagotomy
2) Gastric resection
3) H2 blockers
4) Proton pump blockers
5) Atropine |
|
Definition
All will work, but H2, histamine blockers are the most effective for treating gastroesophageal disorders.
Without histamine release from D1 ECL cells, you get less parietal stimulation and less HCl secretion. |
|
|
Term
What gastric region accomplishes each of the following elements of gastric motility?
1) Filling
2) Storage and Mixing
3) Trituration
4) Emptying |
|
Definition
1) Relaxation of proximal stomach (vagally-mediated) without increase in intra-gastric pressure
2) Corpus and antrum
3) Corpus and antrum (powerful contraction leading to retropulsive jet stream)
**ACh from vagus stimulates M3 receptors and leads to Calcium entry through L-type channels, leading to AP on top of slow waves generated by ICCs**
4a) Liquid- Rapid, because of tonic pressure gradient from stomach to duodenum
4b) Solid- Triturated food (antral contractions) particles are seived through pyloric sphincter into duodenal bulb (larger particles are intermittently emptied by strong, 3-10 minute contractions, though open pylorus during fasting state)
Large-particle "migrating motor complexes" are intestinal house-keepers and occur once every 1.5-2 hours. |
|
|
Term
An infant presents with projectile vomiting. Whats going on?
What is the analogous condition in adults? |
|
Definition
1) Congenital Hypertrophic pyloric stenosis (outlet obstruction), where there is a loss of inhibitory (nitricergic) neurons in the pylorus). Confirm with barium swallow.
2) Outlet obstruction in adults is commonly caused by recurrent ulcers or malignancies (try to treat endoscopically). |
|
|
Term
| How do you diagnose Zollinger Ellison Syndrome? |
|
Definition
Somatostatin.
Excess gastrin secretion through endocrine tumor in upper abdomen (usually pancreas), leads to hypertrophy of gastric folds and proliferated parietal cells.
Somatostatin should reverse these symptoms by inhibiting acid production directly (GPCR inhibition) and indirectly (G cell inhibition). |
|
|
Term
| What is the pathogenesis/diagnosis/treatment of the most common bacterial cause of infective gastritis? |
|
Definition
H. pylori (Gram-negative, microaerophilic, curved bacillus found only on gastric mucosa)
1) Pathogenesis
- Inflammation, cytokine production and activation of ECL cells (histamine production and acid secretion from parietal cells)
- Acid production produces ulcerations that can lead to atrophic gastritis, allowing bacterial colonization and concentration of carcinogens.
**Ongoing stimulation of immune system in chronic infection can cause MAL lymphoma (clonal proliferation of B cells**
2) Diagnose/treat
- Diagnose with urease test/histology
- Treat with Triple therapy (Proton-pump inhibitor and 2 antibiotics) |
|
|
Term
| What are the 2 major types of Atrophic gastritis? |
|
Definition
Atrophy of gastric mucosa associated with intestinal metaplasia and carcinoid tumors.
1) Type A is autoimmune with anti-parietal antibodies attacking the corpus reducing HCl and IF
- Hypochlorhydria (with elevated gastrin) and pernicious anemia may result.
2) Type B is H. pylori-associated, antral-predominant gastritis with normal gastrin levels. |
|
|
Term
A patient presents with burning pain in the epigastrium at night and a few hours after food intake.
How do you confirm your suspicion and what is the pathogenesis of this condition? |
|
Definition
Burning epigastric pain at night and after feeding suggests Peptic Ulcer Disease.
Confirm with Endoscopy or UGI.
Generally, Mucosal lesion result from imbalance between defensive and injurious influences (e.g. increase in acid secretion and decrease in protective HCO3- secretion).
**Ulcers extend into deep muscular layers vs. erosions**
Etiology is most likely NSAID or H. Pylori
1) NSAIDS- COX-1 inhibition decreases protective PGE (should try COX-2 specific if possible)
2) H. pylori |
|
|
Term
What are the most common etiologies of gastric dysmotility disorders (Gastroparesis)?
What are the common treatments? |
|
Definition
Diagnose with Solid-phase gastric emptying study (radio-labeled scrambled eggs)
1)
- Neuropathic (congenital pyloric stenosis-absence of inhibitory neurons)
- Pacemaker cell dysfuction
- Myopathic
2) Treat
- Metoclopramide (central and peripheral dopamine antagonist (antiemetic, but drowsy) and cholinergic agonist via indirect pre-synaptic effects on enteric motor neurons.
**long-term use associated with tardive dyskinesia**
- Erythromycin- motilin receptor agonist and cholinergic agonist (pro-kinetic agent) for acute treatment. |
|
|
Term
| How does the treatment of choice for GERD work? |
|
Definition
PPIs- the "....prazoles" are coated in "enteric gelatin" that protect them from acid pH (only activated at alkaline pH)
- Rapidly absorbed, highly protein -bound and extensively metabolized in liver (CYP2C19 and CYP3A4)
1) Pro-drugs that enter parietal cells from bloodstream and accumulate in acid secretory canaliculi, where they are activated by proton-catylyzed process, forming thiophilic sufenamde or sulfenic acid.
2) Active form covalently binds sulfhydryl group of cysteines on extracellular domain of H+,K+ ATPase (Position 813)
3) Irreversible binding lowers 95% of acid secretion, and secretion resumes ONLY AFTER new pumps are inserted in membrane. |
|
|
Term
| Why do PPIs have such long half-lives? Why is long-term use concerning? |
|
Definition
1) PPIs covalently bind and deactivate proton pumps, which must then bee re-synthesized before function returns!
2) osteoporosis (impaired calcium absorption), hip fractures, CAP and intestinal infections. |
|
|
Term
| How do H2 receptor antagonists suppress gastric acid production? What side effects should you look out for? |
|
Definition
The "Idines" like cimetidine, ranitidine, famotidine with IV (shorter half life than PPi)
1) Prevent H2-mediated activation of parietal cells at basailar membrane surface.
- Reversibly compete with histamine for binding (vs. irreversible covalent binding of PPI)
- Biggest effect on basal acid secretion (during sleep), which may be important for duodenal ulcer healing and to prevent nocturnal-acid breakthrough in patients on PPIs.
- Small amount is protein-bound, with minimal hepatic metabolism (most metabolism/filtration goes by kidney).
2) Cemetidine inhibits CYP450 system and may alter other drugs. |
|
|
Term
| What are the important differences between Proton Pump Inhibitors and H2 receptor antagonists in terms of reducing gastric acid secretion? |
|
Definition
1) PPI is highly protein bound, while H2R-a is minimally protein bound in serum
2) PPI undergoes extensive hepatic metabolism, while H2R-a is mostly renal (watch out in renal disease)
3) PPI generally used for heightened acid secretion, while H2R-a is best to suppress basal secretion during sleep. |
|
|
Term
| How is Misoprostol useful to treat NSAID-mediated peptic ulcer disease? |
|
Definition
Prostaglandin analogue that is rapidly absorbed and undergoes extensive first-pass metabolism (peak at 30 min)
1) PGE2 and PGEI2 inhibits acid production by binding EP3 receptor on parietal cells and reducing production of cAMP.
**Both basal and food-induced acid secretion**
2) PGE is also cyto-protective, stimulating mucin and HCO3- secretion.
**Watch out for diarrhea, pregnancy (contractions) and IBD** |
|
|
Term
| Why would you take Sucralfate on an empty stomach and what is its action? |
|
Definition
(Viscous gel with cytprotective/PGE effects)
Taken on empty stomach, because it is activated by acid and give to prevent acid-induced damage and pepsin-mediated hydrolysis of mucosal proteins
1) Sucrose with an added ammonium hydroxide that undergoes extensive cross-linking to form a viscous gel that adheres to epithelium and ulcer craters to inhibit hydrolysis of mucosal proteins by pepsin.
2) Also cyto-protective (like Misoprostol), stimulating local PGE production and binding bile salts.
**Watch out for renal failure and constipation, because of Al3+ absorption** |
|
|
Term
| What is the basic composition/action of antacids and what are their common side effects? |
|
Definition
Have become less popular over time due to PPi and H2R-a
1) Various conjugated bases (often with Al3+ and Mg2+) that neutralize stomach acid
2) Don't take with lots of milk, or you may get Milk-Alkali syndrome, where over-alkalinazation causes calcium precipitation in kidney leading to renal insufficiency. |
|
|
Term
| What are the mainstay treatments for GERD? |
|
Definition
Goal is to resolve symptoms and heal esophagus.
Try "step-up regimen", where you start an H2RA (less aggressive) and only use a PPi if symptoms fail to respond
1) PPis are better than H2Ras for uncomplicated GERD
**PPis are used to diagnose/treat**
2) IF GERD is complicated or there is Barrett's esophagus, complete acid control and 24h pH monitoring is required (use an H2Ra at bedtime)
**Sucralfate may be useful if bile is an issue**
3) LIFESTYLE MODIFICATIONS (remember, least harm should be tried first). |
|
|
Term
| What are the mainstay treatments for Peptic Ulcer Disease? |
|
Definition
1) Uncomplicated PUD
- PPis are more rapid, but both PPi and H2Ra are effective
- If H. pylori, use "triple therapy" with 2 Antibiotics (Amoxicillin and Metronidazole) and 1 PPi
2) Complicated PUD (bleeding)
- IV PPi as part of triple therapy |
|
|
Term
What are the mainstay treatments for NSAID-related ulcers?
What about for Zollinger-Ellison? |
|
Definition
1) PPI with Misoprostal
2) PPIs for gastrinoma acid secretion (might also try somatostatin) |
|
|
Term
What is the most common cause of chronic active gastritis?
What are the pertinent histological findings and future complications associated? |
|
Definition
H. pylori (active because PMNs are seen)
- Mild chronic (inactive) gastritis often of unclear cause
- Multifocal atrophic gastritis = chronic gastritis with gastric atrophy and intestinal metaplasia, is associated with increased risk of gastric cancer development |
|
|
Term
What is the most common cause of "diffuse corporal atrophic gastritis"
What pertinent histological findings and complications are associated? |
|
Definition
Autoimmune, chronic gastritis
-Autoantibodies to gastric parietal cells and intrinsic factor
- "Body-prominent" chronic Inflammatory response with loss of parietal cell mass (atrophy):
- Associated with carcinoid tumors, because of G cell proliferation (vs. gastric cancer in H. pylori) |
|
|
Term
| What are the most common sites to find Peptic ulcers? |
|
Definition
Breach in mucosa that extends down into muscularis propria (most often associated with H. pylori)
1) First portion of duodenum
2) Gastrum antrum
3) Gastro-esophageal junction (Barrett's association) |
|
|
Term
| What is Menetrier's disease? |
|
Definition
| One cause of hypertrophic gastropathy where over-expression of mucosal growth factor causes massive hyperplasia of surface mucous cells (foveolar hyperplasia), often leading to hemorrhage, epigastric discomfort, weight loss and loss of protein into gastric fluid. |
|
|
Term
| What are the important types of benign gastric tumors? |
|
Definition
Hyperplastic polyp, Fundic polyp, Gastric adenoma
1) Hyperplastic polyp
- Found with chronic gastritis
- Prominent pits
2) Fundic gland polyp
- Prominent gland compartment, crowding pits with fundic-type mucosa
3) Gastric adenoma
- Pre-malignant, dysplastic cells found in setting of intestinal metaplasia |
|
|
Term
| What are the most important risk factors associated with gastric carcinoma? |
|
Definition
1) Enviormental
- H. pylori
- Diet
- Smoking
- Socioeconomic status
2) Host factors
- chronic gastritis (via hypochlorhydria)
- partial gastrectomy (free reflux of bile and alkaline fluid)
- Barrett's esophagus
3) Genetics
- Blood type A
- family history of gastric cancer, familial gastric carcinoma (E-cadherin mutations) and HNPCC
- atrophy, intestinal metaplasia |
|
|
Term
| Which 4 sites when stimulated can induce vomiting? |
|
Definition
"Vomiting center" (D2 and M receptors) is Nucleus solitarius and RF of medulla
1) GI
2) Vestibular system
3) Chemoreceptor trigger zone (CTZ) in area postrema of the floor of the 4th ventricle (5HT3 and D2)
4) CNS centers |
|
|
Term
| What would happen if a vomiting episode stopped during "retching"? |
|
Definition
You would get rhythmic abdominal contractions, but UES would not relax, glottis remains closed and ejection would not occur!
3 basic phases of an emetic episode
1) Pre-ejection
- Gastric relaxation and retroperistalsis
2) Retching phase
- Rhythmic contraction of abdominal muscles, intercostal muscles and diaphragm against closed glottis
3) Ejection phase
- Intense contraction of abdominal musculature with relaxation of UES. |
|
|
Term
Which of the following is not a factor associated with CINV?
1) Female gender
2) H/x of motion sickness
3) Tobacco use
4) Alcohol use
5) Anxiety disorder |
|
Definition
4!
No or low alcohol use is actually more associated due to decreased muscle activity suppression. |
|
|
Term
| What are the 5 major classes and sites of action of anti-emetics? |
|
Definition
Site of action
1) M1
2) H1
3) D2
4) 5-HT3
5) NK1- substance P
M1, D2, 5HT3 (also on vagal afferents), NK1 are in area postrema
H1 is in vestibular nucleus |
|
|
Term
| What drug is given prophyactically to treat motion sickness and what are its mechanism/side effect? |
|
Definition
1) M1 receptor antagonist like Scopolamine is given transdermally to prevent emetic stimulation of area postrema.
2) SE include dry mouth, drowsiness and vision disturbance. |
|
|
Term
| When are anti-histamines are generally used as anti-emetics? |
|
Definition
Inhibit H1 receptor in vestibular nucleus for treatment of motion sickness, PONV and vestibular disorders (vertigo).
1) Diphenhydramine (Benadryl)
2) Dimenhydrinate (Dramamine)
3) Cyclizine (Marezine)
4) Meclizine (Antivert)
5) Promethazine (Phenergan)- extrapyramidal |
|
|
Term
| What are the major classes of Dopamine Receptor antagonists used to treat nausea and vomiting and how do they work? |
|
Definition
All are used for nausea/vomiting and have risks for Tardive Dyskinesia
1) Phenothiazines (Prochloperazine)
- Prevent CINV by antagonizing D2 receptors in area postrema, as well as M1 and H1 receptors.
- Watch out for extrapyramidal symptoms like irreversible TARDIVE DYSKINESIA
2) Butyrophenone (Droperidol and Haloperidol)
- long half life limits use
- similar SE to Phenothiazine
3) Benzamide (Metoclopramide)
- Anti-emetic and Pro-kientic
- Central and peripheral dopamine D2 antagonism and weak 5-HT3 blockade at high doses.
- Good for cytotoxic drug therapy
- TD also a risk. |
|
|
Term
| What is the current protocol for anti-emesis in CINV. What are common side effects? |
|
Definition
5-HT3 receptor antagonists (The "Setrons")
1) Single oral dose of Dolesetron with Dexamethasone (steroid) and Aprepitant (NKI antagonist) (for HIGH RISK)
5-HT3-a include, Palonosetron, Granisetron, Dolasetron, Ondansetron
2) EKG interval changes are common, but usually clinically insignificant, but watch out for QTc prolongation and torsade de pointes
NO evidence of cognitive, psychomotor (unlike D2-antagonists), or affective disturbances |
|
|
Term
1) What do Aprepitant and Fosaprepitant do
2) how should they be used?
3) What side effect/interactions should you look out for? |
|
Definition
Neurokinin receptor (GPCR) antagonists that prevent emetogenic effects of substance P on brainstem nucleus tractus solitarius and area postrema.
Prevent acute and delayed (5-HT3 is only acute) episodes
2) Give with Dolasetron and Dexamethasone for CINV
3) WATCH OUT in patients receiving concurrent drugs that are metabolized through CYP3A4 given their moderate inhibitory activity for the CYP3A4 metabolic pathway. |
|
|
Term
| How are glucocorticoids like Dexamethasone used as anti-emetic agents? |
|
Definition
Good for CINV but watch out for insomnia (45%) and indigestion and agitation (27%)
1) As single agents, they are used for patients at low emetic risk.
2) For moderate risk, they are added to a 5-HT3R antagonist like Dolasetron.
3) For high risk (Cisapride, Cyclophosphamide), you add them to Dolasetron and an NKI inhibitor like Aprepitant/Fasaprepitant |
|
|
Term
| What are Dronabinol and Nabilone and how might they be used? |
|
Definition
Cannabinoid agents used as second-line anti-emetics.
Bind and stimulate CB1 cannabinoid receptors on neurons in vomiting center.
Modest effect with unfavorable SE (vertigo, xerostomia, hypotension) limit clinical utility (2nd line) |
|
|
Term
| Why might you use lorazepan or alprazolam to treat patients suffering from emesis and nausea? |
|
Definition
Benzodiazepines are anti-anxiety drugs that reduce anxiety and akathisia associated with dexamethasone (steroid) and metoclopramide (M1 inhibitor)
Give as adjunct therapy in patients who receive numerous cycles of chemo and anti-emetic effects start to diminish. |
|
|
Term
| How do chemotherapeutic agents induce emesis? |
|
Definition
Cisplatin, Cyclophosphamide and Carmustine are the worst!
2 mechanisms of CINV
1) Direct toxin at CTZ in area postrema (which stimulates vomiting center)
2) Indirectly by stimulating release of 5-HT3 from enterochromaffin cells in small intestine, which binds 5-HT receptors in the vomiting center |
|
|
Term
| What are the 2 major pro-kinetic agents that are currently used for GERD, gastroparesis and other forms of GI dysmotility? |
|
Definition
1) Tetracycline- macrolide antibiotic
- Stimulates motilin receptors in GI tract to increase motility
- Available oral and IV (only for acute)
2) Metoclopramide- anti-M1
- Anti-emetic and pro-kinetic effects
- Used IV when oral Tetracycline does not work, but you worry about Tardive Dyskinesia! |
|
|
Term
How might the following drugs be used as pro-kinetic agents?
1) Domeperidone
2) Cisapride
3) Tegserod |
|
Definition
1) Not FDA approved because of arrythmia risk
2) Facilitates ACh release from myenteric neurons by stimulating 5-HT4 (diffuse action makes it only available in severe cases)
3) Partial neuronal 5-HT4 receptor agonist, stimulating the peristaltic reflex and intestinal secretion, while desensitizing visceral afferents (only used in immediately life-threatening scenarios because of cardiac events) |
|
|
Term
| What are the 4 major structural components of the small intestine and what are their functions? |
|
Definition
1) Plicae circulares
- Folds of mucosa that increase SA and provide mechanical mixing
- Most extensive in jejunum
2) Villi
- Folds of epithelium into the lumen with core of lamina propria (tallest in jejunum and shortest in illeum)
- Epithelium composed of Enterocytes (absorption and bacterial defense) and Goblet cells (Mucins that protect glycocalyx digestive enzymes)
3) Crypts
- Epithelial folds that invaginate into lamina propria containing precursor cells for enterocytes and goblet cells, paneth cells and enteroendocrine cells.
- Crypt enterocytes secrete Cl- and HCO3- (dragging Na+ and water out into the lumen)
- Paneth cells at base of crypts secrete lysozyme, defensins and TNFa
4) Microvilli
- Folds of apical plasma membrane of individual enterocytes coated in glycocalyx (hydrolytic enzymes protected by mucin) and nutrient symporters |
|
|
Term
| What are the important cell types (and their functions) found in the Villi and Crypts of the small intestine? |
|
Definition
1) Villi (neighboring cells connected by tight junctions)
- Enterocytes (absorption and bacterial defense, expressing TLRs)
- Goblet cells (Secrete mucins to protect glycocalyx enzymes on microvilli)
2) Crypts
- Precurosors for enterocytes and goblet cells of villi
- Crypt enterocytes secrete Cl- and HCO3-, which pull Na+ and water into the (reabsorbed Na+ facilitates co-transport of nutrients).
- Paneth cells at base of crypts are large, acidophilic cells that secrete lysozyme, defensins and TNF-a (gut flora control)
- Enteroendocrine cells (VIP, Somatostatin, CCK, Secretin, GIP, Gut-type glucagon, Motilin) |
|
|
Term
| What are the major factors produced by Enteroendocrine cells of the small intestinal crypts? |
|
Definition
A Bunch!
1) VIP
- Increase HCO3- and water secretion from pancreas and small intestine, and relaxes smooth muscle.
2) Somatostatin (D1 cell)
- Feedback to stomach, inhibiting G cells, ECL cells and Parietal cells.
3) CCK (I cell)
- Secreted from duodenum by fats or proteins in the lumen, indirectly stimulating digestive enzyme release from pancreas and gall bladder contraction
4) Secretin (S cell)
- Released in presence of acid in duodenum; resulting in pancreatic secretion of HCO3- and water
5) Glucose dependent Insulinotropic peptide (GIP)
- Induces insulin secretion in response to glucose in lumen and stimulates lipoprotein lipase (lipid deposits increase).
- Also inhibits gastric acid production
6) Gut-type Glucagon (L cell)
- Stimulates hepatic glycogenolysis
7) Motilin (Mo cell)
- GI motility during fasting state at intervals of 100 min (MMC and "housekeeping") |
|
|
Term
| What are the major functional characteristics of the small intestinal microvilli? |
|
Definition
1) Glycocalyx with hydrolytic enzymes; enterokinase (enteropeptidase), dipeptidases and disaccharidases.
- Enterokinase activates pancreatic trypsinogen to trypsin, which activates other pancreatic enzymes.
2) Nutrient symports that use Na+ secreted into lumen on the tail of Cl- and HCO3- secreted by crypt enterocytes. |
|
|
Term
| What is the GALT? What are the afferent and efferent limbs of the system? |
|
Definition
One component of Mucosal immune system containing lymph cells other than PMNs.
Aggregated nodules called Peyer's Patches in the ILLEUM with absent villi (covered in follicle associating epithelium M cells)
M cells and IgA are the players!
1) Afferent sensory limb
- M cells sample antigens by transcyctosis and present them to APCs on basolateral surface.
- APCs activate T cells, which cause B cell rearrangements - B and T cells migrate to LN and proliferate into Th, Tc and plasma cells, which leave LN and follow lymphatic drainage to right heart.
- Once cells enter systemic circulation, they express integrin that leads to them MadCAM-1-expressing endothelial cells and allows them to extravasate into these mucosal organs (GI, respiratory, reproductive).
- Once in lamina propria of organs, they produce a lot of IgA
2) Efferent
- Basolateral membrane of enterocytes express poly-IgA receptor (Pig-4) with a secretory component (SC) that binds IgA, leading to complex endocytosis.
- SC remains complexed with IgA and is transcytosed to apical surface of enterocyte, where fusion and IgA secretion occurs
- IgA binds antigens and enterotoxins. |
|
|
Term
What are the 3 primary sections of the small intestine?
What are the important characteristics of each section? |
|
Definition
Entire small bowel supplied by superior mesenteric arteries at level of hepatic flexure.
1) Duodenum
- curves around head of pancreas
- leaf-like villi with few goblet cells in epithelium and
- BRUNNER's glands in submucosa (alkaline mucous secretion to neutralize chyme)
2) Jejunum
- Best developed plicae circulares with long, finger-like villi (medium number of goblet cells)
- Major area for final digestion and absorption.
3) Illeum
- Longest portion (3.5 m) with Peyer's patches and short, club-like villi.
- Shallow crypts and low plicae circulares.
- Many goblet cells
- Terminal illeum is site for absorption of B12/intrinsic factor complex and reabsorption of bile acids and secretory-IgA |
|
|
Term
| What are the major similarities/differences between the mucosa of the small intestine and large intestine? |
|
Definition
Differences
- Small intestine has plicase circulares and villi, while Large intestine has neither (only crypts)
- LI has no paneth cells or hydrolytic enzymes on glycocalyx
- LI lamina propria lacks lymphatic capillaries
Similarities
- Epithelium of BOTH large intestine and small intestinal villi have enterocytes and goblet cells. |
|
|
Term
| How can you tell histologically that you have exited the rectum and entered the anus? What are the critical features of the anus? |
|
Definition
1) Epithelium becomes stratified cuboidal or squamous (no absorption)
2) Submucosa is well vascularized, with nerves (Pacinian corpuscles for deep pressure).
3) Thickened circular muscularis externa to form internal anal sphincter (smooth muscle).
4) External sphincter is skeletal muscle. |
|
|
Term
| What changes in the epithelium take place moving proximal-distal along the long-axis of the small intestine? |
|
Definition
1) Proximally (duodenum/jejunum), cells are more permeable, with more uptake of glucose, folate, calcium and iron are taken up proximally
2) Distally, cells have higher transepithelial resistance, and B12 and bile acids are taken up (Illeum)
**Vitamin C is taken up the whole way |
|
|
Term
What Antiporter/exchangers are found in the small intestinal epithelium?
Why do you get diarrhea when one of these pumps is inhibited? |
|
Definition
1) Na/K exchanger responsible for sodium uptake
- diarrhea, since less water is absorbed (inflammation can cause this, as well as increased permeability)
2) Cl/HCO3 exchanger transports Cl-in and HCO3- out
-diarrhea, because less H+ is exchanged for Na+ to balance HCO3-** |
|
|
Term
| What is the "pump-leak sequence" of transepithelial transport in the small intestine? |
|
Definition
1) Anion/Cation flux occurs through channels on apical membrane, because of Electrochemical gradient generated by Antiport or channel transport (H+ exchanged for Na+, driving HCO3- release and Cl absorption)
2) On basolateral side of cell, active (ATP-driven) transport processes take place to generate an ionic gradient |
|
|
Term
| Why would you expect diarrhea from a Cholera infection to be less severe in a CF patient? |
|
Definition
In general, Hormonal activation of GPCR (VIP) increases cAMP and leads to phosphorylation/activation of the CFTR, which leads to Cloride secretion and inhibition of ENaC.
- Cholera constitutively activates G-alpha, increasing cAMp and activating CFTR (more inhibition of ENaC leads to less sodium reabsorption and diarrhea.
- In CF, ENaC is not inhibited because of defective CFTR, so sodium is over-absorbed and so is water (leading dehydrated stool). So CF is protective against diarhea in this case |
|
|
Term
| What is the importance of epithelial K+ and Cl- channels in the intestine? |
|
Definition
1) K+ channels lead to K+ efflux and membrane polarization, driving sodium influx and water absorption and nutrient absorption.
**Defective K+ channel might cause diarrhea**
2) Cl- channels like CFTR are important for secreting cloride and leading to sodium reabsorption. |
|
|
Term
| Describe the basic digestive process leading to nutrient reabsorption in the small intestine? |
|
Definition
1) Mastication and digestive enzymes in saliva (amylase)
2) In stomach, mechanical and chemical fragmentation occurs with pepsin (protein) and lipase (fat) from Chief cells.
3) In proximal small intestine (duodenum), bile emulsifies fat and smaller droplets undergo lipolysis by pancreatic enzymes (protein and carb also occur here) |
|
|
Term
| What factors are responsible for chemical fragmentation of carbohydrates, proteins and fats, respectively? |
|
Definition
1) Carbs
- Salivary amylase
- Pancreatic amylase
2) Proteins
- Gastric pepsin
- Trypsin.endopeptidases
3) Fat
- Micelle formation (bile acids)
- Lipase (gastric/pancreatic) |
|
|
Term
How are carbohydrates digested and absorbed?
What would happen if you inhibited SGLT1? |
|
Definition
1) Chemical (amylase) and mechanical fragmentation in mouth, followed by further fragmentation by pancreatic amylase (generating dextrins and ultimately maltose)
2) Maltose and disaccharides (lactose) are broken down by brush-border enzymes (disaccharidases), freeing glucose, fructose and/or galactose.
**lactase normally decreases with age, leading to intolerance (except in US and UK)**
3) Monosacharides are taken up by enterocytes via co-tranport in small intestine (SGLT1 is example of sodium/glucose co-transporter that also drags water in-treat diarrhea)
**IF you inhibit, you get no monosacharide uptake!**
4) Glucose exits enterocyte via facilitated diffusion through basolateral channels (using Na/K pump gradient) |
|
|
Term
Why give a child with severe diarrheal disease glucose?
Why not fructose? |
|
Definition
1) Glucose will be taken up by intestinal enterocytes via SGLT1 channel and drag water with it.
2) Fructose over-saturated GLUT5 channel capacity, leading to luminal buildup and worsening bloating and diarrhea |
|
|
Term
|
Definition
1) Starts in stomach with gastric pepsinogen from chief cells, that is activated (by HCl) to pepsin
2) Chyme enters duodenum and pancreatic enzymes are added until protein is ultimately broken to single AA and di or tripeptides.
3) AA taken up by specialized transporters
**Glutamine decreases "leakiness" of enterocyte epithelium** |
|
|
Term
|
Definition
1) Amphipathic bile acids emulsify fats to form micelles (lipid droplet surrounded by bile acid heads (hydrophillic)
2) Micelles are targeted by gastric/pancreatic enzymes (lipases) that cleave ester bonds and enable cellular uptake
3) In cells, lipids are re-esterified and packaged with apolipoproteins and realeased as chylomicrons or VLDL into lymphatics |
|
|
Term
| What are the secretory and anti-secretory neural factors that regulate intestinal function? |
|
Definition
1) Secretory
- Peptides (VIP, SubP, NT)
- 5-HT
- ACh
- ATP
2) Anti-secretory
- Peptides (NPY, SOM, Enk)
- NE |
|
|
Term
How do each of the following enteric hormones alter intestinal function?
1) CCK
2) PYY
3) Grehlin |
|
Definition
Released by APUD cells and also effect nerves!
1) Release triggered by fat/protein within duodenum, stimulating gall bladder contraction, pancreatic secretion, intestinal motility and decreased gastric emptying.
2) Release also triggered by nutrients, and slows down movement into colon ("ileal break"- I am full)
3) Increases prior to eating and regulated food intake (makes em hungry) |
|
|
Term
| What are the 2 major complex CHO found in modern western diets? |
|
Definition
1) Amylose- alpha 1,4 links of glucose in a straight chain.
2) Amylopectin- alpha 1,4 straight chains with a-1,6 linked branch points
-------------------------------------------------
1) Monosacharides
- Glucose
- Fructose
- Galactose
2) Disaccharides
- Sucrose (glucose + fructose)- table sugar
- Lactose (glucose + galactose)- milk sugar
- Maltose (glucose + glucose)- digestion product of starches |
|
|
Term
| What are the 3 major enzymes involved in carbohydrate digestion? |
|
Definition
**Small intestine (jejunum particularly) is most important site
**Stomach has no pertinent role
1) Salivary a-amylase
- Breaks down internal alpha 1,4 links
2) Pancreatic a-amylase
- Breaks down alpha 1,4 (amylase) and alpha 1,6 (amylopectin)
- Duodenal release of secretin and CCK stimulate exocrine pancreas to produce HCO3- and alpha-amylase, respectively.
3) Brush border disaccharidases/oligosaccharidases
-Glucoamylase, Lactase and Isomaltase/Sucrase
- intestinal villi brush border proteins of glycocalyx produced as pro-enzymes that are cleaved by trypsin and then produce monomers of CHO. |
|
|
Term
How do each of the following proteins function in CHO absorption?
1) Sodium-dependent glucose transporter (SGLT1)
2) Fructose Transporter (GLUT5)
3) Sodium-independent Glucose transporter (GLUT2) |
|
Definition
Absorption of monosaccharides in vicinity of villus
1) SGLT1 (Brush border of intestine and kidney)
- Co-transports 2Na and D-glucose (D-galactose) powered by Na+ gradient (Na/K ATPase)
- Concentrate glucose 10,000 fold
2) GLUT5 (brush border and basolateral)
- brush border for fructose
3) GLUT2 (basolateral membrane)
- Transports glucose/galactose/fructose out of enterocytes and into portal circulation
- High capacity low affinity |
|
|
Term
1) What happens to amino groups that are broken off from protein during degradation?
2) What happens to the remaining carbon skeleton? |
|
Definition
Remember, 40% turnover in GI each day because of caustic environment. Gets hit hard in malnutrition!
1) Processed to urea or bound to Glutamine, because NH4 is toxic to brain.
2) 3 ways
- Oxidation for energy,
- Storage as glycogen
- Synthesis of fatty acids for storage in adipose tissue |
|
|
Term
Which of the following conditions would create a negative nitrogen balance?
1) Growth
2) Pregnancy
3) Lactation
4) Recovery from metabolic stress
5) Uncontrolled DM |
|
Definition
| 5 is the only option where protein degradation exceeds synthesis |
|
|
Term
| What factors determine "biological value" of protein? |
|
Definition
Essential AA content and digestibility
Essential AA
Any Help In Learning These Little Molecules Proves Truly Valuable
Arginine, Histidine, Isoleucine, leucine, Threonine, Lysine, Methionine, Phenylalanine, Tryptophan , Valine
**Ariginine is "conditional" because it is non-essential if intestine and kidney are normal.
**to be useful, source must have all essential AA!** |
|
|
Term
| How is protein digested/absorbed (enzymes, locations, mechanism)? |
|
Definition
1) Stomach
- Acid pH uncoils 4 and 3 structure
- Pepsinogen (Chief cells) activated by HCl (Parietal cells)
- HCO3- from mucous cells prevents self digestion
2) Pancreas
- Proenzymes emptied in duodenum that must encounter enterokinase (intestinal brush border enzyme that cleaves trypsinogen to trypsin, which cleaves other pancreatic enzymes).
3) Small intestine
- Brush border glycocalyx enzymes hydrolyze oligopeptides
- Brush border and basolateral membrane peptidases, amino acid transporters and di and tri-peptide transporters
4) Portal Vein and Liver
- Assimilated AA are carried away by veins to hepatic protal vein and absorbed first by liver transporters.
- Liver makes plasma proteins and deaminates AA to ammonia (becomes urea or combines with glutamine) |
|
|
Term
How do you assess protein status in a nutritional evaluation?
hint; 3 areas |
|
Definition
Most common cause of death with be immunocompromised infection!
Liver proteins, Immune function and Lean body mass
1) Liver
- Albumin (LONG-TERM shits because of 20d half-life)
- Transferrin (half life of 8.8d, but increased in iron deficiency)
- Pre-albumin/Transtheyretin (24-48h half life, reflecting RECENT changes)
2) Immune function
- Total lymphocyte count and delayed hyersensitivity to allergens.
3) Lean body mass
- 24h urinary creatinine (should be 23 for m and 18 for f) |
|
|
Term
| How does lipid digestion take place (enzymes, locations, mechanism)? |
|
Definition
1) Gastric (not-essential if pancreas works)
- Titurition produces fine emulsion
- Gastric lipase (Chief cells) functions at pH 4-5.5 and produces free FA and 2,3-diglyceride
- Acidic stomach protonates FFA (incomplete!)
2) Intestinal
- Acidic chyme neutralized in duodenum by HCO3- from pancreas, biliary ducts and Brunner's glands (duodenal)
- FFA become ionized (lose hydrogen) and stimulate CCK release, leading to gallbladder contraction and bile release into small intestine
- CCK triggers further release of pancreatic enzymes through sphincter of Oddi: pancreatic lipase (pH sensitive), colipase, phospholipase A2 and cholesterol esterase. |
|
|
Term
| What organ should you think of if you see the clinical symptom "Steatorrhea?" |
|
Definition
PANCREAS
**Gastric lipid digestion is non-essential, but pancreatic IS**
- If pancreas is impaired, you lose HCO3- secretion into duodenum, so protonated free fatty acids from stomach cannot be ionized (de-hydrogenated), chyme cannot be neutralized and pancreatic enzymes like lipase are inactivated by low pH.
- Protonated lipids cannot be absorbed and they are excreted in feces. |
|
|
Term
| What are the major enzymes involved in lipid digestion that are released by the pancreas? |
|
Definition
Enter duodenum through sphincter of Oddi
1) Pancreatic lipase (acid-sensitive)
- Requires pancreatic HCO3- release to neutralize chyme prior to activity.
2) CO-lipase
- prevents inhibition of lipase by bile acids (also released through sphincter) by binding to both and locking them on the surface of the lipid droplet
3) Phospholipase A2
- Cleaves fatty acid from glcyerol
4) Cholesterol esterase (requires bile salts)
- Cleaves esters of cholesterol, vit A,D and E and total cleavage of TGA. |
|
|
Term
| How are lipid products that are taken up by enterocytes of the small intestine transported to other sites of the body? |
|
Definition
1) Chylomicrons assembled in enterocyte with inner TGA core and out hydrophilic shell (phospholipids, free cholesterol and apoB48)
2) Chylomicrons carried in lymph to thoracic duct and into right atrium. Once in systemic circulation, they gain ApoE (Remnant recepetor binding and clearance by liver) and Apo CII (cofactor for LPL) from HDL. |
|
|
Term
A patient presents with diffuse abdominal pain and diarrhea. He claims that the diarrhea gets worse after arguments with his father and that it is also more frequent when he feels the pain.
What initial evaluations are indicated for this patient? |
|
Definition
This could be D-IBS so you need to do 5 important things
1) Blood count and electrolytes
2) Stool for ova & parasites (Giardia)
3) 24h stool collection
4) Celiac testing
5) Breath test (small bowel bacterial overgrowth-treated with cipro or metranidazole) |
|
|
Term
Patient presents with abdominal pain and stress-related constipation, but not obvious anatomical defect.
How should you proceed? |
|
Definition
sounds like C-IBS
1) Blood count and electrolytes
2) Calcium levels
3) Thyroid levels (hypothyroidism) |
|
|
Term
What are the effects of IBS on each of the following?
1) Visceral sensation
2) Inflammation
3) Motility
4) Psychological |
|
Definition
1) Visceral hypersensitivity and diffuse abdominal sensitivity (pain, bloating, urge to defecate)
2) Increased TNF-a and IL-6, with some evidence for lymphocytic infiltration of myenteric plexus (not certain).
3) Inconsistent, but delayed/increased motility may explain C-IBS vs. D-IBS
4) Patients with IBS are more likely to have suffered physical, sexual or emotional abuse.
**Corticotropin releasing factor (CRF), which causes anxiety and depression, may also increase abdominal pain and colonic motility more so in patients with IBD** |
|
|
Term
| What is the ROME criterion for IBS? |
|
Definition
3-3-2
Recurrent abdominal pain 3 days per month in the last 3
months associated with at least 2 of the following:
1) Improvement with defecation
2) Onset associated with a change in frequency of stool
3) Onset associated with a change in stool form |
|
|
Term
| What are the 3 important components to successful treatment of IBD? |
|
Definition
1) Therapeutic relationship
2) Patient education
3) Medical therapy
- Treat diarrhea or constipation as well as pain. |
|
|
Term
| How can distinguishing between diarrhea and dysentery help you to localize the site of a GI disease/infection? |
|
Definition
Dysentery involves frequent, low volume stools with blood and pus (usually involving inflammation in the COLON)
Diarrhea is frequent, profuse, water discharge common in bacterial gastroenteritis (toxins in the SMALL INTESTINE). |
|
|
Term
| How do Cholera toxin and E. coli Heat-labile enterotoxin produce infectious diarrhea? |
|
Definition
Increased Secretion
1) Bind ganglioside receptor Gm1 on apical membrane of enterocyte, leading to vesicle-mediated endocytosis.
2) A1 chain is released and ADP-ribosylates Adenylate cyclase in basolateral membrane, leading to uncontrolled cAMP production (prevents inactivation)
3) PKA phosphorylates Apical CFTR (more Cl secretion and less sodium/water reabsorption)
**No inflammation
3) Cholera toxin is an ADP-ribosyltransferease |
|
|
Term
How might norovirus produce infectious diarrhea?
What about C. perfringens? |
|
Definition
| Both decrease intestinal absorption, increasing luminal osmotic pressure by damaging epithelium |
|
|
Term
| How do Salmonella/Shigella induce infectious diarrhea? |
|
Definition
Inflammation due to invasion (remember, Cholera causes no inflammation!)
1) Salmonella undergoes epithelial transcytosis and then binds TLR5 on the on basolateral membrane, which increases Ca2+, activating NF-kb.
2) NF-kb activates IL8, which is released from the basolateral membrane and attracts PMNs.
3) PMNs cause 5' AMP production, which binds A2B receptor and leads to Gs activation.
4) cAMP production leads to PKA phosphorylation and Cl secretion. |
|
|
Term
| How does Rotavirus produce gastroenteritis? How do you diagnose and treat it? |
|
Definition
Endemic infection (occurs in usual living conditions of patient and family) VACCINE NOW GIVEN.
Reovirus with segmented dsRNA genome that exhibits fecal-oral transmission in young children and infants.
1) Kills intestinal cells, resulting in malabsorption (enterotoxin also?)
2) Diagnose with antigen detection in stool and EM, and treat with rehydration. |
|
|
Term
| How does Vibrio cholerae cause gastroenteritis and what kind of infection is it? How do you diagnose/treat? |
|
Definition
Epidemic (more than family unit) presenting with severe dehydration and perhaps cardiac and kidney sequelae
Gram-negative bacterial rod (oxidase positive) usually transmitted in fecally-contaminated water.
1) Enterotoxin-mediated increase in cAMP that increases chloride secretion causing watery diarrhea without inflammation (does not damage mucosa)
2) Culture and treat with fluid/electrolyte replacement and antibiotics. |
|
|
Term
Adult presents with sudden-onset vomiting and diarrhea after a recent cruise.
How do you diagnose/treat this condition? |
|
Definition
Norovirus: Caliciviruses (ssRNA) with fecal-oral transmission in contaminated food/water causing epidemic infection.
1) Damages intestinal mucosa, resulting in malabsorption
2) Diagnose with Em/serology of feces/PCR and treat with FLUID/ELECTROLYTE |
|
|
Term
What are the major food-borne causes of gastroenteritis from in-vivo toxin production??
How do you treat? |
|
Definition
Viable pathogen must be ingested (remember, it will be slower onset/8-16h, than an Intoxication with Botulism or Staph)
1) C. perfringens (damages epithelium and prevents absorption, sort of like norovirus)
2) B. cereus
3) EHEC
Symptomatic treatment without antibiotics |
|
|
Term
What 2 illnesses are caused by EHEC?
How do you treat them? |
|
Definition
Gram-negative rod (O157:H7) ingested through food.
1) Hemorhhagic colitis (4 days after ingestion)
- shiga toxin affects colon, inhibiting protein synthesis and causing bloody diarrhea, but without invasion (no leukocytes in stool or substantial fever)
2) Hemolytic uremic syndrome (mostly in children- life-threatening)
- Shiga toxin is absorbed in gut in high amounts and enter circulation, leading to kidney damage and acute renal failure
3) Treatment depends on disease
- DONT USE ANTIMICROBIALS
- For HUS, may need dialysis
- For H coloitis, fluid replacement is sufficient. |
|
|
Term
Patient presents with bloody diarrhea, 4 days after eating a large hamburger. They have no fever or leukocytes in their stool.
Culture reveals gram-negative rod.
How do you treat? |
|
Definition
| EHEC hemhoragic colitis- fluid replacement with NO antimicrobials |
|
|
Term
Severely dehydrated patient presents with watery diarrhea.
Culture reveals gram-negative bacterial rod (oxidase positive)
How do you treat? |
|
Definition
Vibrio cholerae infection causing diarrhea by enterotoxin-mediated increase in cAMP and CFTR activation.
Treat with fluid/electrolyte replacement and antibiotics. |
|
|
Term
Patient presents with fever and diarrhea with fecal leukocytes. He tells you that he ate some strange food a couple weeks ago, but nothing since then.
Culture reveals gram-negative bacterial rode.
What is the likely diagnosis/treatment? |
|
Definition
Salmoenella typhi infection causing typhoid fever.
S. typhi Sinvades M cells in PPs and is taken up and carried by macrophages to reticuloendothelial tissue, inducing inflammation.
**nontyphoid Salmonella produces a gastroenteritis and remains localized in the intestines following entry through M cells**
Treat with Antimicrobials (may be used for gastroenteritis also, but not necessarily), with fluid and electrolyte replacement. |
|
|
Term
| How do typhoid fever and salmonella gastroenteritis differ in terms of pathogenesis? |
|
Definition
Both gram-negative rods that invade through M cells
1) nontyphoid Salmonella produces a gastroenteritis and remains localized in the intestines
- 1-2 days after ingestion of food
2) S. typhi enters macrophages and is transported to reticuloendothelial organs, producing systemic inflammation (fever).
- takes a while to occur after food ingestion |
|
|
Term
Patient presents with high fever and severe dehydration from diarrhea after being in the hospital for 1 week.
What test should you run to confirm your diagnosis and what is the pathogenesis? |
|
Definition
Pseudomembranous colitis due to C. dificile (SERIOUS).
1) Run fecal toin test for toxin A/B
2) Toxins damage colonic mucosa by glucosylating Rho proteins, causing severe inflammation
**Treat with fluid/electrolyte replacement and metro or vanco** Maybe fidoxomycin or fecal transplant? |
|
|
Term
An AIDS patient presents with severe, chronic diarrhea.
A modified acid-fast stain of concentrated stool reveals cysts.
How do you treat this condition? |
|
Definition
Sounds like parasitic Cryptosporidium parvum infection in immunocompromised individual
Anti-retroviral therapy, but not antimicrobial
**IF immunocompetent, try Nitazoxanide** |
|
|
Term
A patient with a recent travel history presents with watery diarrhea, but no fever.
DNA tests reveal the presence of specific toxins.
What is the pathogenesis of the most likely organism and how do you treat? |
|
Definition
Enterotoxigenic E. coli (ETEC) causing traveler's diarrhea
1) Enterotoxin
- heat-labile increases intestinal cAMP and CFTR activation
- heat-stable increase intestinal cGMP and K+ channel activity.
2) Fluid/electrolyte replacement and symptomatic treatment |
|
|
Term
| What are your initial steps in working up a patient with fever and bloody diarrhea? |
|
Definition
Remember, if this wasn't present, just treat symptomatically.
1) Do microscopic exam for fecal WBCs (may also detect parasites).
2) Culture for routine pathogens; if patient is immunocompromised may need to consider exotic pathogens if there is no response (but don’t attempt culture initially).
3) If on antibiotics, run C. dif toxin test |
|
|
Term
| What is the basic management strategy for an immunocompetent patient with gastroenteritis? |
|
Definition
1) Address fluid/electrolyte loss (particularly in children).
- For mild diarrhea, can use pedialyte or mineral water plus saltine crackers.
- For moderate diarrhea (particularly in developing countries) may use ORS.
-For severe diarrhea, may need to use i.v. fluids.
2) If noninflammatory diarrhea, treat SYMPTOMATICALLY
- Absorbants
- Anti-intestinal motility agents (loperamide)
- Anti-secretory agent (Bismuth salt like Pepto bismol)
3) If inflammatory
- DO NOT use anti-motility agents like loperamide
- Give antimicrobials (watch out for EHEC!) |
|
|
Term
| Why might you give Oral Rehydration Solution to a patient with gastroenteritis? |
|
Definition
ORS is good for fluid/electrolyte replacement in cases of moderate diarrhea (IV for severe).
Salt and glucose enter intestinal mucosal cells and pull water in |
|
|
Term
True or False:
Loperamide should not be given for Cholerea diarrhea |
|
Definition
False.
Should give anti-motility drugs in this case, but NOT in the case of invasive pathogens, where it will increase their infectious time of occupancy. |
|
|
Term
What is meant by each of the following measures of diagnostic value of tests?
1) Sensitivity
2) Specificity
3) PPV
4) NPV |
|
Definition
1) True positive/ (true positive + false negative)
2) True negative/ (false positive + true negative)
3) True positive (true positive + false positive)
4) True negative/ (true negative + false negative) |
|
|
Term
| What diagnostic tests have the highest "relative resolution" |
|
Definition
Sensitivity, Specificity, Resolution metric
1) MRI, CT and Endoscopy have highest
**MRI and endoscopy cost a ton though!
2) X-rays are medium
3) Ultrasound and gastric emptying (radiolabel) have low |
|
|
Term
Why are the stomach, small bowel and colon not well visualized on ultrasound?
What are the advantages/disadvantages to this technique? |
|
Definition
Air containing structures block sound wave
GREAT for gall-stones, but not small bowel obstruction
1) Advantages include the fact that US is safe, painless, non-invasive, available and inexpensive.
2) Disadvantages include operator-dependence, obesity issues, lower resolution than CT for soft tissue lesions and air-blocking. |
|
|
Term
| Why might you decide to order a CT of the abdomen? What might preclude this decision? |
|
Definition
1) Avoids "air" issues of ultrasound and has high organ resolution
**Great for liver, gallbladder, pancreas and small bowel, especially to see masses**
2) Moderate cost and high exposure to radiation are issues, as well as patient must stay still and IV dye allergies. |
|
|
Term
| Why might you decide to order an MRI of the abdomen? What might preclude this decision? |
|
Definition
1) Hemochromatosis (iron deposition in liver) and Hemangiomas (vascular anomalies in liver)
- MRCP is great for bile ducts and pancreatic duct
2) Expensive |
|
|
Term
A patient is showing signs of anemia with "scooped out nails. They have osteoporosis and are complaining of intermittent diarrhea.
What is the genetic association with this disease and why does it influence pathogenesis? |
|
Definition
Celiac disease (more common in people exposed to gluten < 4 month).
Anemia and nails are due to iron and vitamin deficiency, osteoporosis with calcium malabsorption and diarrhea from malabsorption.
1) HLA DQ2 (90%) and DQ8 (10%) encoded on short arm of chromosome 6, by CELIAC1 locus.
2) MHC class II antigen presenting receptor that functions to distinguish self from non-self antigens (abnormal antigen reaction makes this really an autoimmune condition).
3) Anti-gliadin antibodies bound to APCs with HLA DQ2 or 8 stimulate CD4+ T cells in lamina propria to produce inflammatory cytokines (IF-y)
- Anti-tTG (tissue transglutaminase) and Anti-Endomysial antibodies |
|
|
Term
| What type of GI injury is common in patients who suffer from the autoimmune inflammatory condition associated with HLADQ2 and DQ8? Why? |
|
Definition
1) Greatest small bowel injury in proximal region (duodenum), related to nutrient deficiencies secondary to malabsorption from chronic inflammation and mucosal damage.
2) Fat soluble vitamins (ADEK), zinc, calcium and Iron (MOST COMMON) are usually deficient |
|
|
Term
A patient is showing signs of anemia with "scooped out nails. They have osteoporosis and are complaining of intermittent diarrhea.
What are the critical histological findings to make the diagnosis? |
|
Definition
Short: Blunted duodenal villi and IELs (inflammation)
1) "Blunted duodenal villi" ***
2) Villus atrophy
3) Crypt hyperplasia
4) Inflammatory infiltrate (IELs)
5) Cuboidal enterocytes with loss of brush border and basal polarity of nuclei
6) Increased intra-epithelial lymphocytes |
|
|
Term
A child presents with abdominal distention, diarrhea and failure to thrive after eating cereal in the mornings.
What serology measures could help you make the diagnosis? |
|
Definition
1) IgA endomysial Ab (100% specific and 90% sensitive)
- IF or ELISA of tTG
2) tTG autoantigen- intracellular enzyme that covalently binds glutamine to lysine (tTG:gliadin complexes form)
3) Since IgA deficiency is common, make sure to measure total IgA also!
Childhood presentation of Celiac is different from adult.
Adult
- Anemia (iron), Osteoporosis (calcium), Diarrhea (water/electrolytes), Weight loss/bloating (protein and carbs). |
|
|
Term
| What are potential explanations for lack of initial response to gluten-free diet in confirmed celiac cases (antibodies + biopsy)? |
|
Definition
MOST COMMON REASON IS DIET RELAPSE
1) Auto-immune enteropathy, which may evolve to collagenous colitis
2) Lymphoma of small bowel (MAL lymphoma associated with H. pylori ulcers and T cell lymphoma in Celiac) |
|
|
Term
You perform a biopsy on a central american patient who presented with diarrhea, anemia and weight loss and who did not improve with a gluten-free diet.
How does they treatment differ from the treatment that would be given if the disease did improve? |
|
Definition
Villus atrophy that does not respond to dietary changes.
Tropical Sprue due to infection of small intestine needs antibiotics.
Celiac is only treated with dietary restriction and nutrient supplementation. |
|
|
Term
| Why do you often see pruritic, blistering skin lesion on the elbow, buttocks, knees, trunk of patients who have gluten allergy? |
|
Definition
Dermatitis herpetiformis
elbow> buttocks> knees> trunk>face
- Gluten binds IgA antibodies in circulation, obstructing small vessels.
**Speckled IgA deposits are found on IF of un-involved skin. If it is homogenous and linear, it is NOT CELIAC** |
|
|
Term
| How do M cells function in mucosal immunity? |
|
Definition
Epithelial cells overlying GALT tissue.
1) Uptake bacterial and viral antigens (sampling), which are transcytosed and taken up by underlying APCs, which deliver antigens to PPs
2) Cells activated in PPs express a4b7 integrin, which serves as "homing signal" to MadCAM-1 expressing mucosal sites
- B cells in PP receive soluble signal (TGF-b), switching their IG expression from IgG to IgA.
3) Cells leaving PP migrate to mLN and are drained by thoracic duct, ultimately entering the IVC and the right atrium.
4) Once in systemic circulation, cells use a4b7 to find GALT sites, where B cells terminally differentiate into plasma cells and T cells attain activated phenotype. |
|
|
Term
Which of the following characteristics is unique to the GALT (as opposed to the MALT)?
1) M cells
2) Peyer's patches
3) Lamina propria
4) T cells |
|
Definition
2
MALT has "MaLT": M cells, Lamina propria and T cells |
|
|
Term
| What are the 2 major functions of IgA "secretory component" |
|
Definition
Remember, IgG is most abundant IG in serum, but IgA is most abundant in secretions (and serum IgA differs from secreted IgA- monomer vs. dimer joined by J chain in secretions)
Secreted IgA dimers are coated in specialized glycoprotein, "secretory component" which
1) Transports IgA from lamina propria to lumen (vesicle mediated transcytosis)
2) Within lumen, secretory component protects IgA from degradation by proteases and gastric acid by binding the Fc portion and the hinge region of IgA.
IgA DOES NOT BIND Fc RECEPTORS OR ACTIVATE COMPLEMENT (NO INFLAMMATION) |
|
|
Term
| What is the major function of IgA secreted into the intestinal lumen? |
|
Definition
In lumen, IgA is protected by secretory component.
1) Prevent bacterial binding to epithelium and causing agglutination of bacterial/viral particles.
2) Reabsorbed by distal small intestine (ileum) and through enterohepatic circulation can be reutilized. |
|
|
Term
| How is IgA complex with antigen reabsorbed and recycled? |
|
Definition
Distal ileum-Liver-Bile duct- Duodenum- Distal Ileum
1) Taken up by distal illeum, traveling via portal vein into liver sinusoids
2) In liver, Kupffer cells take up complex, destroy microbial antigen and release free secretory IgA
3) Bile duct expresses polymeric Ig receptor on basal surface, so IgA is actively transported into bile duct and released into the duodenum to be re-used. |
|
|
Term
| What are intestinal epithelial lymphocytes and what is their importance? |
|
Definition
| IELs are CD8+ cells with yd TCRs that express activation markers such as CD45RO+ and aEb7 integrin (long-lived and slowly renewed) |
|
|
Term
| What are the important types of mucosal T cells and what are their functions? |
|
Definition
1) Th1- cell-mediated immunity (IL-2 and INF-y)
IL-10 dampens Th1 response (produced by both Th2 and Tregs)
2) Th2- b cell Ab production (IL-4, IL-5, IL-10, IL-13)
3) Tregs make IL-10 |
|
|
Term
| How do intestinal epithelial cells (IECs) respond to invasive pathogens such as Salmonella, Shigella, Yersinia and Listeria? |
|
Definition
**Actually express MHC-II/important for oral tolerance
1) Up-regulate expression and secretion of pro-inflammatory cytokines (CXC and CC family members)
**also release TNF-a, GMCSF, IL-1a and IL-1b**
2) Normal program of gene expression requires commensals |
|
|
Term
| Describe the phenomenon of "Oral Tolerance" |
|
Definition
1) Oral soluble protein delivery induces antigen specific non-responsiveness (animal will not respond to injection after oral administration)
2) TGF-b produced in response to oral antigen suppresses T and B cells and activates IgA pathway, where higher oral doses can cause cellular anergy. |
|
|
Term
| What is the "bystander effect" and how might it be exploited to treat autoimmune disease? |
|
Definition
Remember, induction of oral tolerance is antigen specific, but effector arm (TGF-b) is not.
Give a bunch of a given antigen and then hope that TGF-b will suppress "bystander" auto-antigens in diseases like MS. |
|
|
Term
| How can "pre-biotic" (Fiber, lactulose, ect) use modify bacterial flora and modulate immune responsiveness? |
|
Definition
| Non-digestible food ingredients that selectively stimulate growth and/r activity of limited umber of bacteria in the colon |
|
|
Term
| How might fish oil treat inflammation? |
|
Definition
| Partially replace AA in COX pathway, leading to less LTC and prostaglandin production. |
|
|
Term
| Describe the molecular evolution of a food allergy. |
|
Definition
1) Undigested fragments are tagged by IgE and fool immune system into thinking it is harmful
2) Mast cells degranulate and inflammation ensues causing some combination of dermatitis, respiratory symptoms and GI symptoms. |
|
|
Term
| Why might you use Nataluzimab to treat IBD? |
|
Definition
Antibody against a4b7 integrin (inhibit T cell immune response)
**ASSOCIATED WITH PML** |
|
|
Term
| What are the 3 major mechanisms underlying oral tolerance? |
|
Definition
1) Clonal deletion
- Self antigens in the thymus
- Apoptosis after ligation of TcR
2) Clonal anergy
- Self antigens in periphery
- TcR ligation in the absence of co-stimulation
3) Regulatory T cells
- CD4+/CD25+ T cells actively inhibit priming/functions of other naive cells
- Treg cells produce IL-10/TGF-b |
|
|
Term
| What is the clinical significance of oral tolerance? |
|
Definition
1) Associated with food allergy and diseases such as celiac disease/food allergy / IBD
2) May diminish effectiveness of oral vaccines
- Can be overcome with use of Cholera B toxin adjuvant
3) OT may be useful in treating disease |
|
|
Term
| What happens when the vitelline duct fails to involute during development? |
|
Definition
Meckel's diverticulum, with a blind pouch located on the anti-mesenteric side of the bowel, following "rule of twos"
- Can cause pain, bleeding and other problems. |
|
|
Term
What are the most important causes of invasive bacteira diarrheal illness (Enterocolitis)?
How do you distinguish between the causes clinically? |
|
Definition
Small volume of bloody diarrhea is termed "dysentery" and inflammatory conditions that produce diarrhea are called Enterocolitis.
1) Yersinia (gram negative coccobacillus)
- Involves lleum, colon and appendix
- causes "right lower quadrant pain"
- can involve PP, causing granuloma infection
2) Salmonella (gram-negative invasive)
- Invade lymphoid tissue and causes ulcerations like 1
- "crypt abscess" on histology
3) C. jejuni
- more common, found in unpasteurized milk, contaminated water, uncooked chicken
- dysentery; proliferation in lamina propria and lymphoid tissue leads to enteric fever
- Villous blunting, ulcers, purulent exudate
Can mimic ulcerative colitis, with crypt abscesses and ulcers |
|
|
Term
| What protozoan infections can cause enterocolitis and how? |
|
Definition
1) Giardia lamblia (most common infection in humans)
- drinking contaminated water (cyst form ingested, excysted trophozoites (“trophs”) proliferate in small bowel)
- Severe diarrhea with steatorhea
- Trophs seen on biopsies (binucleate, pear-shaped)
2) Entamoeba histolytica
- Quadrinucleate cyst forms in the distal ileum, releasing trophozoites that invade through epithelium and spread out on the muscularis mucosa.
- Look for “flask-shaped” ulcers that look like macrophages with RBCs in them on biopsy
3) Cryptosporidium parvum (problem in immunocompromised)
- Intestinal parasite (affects small intestine and colon) via fecal-oral
- Very tiny (2-4um); cysts attach to enterocyte surface; merozoites end up in the apical cytoplasm
- Look for merozoits in ovocysts on EM. |
|
|
Term
Which parasitic enterocolitis is described histologically by each of the following?
1) Trophs seen on biopsies (binucleate, pear-shaped)
2) “flask-shaped” ulcers that look like macrophages with RBCs
3) Tiny cysts and merozoits withinin ovocysts on EM. |
|
Definition
1) Giardia (water-born)
2) Entemoeba histolytica
3) Crypto (problem in immunocompromised) |
|
|
Term
Infant presents with bloody stools, shock and gangrene.
What would you see on biopsy? |
|
Definition
Acute ischemic necrotizing inflammation from Necrotizing Enterocolitis.
Would probably see necrotic small bowel with adhesions. |
|
|
Term
| What are the classic features of a biopsy taken from a patient with radiation-induced enterocolitis? |
|
Definition
1) Regenerative appearance to epithelial cells
2) Amorphous, pink (“hyalinized”) lamina propria
3) Thick-walled blood vessels
4) Atypical (possibly bizarre) stromal cells/fibroblasts/endothelial cells |
|
|
Term
| What are the 3 primary components of digestion that might be disrupted in malabsorption syndrome? |
|
Definition
Common causes are Celiac, infection, pancreatic insufficiency and IBD
1) Intraluminal digestion
- large molecules broken down into smaller parts
- Saliva, gastric acid, pancreatic enzymes
2) Terminal digestion
- hydrolysis of CHO and peptides by enzymes on SI brush border
3) Transepithelial transport
- nutrients, fluid, ions absorbed by the mucosa and delivered to the bloodstream |
|
|
Term
Why is megaloblastic anemia more commonly encountered in tropical sprue than in celiac disease?
How can you distinguish the two on biopsy? |
|
Definition
TS tends to occur in distal small bowel (where B12 is absorbed).
They are indistinguishable on biopsy! |
|
|
Term
| What malabsorptive, diarrheal disease involves lymphatic obstruction with dilation of the superficial lymphatics and inclusions within mucosal macrophages that are bright pink on PAS stain? |
|
Definition
hipple's disease from gram positive Tropheryma whillplei infection.
Actually a systemic disease with extra-GI sites (joints, LN, CNS) |
|
|
Term
| What are the classic gross and histological findings associated with the form of IBD that can affect the GI tract anywhere from mouth to anus? |
|
Definition
Crohn's Disease
1) Gross
- Inflammatory "skip lesions"
- Transmural inflammation (ulcers and "fat wrapping" common)
- Thick-walled intestine
2) Histology
- Early-on, PMNs in surface epithelium over lymphoid aggregates (aphthous ulcers)
- Later, PMNs may fill and destroy crypts (“crypt abscesses”)
- Increased acute and chronic inflammation in lamina propria |
|
|
Term
| What kinds of primary small bowel tumors are found? |
|
Definition
Remember, most common tumor is a metastasis (common from breast)
1) Adenoma/carcinoma
2) Endocrine (carcinoid)- well differentiated
3) Mesenchymal (soft tissue) |
|
|
Term
True or False:
The major function of taenia coli in the colon is to produce strong, coordinated contracts that enable fecal excavation. |
|
Definition
False!
Important for retarding propulsion and enhancing residence time in ascending colon (reabsorption and solidification of fecal material |
|
|
Term
| What is the intrinsic innervation of the colon and what myogenic elements/processes regulate colonic motility? |
|
Definition
1) Submucosal, Meisner's plexus for secretions and Myenteric plexus in between circular and longitudinal smooth muscle layers.
2) Electrical slow waves dictate contractions
- Short duration bursts are stationary motor patterns that facilitate water extraction/ circular muscle
- Long duration contrasting are important for segmentation/ longitudinal smooth muscle
- Giant migrating contractions (GMCs) are for mass fecal movement and arise from myenteric potential oscillations (induced by rectal distention and intra-colonic glycerol)
** Slow waves occur in longitudinal and circular smooth muscle, but are only coordinated by ICCS when required. |
|
|
Term
| Why might you give atropine to a patient with IBD? What would you do if you wanted to treat constipation instead? |
|
Definition
1) Stop the diarrhea!
Inhibit giant migrating contractions (GMCs) that arise from myenteric potential oscillations and cause mass movement of feces.
2) Glycerol activates these GMCs, so glycerol suppositories can be used! |
|
|
Term
| What are the basic neurohumoral elements that regulate colonic motility? |
|
Definition
Visceral afferents responding to wall tension increases colonic tone.
1) CCK, motilin, 5-HT and gastrin all excite contractions
- After meal, gastrocolonic response causes urge to defecate with GMCs (most important stimulant is fat)
2) Secretin, glucagon, VIP, neuropeptide Y and NO inhibit smooth muscle contractions |
|
|
Term
| What is the functional anatomy of the anorectal canal and how does it maintain continence? |
|
Definition
1) Internal anal sphincter (circular smooth muscle)
2) External anal sphincter (striated muscle innervated by pudendal nerve S2-4)
3) Puborectalis muscle (striated with efferent innervation by S2-4) maintains anorectal angle
Rectal sensation, storage capacity, resting IAS tone, contractile responses of PRM and EAS and motivation are all critical to maintain continence. |
|
|
Term
| What is "adaptive compliance" in relation to the rectum? |
|
Definition
Determines rectal reservoir capacity
- Rectal pressures increase relatively little in response to increases in volume.
- Can be measured by rectal balloon (increased in Megarectum and Decreased in Proctitis) |
|
|
Term
| What process is primarily disturbed in constipation? |
|
Definition
Colonic or Anorectal motility
Can be classified as either
1) Normal transit
2) Colonic inertial (decreased motor activity after meals)
- transit proximal to rectum is delayed because of decreased propulsive activity (can occur in megacolon)
3) Outlet delay
- Delayed signmoid/rectum emptying because of disorder of anorectal function (Megarectum, Hirschsprung's, Dyssynergic defecation) |
|
|
Term
| How should you treat a young women who has persistent difficulty defecating following meals? |
|
Definition
Most likely Colonic inertia constipation (common in women following meals)
Treat with osmotic laxative (Polyethylene glycol) + stimulant laxative (Anthraquinone or diphenylmethane) + Pro-kinetic agent (Metaclopramide or Tetracycline) |
|
|
Term
How can each of the following disorders cause outlet delay constipation?
1) Megarectum
2) Rectocele
3) Hischsprung's disease
4) Dyssynergic defecation |
|
Definition
Anorecetal dysfunction.
1) Weak propulsion
2) Misdirection of propulsion
3) Failure of IAS relaxation (sort of like achalasia for rectum)
4) Failure of striated muscle relaxation |
|
|
Term
A young boy presents with constipation, which he claims he has had since birth.
What tests would you run to diagnose/treat him? |
|
Definition
Sounds like Hirschsprung's, which is congenital absence of intramural ganglion cells of submucosal and myenteric plexuses in the distal bowel, always involving the IAS and producing Megacolon.
**Requires surgery with excision (Swenson) or Bypassing diseases segment (Duhamel)**
1) Barium X-ray (Diagnostic in 80% of patients)
- demonstrate functional vs. mechanical obstruction
- demonstrate transition zone between ganglionic and aganglionic bowel.
2) Anorectal manometry
- Evaluate IAS tonic constriction
3) Rectal biopsy
- Normal # of submucosal ganglion cells excludes HD
- Stain for Acetylcholinesterase to distinguish heavily-staining nerves and ganglion cells |
|
|
Term
| How does treatment for Desyinergstic defecation differ from that used in Hirschsprung's disease? |
|
Definition
1) HD is lack of innervation of IAS smooth muscle and requires surgery (bypass or excision or un-inervated tissue)
2) Dyssynergia is inability to relax PRM and/or EAS, an unconsciously learned behavior that can be modified in adults with biofeedback. |
|
|
Term
A patient in the hospital who recently underwent a hip-replacment surgery presents with constipation, but a functional or mechanical obstruction cannot be found.
How do you treat? |
|
Definition
Pseudo-obstruction from Acute Megacolon (imbalance between sympathetic and parasympathetic regulation of colonic motor activity).
1) Conservative
- Nothing by mouth
- Correct fluid and electrolytes
- Nasogastric suction
- Rectal tube decompression
- Stop offending medications
- Frequent position changes (ambulation is good)
2) Pharm
- if aggressive interventions are required, try Neostigmine (reversible AChE-i) to increase parasympathetic input.
3) Colonoscopic decompression (if 1-2 fail)
4) Surgical decompression (if ischemia or perforation). |
|
|
Term
| What are the possible etiologies of Fecal Incontinence and how are they treated? |
|
Definition
1) Overflow
- Fecal impaction/megarectum/blunting of rectal sensation
- Medical therapy only, with disimpaction, bowel cleansing and habit training.
2) Reservoir
- Decreased rectal compliance, or tumor
- Treat medically with reduced fiber, anti-inflammatories/Loperamide, or surgically with a colostomy.
3) Internal sphincter incontinence
- Weakness of IAS due to trauma, degeneration, autonomic
- Loperamide or cotton plug treatment.
4) Rectosphincteric incontinence |
|
|
Term
| What systemic diseases are associated with rectosphincteric incontinence? |
|
Definition
(DM, MS, spinal chord injury, systemic sclerosis)
1) Diabetes (peripheral neuropathy)
- maintained rectal sensation, with decreased squeeze pressure and PRM contraction
2) Spinal chord injury
- Sacral chord lesions (no rectal sensation or tone)
- Suprasacral lesions (preserved reflex and prevented by planned defecation by rectal stimulation)
3) Systemic sclerosis (GI smooth muscle disorder)
- Atrophy of circular smooth muscle and replacement with collagen (EAS and PRM should be normal)
- lowered resting pressure of IAS only.
4) Multiple sclerosis (central neurological)
- Alterations of rectal sensation and EAS (pudendal nerve injury) |
|
|
Term
What do each of the following tell you about the origin of rectrosphincteric fecal incontinence?
1) Lowered resting pressure only
2) Lowered squeezing pressure only
3) Lowered squeezing pressure and PRM contraction
4) Lowered squeezing pressure, PRM contraction and rectal sensation. |
|
Definition
1) IAS weakness (Systemic sclerosis- GI smooth muscle)
2) EAS trauma
3) Peripheral neurogenic (Diabetes)
4) Central neurogenic (MS) |
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Term
A patient presents with painless diarrhea and bleeding with "fresh appearing blood."
On PE, you find pale mucosal membranes and orthostatic hypotension, but no pain on abdominal palpation.
How do you confirm your diagnosis and what common complications of this disease worry you? |
|
Definition
Ulcerative Colitis (inflammation/ulceration confined to mucosa, always involving rectum and spreading contiguously proximally to involve a variable portion of the colon as well).
Painless diarrhea and Hematokezia are classic UC, and pale mucosal membranes (anemia) and orthostatic hypotension (dehydration) are characteristic PE findings.
1) Diagnosis
- Run stool tests to rule out infectious (salmonella, shigella, C. jejuni, EHEC) and drug-induced (NSAID) causes
- Endoscopy/Colonoscopy should show "wet sandpaper," diffuse granularity of mucosa, erythema, friability and spontaneous bleeding.
- Biopsy shows inflammatory infiltrate within mucosa, crypt abscesses and fewer goblet cells
2) Complications
- bleeding with anemia
- Toxic megacolon/perforation*****
- growth delay
- cancer with stricture formation (less common in CD) |
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|
Term
An 18 year old male patient presents with abdominal pain, fever, abdominal distention and diarrheal bleeding with "fresh appearing blood." They appear "toxic."
What is going on? |
|
Definition
| Toxic megacolon complicating Ulcerative Colitis. However, you need to rule out infectious and NSAID-induced colitis. |
|
|
Term
What % of crohn's disease patients have
1) Only small bowel disease
2) Ileocolonic disease
3) Colonic limited |
|
Definition
All have transmural inflammation in patchy distribution.
1) 35% have only small bowel
2) 45% have ileocolonic
3) 20% have Colitis |
|
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Term
A young woman presents with fatigue, abdominal pain (right lower quadrant), weight loss, fever and diarrhea.
On PE, the patient has orthostatic hypotension and you palpate an abdominal mass. You also note high pitched bowel sounds, indicating an obstruction.
How do you definitely diagnose this condition and what are the common complications? |
|
Definition
Sounds like Crohn's disease (transmural inflammation with patchy distribution in small bowel and/or colon)
1) Diagnosis
- Colonoscopy/Endoscopy ("Serpiginous" ulcers, pseudopolyps, "cobblestone" appearance of mucosa, strictures)
- Biopsy shows transmural inflammation (instead of mucosal as in UC)
- GRANULOMA is pathognomoic but only present in 50%
- Radiographic tests include barium swallow ("string sign" of strictures, CT ("creeping fat") and MRI, and are often necessary.
2) Complications
- Fibrostenoic strictures with obstructive symptoms.
- Cancer is rare |
|
|
Term
| What are the common extra-intestinal manifestations of IBD? |
|
Definition
1) Arthritis
- peripheral arthritis "flares" with IBD "flares
- central arthritis does not correlate
2) Eye inflammation
- Uveitis/painful
3) Skin lesions
- Erythema nodosum: red, raised lesions on lower extremeties
- Pyoderma gangrenosum
4) Oral lesions
5) Vascular complications
- Autoimmune hemolytic anemia and thrombotic disease
6) Primary sclerosing cholangitis
- Progressive inflammation, fibrosis and destruction of intra and extra hepatic bile ducts, resulting in cirrhosis and portal htn.
- Occurs in 5% of UC (less common in CD)
- 75% of people with PSC have IBD
- Associated with HLA-DRw52a and HLA-B8 and p-ANCA
- Course does NOT parallel IBD |
|
|
Term
| What is the importance of Primary sclerosing cholangitis? |
|
Definition
If you see PSC, think of IBD (UC, usually). If you see IBD, only 5% will have PSC.
Progressive inflammation, fibrosis and destruction of intra- and extra- hepatic bile ducts, resulting in cirrhosis and portal HTN.
1) Occurs in 5% of UC (less common in CD)
2) 75% of people with PSC have IBD
3) Associated with HLA-DRw52a and HLA-B8 and p-ANCA
4) Course does NOT parallel IBD |
|
|
Term
| What major genetic associations have been found in IBD? |
|
Definition
CD is more heritable than UC
1) Several HLA associations
2) Chromosomal linkages
- IBD1- chromosome 16 (CD)
- IBD2- chromosome 12q (UC)
- IBD3- chromosome 6p (CD)
- IBD4- chromosome 14q (CD)
3) Genes
- NOD2 mutations at IBD-1 locus (CD) associated with inappropriate innate immune responses to normal bacteria (LPS), with decreased NF-kb response, decreased defensin 5 production by paneth cells and an exaggerated adaptive immune response. |
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|
Term
| What does NOD2 have to do with IBD? |
|
Definition
Within IBD1 locus of chromosome 16 (CROHN's)
1) Mutations in NOD2 lead to inappropriate innate immune responses to normal bacteria (LPS), with decreased NF-kb response, decreased defensin 5 production by paneth cells and ultimately an exaggerated adaptive immune response.
2) Adaptive response leads to tissue damage in CD
**Only 10% of individuals with mutation actually get CD!** |
|
|
Term
| Why is IBD thought to have an infectious component to its pathogenesis? |
|
Definition
IBD does not follow simple mendelian inheritance and there is not a 100% concordance in monozygotic twins.
1) Specific associated pathogens
- M. paratuberculosis, Measles, Listeria, H. hepaticus.
2) Putative role of "normal" enteric bacteria present in all people
- defective mucosal barrier in IBD |
|
|
Term
| What are the 5 main categories of treatment for IBD? |
|
Definition
urgery works to cure UC and treat CD
1) 5-aminosalicylates (anti-inflammatory for UC>>CD)
- interfere with AA production by affecting thromboxane and lipoxygenase synthesis
- example is Sulfasalazine
2) Corticosteroids (anti-inflammatory and immunosuppressive for both UC and CD)
- Induce but NOT MAINTAIN remission
3) Antibiotics (Inhibit chemotactic peptides in CD only)
- Metronidazole (Flagyl) for pre- and post-operative CD maintenance.
- Cipro is also good alternative, but not in children
- Rifaximin (XIfaxan) works only on GI tract, and may be most specific.
4) Immunomodulators
- Azathiprine/6-mercaptopurine for CD (MOST) and steroid-dependent UC (inhibit ribonucleotide synthesis and prevent activated lymphocyte proliferation), but can cause transient PANCREATITIS
- Methotrexate (parenteral) inhibits dihydrofoltate reductase and purine synthesis in treatment of CD, with shorter onset of action than Azothioprine/6-MP (TERATOGEN!)
- Cyclosporine (IV lipophillic peptide for severe UC) has incredibly short onset of action (days) and inhibits proliferation and activation of Th cells by interfering with IL-2 production (if you give with other immunomodulators/steroids, treat Pneumocystis prophylactically!)
5) Biologics
- Anti-TNFa (Infliximab, adalimumab and certolizumab)
- Anti-adhesion agent (Natalizumab- but watch for PML) |
|
|
Term
| What drugs are available to treat UC, specifically? |
|
Definition
Surgery can be curative and Antibiotics/Biologics will not work.
5-ASA, Steroids, Cyclosporine,
1) 5-aminosalicylates (anti-inflammatory for UC>>CD)
- interfere with AA production by affecting thromboxane and lipoxygenase synthesis
- example is Sulfasalazine
2) Corticosteroids (anti-inflammatory and immunosuppressive for both UC and CD)
- Induce but NOT MAINTAIN remission
3) Immunomodulators
- Cyclosporine (IV lipophillic peptide for severe UC) has incredibly short onset of action (days) and inhibits proliferation and activation of Th cells by interfering with IL-2 production (if you give with other immunomodulators/steroids, treat Pneumocystis prophylactically!) |
|
|
Term
| What drugs are available to treat CD, specifically? |
|
Definition
Surgery for symptoms and 5-ASA does not work as well as for UC.
1) Corticosteroids (anti-inflammatory and immunosuppressive for both UC and CD)
- Induce but NOT MAINTAIN remission
2) Antibiotics (Inhibit chemotactic peptides)
- Metronidazole (Flagyl) for pre- and post-operative CD maintenance.
- Cipro is also good alternative, but not in children
- Rifaximin (XIfaxan) works only on GI tract, and may be most specific.
3) Immunomodulators
- Azathiprine/6-mercaptopurine for CD (MOST) and steroid-dependent UC (inhibit ribonucleotide synthesis and prevent activated lymphocyte proliferation), but can cause transient PANCREATITIS
- Methotrexate (parenteral) inhibits dihydrofoltate reductase and purine synthesis in treatment of CD, with shorter onset of action than Azothioprine/6-MP (TERATOGEN!)
4) Biologics
- Anti-TNFa (Infliximab, adalimumab and certolizumab)
- Anti-adhesion agent (Natalizumab) |
|
|
Term
| How does Cyclosporine differ from Methotrexate and Azothioprine/6-MP in terms of drug action? |
|
Definition
Lipophillic peptide that inhibits IL-2 production and used for severe UC (Methotrexate usually for CD)
Onset is within DAYS for Cyclo IV, vs. weeks for others.
Remember, if you give as combination with azathioprine or 6-MP and steroids, you better treat opportunistic infections (Pneumocystis) prophylactically! |
|
|
Term
Which of the following should be avoided during pregnancy for IBD treatment?
1) Methotrexate
2) Cyclosporine
3) Azathioprine
4) 6-mercaptopurine |
|
Definition
1) Methotrexate is a teratogen (it inhibits dihydrofolate reductase and purine synthesis, decreasing inflammatory cytokine production).
All are immunomodulators (1,3 and 4 are for CD and 2 is for UC)
- Cyclosporine inhibits IL-2 and if given in combination with other immunomodulators and steroids, Pneuomocystis should be treated prophylactically.
- Azathioprine and 6-MP are useful in CD (T cell and NK cell suppression), and can cause transient pancreatitis. |
|
|
Term
| Why might you prescribe Sulfasalazine? |
|
Definition
To treat UC>>CD
- Inhibits lipoxigenase and thromboxane synthesis, modulating AA production and decreasing inflammation.
- Remember to supplement with folic acid
- Can be given topically for distal UC |
|
|
Term
Which of the following describes the action of cyclosporine in treating UC?
1) Inhibits dihydrofolate reductase and purine synthesis (decreasing inflammatory cytokine production)
2) Inhibits ribonucleotide synthesis and decreases lymphocyte proliferation
3) Inhibits IL-2 production and T-cell activation
4) Inhibits AA production and Lipoxygenase synthesis |
|
Definition
3
1) Methotrexate (Teratogen)
2) Azathioprine/6-MP (Transient Pancreatitis)
4) 6-ASA (Sulfasazaline) |
|
|
Term
| What biologics are used to treat CD and how do they each work? |
|
Definition
- Anti-TNFa (Infliximab, adalimumab and certolizumab) ALL teratogenic
- Anti-adhesion agent (Natalizumab)
1) Infliximab (Remicade)
- chimeric (human/murine) monoclonal Ab against TNF-a for CD not responding to standard therapy
- well-tolerated, but watch for opportunistic infections
2) Adalimumab (Humira)
- humanized anti-TNF is sub-q
- Also acts as IgG1 antibody
3) Certolizumab pegol (Cimzia)
- pegylated monoclonal Ab (prevent rapid renal clearnce)
- No IgG backbone, so no complement-mediated cell lysis
4) Natalizumab (Tysabri)
- humanized IgG4 Ab targeting integrin (a4 or a4b7) on leukocytes and preventing trafficking of white cells to MadCAM-1 or VCAM-1 expressing endothelial cells.
- Secondary treatment if Anti-TNF fails. |
|
|
Term
Which of the following is NOT correct?
1) Crohn's disease can occur anywhere in the GI tract
2) Ulcerative colitis is usually continuous and always involves the rectum.
3) Surgery is curative for Ulcerative colitis
4) Smoking is detrimental in Crohn's disease
5) Risk of colon cancer is higher in Crohn's than UC |
|
Definition
5- UC has a higher colon cancer risk
1) Crohn's does occur anywhere, while UC is only in large bowel
2) UC is continuous, while Crohn's is skip lesions with or without the rectum (always the terminal ileum)
3) Surgery is curative for UC and treats complications in CD
4) Smoking is protective for UC and detrimental for CD |
|
|
Term
Which of the following is NOT correct?
1) Ulcerative colitis is limited to the mucosa
2) Crohn's disease complications usually involve strictures and fistula
3) Crohn's is treated with Corticosteroids and 5-ASA agents
4) Smoking is protective in Ulcerative colitis
5) Crohn's disease often affects the terminal illeum. |
|
Definition
3) Crohn's is treated with corticosteroids, immunomodulators and biologics, while UC is treated with 5-ASA and steroids.
1) UC is mucosa, CD is transmural
2) CD has strictures/fistula that require surgery/UC does not
4) Smoking protects against UC but hurts CD
5) Crohn's hits terminal illeum and UC always hits rectum |
|
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Term
| What are the 3 basic molecular events of the adenoma/carcinoma pathway? |
|
Definition
3 pathways
1) Chromosomal instability
- LOH in genes like APC gene on 5q, K-ras on 12p, p53 on 17p, SMAD2 on 4 and 18q
- Aneuploid tumors
2) MIcrosatellite instability (MSI)
- Operative in HNPCC, involving mutations in DNA mismatch repair genes like MSH2 on 2[ and MLH1 on 3[
- Diploid tumors
3) CIMP, CpG island methylator phenotype
- Methylation of promotor region and transcriptional inactivation |
|
|
Term
| What is the pathogenesis of the rare colorectal cancer that appears with adenoma proliferation and "carpeting colon"? |
|
Definition
autosomal dominant FAP with chromosomal instability (issues with bone, eyes and soft tissue)
1) Germ-line mutation in APC (5q) gene, preventing phosphorylation of Beta-catenin.
2) Beta-catenin accumulates, enter nucleus and complexes with DNA-binding transcription factors that stimulate unbridled cell growth and neoplasia.
***Extra-intestinal manifestations include CHRPE (congenital hypertrophy of retinal pigment epithelium), osteomas and soft tissue tumors** |
|
|
Term
| What is the pathogenesis of Hereditary Non-Polyposis Colorectal Cancer (HNPCC)? |
|
Definition
Autosomal dominant mismatch-repair issue with high penetrance, that looks like sporadic cancer (no colon carpeting with polyps)
1) Defect is mismatch repair genes (MMR) that control fidelity of DNA replication
2) Mutations lead to abnormalities in DNA scattered about genome (ex: TGF-b) |
|
|
Term
| Why is screening for CRC considered a grade A indication? |
|
Definition
1) Early detection can facilitate treatment
2) Removing early polyps can Prevent cancer. |
|
|
Term
| What % of people with FAP get CRC? |
|
Definition
ALL OF THEM (100% penetrance of the APC mutation on 5q).
Remove the colon. |
|
|
Term
| What types of adenomatous polyps are at high risk of developing CRC? |
|
Definition
1) Those > 1cm
2) Villous or high-grade dysplasi |
|
|
Term
What is the Fecal Occult Blood Test (FOBT) and how is it used in CRC?
What about the fecal immunochemical test (FIT)? |
|
Definition
FSG is actually better than both
1) FOBT is screening method associated with 33% reduction in mortality and 20% decrease in incidence
2) FIT has better sensitivity for advanced adenoma and CRC without increasing false positive rate. |
|
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Term
| What is flexible screening sigmoidoscopy (FSG) and what is its utility? |
|
Definition
Effective triage to colonoscopy (also less effective in proximal colon)
Effective endoscopy screening that reduces CRC incidence in proximal and distal cases but only mortality in DISTAL cases (stage IV cancer cause the mortality, and are usually found proximally) |
|
|
Term
| What are the major etiologies of CRC? |
|
Definition
1) IBD (20%)
2) HNPCC (4%)
3) FAP (1%)
4) Sporadic |
|
|
Term
| What are the 4 pathophysiolgoical mechanisms that generate diarrhea? |
|
Definition
1) Osmotic diarrhea
- unusual amount of poorly absorbable, osmotically active solutes in gut lumen
- alcohols or ions (laxatives) prevent maintenance of osmotic gradient between lumen and bodily fluids.
- Stool osmolol gap > 100 mOsm/kg
2) Secretory diarrhea
- Intestinal ion secretion or inhibition of normal active ion absorption often due to infection
- Stool osmolol gap < 50 mosm/kg
3) Deranged intestinal motility
- Neurohormonal due to anxiety, stress, nicotine, methylxanthine.
4) Exudation/Inflammation
- mucus, blood and protein from sites of inflammation. |
|
|
Term
| Why is cholestyramine often given to patients with Crohn's disease? |
|
Definition
Bile salt binder to prevent bile salt diarrhea.
CD patients will have illeum issues, so bile salts that are usually absorbed in the terminal illeum and recycled via enterohepatic circulation and instead fed to the colon, where they stimulate water secretion and intestinal motility. |
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Term
A patient presents complaining of straining while trying to pass bowel movements, bloating, incomplete evacuation and hard/small stools.
How do you objectively determine whether a patient is constipated or not? What are the 2 mechanisms generating constipation? |
|
Definition
By ROME criterion, you already have 2 characteristics, but usually need BM < 3 times per week
1) Obstruction of movement of luminal contents
2) Decreased colonic propulsive activity. |
|
|
Term
True or False:
Acute constipation is more associated with organic disease than long-standing constipation. |
|
Definition
True! Also more associated than acute diarrhea!
You must discern whether patient has signs or symptoms of neurological, endocrine, neoplastic or metabolic disorder |
|
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Term
| Which adults with constipation should receive a colonoscopy? |
|
Definition
FSG for Blood, iron and cancer
1) Positive guaiac test (blood)
2) Iron-deficiency anemia
3) First degree relative with colon cancer. |
|
|
Term
| What are the primary available treatments for chronic constipation? |
|
Definition
Laxatives
1) Bulk-forming (fiber)- safest
2) Stimulants- Bisacodyl and senna are OTC options
3) Osmotics (polyethylene glycol:Mirilax)
- cause fluid to flow into colon and cause bowel distention (useful for idiopathic cases)
4) Stool softener
- Docusate- use in people who should avoid straining
5) Lubricant- Fleet and Zymenol to greese stool
6) Saline- acts like sponge to draw water into colon (Milk of Magnesia)
- use in acute constipation if no indication of obstruction
7) Chloride channel activator (Lubiprostone) for those with fiber/laxative-refractory cases. |
|
|
Term
| What kind of diarrhea is caused by lactose intolerance? What wold the osmol gap be? |
|
Definition
| > 100 in osmotic diarrhea |
|
|
Term
Which of the following is NOT correct.
1) Acute diarrheal illness tends to be a benign and self-limiting event
2) Acute onset of constipation more commonly indicates an organic cause
3) Chronic diarrhea is more likely to involve significant pathology
4) Chronic constipation is less likely to be functional and lifestyle-related |
|
Definition
4) Chronic constipation (unlike acute), is usually a functional/life-style issue and not organic disease.
Chronic diarrhea on the other hand IS organic-disease related, unlike acute diarrhea, which is usually self-limited and not serious. |
|
|
Term
| How can pro-biotics be used to treat diarrhea? |
|
Definition
1) Prophylaxis for drug-induced diarrhea
2) Decrease length of infectious diarrhea (traveler's, rotavirus, C. dif) |
|
|
Term
| What is S. boulardii, and how is it used clinically? |
|
Definition
Secondary prevention of CDAD (C dif. diarrhea) when used in combination with vancomycin to treat recurrent episode.
- a yeast found on the lychee fruit, works by producing a protease that destroys the toxin A receptor site. |
|
|
Term
| How can probiotics be used in IBD patients? |
|
Definition
| ONLY in MAINTENANCE OF REMISSION for pouchitis in post-surgical CD patients and UC |
|
|
Term
| What group of IBS patients benefit from probiotic treatment? |
|
Definition
- Only short-term outcomes demonstrated with modest benefit.
- Appear to be most beneficial in diarrhea-predominant subset of patients. |
|
|
Term
| What are the major indicated uses of probiotics currently? |
|
Definition
AIM HuNt
1) Antibiotic associated diarrhea
2) Infectious diarrhea (including rotavirus and CDAD –treatment, primary and secondary prevention)
3) Maintenance of remission in ulcerative colitis
4) Maintenance of remission for pouchitis
5) Treatment of minimal hepatic encephalopathy
6) Prevention of NEC in premature infants |
|
|
Term
A patient presents with acute periumbilical pain that has been coming in waves. They have been vomiting as well and are running a high fever.
What is the pathogenesis of this condition? |
|
Definition
Sounds like Acute Appendicitis (colicky, peri-umbilical pain and vomiting) with onset of peritoneal inflammation from bacterial infection (fever).
1) Calculi or Fecalith (stone feces) obstructing appendiceal lumen causes acute inflammation and obstruction.
2) Secretions accumulate under pressure behind obstruction and bacterial infection takes place.
3) Following infection, vascular occlusion, gangrene and perforation develop quite quickly.
**Inflammation may extend into surrounding fat and produce periappendicitis!** |
|
|
Term
| What are the gross and histological signs of the disease that causes periumbilical, colicky pain, vomiting and sometimes fever? |
|
Definition
Acute appendicitis (fecalith obstruction)
1) Gross
- Swollen, edematous appendix with purulent exudate
2) Histology
- acute inflammation with necrosis and complete destruction of appendiceal wall. |
|
|
Term
| What is the most common location of intussusception and how is it treated? |
|
Definition
Ileocecal valve in kids 6 month-2 years of age.
Surgery is curative. |
|
|
Term
What gross/histological features of each infectious colitis described below?
1) Bloody diarrhea, severe cramping abdominal pain, thrombotic, thrombocytic purpura and low-grade fever following consumption of fast-food meat.
2) Diarrhea and abdominal pain following clindamycin administration
3) Child with intense crampy abdominal pain, fever, vomiting, watery diarrhea and dysentery (bloody mucoid) |
|
Definition
1) EHEC (O157:H7) Toxin that damages vascular endothelium of kidney and intestine, causing bacillary dysentery and hemorrhagic colitis.
- See epithelial and endothelial ischemia with submucosal edema, hemorrhage and pseudomembranes with PMNs in crypts, LP and pseudomembranes.
2) C. dif
- Grossly, you see Pseudomembranes on endoscopy, with raised mucosal plaques of fibrin, RBCs, PMNs.
- Histologically, mucosal biopsy shows surface glandular drop-out and necrosis.
3) Shigella (invasive, non-motile gram-negative bacillus).
- Grossly, you see friable, ulcerated mucosa with recto-sigmoid inflammation and serpiginous ulcers.
- Histology shows small aphthous ulcers, PMNs, crypt abscess and goblet cell depletion. |
|
|
Term
A patient presents on antibiotics presents with very variable, cramps, diarrhea, voluminous watery stool, leukocytes in stool (not bloody) peripheral leukocytosis and fever.
On biopsy, you discover pseudomembranes.
What should you look for on stool sample and how do you treat? |
|
Definition
| C. dif toxin in stool and stop offending antibiotic (metro and vanco) |
|
|
Term
Patient presents with bloody diarrhea and lower abdominal pain.
Histology reveals "flask-like" ulcers and red trophozoites.
What is going on? |
|
Definition
|
|
Term
| Describe 3 non-infectious causes of colonic diarrhea. |
|
Definition
All present with chronic diarrhea and a NORMAL colonoscopy
1) Collagenous colitis
- females with h/x of NSAID use producing watery, non-bloody diarrhea >20 times per day.
- Look for broad, continuos hypocellular, linear, subepithelial fibrous band.
2) Lymphocytic colitis
- chronic water diarrhea with increased intra-eptithleial lymphocytes at luminal surface (>20 per 100 epithelial cells)
- also see IELs in celiac
3) Amyloidosis
- Beta-amyliod deposition (congo red stain with positive green birefringence.
- Eosinophilic deposits in the submucosal vessels |
|
|
Term
| What are the 3 primary causes of iatrogenic colitis? |
|
Definition
UNDERDIAGNOSED.
1) NSAID
- look for intra-epithelial lymphocytes and normal crypt architecture after use of Diclofenac (Voltaren), Naproxen (Naprosyn), Indomethacin (Indocin) or Piroxicam (Feldene).
2) Oral contraceptive
- small bowel thrombosis (especially in left colon at splenic flexure)
3) Melanosis coli
- brown pigmented appearance of colonic mucosa due to habitual anthraquinone laxative use (lipofuscin in macrophages in lamina propria) |
|
|
Term
Where are the weak points or "watershed areas" of Ischemic bowel disease?
What are the 3 main causes? |
|
Definition
1) Watersheds
- Splenic flexure (Griffith's point)
- Rectosigmoid region (Sudeck's point)
2) Causes
- Vascular occlusion (Inferior mesenteric handles this portion)
- non-occlusive ischemia from hypotension in shock and ventricular failure
- mechanical vascular compression. |
|
|
Term
| What histopathological features can help you distinguish between UC and CD? |
|
Definition
1) UC will involve distal colon and show DIFFUSE inflammatory infiltrate of mucosa only
- distorted crypt architecture in un-inflamed areas.
- Crypt abscess and cryptitis
2) CD will involve entire colon, with"skip areas" and "cobblestoning," with FOCAL, TRANSMURAL inflammation
- stricture formation, fistula and "bear claw ulcers"
- FOCAL inflammatory infiltrate
- Granuloma |
|
|
Term
| What are the major types of colon polyps? |
|
Definition
1) Hyperplastic Polyp: Serrated or “sawtooth” lumens
2) Adenomatous Polyp: pedunculated or scissile
- Enlarged, elongated
- Pencil or cigar-shaped
3) Serrated Adenoma
4) Juvenile Polyp: SMAD4 pathology in colon
5) Peutz-Jeghers Polyp: Pigmented spots on the lip and buccal mucosa, small intestine polyps |
|
|
Term
| How does the presentation of right and left colon cancer differ? |
|
Definition
1) Right will have anemia
2) Left with have changing bowel habits and bleeding |
|
|
Term
How does 5-flourouracil work to treat cancer?
What about Capecitabine? |
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Definition
Anti-metabolic
1) Pyrimidine analogue that is converted to GdUMP by thymidylate synthase and incorporated into BOTH DNA and RNA, affecting both synthesis and function
2) Orally administered prodrug that is converted to 5-FU in tumors |
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Term
| How does Gemcitabine inhibit cancer growth? |
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Definition
Converted to F-dCTP and is incorporated into DNA (vs. DNA and RNA for 5-FU)
Terminates growing DNA chain and is resistant to repair. |
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Term
What drug is described by each of the following mechanisms
1) Incorporates in DNA and RNA, halting synthesis and function
2) Forms bulky DNA adducts
3) Incorporates into growing DNA chain, halting growth and resisting repair.
4) Interferes with microtubule synthesis/degradation, inhibiting cell division |
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Definition
1) 5-FU
2) Oxaliplatin (platinum coordination complex)
3) Gemcitabine
4) Paclitaxel/docetaxel (anti-mitotic) |
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Term
Which of the following drugs requires pretreatment with anti-histamines or glucocorticoids and why?
1) 5-FU
2) Docetaxel
3) Gemcitabine
4) Ironotecan |
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Definition
2) Anti-mitotic agents that inhibit microtuble synthesis/degradation
- Reduce adverse hypersensitive reactions to vehicles used for insoluble anti-mitotics |
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Term
What are the major limitations of using Irinotecan and Epirubicin to treat colorectal cancer?
How do their mechanisms of action differ? |
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Definition
1) Topoisomerase inhibitors act on S phase and require LONG exposure for any benefit
2)
- Irinotecan stabilizes covalent complex between nicked DNA strand and topoisomerase, forming dsDNA breaks during synthesis (S phase) and cell death.
- Epirubicin forms tripartite complex with DNA and topoisomerase II blocking re-ligateion of dsDNA breaks generated during replication |
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Term
| Why might you give Mitomycin C to treat cancer? |
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Definition
| Antibiotic used in combination with other agents that alkylates DNA, leading to inhibited synthesis and formation of ssDNA and dsDNA breaks |
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Term
What are the major risk factors/treatment for each of the following?
1) Liver cancer
2) Biliary track and Gallbladder cancer
3) Small bowel cancer
4) Anal cancer |
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Definition
1) Hep C in Men more than women (targeted chemo with
multi-kinase inhibitor "sorafenib")
2) Gallstones/ more in women- Cisplatin and gemcitabine
3) Adenocarcinoma of dueodenum in CD patients: surgery
4) HPV-16- Mitomycin/5-FU |
|
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Term
| What is the mainstay treatment for Colorectal cancer? |
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Definition
Anti-metabolite with agent to increase effectiveness
- Combination of Leucovorin (reduced folic acid)/5-FU/Oaliplatin (FOLFOX)
- Leucovorin enhances inhibitory effects of 5-FU
**Oxaliplatin is sometimes replaced with ironotecan (FOLFIRI)** |
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Term
Why is cetuximab used in colorectal cancer?
Why does bevacizumab show promise? |
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Definition
EGFR is over-expressed in 60-80% of tumor cells, so it makes sense as a targeted chemotherapy agent.
Bevacizumab is againsr VEGF-R and also shows promise. |
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Term
Why are NSAIDs considered to be potential chemo-preventative agents for colorectal cancer?
What limits their use? |
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Definition
1) Inhibit inflammation that predisposes patients to cancer.
2) Adverse CV effects |
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Term
| Why is Pemetrexed sometimes given with Gemcitabine to treat pancreatic cancer? |
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Definition
Salvages nucleotides loss with Gemcitabine treatment.
Pemetrexed triggers induction of enzymes involved in salvage nucleoside pathway to compensate for inhibition of thymidylate synthase by Gemcitabine (depends on ENT1 transporter because of hydrophillicity) |
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Term
| What lab measures can identify nutritional status? |
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Definition
1) Albumin (3.5-5.2 g/dl)
- Lagging indicator with 21d half life
2) Prealbumin (transthyretin) (10-43 mg/dl)
- monitors improvements in nutritional status
3) BUN (7-20 mg/dl)
- reflects protein breakdown
- elevated in high catabolic state or with high intake
- decreased in low metabolic state or with low intake.
4) Creatinine (0.5-1.1 mg/dl)
- In stead state and normal renal function, it can reflect lean body mass
5) H/H: Anemia and mean corpuscular volume (MCV) can indicate iron (low MCV), or B12/folate deficiency (high MCV) |
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Term
What micronutrient deficiencies are associated with each of the following.
1) Glossitis
2) Chielosis/Angular stomatitis
3) Pallegra (Dematitis):
4) Koilonychia (spoon nails): |
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Definition
1) Glossitis: Thiamine, Niacin or B12
2) Chielosis/Angular stomatitis: Riboflavin and/or Folic acid
3) Pallegra (Dematitis): Niacin
4) Koilonychia (spoon nails): Iron deficiency |
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Term
| Why is Enteral Nutrition usually preferred to total parenteral nutrition (TNP)? |
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Definition
TNP requires venous access, is constantly and is associated with complications like infections, hepatic steatosis, cholestasis and bone metabolic complications.
Enteral nutrition has added benefits of trophic effects on gut barrier integrity. |
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Term
How does stress affect body energy stores differently than starvation?
How can this help you differentiate with kwashiorker and marasmus? |
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Definition
1) Starvation decreases all body compartments (fat, glycogen and protein)
2) Stress (excessive expenditure of energy and body protein) only reduces BCM (intracellular water, glycogen and protein), increasing extracellular water.
**Ascites seen in kwashiorker, but not marasmus** |
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Term
| What are the events that occur in early, medium and late starvation? |
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Definition
1) Early (<24h)
- Glycogen stores used to provide glucose
- Insulin decreases as glycogen is depleted and Glucagon increases.
- AA moved from muscle and fat from adipose for additional energy.
2) Medium (<3 weeks)
- Glycogen depletion/glucose comes from gluconeogenesis from protein breakdown
- Lipolysis provides primary energy (ketone bodies from FA metabolism)
3) Late (>3 weeks)
- Ketone body production accelerate and blood levels rise to supply brain (reduced rate of protein breakdown)
- Hormonal adaptations (growth hormone, TSH, cortisol, renin, aldosterone and ADH all increase). Glucagon and insulin decrease. |
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Term
Which of the following is NOT a cause of starvation (without stress)?
1. Diabetic gastroparesis
2. Celiac disease
3. Dementia
4. Acute sepsis |
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Definition
| 4. Acute sepsis is starvation with stress (increased basal metabolic rate, protein breakdown, insulin resistance and hyperglycemia) |
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Term
| How do the clinical presentations of Marasmus and Kwashiorkor differ? |
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Definition
1) Marasmus is "skin and bones" of infants, with sunken cheeks, protuberant bellies, NORMAL serum albumin, no edema and "crie du chat" cry.
2) Kwashiorkor has EDEMA in slightly older kids (9 mos- 2 yrs) |
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Term
Under what conditions might each of the following be decreased?
1) Albumin
2) Pre-albumin
3) Retinol binding protein
4) Transferrin |
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Definition
All in malnutrition.
1) Nephrotic syndrome, liver disease, malignancy, fluid overload, pregnancy
2) Inflammation, fluid overload, hyperthyroid, liver, pregnancy
3) Hyperthyroidism, malnutrition, liver disorder, vitamin A
4) Inflammation, nephrotic, liver disease. |
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Term
Under what conditions might each of the following be elevated?
1) Albumin
2) Pre-albumin
3) Retinol binding protein
4) Transferrin |
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Definition
1) Dehydration (>5.2 g/dl)
2) Renal failure or dehydration (>43 mg/dl)
3) Reduced GFR and Alcoholism (>6.4 mg/dl)
4) Iron deficiency, estrogens/oral contraceptives, hepatitis, pregnancy (>400 mg/dl) |
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Term
| What differentiates Peripheral parenteral nutrition from total? |
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Definition
PPN involves lower osmotic solution of AA, dextrose and lipids + vitamins and mineral salts that can be given by peripheral IV
TPN involves high osmotic solution and can only be given by central venous access |
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Term
A patient who was in a traumatic car accident presents with Increased resting energy expenditure and appears to be retaining fluid.
What kind of nutritional issue is this?
What will his blood glucose levels be like? |
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Definition
Stress (Kwashiorkor-like) protein malnutrition from trauma.
Increased resting expenditure from catecholamine release and water/salt retention from RAAS
1) Metabolic response to injury / inflammation
Gluconeogenesis
Insulin resistance
Hyperglycemia |
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Term
Patient with esophageal cancer presents with weight loss, depleted fat and muscle, but relatively maintained plasma proteins.
What kind of malnutrition is this? |
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Definition
Unstressed, marasmic-predominant
Body relies on fat metabolism, and later on muscle catabolism, for energy during insufficient calorie intake |
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Term
| What are the major functional changes that occur in starvation? |
|
Definition
General: decreased REE (vs. increase in stress), physical activity and body Temp
Body Composition:
- Na+, H20 retention (renin)
- EC H20 (edema), decreased IC H20
- K+, Mg ++
- Fatty liver
Immune:
- predisposition to infection |
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Term
| What is the molecular basis for "set point theory"? |
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Definition
When fat stores are depleted, adipostat signal (Leptin) is low in hypothalamus.
When fat stores are high, Leptin (Ob gene) is high and hunger is suppressed. |
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Term
| What does average total energy expenditure decrease with weight loss from obesity? |
|
Definition
1) Loss of lean body mass
2) Decreased sympathetic activity (decreased thermogenesis) |
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Term
| What are the major excitatory and inhibitory monamines and peptides that affect feeding? |
|
Definition
1) Excitatory
- NPY
- Opioids
- Grehlin
- Growth hormone releasing hormone
2) Inhibiting
- Leptin
- CCK
- 5-HT
- CRH, Glucagon-like peptide, Enterostatin. |
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Term
| How does Substance PYY signaling influence diet? |
|
Definition
PPY= Illeal break for satiety
Secreted by endocrine L cells lining distal small bowel and colon after meals (postprandially), in proportion to calories taken in.
- decreases food intake through inhibition of gut motility (acting as an “ileal brake” to cause a sense of satiety.
**initially secreted before nutrients hit lumen, but also secreted after nutrients are digested**
**Signals satiety!** |
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Term
| How does Grehlin function to stimulate appetite? |
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Definition
Released pre-perandilly by oxyntic cells in stomach fundus, acting on growth hormone receptors to increase GH release from pituitary (decreases post-parandially)
**Signals hunger!**
- Increases food intake by stimulating Ghrelin receptors on hypothalamic NPY-expressing neurons and agouti-related-protein-expressing neurons. |
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Term
| How is "metabolic syndrome" defined clinically? |
|
Definition
3 of 5
1) Waist circumference (men >40 and women >35)
2) Triglycerides >150 mg/dL
3) HDL (M <40 and W < 50)
4) Fasting blood glucose (>110 mg/dL)
5) BP > 130/85 |
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Term
| How does obesity cause HTN? |
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Definition
SNS activity induces pro-inflammatory state by IL-6 production, leading to systemic inflammation
1) Visceral fat is prone to lipolysis; an effect mediated by catecholamine binding to b3 receptors in intra-abdominal fat
2) Central fat distribution disturbs HPA axis
3) Lower NO in obese people |
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Term
| What is heart disease so common in obese individuals? |
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Definition
Increased cardiac weight= increased cardiac work
HTN in normal people causes concentric hypertrophy, but in obese patients, it is ECCENTRIC dilation, with increased preload and stroke work, leading to thickening and failure. |
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Term
| Describe 2 important signaling molecules released from adipocytes themselves. |
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Definition
1) Leptin is correlated with body fat stores (signals satiety)
2) Adiponectin is anti-inflammatory and is inversely correlated with body fat stores (increases glucose uptake) |
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|
Term
|
Definition
| A constellation of liver abnormalities associated with obesity, including hepatomegaly, elevated liver enzymes, and abnormal liver histology--steatosis, steatohepatitis, fibrosis, and cirrhosis |
|
|
Term
| What are the long-term and short-term molecular signals of satiety/hunger (body-fat stores)? |
|
Definition
1) Long-term signals associated
- leptin and insulin.
- also modulate short-term signals that determine meal initiation and termination.
2) Short term:
- Gut hormones, such as cholecystokinin, ghrelin, and PPY
- Signals from vagal afferent neurons within the gastrointestinal tract that respond to mechanical deformation, macronutrients, pH, tonicity, and hormones |
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Term
| Why do disorders of maldigestion and malabsorption commonly occur sub-clinicaly before symptoms of diarrhea and nutrient deficiency develop? |
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Definition
Intestinal Reserve
- Redundancy in both presence of many digestive enzymes as well as location along GI tract.
**Diarrhea is a SYMPTOM, not a diagnosis, - follow with 24-36h fast** |
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Term
| How can damage to the stomach impact digestion/absorption? |
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Definition
No absorption takes place here (still, Vitamin B12 deficiency and Zollinger-Ellison are associated with gastric function), but mechanical breakdown (contractions) and digestion/emulsion does occur here.
Damage will not cause maldigestion, because of intestinal redundancy, but you will EAT SMALLER MEALS. |
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Term
| Which two malabsorption syndromes are associated with gastric function? |
|
Definition
1) Vitamin B12 (cobalamin) deficiency
- Intrinsic factor produced by parietal cells protects B12 until terminal illeal absorption.
- Associated with pernicious anemia and neuro symptoms.
2) Zollinger-Ellison syndrome
- Gastrin secreting tumor of stomach and/or pancreas with increased acid secretion and duodenum issues that prevent absorption. |
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Term
| What stimuli activate pancreatic, intestinal and biliary secretions in the upper small intestine (duodenum) |
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Definition
Site of most digestion and much of absorption
1) Mechanical distention- reflex increase in motility and ACh secretion
2) Osmolarity (protein and fat)- stimulate CCK and cause pancreatic enzyme release
3) Low pH (4-6)- stimulates Secretin secretion, which elicits pancreatic HCO3- release to neutralize pH and allow enzymes to function. |
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Term
| What minerals and nutrients are actively absorbed in the proximal small intestine (duodenum) |
|
Definition
Disrupted with gastric bypass surgery
1) Calcium (osteoporosis)
2) Iron (cup nails)
3) Niacin (pallegra)
4) Fat soluble vitamine (ADEK) |
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Term
| What are the 3 common causes of impaired fat digestion/absorption in the proximal small intestine? |
|
Definition
1) Chronic pancreatitis (MOST COMMON) with steatorhea
2) Zollinger-Ellison - pH is too low for enzymatic activation
- Treat with PPi or surgery for tumor
3) Biliary function
- Deceased fat absorption (micelle formation impaired)
- Gallstones often cause pancreatitis |
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Term
| Describe the basic strategy of a malabsorption workup. |
|
Definition
1) Determine secretory, malabsorptive/omsotic or both
- 24h fast (malabsorptive/osmotic will improve)
2) If Malabsorptive
- most common CHO is lactose intolerance (H2 breath test and h/x)
- Test for high pancreatic enzymes (pancreatitis)
- Test for B12, folate, minerals
- Steatorrhea
3) If Secretory
- Stool analysis (osmolality), serum electrolytes, mucosal biopsy and serum microbiology. |
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Term
| What are the 2 clinically significant causes of INCREASED absorption? |
|
Definition
1) Hemochromatosis- increased iron absorption
**detected on abdominal MRI**
2) Wilson's Disease- Increase copper ion absorption. |
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