DEMS+LOs+Unit+I

Preamble Monday, September 21st, 2009toc

What follows is the original preamble (more or less the same as those from M2M, etc). A few notes on DEMS: 1) Dr. Michaels is approachable, will answer your questions, and will in many other ways stand in for your mom just like she did in Anatomy. This does not mean she’s a pushover, so be warned. 2) Biochem is a small part of DEMS and a comparatively enormous part of Step One. If you can nail biochem here, in this course, you will save yourself an enormous headache trying to cram it in April. 3) To this end, I recommend Lippincott’s Illustrated Biochemistry (and I can’t stand studying from textbooks). Really good book for that part of this course and for the USMLE. 4) Everything in Endocrine is a feedback loop. If you approach it from that perspective rather than as a bunch of individual factors influencing each other you will drive yourself much less crazy. 5) The DEMS material is so-so, interest-wise—above M2M and Life Cycle but below Neuro and CVPR. Don’t expect to be wowed by clinical application here. However, the LOs generally match up to what they want you to know pretty well. Also, this is high-yield stuff for USMLE: stuff most people don’t bother studying because, well, it’s the guts, and who cares about the guts? Easy points. 6) Many people start their abstinence from class to study for the boards about this time of year. Don’t be surprised if the lecture halls start looking a little empty. On a personal note, I think that’s nuts.

–jcr

 PS- if you find these useful and can go without a latte for a couple of days, I’d like you to give another $5 to charity.

Hey, everybody. These are my compiled learning objectives for DEMS when I took it in the fall of 2008. I hope you find them useful. A few notes:

1. These aren't to be taken as everything-you-need-to-know material, or anything close to it. They can be, however, extremely useful, if only to look at the material a second time in a different format. 2. Learning objectives change. Granted, in our vaunted institution, they often don't change a lot. But it's worth figuring out where these overlap with what you're studying and where they don't to avoid any unnecessary learning (God forbid). 3. They can be incorrect. I hope this is infrequent, but I'm sure there are things in here that aren't accurate. I've tried to curate them reasonably well; I hope one of your classmates will do likewise. If you find an error, kindly let him or her know. 4. They are nothing more or less than my personal take on what we happened to be learning on a given day. Sometimes they're very detailed, sometimes they're uncomprehending, frequently they're irreverent. I occasionally call babies vampires and things like that (dude, they are). Internet lesson: free trumps tasteful. In any case you are free to disagree with me. 5. To anyone who's wondering: I honored this block and all the rest in my first two years. That's not supposed to impress you, but it is supposed to give you some kind of confidence that I have a reasonably good handle on what's going on. 6. To the many of you who are thinking, "How can I repay this wonderful, wonderful man?" I would reply that I never turn down free beer if I can help it. The problem with that is that I suspect I will never meet most of your class, and beer-buying in absentia is a cold and heartless thing. So if you find these useful and would like to do something for me, I would prefer it if you donated $5 to the charity of your choice; if you're stumped, I suggest browsing [|www.charitynavigator.com] for some good options. Kindly do not donate money to armed insurrectionist groups.  i. Addendum on donating to charity: always always ALWAYS have an email account that you set aside purely to sign up for or donate to things (thus ducking all the spam associated therewith). I think I have 1,200 emails in mine, mostly from a donation I made to the SPCA a couple of years ago. Gmail and Hotmail work well. I also recommend using a false street address to avoid direct-mail campaigns.  ii. "That seems like a lot of trouble to go through to donate five bucks"-- yeah, well, welcome to the world, sonny Jim. Doing things for other people frequently is a pain in the ass. Doesn't make it less worth doing. <span style="border: initial none initial; display: block; padding-bottom: 1pt; padding-left: 0in; padding-right: 0in; padding-top: 0in;">

Digestive System Overview
Monday, October 13, 2008 7:51 AM **Digestive System Overview, 10/13/08:**

[Note that I have given up trying to fight the new LO numbering system on Blackboard and henceforth these things will have numbers instead of nice clean bullet points (bullet points, precious). Direct complaints, bomb threats, etc to Thomas.French@uchsc.edu.]

1. Discuss the role of the intrinsic (enteric) nervous system in gut motility. What is the advantage of having extrinsic nervous system input? • The __enteric__ autonomic nervous system (not parasympathetic or sympathetic) is comprised of postganglionic sympathetic- and parasympathetic-like fibers (in/from Meissner's and Auerbach's plexi, see below) that participate in what seems to be a kind of GI reflex arc: they release parasympathetic signals based on local input without going through the CNS. • So I asked Dr. Michaels about all this nervous system coordination. Here's what I got out of her response. • There's three layers of nervous activity going on. • One isn't technically part of the nervous system at all. That's the intrinsic pacemaker activity in the smooth muscle cells of the GI tract. Effectively these function somewhat similarly to cardiac pacemaker cells: the impulse is conveyed through gap junctions to provide some extent of rhythmic depolarization across the smooth muscle in the digestive system. • The next is the enteric nervous system (which, recall, isn't technically part of the CNS-- it's kind of a very local reflex arc). This responds to local conditions (ie. a stretch in local smooth muscle from a nearby bolus of food) by triggering a cascade of local nervous system activity (contracting the lumen upstream of the food, widening the lumen downstream, etc). You can sever all CNS input and still produce peristalsis due to this mechanism. • The final one is the CNS-directed sympathetic and parasympathetic input, which is important for coordinating the response of the system as a whole. • How these fit together: it seems like the pacemaker cells allow the cell-polarity underpinning that allows the enteric and CNS signals to take place rhythmically rather than all at once (you'd like movement in the gut to be pulselike rather than tetanic)-- the cells are only depolarized enough to be susceptible to further nervous-system-signaled depolarization at particular, regular intervals. Then the enteric system controls local flow during those intervals and the CNS controls overall flow and coordination. • My clumsy attempt at metaphor: my impression is that the pacemaker muscles are like the electricity grid of a city street. Without them, nothing happens. The enteric nerves are the individual stop lights that direct traffic along a given street-- they'll turn green when someone's waiting. The CNS nerves are the circuitry that makes sure that if one light turns green, the next light down isn't turning red, ensuring that traffic down the entire street flows smoothly. 2. Describe the structural properties of smooth muscle in the gut that contribute to its performance as a single functional unit. What factors influence the behavior of smooth muscle in the gut? • Stretching of the GI tract by a food bolus sets off a cascade of events in peristalsis: • Upstream of the bolus, the circular muscular layer constricts and longitudinal muscle layer relaxes (preventing retrograde movement); downstream, the opposite happens (circular relaxes, longitudinal contracts) to promote anterograde movement. Different neurotransmitters are used to make each of these happen. • Note that at certain periods of time, particularly in the small bowel and colon, you actually use the same contractions upstream and downstream, the theory being that you really just want to smush the food against the side of the intestine (thus increasing contact with absorptive factors on the intestinal walls) without moving it along. This is called __segmentation__ and is a separate concept from peristalsis. • Recall that smooth muscle can maintain a contraction for long periods of time without using up a lot of ATP. • The smooth muscle found in the GI tract is called "__single unit__" or unitary smooth muscle; distinct populations of smooth muscle cells act in concert as a single unit (thus the clever name). This is in contrast with (for example) the smooth muscle controlling the iris, which are called "multi-unit" and contain populations of muscles that act independently. • How the single-unit smooth muscle cells work together: § Adherence junctions (structural connections) § Nervous system innervation of multiple areas by a single nerve (ensure widespread response to one stimulus) § Gap junctions between cells that carry the pacemaker current, as mentioned above. • But note that, obviously, working as a unit doesn't mean that you want everything to be doing the same thing as once (otherwise the next portion of the GI can't open up when the portion containing the food bolus contracts). If you'll permit another metaphor, it's the difference between a concerto and a bunch of different people playing whatever they want at their own tempo. One is classical music, the other is postmodern art (the creative trash bin of artistic history). Classical music is peristalsis; postmodern art is spasm. • Factors influencing smooth muscle behavior: mainly, the enteric (local-response) and CNS (global-response) innervation. 3. Identify the four layers of the GI tract wall and the basic structural components of each. How does the digestive system protect itself from auto-digestion and pathogenic bacterial invasion? • From lumen outward: • (1) __Mucosa__: three layers: § (a) Epithelial cells. These are specialized according to the region of the GI tract they're in (water absorption, acid secretion, etc). • [Stratified squamous (protective) epithelium covers skeletal muscle layers at either end of GI tract (esophagus and rectum). In between there's generally simple columnar epithelial cells.] • [Apical region of the epithelium: everything above (towards the lumen from) the __tight junction plane__. Basal region: everything below that plane.] § (b) Lamina propria: loose connective tissue containing blood vessels, lymphatics, immune cells, nerves, etc. § (c) Muscularis mucosa: very well-vascularized muscular layer, used in local movement/folding (think rugae! ..which should be on a t-shirt). § Recall that in the small intestine, "fingers" of epithelial cells filled with lamina propria poke up into the lumen to increase absorptive surface area (the intestinal villi). § Throughout the stomach/intestines, also see invaginations: gastric pits and glands in the stomach, crypts of Lieberkuhn in intestines. These seem to be important in protection from auto-digestion and/or bacteria, though recall also that the gut associated lymphatic tissue is located in the mucosa. • (2) __Submucosa__ § Denser connective tissue; contains most of the larger blood vessels. § In the __esophagus__ and __duodenum__, the submucosa also contains glands (in the esophagus and duodenum) that can be used to localize a histology section (submucosal glands are only found in those two locations). § Towards the basal side of the submucosal layer, there are ganglia called **Meissner's plexi** (part of the enteric system, see above). • (3) __Muscularis externa__/__Muscularis propria__ (same thing) § Two muscular layers (from inner to outer): • (a) Circular muscle that constricts the lumen • (b) Longitudinal muscle that widens the lumen § In stomach there's an additional, innermost, obliquely directed layer to aid churning of contents. § There are enteric ganglia between the circular and longitudinal muscle layer of the muscularis externa called **Auerbach's plexi**. • (4) __Adventitia__ or __serosa__ § Resists over-expansion of GI tube. § If it's just connective tissue: called adventitia. § If it's surrounded by a mesentery (mesothelium): called serosa.

Upper GI Histology
Monday, October 13, 2008 10:59 AM **Upper GI Histology, 10/13/08:**

1. Be able to identify and describe the normal histology of the esophagus including the epithelial transition at the junction with the stomach. • There's skeletal muscle in the top half of the esophageal muscularis externa (sphincter/voluntary control); the rest is smooth muscle (involuntary). • Epithelium in the esophagus: __stratified squamous__. • Recall that one of the distinguishing features of the esophagus (and duodenum) is __submucosal glands__: these produce lubrication in the esophagus. • Note that the __muscularis mucosa__ is particularly thick in the esophagus. • At gastroesophageal junction: see a sharp transition from stratified squamous to simple columnar epithelium (no gradual transition). 2. Identify and describe the normal histological features of the stomach. • 3 regions: • __Cardiac__ region at the intake produces mainly mucus to lubricate the food bolus. • __Pyloric__ region at the exit produces mucus to neutralize the chyme before it gets to the duodenum. It also produces **gastrin** to stimulate HCl secretion from the parietal cells in the presence of increased pH. • Body and fundus region (histologically indistinguishable from each other): what we're mainly interested in here. § Initially, relaxes (stretches) to allow food entry. § Upon stretching, a vagal reflex is activated to trigger rhythmic mixing and churning. § Histologically, contain shallow pits (as opposed to the cardiac and pyloric layers, which have deep pits) that terminate in a narrow isthmus with gland-cell-containing recesses spreading out beneath. More on these and their histology in the next LO, but above the isthmus they're called __gastric pits__; below that, they're called __gastric glands__. • Recall that there's a special muscular layer in the muscularis externa of the esophagus called the __oblique layer__ that drives the churning and mixing. • Rugae: folds of mucosal and submucosal layers when the stomach is empty to allow expansion when you eat four pizzas. Also allow greater surface area to allow for more mucus and acid secretion. 3. Identify and describe the major cell types in the stomach epithelium. What are the major cell types in the epithelium (as discussed in lecture and lecture notes), how do they protect themselves from the stomach acid, and what do they produce? What is the overall effect of the product on the digestive process and what are the clinical implications of increased or decreased activity of these cells? • In the __pit__ region (above the isthmus) there's only one cell type: __surface mucus cells__. These produce the mucus that lines the stomach surface and contain lots of mucus granules near the apical surface. • Note that surface mucus cells have really, really tight junctions to forbid intracellular proton movement into the deeper layer. Note further that //H. pylori// destabilizes these tight junctions. • The other thing they do is to produce and release __bicarbonate__ into the mucosal layer. This neutralizes protons that come into contact with the mucus layer (pH in the apical space: around 2; pH on the surface of the epithelial cells: 7). • Even so, cells in the surface epithelium turn over very rapidly (lifetime of about 3-5 days). • In the __neck__ region (just below the isthmus) there are several different types of cells: __stem cells__, which produce new cells, __neck mucus cells__, which produce a slightly more acidic mucus than the surface mucus, and **__parietal cells__**, which produce acid. • Neck mucus cells: look like champagne glasses with a bunch of mucus vesicles (olives?). • Parietal cells: look like fried eggs; eosinophilic due to their very very high mitochondrial content. § 3 things that activate acid production: hormones (eg. gastrin), acetylcholine from the PNS, and histamine. All of these activate G protein-coupled receptors on the apical surface of parietal cells. § Recall that carbonic anhydrase facilitates this reaction: //H2O + CO2 <--> H2CO3 <--> H+ + HCO3-//. The bicarbonate (HCO3-) is exchanged for a chloride atom at the basal side of the cell and thence diffuses into the blood. § There's a H+/K+ ATPase pump in the apical surface of the parietal cell; this extrudes the protons out into the lumen. Chloride follows. § Note that when parietal cells are activated, deep folds (canaliculi) appear in their apical surfaces to increase the surface area of secretion. § Notice that **__intrinsic factor__** __is also produced by parietal cells__. Recall that IF safeguards vitamin B12 (cobalamin) until it gets to the terminal ileum; dysfunction of parietal cells (as due to erosion in the stomach) can cause B12 deficiency. • In the base region (below the neck, at the bottom of each glandular recess), you see __chief cells__, which produce pepsinogen (these are more basophilic with a washed-out appearance), and __enteroendocrine cells__, which secrete various hormones (of which the most notable is __gastrin__, from G cells) into the bloodstream. • Pepsinogen is cleaved to its active form (pepsin) at pH 1-3. § Recall that the name of an enzyme that's secreted in an inactive form and cleaved to become activated under certain conditions is __zymogen__. • Chief cells also produce lipase and, in newborns, a milk clotting enzyme, rennin. • Recall that gastrin promotes release of HCl (from parietal cells) and pepsinogen (from chief cells; it'll be activated by the HCl-lowered pH).

Lower GI Histology and Accessory Organs
Tuesday, October 14, 2008 7:51 AM **Lower GI Histology and Accessory Organs, 10/14/08:**

1. Discuss the functional significance of increased surface area in the small intestines. • Maximizes absorption. • 3 mechanisms for this: permanent, spiral folds (the __plicae circulares__, increase surface area 2x), **villi** projections covering the plicae (increase surface area 10x), and **microvilli** projections covering the villi (increase surface area 30-40x). • Note the distinction between the __rugae__ in the stomach and the __plicae__ in the small intestine: the rugae are there so that the stomach can expand, while the plicae are there to increase surface area contact with the contents. • Note also that the plicae circulares are particularly pronounced in the jejeunum, since this is where most of the absorption actually takes place (the duodenum is more concerned with breaking down and neutralizing the incoming stomach contents). • Note further that each villus has its own blood and lymph supply. This is important (since that's where the absorbed nutrients go into the circulation). 2. Discuss the structure of the intestinal villus in terms of its role in nutrient absorption. • As mentioned, it sticks out into the lumen to increase its contact with nutrients. • Cell types in the villi: • (1) __Goblet cells__ (shaped like goblets with a basal nucleus and apical granules): produce mucus. • (2) __Enterocytes__ (very distinctive microvilli on apical surface called the **brush border**, with delicate lipoproteins coming off them called the **glycocalyx**): responsible for the absorption of nutrients (see following lectures). § Enterocytes contain, on their brush border, an enzyme called __enterokinase__; this cleaves (and activates) __trypsin__, a pancreatic peptidase and major activator/cleaver of other pancreatic pepsidases. § The brush border also contains lots of other enzymes for processing fats, carbohydrates, etc. More on this in a few lectures. • The point of having all these enzymes here seems to be to do the final processing of ingested materials as close to the actual site of absorption as possible, to deny the intestinal bacteria access to pre-processed, ready-to-eat peptides and monosaccharides. § The glycocalyx and mucosal layer help prevent bacteria from sticking to the brush border. • Note that intrinsic factor absorption in the terminal ileum requires special IF receptors in its epithelial membrane. • Note also that fat absorption (in chylomicrons) takes place through large fenestrations (**lacteals**) in the lymphatic channels in the villi (chylomicrons are too large to get directly into the capillaries); these eventually get dumped back into the venous circulation through the thoracic duct. Again, more on this later. 3. Identify and describe the structure, location and function of Brunner’s Glands. • **Brunner's Glands**: submucosal glands (recall that submucosal glands are found only in the esophagus and duodenum); release a mucosal alkaline secretion that liquefies and neutralizes the chyme from the stomach. Their ducts release into the crypts of Lieberkuhn and from there out into the lumen. • These glands are particularly numerous in the upper part of duodenum. 4. Identify and describe the structure of the crypts of Lieberkuhn. What do cells in the crypt produce and what is their overall effect on the digestive process and on the process of epithelial cell turnover? • Crypts of Lieberkuhn: invaginations from the mucosal layer into the laminal layer. • Cell types in the crypts of Lieberkuhn: • Stem cells in the crypts make the cells in the epithelium of the crypt and also the villi (they migrate up out of the crypt, up to the tip of the villus, and desquamate off). • Endocrine cells that secrete cholecystokinin (stimulates pancreatic enzyme secretion and bile release from gall bladder) and secretin (stimulates pancreatic fluid and bicarbonate release). • **Paneth cells** (eosinophilic cells): produce **lysozyme** (antibacterial) and **defensins** (positively-charged, amphipathic small peptides that insert in and destabilize the cell membranes of bacteria). § A side note on this: some commensal bacteria promote Paneth cell development-- they're resistant to the defensins but they make sure the defensins are secreted (sort of like burglars who break in and then install burglar bars, who basically just want to watch your TV and maybe drink one or two of your beers). 5. Compare and contrast a cross section of a villus with a cross section of a crypt of Lieberkuhn. • Villus: Whitish-looking cells (goblet cells) surrounded by fairly uniform enterocytes in the epithelium; may be able to see the brush border. Lots of nerves and blood vessels in the middle of the villus. • Crypt: Highly eosinophilic (defensin) Paneth cells are characteristic; look for the empty lumen in the middle. 6. Identify and describe the structure of the colon. Compare and contrast the cell population in a crypt of the small intestine to one of the large intestine. • Colon: water/mineral absorption; no digestion; lots of commensal bacteria. • Note it has an incomplete longitudinal muscular layer (three bands, the __taenia coli__). Because of this relatively weak muscularis externa, the large intestine is more vulnerable to being pushed out from within (diverticulosis). • Note there are no villi in the large intestines, only crypts. • Cell types in large intestinal crypts: • __Goblet cells__, as in the villi (but not the crypts) of the small intestine. • __Stem cells__ • __Absorptive cells__ (not enterocytes, since they have no enzymatic activity). • A cross-section of a large-intestine crypt cell would show lots and lots of goblet cells and __no Paneth cells__ (both distinguishing it from small intestinal crypts). • Once it gets to the rectum, you transition back from simple columnar to stratified squamous epithelium. 7. Identify and describe the normal histology of the pancreas and discuss how enzymes released in their inactive form become activated. • As mentioned, the pancreas produces lots of zymogens that are activated by trypsin-mediated cleavage, as well as a bicarbonate solution that liquefies and neutralizes the chyme. • Histologically, see lots of acini: terminal cul-de-sacs of gland cells which produce enzymes. Note there are __centroacinar__ cells that secrete bicarbonate solution into the enzyme solution up at the beginning of the duct. • Enzyme-producing cells: Eosinophilic apical surface, basophilic basal surface. All cells make all pancreatic enzymes. • Centroacinar cells (bicarbonate-producing cells): lots of granules on the apical surface. 8. Identify and describe the normal histology of the gallbladder. Compare and contrast the histology of the gallbladder and the small intestines. • Gall bladder functions: storage and concentration of bile (bile salts, bilirubin, cholesterol). • Grossly, bumpy, rough surface, similar to stomach. • Histologically, similar to layers of the gut (other than __no muscularis mucosa layer__). Cells are simple columnar; epithelium has lots of microvilli. These cells take up sodium and pump it into the basolateral region (water follows). 9. Be able to identify and describe the normal histological features of a salivary gland. Compare and contrast the structure of acini in the salivary gland with those of the exocrine pancreas. • As in the pancreas, you see gland cells organized into clusters of acini (gland cells, contained in a cul-de-sac, that secrete __mucus__ into a duct; the duct cells in turn secrete __serous__ products that modify the secretion of the gland cells). o Mucus-producing cells: washed-out appearance, flattened nucleus at basal side. o Serous-producing cells: bigger, more centrally-located nuclei. o Notice submandibular glands release a mixed serous and mucosal product (serous cells surrounding mucosal cells). Sublingual glands are mucus-secreting, while parotid glands are serous-secreting. o Specialized smooth muscle cells wrap around acinae (myoepithelial cells), only in salivary gland cells: contract to help expel gland contents into the mouth. • Distinctions between pancreas and salivary glands: the acini of the salivary glands secrete all the expelled solution, while the acini of the pancreas secrete the enzyme part of the solution and the centroacinar cells in the duct add bicarbonate to it.
 * [Note a handy little table on the bottom of page 8 of these notes describing regional differences between duodenum, jejeunum, and ileum.]
 * [Note that in the ileum, you start to see much less plicae folding and more Peyer's patches:]
 * Peyer's patches: contain M cells that take samples of material in the lumen and transport them to antigen-presenting cells, which in turn present them to local B cells, which consequently turn into plasma cells and make **IgA**, which is then transported into the luminal surface.

GI Motility and Regulation
Tuesday, October 14, 2008 9:00 AM **GI Motility and Regulation, 10/14/08:**

1. Be able to describe how the neurotransmitter acetylcholine causes contraction of the smooth muscle cells in the GI tract. • [Ca++ + calmodulin activates myosin light chain kinase, which phosphorylates myosin and allows actin-myosin cross-bridge cycling activity.] • ACh: causes action potentials to fire at each peak of the basic electrical rhythm (see next LO). Binds to Gq muscarinic receptors and causes an increase in intracellular calcium. 2. Describe the characteristics of the basic electrical rhythm (BER) of the small intestine and its relation to smooth muscle contractile activity. • As described in "Digestive System Overview," the GI tract has pacemaker cells that create cardiac-like depolarizations of about 15 mV every 5 seconds or so. Most of the time, those depolarizations don't result in an action potential, but they do provide the "kindling" for ACh to provoke action potentials at the peak of each depolarizations. This rhythmic, basal depolarization is called the **basic electrical rhythm**. 3. State the stimulus that initiates the swallowing sequence. Identify the point at which the swallowing sequence becomes automatic (independent of voluntary control). • Food enters the pharynx, pushed by the tongue; the soft palate elevates and the upper constrictor muscle contracts. After this point everything is automatic. • Note that respiration is centrally suspended for a couple of seconds during the swallowing phase. 4. Describe the storage, digestion, and motility roles of the stomach. • Not sure on this. It stores, it digests, it's motile. 5. Describe the mechanisms which regulate gastric secretion (i.e. the effects of acid, fat, and solutions of high osmolarity in the duodenum, etc.). • Acidity and high osmolarity (from the stomach's chyme mixture) in the __duodenum__ causes increased __contraction__ of the pyloric sphincter (the duodenum is already full). • The presence of fat in the duodenum causes release of __cholecystokinin__ by enteric endocrine cells and, again, a decrease of gastric motility. • More gastro-centric mechanisms in the next lecture. 6. Describe the origin of the progression of peristaltic waves across the body and antrum of the stomach. Include their role in mixing and propulsion of gastric contents. • The peristaltic waves begin in the mid-stomach after the stomach has stretched to accommodate the food bolus. • The funny thing about the stomach is that the peristaltic waves get faster and stronger and begin to outrun the food bolus. They reach the pyloric sphincter, and are __reflected back__ towards the body of the stomach, pushing the bolus back towards the fundus-- churning. This allows more exposure of the bolus to gastric fluids and also mechanically breaks it down into smaller particles. • Note that the stronger the gastric contractions, the more chyme is forced out through the pyloric sphincter. 7. Contrast the patterns of intestinal motility seen during the absorptive phase (segmentation) with that of the post-absorptive phase between meals (the migrating motility complex (MMC)). • Segmentation: "mixing without net propulsion." That is, everything contracts around the bolus, squeezing it around in both directions and pressing it into the surrounding GI tract; then everything relaxes, and the bolus returns to its original position in the GI tract. The point here is to absorb more nutrients by increasing the exposure of the bolus to the absorptive surface of the GI tract, but not to move it along until all available nutrients have been harvested. • (note: past the stomach, you don't really have a bolus any more; it's just chyme or post-chyme. But for ease of discussion I'm going to still call it a bolus. I'm a born rebel, me.) • Migratory/peristaltic: once all the nutrients have, in fact, been harvested, __migrating myoelectric motor complexes__ (MMCs) use peristaltic (as opposed to segmentation) contractions to move along the nutrient-exhausted bolus. This process begins about once every 90 minutes (notes also seem to say every two hours) or so-- a long wave of peristalsis begins in the stomach, travels all the way down to the end of the ileum, and then begins again in the stomach. In each GI region it takes about 10-15 minutes to go through (about 40 cm of the GI tract is involved at any given time)-- hence the long time taken to travel to the terminal ileum. Note that MMCs shouldn't originate during or immediately following meals. 8. Contrast the colonic motor activity during a “mass movement” with that during haustral shuttling and the consequence of each type of colonic motility. • Haustra: pouches of large intestine that result from the fact that the three taenia coli (longitudinal bands in the muscularis externa) are shorter than the rest of the colon, causing bunching. • At least that's what Wiki implies. The notes seem to indicate that the segmentation contractions are what form the haustra. • Dr. Michaels on this seeming discrepancy: "Both are correct on some level, James. The taenia are shorter than the colon so they do contribute to the haustra 'pouches'....and you see this even in the anatomy lab cadavers (i.e. when there is no segmentation...).....so anatomically, that’s probably the best answer. I think Dr. G means that when you have segmentation in the colon, haustra become more prominent and during mass movement, the haustra become far less prominent (it’s a noticeable difference during imaging!)." • The segmentation process is particularly pronounced in the large intestine. These segmentation processes, during which contents can shift back and forth between one haustra and another, are called haustral shuttling. By contrast, the mass movements are peculiar to the large intestine and involve a intense, prolonged peristaltic contraction. • Notes say that "the most prominent patterns of motility" are segmentation, while the mass movements are responsible for "forward propulsions." Take it for what it's worth. 9. Describe the sequence of events occurring during reflexive defecation, differentiating those movements under voluntary control and those under intrinsic control. • The mass movements just described push fecal material into the rectum, stretching it and initiating the defecation reflex (relaxes the internal sphincter). This can be controlled by voluntary contraction of the external sphincter. • Note that this generally occurs right after a meal (need to clear out the old stuff to make room for the new).

GI Secretion and Digestion
Tuesday, October 14, 2008 9:58 AM **GI Secretion and Digestion, 10/14/08:**

1. Describe the mechanism of gastric acid generation and secretion, including the role of K+, Cl /HCO3, carbonic anhydrase and H+-K+ ATPase. • As mentioned in "Upper GI Histology," carbonic anhydrase facilitates the conversion of CO2 (from the blood) and H2O to HCO3- and H+. The H-K ATPase pumps H+ out and K+ in from the apical surface. HCO3- is expelled from the basal side of the cell in exchange for Cl- uptake; the Cl- follows the H+ out the apical surface. • Note that H2O follows H+ and Cl-, leading to a efflux of water into the lumen of the stomach. • Note also that the blood leaving the parietal cell is basic (high pH) due to the basal efflux of HCO3-. • Note further that luminal K+ depletion can occur near the apical H/K ATPase pumps. Thus you have potassium channels in the apical surface to allow K+ to maintain a sufficient level to allow the pump to function. Note that this is kind of like spilling your drink (K+ release) on someone you like, in order to clean it up (K+ uptake), because that's the only way you know how to start a conversation with them (H+ intake). Yeah, the parietal cells are kind of desperate. • Note, finally, that the secretion of H+ is more of a spurt than a trickle, to clear the surrounding mucosa. The muscularis mucosa contracts around the crypts to do this. 2. Describe how the three acid secretagogues induce acid secretion by parietal cells. • "Secretagogues" (which is now the leading contender for the name of my firstborn): • (1) __ACh__ § Binds to Gq muscarinic receptors and causes an increase in intracellular Ca++. This causes increased activity of protein kinase C.  • (2) __Gastrin__ § Causes an increase of intracellular Ca++ (mechanism not clear). Likewise, increased PKC activity. § Recall gastrin also stimulates chief cells to release pepsinogen. • (3) __Histamine__ § Binds to a different G protein-coupled receptor (the Gs histamine H2 receptor) to increase adenylyl cyclase, increasing cAMP levels-- this causes increased protein kinase A activity. • The point of all this is that the increased PKA/PKC activity phosphorylates the H/K ATPase pumps, increasing their activity to increase proton efflux (and, by Le Chatelier, increasing the rate of water/CO2 breakdown). • Note that the abovementioned pathways are all called the __direct__ pathway of acid secretion stimulation. The __indirect__ pathway, then, is when ACh and gastrin stimulate "enterochromaffin-like" (ECL) cells to secrete histamine (which in turn acts directly). This seems to be the major route for gastrin to affect H+ secretion. 3. Describe the modulation of gastric acid secretion throughout the day and night. • The rate of acid secretion follows a circadian rhythm, regardless of food intake. • It's highest in the evening and lowest in the morning. • Smelling, looking at, or tasting food initiates a vagal nerve reflex (cephalic phase), which releases ACh and gastrin (and thus histamine), and inhibit somatostatin release (somatostatins block cAMP formation). • Entry of food into the stomach (gastric phase) distends the gastric mucosa, which stimulates another vagal reflex with much the same consequences. Partially digested proteins also stimulate gastrin-releasing cells in the stomach and also in the duodenum (gastric and intestinal phases, respectively) • Not sure if it's important, but the percent of total acid secretion from each of the cephalic, gastric, and intestinal phases is 30%, 60%, and 10% respectively. 4. Describe the protective barrier of the gastric surface. • What you're looking to protect yourself against: pepsin (proteolytic enzyme) and acid. • Recall that mucus infused with bicarbonate coats the entirety of the stomach mucosa. Recall also that there's something like a 6.4 pH gradient (ie. 10^6.4 = about a 2.5-million fold concentration difference) between the lumen of the stomach (pH 1) and the blood beneath the cell (pH 7.4) due to this bicarb in the mucosa. • So much for the acid. As for pepsin, it doesn't function above pH about 5 or so-- thus by the time the pepsin gets to the surface of the cell, the ambient pH is high enough that it doesn't autodigest the stomach epithelium. • Note, however, that this mucus-bicarb layer would prevent HCl from getting out into the lumen if the HCl was passively secreted. As mentioned, what happens is that the HCl is not just secreted but squirted out into the lumen (contraction of the muscularis mucosa by the parietal cells)-- this gets it clear of the mucus/bicarb solution and out into the lumen. 5. Discuss possible targets of the current generation of ulcer drugs. • Essentially you're looking to stop acid secretion. You can do this by blocking the H/K ATPase pumps (proton pump inhibitors) or by blocking the activators of the H/K pumps (antimuscarinics, anticholinergics).
 * [Functions of the stomach: motor, secretory, endocrine.]
 * [Secretory products of the stomach: HCl, pepsinogen, mucin, HCO3-, intrinsic factor, and water.]

GI Digestion and Absorption
Tuesday, October 14, 2008 10:34 AM **GI Digestion and Absorption, 10/14/08:**

1. Describe the role, if any, of HCl in the gastric digestion of carbohydrates, proteins and fats. • Proteolytic enzymes like pepsin are activated (from pepsinogen) by low pH (HCl). Low pH also denatures proteins and exposes their cleavage sites to pepsin. HCl contributes to the breakdown of all food to some degree, but the great majority of the breakdown of carbohydrates and fats occurs due to salivary and duodenal/pancreatic enzymes. • Note that intrinsic factor is the only indispensable secretion of the stomach (can do pretty well without HCl or pepsin). 2. List the chemical classes of the carbohydrates entering the duodenum from the stomach, and identify mechanisms mediating further digestion and absorption across the apical and basolateral membranes of the intestinal epithelia. Include pancreatic secretions and brush-border enzymes. • [A couple introductory notes will make the section on carb digestion much easier.] o Most dietary carbohydrates are composed of plant starch of amylopectin, a poly-glucose saccharide in which adjacent glucose molecules can be linked by either or both of alpha-1,6 bonds and alpha-1,4 bonds. o Alpha-limit dextrin is amylopectin in which most of the 1,4 bonds have been broken (so there's two or three 1,4-linked glucose molecules that are tagged through a 1,6 link to two or three other 1,4-linked glucose molecules). o Maltose is two 1,4-linked glucose molecules. Maltotriose is three 1,4-linked glucose molecules. • Classes of carbohydrate coming in: • Plant starch, or __amylopectin__ (the main carbohydrate in most human diets): contains both alpha-1,4 and alpha-1,6 glucose linkage bonds. • __Cellulose__: contains beta-1,4 linkages, thus it passes through the GI tract undigested, as dietary fiber. • __Enzymes and stuff in the lumen of the duodenum__: • Alpha-amylase (breaks alpha-1,4 bonds) from the salivary glands and also the pancreas <span style="font-family: Verdana,sans-serif; font-size: 10pt;">1. Since alpha-1,6 glucose linkages are not digested by amylase, __amylase never produces free glucose__ (it tends to produce alpha-dextrin). • HCl and pepsin from the stomach • About 30 zymogens from the pancreas including trypsinogen • Bile salts and bile acids from the liver • HCO3- from all over • __Enzymes on the brush-border__: • Sucrase-isomaltase (breaks alpha-1,6 glucose bonds to get maltose and/or maltotriose) • Maltase-glucoamylase (breaks down maltotriose and maltose to glucose) • Lactase (breaks down lactose to glucose and galactose) • Sucrase (breaks down sucrose to glucose and fructose) • So around the brush border, you're getting things boiled down to individual __glucose__, __fructose__, and __galactose__ molecules (monosaccharides). • The monosaccharides are then absorbed by the enterocytes in the following manner: • Na+-glucose cotransporter functions along the sodium gradient created by Na/K ATPase pumps on the basal membrane. Co-transporter = SGLT1. • Same thing with galactose (cotransport with sodium down its gradient). • Fructose can enter independently of the sodium intake (transporter = GLUT5); thus if an infant has no working SGLT1 transporters, can avoid malnutrition by a fructose diet. • All three monosaccharides are transported out the basal side of the cell by the same transporter (GLUT2) and go into the capillary system. 3. Predict the small intestine and colonic consequence of a deficiency in the enzyme lactase, and identify age groups who commonly exhibit this deficiency. • Can't digest milk sugar (lactose). Unabsorbed lactose draws water back into the intestinal lumen by osmosis, causing diarrhea. Colonic bacteria also metabolize the lactose, creating byproducts of methane, CO2, etc-- pain, bloating, etc. This mainly shows up in older populations. • [Note SGLT1 deficiency also causes osmotic diarrhea.] 4. State the mechanism for activating pepsinogen, and describe the digestion products of pepsin activity. • As mentioned, pepsinogen is cleaved and activated by low pH due to HCl secretion. • It's an endopeptidase (see below) that cleaves next to aromatic amino acid residues-- so its digestion products are smaller peptides, like any peptidase. • It's not essential for normal protein digestion. 5. List the chemical classes of the proteins entering the duodenum from the stomach, and identify mechanisms mediating further digestion and absorption across the apical and basolateral membranes of the intestinal epithelia. Include pancreatic secretions and brush-border enzymes. • Chemical classes of the proteins: I wouldn't know where to begin. They're proteins. • Digestion begins in the stomach with pepsin. • __Digestion__: In the duodenum, recall that the brush border consists largely of enterocytes, which secrete enteropeptidase-- which converts trypsinogen to trypsin. Trypsin, in turn, activates all the other secreted zymogens (including other trypsinogens), which are all proteolytic. • Note, however, that there are two distinct classes of peptidases (ie. proteolytic enzymes): endopeptidases and exopeptidases. Endopeptidases, as the name implies, cleave amino acid linkages within proteins (between two non-terminal residues). Exopeptidases cleave off the last amino acid residue from either the C- or N-terminus of the protein. • Endopeptidases (all are secreted by the pancreas in zymogen form): § Pepsin (cleaves next to aromatic amino acids) § Trypsin (cleaves arginine-lysine linkages) § Chymotrypsin (cleaves next to aromatic amino acids) § Elastase (cleaves next to small, hydrophobic amino acids) • Exopeptidases: § Carboxypeptidases A and B target the C terminus and are secreted by the pancreas. § Aminopeptidases target the N-terminus and are contained in the brush border. • How this works: • The secreted peptidases in the lumen of the duodenum digest ingested proteins to small oligopeptides. • At the brush border, aminopeptidases (and a few others) further digest the oligopeptides into single amino acids or the di- and tripeptides are absorbed intact. • Eventually, the pancreatic enzymes digest themselves and each other (so that they don't act on the walls of the intestine all the way down). • __Absorption__: • PePT1 transporter co-transports di- and tripeptides into the cell along with H+ down the H+ gradient (the H+ concentration inside the cell is kept low by an adjacent apical Na/H transporter). From there they're digested to single amino acids in the cytoplasm. • Single-amino-acid transporters can generally be grouped by whether they transport neutral, basic, acidic, or proline/glycine amino acids. They're all co-transporters with Na+. • Cytoplasmic single amino acids follow their concentration gradients out the basal side of the cell and are absorbed by the capillaries. 6. Contrast the secondary active transport of amino acids with that of di- and tri-peptides, including the ion used as the energy source. • Amino acids: co-transport with __Na+__. Di- and tripeptides: co-transport with __H+__. 7. List the chemical classes of the lipids entering the duodenum from the stomach, and identify mechanisms mediating further digestion and absorption across the apical and basolateral membranes of the intestinal epithelia. Include the roles of pancreatic lipase, colipase, and micelles. • Classes: the most important dietary lipid is __triglycerides__ (glycerol with three ester bonds to fatty acids). These are way, way too big and lipidey to get into the intestinal cells. Here's how we work around it. • First, triglyceride droplets (separated out by mastication and stomach-churning) are emulsified by __bile salts__ and __lecithin__ to form microparticles (~1 micron in diameter). • Next, __lipase__ anchors to the surface of the fatty microparticles (with the help of colipase) and digests them into monoglycerides and fatty acids. These are small enough to actually take into the cell, but they're still too hydrophobic to travel in the fluid of the lumen. • So next, the monoglycerides and fatty acids are solubilized in __bile salts__ to form __micelles__ (like soap foam: hydrophilic outside, hydrophobic inside). The micelles can be transported to the brush border. When they get there, the lipids diffuse out and through the brush border membrane (lipid-emptied bile salt micelles return to the lumen to pick up more lipids). • Inside the enterocytes, the triglycerides - which have just been laboriously broken down into monoglycerides and fatty acids - are now reassembled into triglycerides again. Then they're packaged into lipoproteins called chylomicrons (remember these from CVPR?) and migrate out into the lacteals and thence into the __lymphatic__ system (see "Lower GI Histology and Accessory Organs"), and from there gets dumped back into the venous circulation, whence to the liver. • Again, if fat can't be absorbed from the lumen of the intestine, it pulls water back with it, causing fatty diarrhea (which sounds like a ton of fun, let me tell you). Fatty stool is called **steatorrhea** and is a hallmark of fat malabsorption. Naturally, if you've got steatorrhea, your absorption of the ADEK fat-soluble vitamins is going to be pretty poor. 8. Describe the composition and formation of chylomicrons, their movement across the enterocyte basolateral membrane, and the route of entry into the cardiovascular system. • See above and CVPR notes ("Lipids, Lipoproteins, and Atherosclerosis I + II;" specifically, apoB48 units are packaged into chylomicron backbones). 9. Define steatorrhea, and predict the effects of steatorrhea on the absorption of fat-soluble vitamins. • See above. 10. Describe the absorption of water-soluble vitamins, including the role of intrinsic factor in the absorption of vitamin B12. • Water-soluble vitamins are absorbed either by co-transport with Na+ or passive diffusion. This all takes place in the upper small intestine. • Note the exception of cobalamin, which is bound to IF in the stomach and reabsorbed by a special transport receptor in the terminal ileum. 11. Describe the pathways, if any, by which Na ions and water are absorbed in the small intestine and colon. • In the small intestine, the Na+ is absorbed down its concentration gradient (driven by Na/K ATPase pumps in the basal membrane) and the water follows. There's also an apical Na/H exchanger (mentioned above in the section on amino acid absorption). • In the colon, there are also apical sodium channels that are down- or up-regulated in response to plasma aldosterone increases and decreases, respectively. Note that increased Na absorption through this route means more K secretion into the lumen.

Diseases of the Upper GI: Pathology of the Esophagus
Wednesday, October 15, 2008 8:02 AM **Diseases of the Upper GI: Pathology of the Esophagus, 10/15/08:**

[For those like myself who had no idea what "H+E stain" meant: it stands for **hematoxylin and eosin stain**.]

1. Define Mallory-Weiss tear and explain its relevance in alcoholic patients. • **Mallory-Weiss tear**: repeated retching causes an increase in esophageal pressure, resulting in a small tear of variable depth down by the gastroesophageal junction. • Alcoholics, obviously, retch a fair amount. M-W tears can also cause esophageal varices (which result with some frequency from alcoholic liver cirrhosis) to tear open. • [Note the distinction in depth between Mallory-Weiss tears and Boerhaave Syndrome (full-depth perforation of esophagus).] 2. Define achalasia. • **Achalasia**: Motility disorder, mainly due to degenerative neural changes-- upper sphincter of the esophagus can't relax after swallowing. • Note that Dr. Peterson discusses achalasia in terms of the lower, not upper, sphincter. • Achalasia can result from Chagas disease (parasitic disease around Amazon basin), which I actually saw quite a bit of this summer. If you ever head down to Bolivia it's all over the place and is a leading cause of heart failure (dilated cardiomyopathy). 3. List the two most common classes of esophagitis and three etiologies within each class. • __Non-infectious__ esophagitis: • Chemical injury (acid, lye, detergent)-- scar, form strictures. • Pill esophagitis: alendronate (Fosamax), quinidine, potassium chloride, etc, can get stuck in the esophagus and release their contents there, causing ulcerations. Tends to occur where the aortic arch compresses the esophagus or in the lower esophageal sphincter. Patients not taking enough fluid with pills can be a cause. • __Reflux__: § GERD is the most common type of esophagitis. § Note that obesity can cause poor functioning of the lower esophageal sphincter, as can caffeine, CNS depressants, tobacco, nasogastric tubes, etc.  • Radiation injury (particularly in radiation therapy to the chest) • Thermal injury • Some anti-cancer drugs • __Infectious__ esophagitis: (more common, as you would expect, in immunocompromised or elderly) • There's no evidence of bacterial involvement in esophageal ulcers (as opposed to gastric ulcers, where they're the main players). • Fungal: frequently due to //Candida// infection (classic for AIDS), //Aspergillus//, histoplasmosis, or blastomycosis (all mainly in immunocompromised patients). • Viral: § Mainly due to a herpes simplex virus (which infects squamous epithelium) or a cytomegalovirus (which infects endothelial cells in blood vessels and glandular epithelium). Sometimes direct HIV infection. 4. List the four histologic features of "non-specific" esophagitis as well as the microscopic findings that indicate specific diagnoses (reflux, also called GERD, or viral or fungal disease). • Histologic features of non-specific esophagitis: mixed inflammatory infiltrate; inflammation-reactive epithelium. • __Histology of GERD__: • basal epithelial cells undergo hyperplasia, aka reflux-associated squamous hyperplasia (RASH). • Also see mixed inflammatory infiltrate with PMNs and, especially, __eosinophils__. • Also get elongation of the fibrovascular papillae of the lamina propria. • Note that GERD can cause metaplasia to a columnar epithelium. More on this later. • Histology of fungal esophagitis: Candida shows up as yeast/pseudohyphae forms; use PAS-D (Periodic Acid-Schiff diastase stain) and GMS (a silver stain) to detect. • Histology of viral esophagitis: • Herpes infection causes __multinucleation__ of infected cells-- look also for an eosinophilic nuclear inclusion. Sample the edges of the ulcer (living part), not the middle (dead part). • CMV infection causes increase in cell size (__cytomegaly__). Also look for both eosinophilic nuclear inclusions and basophilic cytoplasmic inclusions. • [HIV infection causes multiple small thrush-like lesions early; later it can cause necrosis of squamous cells, leading to ulcers and fistulas.] 5. Define Barrett esophagus and describe the most dangerous form. State how this form is recognized microscopically. • Barrett esophagus: metaplastic changes of squamous epithelium to columnar. 2 types: • Cardiac-type epithelium: distal 2-3 cm of esophagus looks like columnar cells without goblet cells (as in the cardiac region of the stomach). Note this may not actually be Barrett esophagus (could just be the normal boundary of the stomach with the esophagus). • Small-intestinal epithelium: distal 2-3 cm of the esophagus looks like columnar cells with goblet cells. This second form is more predisposed to dysplasia and is hence more dangerous. § Microscopically, you look for columnar epithelium with goblet cells. § Risk of progression to adenocarcinoma seems to increase the farther up it projects from the gastroesophageal junction. • Grossly, looks like a salmon-pink patch of esophagus down by the junction on endoscopy. But note that it's a diagnosis that can only be made histologically. • 10% of patients with GERD acquire Barrett esophagus; 10% of those develop adenocarcinoma of the esophagus. 6. List the five classifications (with respect to premalignant changes) that should be used to describe Barrett esophagus. Describe in general terms how these classes of changes are related to each other. • [Nuclear abnormalities: most important prognostically is stratification; look for variation in size and shape, increased nuclear:cytoplasmic ratio, loss of goblet cells, etc.] • (1) Negative for dysplasia: inflammatory-reactive changes only. • (2) Indeterminate for dysplasia: hard to tell if it's dysplasia or inflammation reaction. • (3) Low-grade dysplasia: retention of goblet cells, still has mucin; some nuclear crowding. • (4) High-grade dysplasia: less goblet cells, some mucin but much less. Increased stratification, nuclear changes. • (5) Carcinoma (in situ, not yet breaking through the basement membrane, or invasive, in which it's already broken through the basement membrane): FUBARed cells. You know. 7. List the two common types of esophageal carcinoma and state the commonly associated or predisposing conditions for each type. Describe how the incidence of these tumors has been changing over recent decades. • **Squamous cell carcinoma**: dysplasia arising from tobacco or alcohol use. More likely to be in the __middle__ esophagus. • Increased risk: Plummer-Vinson syndrome (congenital esophageal webs) and hyperkeratosis in acral skin. • **Adenocarcinoma**: Dysplasia arising from Barrett's esophagus. More likely to be in the __lower__ esophagus. • Esophageal adenocarcinoma is the cancer with the __most rapidly increasing incidence__ in the US (GERD from obesity = one proposed reason). • Survival rates for both types at 5 years is poor, around 30%; most patients present with metastatic, highly invasive disease states. • Clinically, look for progressive dysphagia.

Diseases of the Upper GI: Pathology of the Stomach and Small Bowel
Wednesday, October 15, 2008 8:55 AM **Diseases of the Upper GI: Pathology of the Stomach and Small Bowel, 10/15/08:**

1. State the difference between erosion and ulcer in microscopic terms. • **Erosion**: destroys the superficial mucosa (epithelium, lamina propria) but not the muscularis mucosa or deeper layers. • **Ulcer**: all mucosa (including muscularis mucosa) has been destroyed; injury extends into the layers beneath. 2. Define acute gastritis and describe its microscopic appearance. List two main classes of etiologically associated factors. • **Acute gastritis**: As might be surmised from the name, rapid-onset gastritis. Histologically, look for mucosal edema, intramucosal hemorrhage, and some degree of erosion. • Etiologically, think __chemical__ (NSAIDs, EtOH, tobacco, chemotherapy, bile reflux) or __stress__ (due to infection, trauma, surgery, or shock)-- things that destroy the protective mucus coating in the stomach. • Note that NSAID-induced injury is more complicated than these notes would suggest, on account of prostaglandins do quite a number of things in the stomach. More on this later, but I think you can classify NSAID injury into both an acute and a chronic phase. 3. State the relationship between acute gastritis and chemical gastropathy, and the principal difference in their microscopic appearances. • Chemical gastropathy: as mentioned, a subtype of acute gastritis caused by various chemicals. • Principal difference: in chemical gastropathy, the pits in the gastric epithelium become __hyperplastic__ (possibly to increase protective mucus secretion?). 4. Define chronic gastritis and list the two most important forms. State the underlying etiology of these two forms. • Chronic gastritis isn't just a chronic form of acute gastritis-- there's a different underlying pathology. • Both acute and chronic gastritis destroy the mucus-producing cells in the gastric pits. The difference is that in acute gastritis, the cells can recover or be replaced, while in chronic gastritis, the cells never regenerate (and thus progression to ulceration and perforation is more common). • Histologically in chronic gastritis, look for an infiltration of the lamina propria with plasma cells and lymphocytes, with or without neutrophils. Also look for __atrophy__ of the mucus glands and pits (in the antrum/pylorus), and parietal cells (in the body/fundus). • Note the contrast: in chemical acute gastritis, you look for epithelial hyperplasia in order to secrete more mucus; in chronic gastritis, you look for epithelial atrophy instead. • **Type A chronic gastritis**: __autoimmune__ etiology. • Loss of __parietal cells__ due to **autoantibodies** • Less common (10%) • Watch out for __B12 malabsorption__ (no IF) • Increased rate of adenocarcinoma/carcinoma of neuroendocrine cells • Mainly targets body and fundus of stomach. • **Type B chronic gastritis**: mainly infectious; "active" gastritis (PMN infiltration) or follicular with lymphocyte germinal centers. • Main etiology is **//Helicobacter pylori//**, which burrows into the gastric mucosa. • More common (90%) • H. pylori produces ammonia, raising the pH in the stomach. • Look for __peptic ulcers__; also __MALT lymphoma__ (can be resolved with antibiotics). • Mainly targets antrum and pylorus of stomach. • [Dr. Peterson: all atrophic (chronic) gastritis is due to //H. pylori//, autoantibody- and infectious mechanisms alike. Where this leaves Crohn's disease gastritis is sort of up in the air.] 5. Describe the histological appearance of active gastritis, atrophy and intestinal metaplasia. • "Active" gastritis: neutrophils in the epithelium. • Atrophy: loss of parietal cells (type A) or mucus glands/pits (type B)  • Intestinal metaplasia: makes the stomach epithelium look either like the small intestine (complete) or colon (incomplete). 6. List six special types of gastritis that can be recognized histologically. • Sarcoidosis, Crohn's disease, amyloidosis, eosinophilic, lymphocytic, graft-vs-host. 7. List four mechanisms that protect the gastric mucosa from ulceration. • (1) Mucus (surface mucus cells in pits) • (2) Bicarbonate (also surface mucus cells in pits) • (3) Tight junctions between epithelial cells • (4) Mucosal blood flow (under prostaglandin control, thus the influence of NSAIDS) to wash away acid that makes it through the tight junctions • [(5) The notes also mention the rapid turnover rate of these cells.] 8. List four clinical factors that predispose to ulcer formation. • (1) Helicobacter infection (about 90%) • (2) NSAID use (about 10%, although lots of comorbidity with H. pylori infection) • (3) Tobacco/EtOH • (4) Alcoholic cirrhosis • (5) Corticosteroid use. 9. Compare and contrast the epidemiologic trends, predisposing factors, and histologic features of the two common variants of gastric carcinoma. • 3% of all cancer mortality. • Associated with EtOH, tobacco, and certain diets (common in Japan). • Two histological types of gastric carcinoma: • __Diffuse__ type: poorly differentiated ("signet ring") cells; usually found in younger patients; some familial forms (associated with cadherin mutations). • __Intestinal__ type: atrophy with intestinal metaplasia. Adenocarcinoma cells look like colonic adenocarcinoma. • Intestinal type has gotten less common; diffuse type has stayed about constant. 10. Compare and contrast the clinical and histologic features that allow differentiation of the three hypertrophic gastropathy syndromes. • __Hypertrophic gastropathies__: easily mistaken for carcinoma; see prominent rugal folds and thickening of the gastric wall. • **Zollinger-Ellison syndrome**: § __High serum gastrin__ levels (neuroendocrine tumor) leads to hyperplastic parietal cells, creating high HCl concentration in lumen. § Note there seems to be some disagreement about where these gastrinomas are actually located; the one thing that seems reasonably sure is that they're not in the stomach itself. They're in either the pancreas or duodenum, from which they release gastrin into the circulation; the circulating gastrin then goes back to the stomach and causes increased acid secretion. § High risk of peptic ulcers, but in __distal duodenum only__. • **Hypertrophic-hypersecretory gastropathy**: § Idiopathic (__no high gastrin__), but still get hyperplastic parietal cells, creating high HCl concentrations in the lumen. § High risk of peptic ulcer. • **Menetrier disease**: § Hyperplasia of mucus-producing cells in pits of stomach; no increase in parietal cells or HCl levels. § No risk of peptic ulcer. 11. List the two common histologic patterns of small bowel mucosa in patients with **symptomatic malabsorption** and give at least three examples associated with each pattern. • __Villous blunting__: short, stunted villi. Mainly caused by __autoimmune disorders__ (eg. **celiac disease**) reacting to either gluten or the transporters that bind to gluten. Malabsorption and diarrhea stops with a gluten-free diet. Can also be caused by viral infections in kids, "tropical sprue" (the other leading contender for name of my firstborn), "non-tropical sprue," or T-cell lymphomas. For celiac disease, look for T cell infiltration in villi. • __Villous distention__: long, spindly villi. Caused by: • Dilated lymphatics (lymphangiectasia): either a congenital disorder (primary) or acquired by lymphatic obstruction (tumors, sarcoidosis, fibrosis). • Macrophage accumulation in villi: § __Whipple disease__: macrophage infection with an intracellular bacterium (//Tropheryma whippelli//). Also seen in joints and CNS. Can be addressed by antibiotics. § In immunocompromised: //Mycobacterium avium-intracellulare// infection (MAI). Use PAS (Periodic acid-Schiff) and acid-fast stains to distinguish from Whipple's. 12. Describe the two common immune reactions that underlie gluten enteropathy. State what features of gluten peptides influence immunogenicity and deduce which grains would be appropriate to recommend to patients with this condition. • As mentioned, reactions against either gluten or the gluten transporters in the villi. • Intensity of immune reaction correlates with basic-amino-acid content: wheat is highest, then rye, barley, and oats. Recommend oats, I guess. This is weird. 13. Describe an appropriate histochemical evaluation to differentiate Whipple's disease from Mycobacterium avium-intercellulare infection. • As mentioned, PAS and acid-fast to distinguish. • Note that a quick Internet search seems to indicate that both MAI and Whipple's stain positive for PAS, but only MAI will be positive for the acid-fast stain. Maybe you use them both, PAS to make sure you're in the right ballpark and acid-fast to distinguish. 14. List two histologic variants of gastrointestinal stromal tumors and describe the features that allow differentiation of benign and malignant forms. • GIST (gastrointestinal stromal tumors): generally arise from over-expression of a tyrosine kinase (CD117). Note this, like CML, is also treated with Gleevec. • Types: can have either predominantly spindle cells or predominantly epithelioid cells. Epithelioid are slightly worse prognostic markers. • Benign vs malignant depends on the size and number of tumors and the mitotic/dysplastic features on histology.
 * [Note that most gastritis is asymptomatic most of the time.]

Diseases of the Upper GI: Stomach and Duodenum, Part I
Wednesday, October 15, 2008 9:59 AM **Diseases of the Upper GI: Stomach and Duodenum, Part I**

[Good to look at slides for this-- lots and lots of material not covered by these LOs.]


 * Note that dysphagia for solids is usually an obstruction. Dysphagia for liquids is usually a motility disorder.

1. Given a patient with esophageal symptoms and esophageal manometry, be able to diagnose systemic sclerosis, achalasia, and gastroesophageal reflux (GER). • Manometry: catheter placed into the esophagus; measures pressure at various points. • __Systemic sclerosis__ (like scleroderma)-- fibrosis leads to destruction of smooth muscle: no peristaltic pressure in esophagus; weak or absent lower esophageal sphincter pressure (which can lead to GERD). • __Achalasia__ (incomplete relaxation of the lower esophageal sphincter due to degeneration of inhibitory vagal neurons in the esophageal wall). Often see low levels of peristaltic pressure and inability to relax LES (high pressure at base). • __GERD__: note that it's not just acid; pepsin, bile, and pancreatic enzymes reflux as well. The lower esophageal sphincter pressure either is uniformly weak or relaxes at inappropriate times (transient lower sphincter relaxations or TLSRs). • Note that we don't really have drugs that target TLSRs themselves-- instead we target the contents of the stomach to make the reflux less harmful. 2. List the four major structural complications of GER. • (1) Esophagitis • (2) Stricture (scarring-- much less common now due to ready access to anti-acid-secretion meds) • (3) Barrett's esophagus • (4) Mucosal rings (ie. Schatski's rings or B rings: weblike obstructions in esophagus) • [Maybe less common but important:] • Dental erosions • Asthma and alveolar injury from aspiration of reflux contents • Laryngitis and vocal cord injury 3. Compare and contrast the two types of esophageal cancer. • Squamous-cell vs. adenocarcinoma: for pathology, see 2 lectures back. • Squamous: especially common in Asian/African ancestry. Other risk factors: cigarettes, EtOH, salty/spiced foods, low vitamin A/C, Mg, Se, Zn. In relative decline but still prevalent. • Adenocarcinoma: especially common in fat white dudes with GERD. Increased incidence lately, probably due to increase in obesity/GERD. • In general, both types have high mortality and are much more common in men. 4. List the three major stimuli and two major inhibitors of parietal cell acid secretion and their role in normal gastric physiology. • Stimuli: • (1) Gastrin (from enteroendocrine cells in pits) • (2) Histamine (mainly from ECF cells) • (3) Acetylcholine (from vagus) • Recall that gastrin and ACh stimulate histamine production by ECL cells. This seems to be their main mechanism of acid secretion stimulation; histamine is the major direct stimulator of parietal cells. • Note that parietal cells, when activated by these stimuli, open up __canaliculi__ to increase their surface area available for excretion. • Physiological inhibitors: • Somatostatins (somatostatin production is inhibited by ACh). • Prostaglandins also prevent acid secretion. This is why NSAIDs can be bad for gastric business. § Note that prostaglandins also increase mucosal blood flow and mucus/bicarbonate secretion (three other reasons why NSAIDs are trouble for the stomach). More on this in the next lecture. • Note also that protons have a negative feedback effect on gastrin secretion-- when there's lots of acid, the gastrin secretion rate goes down, and when there's not much acid, the gastrin secretion rate goes up. This is the basis for the development of gastric tolerance to antihistamines (see "Upper GI Pharmacology"). 5. Describe how cobalamin is absorbed. • Recall that intrinsic factor is secreted by the parietal cells in the necks of gastric pits. • __Cobalamin is isolated from ingested food by acid and pepsin in the stomach__. • In the saliva there's something called **R factor**- this binds to cobalamin once it's isolated in the stomach. • R factor is __split off__ from the B12 by pancreatic enzymes in the duodenum; at this point, the IF binds to it and allows it to be taken up in the terminal ileum. • To repeat: R factor is secreted in saliva but doesn't bind B12 till the stomach; IF is secreted in the stomach but doesn't bind B12 til the duodenum. The entire normal pathway requires adequate supply of B12, normal salivation, normal parietal cells, normal pancreatic enzyme release, and normal IF receptors. • Note that inadequate dietary B12 is extremely uncommon. • Failure to absorb cobalamin can also result from small bowel bacterial overgrowth or ileal disease. • Note that, evidently, proton pump inhibitors can cause diminished B12 absorption due to diminished B12 isolation (secondary to decreased acid secretion), though perhaps not enough to make a clinical long-term difference. • Recall Schilling test from Blood and Lymph ("Under-Production Anemias").
 * [MMCs begin in 'pacemaker' cells in stomach (not to be confused with the basic electric tone pacemaker activity) every 90 minutes or so in the unfed state.]
 * [Note duodenal reflexes that slow down gastric emptying: decrease in pH, increase in osmolality, increase in fat and caloric content; also viral enteritis. Note that by slowing gastric emptying, these can produce vomiting if the stomach becomes overly distended.]
 * [Note advanced age, of itself, has no effect on acid secretion rates.]
 * [Note that gastritis, as a diagnosis, can only be made histologically.]
 * Classes of gastritis as told by Dr. Peterson: infectious, lymphocytic, eosinophilic, systemic-disease-associated.
 * Note, again, that most gastritis is asymptomatic.

Diseases of the Upper GI: Stomach and Duodenum, Part II
Thursday, October 16, 2008 7:47 AM **Diseases of the Upper GI: Stomach and Duodenum, Part II, 10/16/08:**

[In case you're confused about definitions: peptic ulcers are just ulcers in an acidic area of the GI tract. The word presumably has a relationship with "pepsin;" both etymologies are from Latin //pepticus//, from Greek //peptikos// "able to digest," from //peptos// "cooked, digested," which is the verbal adjective of //peptein// "to cook." Gotta love online etymology dictionaries.]

[Evidently "Pepsi," of second-tier cola fame, has the same root-- it was originally marketed as a digestive aid. No kidding.]

1. Describe the pathophysiology of the two most common causes of ulcer disease. • (Inflammatory) Gastritis: generally due to //H. pylori// (Gram-negative rod) infection. • One of the most common human bacterial infections; never completely eradicated without antibiotics. Sets off a robust immune response which, along with the ammonia produced by the bacterium, destroys the surrounding gastric cells. • Mainly contracted during childhood; the degree of crowding during childhood correlates with the likelihood of contracting H. pylori. Socioeconomic status likewise. • Transmission is person to person; fecal-oral, oral-oral, gastro-oral routes. • Tests: § With a biopsy: • Culture (though it's difficult to culture due to a long growth time) • Histology (most stains work) • Rapid urease test (H. pylori has urease action) § Non-biopsy-based tests: • Urea breath test (radiolabeled carbon), urea blood test • Blood anti__body__ test (probably the most reliable, cheapest test) • Stool anti__gen__ test • Localizations of symptoms: § Antrum and pyloric gastritis (APG): in the antrum and pylorus, no kidding. High levels of acid; possibility of developing duodenal ulcers. § Chronic active superficial gastritis (CASG): all over the stomach; mild (asymptomatic) form. __Most common__ (p. 11, 10-15-08 11-12 AM). Note that I think he said in class that APG is most common. § Multifocal atrophic gastritis: all over, severe form; look for atrophy of the body and fundus. Carries the highest risk for gastric ulceration. § Note that H. pylori infection can also cause proximal duodenal ulcers. • Signs: § See increased serum gastrin with H. pylori infection. Recall that you can also get MALT lymphoma. § Acid secretion: varies inversely with the degree of stomach body involvement. APG = low body involvement = high acid levels; MAG = high body involvement = low acid levels. I would guess that CASG's acid levels are relatively normal. • Treatment: § Triple therapy: PPI plus two antibiotics (generally metronidazole or amoxicillin and clarithromycin) for 10-14 days. § 'Rescue' therapy for non-responders: quadruple therapy: PPI, bismuth, and two antibiotics. • Who to treat: § Patients with peptic ulcer disease § Patients with gastric lymphoma § Patients with a family history of gastric carcinoma § Anyone who has H. pylori infection and wants treatment • (Non-inflammatory) Gastropathies: generally caused by NSAIDs, EtOH, and stress-related mucosal damage. • NSAID use: § Prostaglandins increase mucosal blood flow, decrease acid secretion, and increase mucus and bicarbonate secretion-- so NSAIDs do the opposite. § Acutely, you see hyperemia, small local hemorrhages, and erosions due to direct depletion of local prostaglandins. These don't seem to have a lot of clinical effect. § Chronically, you deplete systemic stores of prostaglandin and begin to be at risk for ulceration. § Diagnosis: • Symptoms: heartburn, nausea, dyspepsia, vomiting, abdominal pain. • Mucosal lesions • Perforated ulcers or GI bleed (can be ulcers in stomach or duodenum) § Recall that COX-2 specific NSAIDs don't cause ulcers. Celecoxib (the only one still widely used) actually has some COX-1 activity as well and so still poses some risk (though not as the doses generally prescribed). • EtOH use: § Dr. Peterson is adamant about the idea that ethanol, while it causes erosion and erythema, does not cause inflammation-- it causes gastropathy, but not gastritis. This means it shouldn't bleed much, perforate, or cause pain. (that said, it still presumably exacerbates existing inflammatory conditions.) • (yes, what this seems to be saying is that EtOH shouldn't cause bleeding, perforation, or pain, because it's non-inflammatory. Why NSAIDs then cause all of the above while still being non-inflammatory is one of those questions. What I think he's trying to say is that EtOH, like NSAIDs, has an acute effect that doesn't seem to be terribly clinically important. Unlike NSAIDs, there is scant chronic effect of EtOH use in the stomach.) • Stress-related mucosal damage (SRMD): § Now relatively infrequent due to improved ICU care, but related to systemic physiological stress, possibly causing mucosal ischemia or increased acid secretion. • [Peptic ulcer disease:] • Dr. Peterson: unless you have Zollinger-Ellison syndrome, acid doesn't cause peptic ulcers unless your mucosal defense is already compromised. What compromises it: H. pylori, NSAIDs, tobacco, some other junk. On the other hand, if you've already got a mucosal defect, then increased acid is going to contribute to an ulcer. • The key thing I think he wants us to know here is that the sine qua non of peptic ulcer disease is mucosal problems and not an over-abundance of acid secretion. • Note that duodenal ulcers tend to be due to Zollinger-Ellison (more distal), H. pylori infection (proximal in the bulb), or NSAID use (proximal in the bulb). 2. Given the clinical presentation of any patient with ulcer disease, be able to recognize when bleeding, perforation, obstruction and penetration are present. • Bleeding (30% lifetime risk in ulcer patients, particularly with aspirin use): most clinical ulcers are bleeding ulcers at this point. Look for anemia, melena, shortness of breath, pallor, or pale conjunctiva, or just scope them and look for ulcers and blood. • Perforation (almost always with NSAIDs): __rigid belly__ from peritonitis. Most should go to surgery. • Penetration: perforates into a surrounding organ rather than into the peritoneum; eg. into the pancreas, causing pain radiating to the back. • Obstruction: scar formation causes gastric outlet obstruction (scar squeezes shut the pylorus). Not very common anymore due to a much lower prevalence of H. pylori and an abundance of antacids. That said, look for nausea, vomiting, and early satiety. 3. Compare and contrast the five most common gastric neoplasms. • (1) Gastric adenocarcinoma: • Worldwide, it's the second most common cancer/cause of death from cancer. • H. pylori is __necessary__ but not __sufficient__ to cause gastric adenocarcinoma-- the other factors are unknown. It's unlikely that antibiotic therapy to get rid of H. pylori will cause regression of neoplasms. • (2) Gastric polyps: • Hyperplastic polyps: in the colon, these are premalignant lesions; in the stomach, however, they have __no malignant potential__. Generally secondary to hypergastrinemia. • Adenomatous polyps are premalignant (remember Dr. Low's lecture on colon cancer and familial adenomatous polyposis in D+D? Thought not. He's lecturing again on it next week in case you somehow fell asleep the first time). • Fundic gland polyps: related to chronic PPI use? Uncertain significance. • (Generally we take all polyps out.) • <span style="font-family: Verdana,sans-serif; font-size: 10pt;">(3) Stromal tumors: leiomyoma/sarcoma, lipoma/sarcoma, or GISTs (gastrointestinal stromal tumors): • __GISTs__: most common mesenchymal tumor of the stomach: progression to malignancy is relatively common (10-30%), but can be treated with Gleevec (tyrosine kinase inhibitor). • (4) Neuroendocrine tumors: • Gastrinomas, insulinomas, VIPomas (vasoactive intestinal peptide; these occur at the rate of about 1 per 10 million according to Wiki). • __Carcinoids__: arise from ECL cells; found in fundus/body. Sporadic type are more dangerous than clumped type; latter seem to be related to hypochlorhydria (low acid secretion), and resection of the antrum often resolves them). Possibly the second most common neoplasm in the duodenum after adenocarcinoma.  • (5) Gastric lymphoma:   • Arises in MALT as a result of H. pylori infection. Eradication of H. pylori induces regression of the lymphoma.
 * [A theme here: duodenal ulcers tend to be due to increased levels of acid (Z-E, NSAIDs, pyloric H. pylori infections). Gastric ulcers tend to be due to atrophy of the stomach body itself (multifocal H. pylori, also NSAIDs).]

Upper GI Pharmacology
Thursday, October 16, 2008 8:54 AM **Upper GI Pharmacology, 10/16/08:**


 * [Factors that lead to increased acid production: increased H-K ATPase pump activity, H2 receptor activity, and M3 receptor activity; or decreased prostaglandin receptor activity.]
 * [Factors that lead to increased mucosal production: increased prostaglandin receptor activity or somatostatin receptor activity. Decreased by H. pylori and NSAIDs.]

1. ANTACIDS: Describe the general properties, primary ingredients [CaCO3, Mg(OH)2, Al(OH)3, NaHCO3], and general mechanisms of action, and guidelines for use. • Extremely cheap and fast-acting. • Primary ingredients: CaCO3, Mg(OH)2, Al(OH)3, NaHCO3. • Pharmacokinetics: not systemically absorbed. • MoA: Chemical antagonism (neutralization, no receptor action). • Uses: acute gastritis. Not for chronic high-dose use (see below). • Adverse effects: Calcium and aluminum are constipating; magnesium is diarrheic (maalox and mylanta combine aluminum and magnesium to balance effects). In patients with renal dysfunction, you can start to see hypercalcemia. Sodium bicarbonate increases sodium uptake (and hence H2O), which can be problematic. 2. ANTISECRETORY AGENTS (plus sucralfate): Describe the site and mechanism of action and the relative efficacy of: • **Antimuscarinic agents**: • Note these aren't actually mentioned in his notes or his drug list for upper GI symptoms; not used much for this. • MoA: block muscarinic receptors. Problem is that the muscarinic tone in the stomach is much lower than the tone in the mouth, etc (see next point). • Adverse effects: at the levels necessary to be efficacious, see antimuscarinic side effects: dizziness, mydriasis, dry mouth, tachycardia, constipation, urinary retention. • **H2 receptor blockers** [ranitidine / cimetidine / famotidine / nizatidine]: • Often given at night to decrease nocturnal acid secretion. Cheap as hell. • Suffix: -tidine (note distinct from "lorat__a__dine") • Pharmacokinetics: rapid onset; renally excreted. • MoA: Reversible, competitive antagonist of H2 receptors. • Uses: GERD, peptic ulcer disease (second-line to PPIs due to lower efficacy) • Adverse drug reactions: few. Decrease the dose in renal dysfunction. Note that cimetidine, specifically, decreases CYP450 function. • **Proton pump inhibitors** [omeprazole, esomeprazole, pantoprazole]: • Available over the counter. Can be fairly expensive, even generics. • Suffix: -prazole. • Pharmacokinetics: Enteric coated (it's acid-labile)-- absorbed into bloodstream from duodenum first, then returns to the stomach and act. May take 2-5 days to reach steady-state (not good for acute onset). Increased half-life for S-omeprazole (Nexium). • MoA: __Irreversibly__ binds, when activated by protons, to the H/K ATPase. Note __no tolerance__ develops. • Uses: GERD, peptic ulcer disease, NSAID-induced ulcers, Zollison-Ellinger • Efficacy: no particular difference between varieties. • Adverse drug reactions: few. Minor inhibition of CYP450 system. • **Prostaglandin analogs** [misoprostol]: • Suffix: -prostol. • Pharmacokinetics: short half-life (30 minutes), acute onset. Rarely used since you have to dose 4 times a day. • MoA: Acts like endogenous prostaglandins: decreases acid secretion, increases mucus/HCO3- production. • Uses: NSAID-induced ulcers. • Adverse drug reactions: Diarrhea, cramping. • **Sucralfate**: • Pharmacokinetics: non-systemic, activated by low stomach pH. • MoA: coats ulcer; decreases pepsin activity. • Uses: peptic ulcer disease, but currently limited use. • Adverse drug reactions: bloating, flatulence. 3. Describe the possible side effects and drug interactions of H2 receptor blockers. • Recall that they're mainly renally excreted, which means the dose needs to go down in kidney-impaired patients. • Also recall that cimetidine decreases CYP450 function. • If you really slug the stuff you can see CNS/mental status dysfunction. • Note tolerance develops to H2 antagonists-- decreased H+ increases gastrin secretion, which increases histamine secretion, which outcompetes the blockers. 4. Explain the rationale for antibiotic therapy of peptic ulcers. • (1) Eliminate H. pylori. • (2) Prevent recurrence of ulcers. 5. Describe the actions of proton pump inhibitors and prostaglandins in protecting the gastrointestinal tissues. • PPIs: block H/K ATPase pumps. Reduces scarring and exacerbation of ulcers. • Prostaglandins: increase mucosal blood flow; decrease acid secretion; increase mucosal and bicarbonate secretion. 6. PROKINETIC AGENTS: Describe the site and mechanism of action and list the side effects of: cisapride, metoclopramide. • Haven't gotten to these yet. 7. ANTIEMETIC AGENTS: Describe the site and mechanism of action and the relative efficacy and list the side effects of: antihistamines (dimenhydrinate) metoclopramide, ondansetron, and phenothiazines (prochlorperazine). • Haven't gotten to these yet either.

Pediatric Gastrointestinal Diseases
Friday, October 17, 2008 11:02 AM **Pediatric Gastrointestinal Diseases, 10/17/08:**

1. Describe the major features (as featured in this handout) of: • __Tracheo-esophageal fistula__: • Connection between the distal esophagus and the trachea; generally co-occurs with esophageal atresia. • Depending on the extent of esophageal atresia, this can present with polyhydramnios in utero (can't swallow amniotic fluid) or postnatally with dysphagia/pneumonia. § ["H-type atresia": counterintuitively, has no esophageal atresia, but has an open fistula between the esophagus and the trachea (like the middle arm of a capital "H"). Often presents postnatally with pneumonia.] • 1/3,000 live births. • Associated with a high incidence of other congenital defects, especially cardiac. • __Infantile hypertrophic pyloric stenosis__: • Hypertrophy/hyperplasia of gastric smooth muscle in the pylorus-- obstructs passage to duodenum. • Typical clinical presentation is __projectile vomiting__ at about 3 weeks postnatally; also look for upper abdominal mass. Note that the vomitus isn't biliary (from stomach, not small bowel). • Male predominance; 1/200 live births. • __Meckel's diverticulum__: • Small blind pouch protrudes from the terminal ileum, containing mucosa from another part of the GI tract (often gastric mucosa-- can thus get __gastric ulcers__ in the __ileum__). The pouch is a remnant of the connection between the intestine and the yolk sac through the umbilicus (the vitelline duct). • This can cause small bowel obstruction or umbilical herniation. • __Most common__ congenital small bowel malformation (2-4% of population); typically asymptomatic. • __Omphalocele__: • During development, the fetal intestines don't return from the coelom to the abdominal cavity properly (recall they come out about week 6, then rotate and go back in around week 10). • See a defect in the abdominal wall at the umbilicus, through which a sac filled with bowel protrudes. Sac is composed of peritoneum and __amniotic membrane__. • Associated with other congenital defects (30-50%). • 1/2000 live births; associated with advanced maternal age (as I recall, > 35). • [Note contrast with __gastroschisis__, in which the abdominal wall itself doesn't develop properly; in this case the bowel herniates out between the muscle groups. No amniotic membrane covering. Not associated with other malformations.] • __Malrotation__: • As might be guessed, during development, here the intestines don't rotate properly when they're returning into the abdominal cavity. They also tend not to fixate correctly. • This can complicate omphalocele or gastroschisis. • Most cases are asymptomatic; can present with midgut (small and most of large intestine) bowel obstruction. • 1/500 live births. • [Normal rotation of bowel:] § Small intestine rotates 270 degrees counterclockwise around the SMA. § Large intestine rotates 270 degrees clockwise around the SMA. • Note that certain malrotations can cause the appendix to locate in a variety of other places (cited as upper right quadrant)-- so __appendicitis__ can show up in eclectic locations. • __Duplications/Cysts__: • Cystic or tubular structures that duplicate normal GI structures; these may or may not communicate with the functional GI tract. Can occur anywhere along GI tract; most commonly near small intestine. • They can cause bowel obstruction, but are generally innocuous/asymptomatic. • __Intestinal Stenosis or Atresia__: • Stenosis: narrowing. Atresia: blind ending. • Most common site is the duodenum; up to 40% of these occur in __Down's Syndrome__ (tri-21) kids. • Present with polyhydramnios in utero (generally when it's complete atresia), or bilious vomiting postnatally. • 1/3000 live births. • __Imperforate anus/Rectal agenesis__: • Imperforate: thin membrane covering the anus. Rectal agenesis: no development of the rectum at all. The former is easily dealt with; the latter is more serious. • Associated with fistulas (rectovaginal or rectovesical). • Associated with other congenital abnormalities. • 1/5000 live births. 2. List and describe the major features of Hirschsprung Disease. • Hirschsprung, aka "congenital megacolon:" __massive dilation__ of the intestinal lumen. • Caused by lack of ganglionation of various lengths of intestine; this causes them to constrict somewhat and be unable to participate in peristalsis, causing ingested matter to build up behind the stricture and expand the preceding length of bowel. • In newborns, look for a __failure to pass meconium__ (viscous, sticky fetal stool) shortly after birth. In adults, can present with __perforated bowel__ from overexpansion. • Treatment is surgical; outcomes are generally good unless the section is pretty long. • Pathogenesis: commonly (50%), mutations in __RET__ receptor/ligand genes that drive the migration of neural crest cells to form the enteric nervous system. • More common in males (4:1). 3. List and describe the major features of Neonatal Necrotizing Enterocolitis. • Develops in the first week or so postnatally; look for __abdominal distention and bloody stools__. • Strongly associated with __prematurity__, particularly extreme prematurity. • Caused by intestinal hypoxemia (recall that premies' lungs are usually kind of crap, especially real early on) and resultant ischemia and inflammation, causing commensal bacterial invasion below the mucosal layer. This can lead to peritonitis and gas gangrene in the intestine.

Diseases of the Lower GI: Pathology
Monday, October 20, 2008 7:58 AM **Diseases of the Lower GI: Pathology, 10/20/08:**

1. Describe the histologic features associated with bacterial enterocolitis and the clinical symptoms (e.g. type of diarrhea), and state a common non-bacterial entity that also shows this histologic pattern. • Clinical symptoms of enterocolitis: depends to some extent on the bacterium involved: • **Toxin-producing bacteria** (Vibrio cholerae, Clostridium perfringens/botulinum, noninvasive E. coli, Clostridium difficile, Campylobacter, etc) cause __explosive diarrhea__ with a rapid onset after exposure. Recall that pseudomembranous colitis is caused by C. difficile toxin, among other things (see below). • **Invasive bacteria** (invade the bowel wall: Shigella, Salmonella, Yersinia) cause __marked abdominal pain__ and __exudative, usually bloody diarrhea__ (invasive bacteria tend to cause a more extensive mucosal necrosis). • Histologically: • See __PMN infiltration__ ("active," acute inflammation). • Clostridium difficile: "explosion" of fibrinopurulent exudate (putting the "pseudomembrane" in "pseudomembranous colitis"). Also associated with antibiotic use (due to C. difficile resistance and overgrowth) and a number of other organisms (Salmonella, etc). • __Ischemic colitis__ **also** shows pseudomembrane formation (breakdown of mucosa and tight junctions allows commensal bacteria below the mucosal layer). • Note this can be due either to primary vascular compromise (stenosis of arteries or thrombosis) or secondary to a section of strangulated bowel. • Particularly vulnerable to ischemia: watershed areas of colon near __splenic flexure__ and __rectosigmoidal junction__. 2. List four microscopic parasites that can be identified in stool samples or in biopsy material from infested patients. • Infect __immunocompetent__ individuals: //Giardia// and //Entamoeba histolytica// (amebiasis). • Infect __immunocompromised__ individuals: //Cryptosporidium// and //Microsporidium//. • (quick recall: if it's got spores in it, it's probably an immunocompromised deal.) • Ova and Parasite test (O+P) on stool is the best way to identify GI parasites; can be done somewhat less effectively in biopsies. 3. Explain how the life cycle of Entamoeba histolytica determines the gross and microscopic appearance of associated lesions. Discuss the clinical symptoms and possible complications of this disease. • Amebiasis: associated with travelers outside US; acquired through oral-fecal route. Up to 90% of patients asymptomatic, but can get necrotizing colitis and liver cysts, particularly in immunocompromised patients. • Life cycle: • Cyst is ingested by human. • Organism breaks out of cyst __near ileocecal junction__ and forms trophozoite. • Trophozoites can get into blood and go to liver (forming large cystic spaces), can invade the colon (usually near the ileocecal junction), or can passively colonize the colon (asymptomatic). § Invasion: Since it happens in the terminal ileum, the symptoms can be confused with Crohn's Disease. • They form cysts in the colon which are expelled with stool. 4. Explain the role of biopsy in diagnosis of colon disease causing diarrhea. • Stool samples are more reliably diagnostic than biopsy in determining the causative organism, whether bacterial or parasitic. • He also mentioned that a clinical history is often important, since histologically ischemic and bacterial enterocolitis can look identical. 5. Describe the anatomic process underlying diverticulosis. List the clinical factors that predispose to this illness. Describe the clinical staging of diverticulitis. • Diverticulum: a herniation in which all three layers of the normal wall are present. The appendix can therefore be described as a normophysiological diverticulum. • By contrast, what we describe as diverticula don't actually qualify; they're stretched so much that there's no muscularis propria. Therefore "diverticulosis" actually only causes "__pseudodiverticula__." No, it doesn't really matter. • Etiology: straining at stool causes increase in pressure, resulting in herniation at points of structural weakness. • Predisposing factors of diverticulosis: • Mainly age. If you see it in a patient under 40, that's unusual and suggest an underlying collagen defect. Poor diet also has an impact. • Staging of diverticulitis (inflammation resulting from diverticulosis): • Stage 1: abscess confined to the pericolic region • Stage II: distant abscess (in pelvic organs or retroperitoneum) • Stage III: generalized peritonitis without communication with bowel lumen • Stage IV: fecal peritonitis with open perforation • Note can cause fistula formation (interbowel openings due to inflammatory ulceration) or bowel obstruction. • Note these are called the "Hinchey classification" if you want more info online. • Note the distinction between diverticulosis and diverticulitis: the latter is an active inflammation with PMN infiltration that results from the former, frequently caused by fecal obstruction. • Random info: • Diverticulosis is found mainly on the left side of the colon. • Note that diverticulosis tends to occur in pairs: this follows the pairs of arteries that pass into the colonic wall. 6. Compare and contrast Crohn's disease and ulcerative colitis. What four (or more) pieces of information are useful in differentiating these diseases, and what is their relative importance? • __Idiopathic inflammatory bowel disease__: broken down into Crohn's Disease and ulcerative colitis. No evidence of causative organisms. Probably an autoimmune condition, reacting to bowel contents. • **Crohn's Disease**: § Can involve anywhere from the mouth to the anus, but mainly in: • Terminal ileum • Proximal colon • **Anus** (1/3 of patients, heavily emphasized) § Characteristics of Crohn's:  • Skip lesions (__lesions with large intervening areas of normal bowel__). • **Full-thickness** inflammation and scarring (which can lead to fistulas and fissures/perforation). • Non-necrotizing granulomas show up in the lamina propria. Note that not all Crohn's patients have them. • Lymphoid aggregates, particularly transmural ones. • You can also see blunting of the villi in the ileum. • "Creeping fat:" fat becomes adherent to bowel, as opposed to hanging freely, due to full-thickness inflammation spreading into the fat. It sort of works circumferentially around the perimeter of the colon and can extend into the small bowel. • Grossly, also see a __cobblestoned__ mucosal pattern in the lower GI tract (preserved mucosa interspersed with deep ulcerations). • On barium swallow: "__string sign__": the lumen is so constricted that the lumen of the bowel shows up as a thin string. § Incidence: 7 per 100,000. • **Ulcerative colitis**: § Spreading involvement from the **rectum** (he made a point of saying the rectum is always involved with ulcerative colitis): rectum to sigmoid colon to descending colon to splenic flexure to transverse colon to ascending colon. § Tends to be a __more continuous involvement__ than Crohn's Disease, but also more **superficial** (ulcers are rarely full-thickness; inflammation limited to mucosa and superficial submucosa). § Note that ulcerative colitis leaves behind normal areas between ulcerative areas ("pseudopolyps," wind up looking like a shag carpet), whereas in Crohn's you see less complete ulceration coverage but they go very deep. § About 7 times more common than Crohn's Disease; incidence is 50/100,000. • [**Point here**, I think, is that UC ulcers are less deep but more continuous, while Crohn's are deeper but more sporadic. Also the anal-Crohn's, rectal-UC distinction.] • Common histological features with both; hard to make histological diagnosis. § See inflammation and PMN infiltration inside the crypts and lamina propria (cryptitis). § See crypt abscesses-- distended, can burst and release PMNs into the stroma. • Note both idiopathic IBDs are characterized by relapsing-remitting courses; this means current biopsies should be compared with former biopsies to sketch the arc of the disease progression. • Note also that both diseases are associated with an increased risk of cancer; thus biopsies also need to be scanned for dysplasia. § A point that seems to have been made repeatedly since then is that __ulcerative colitis shows a higher risk of cancer development than Crohn's__. • Note that in both diseases you see a decreased number of crypts and 'blunting' of them, as opposed to acute self-limiting conditions. This is due to chronic, fibrotic change and can also be seen after long courses of infectious or diverticular disease. 7. Describe the two common histologic patterns associated with the clinical entity of microscopic colitis. What features do they share and which feature differentiates them? • Microscopic colitis: chronic thin, watery diarrhea, with normal-appearing mucosa on endoscopic inspection. • Histologically, can see either lymphocytic invasion of the superficial epithelium by itself (__lymphocytic enterocolitis__), or can see it with a thick band of __subepithelial__ __collagen__ beneath that epithelium (__collagenous colitis__). • Note that the former type is 1:1 men to women and idiopathic, while the latter (collagenous) type is 10 times more common in women and is associated with NSAID use. 8. Describe the histologic features of melanosis coli. What causes it? • Melanosis coli: macrophages in the lamina propria acquire a __brown pigment__; sometimes, this hue can be seen endoscopically. • Caused by overuse of cascara laxatives.

Pathophysiology of the Lower GI, Parts I + II
Monday, October 20, 2008 10:00 AM **Pathophysiology of the Small Intestine and Colon, Parts I + II, 10/20/08:**

[__Note his LOs have been changed for this lecture__.]

1. List the four major organ systems required for fat absorption and describe their roles and interactions. • Liver (necessary for bile salt formation and storage, as well as fat storage and mobilization) • Stomach (grinds up food and secretes lipase from the chief cells) • Small intestine (breaks down macronutrients and absorbs micronutrients) • Pancreas (secrete lipase and other lytic enzymes) • Severe pancreatitis, generally caused by alcoholism, can cause fat malabsorption; this is the most common cause of impaired lipolysis. 2. Describe the clinical presentation of patients with fat malabsorption. • Weight loss, diarrhea, steatorrhea ("ring on the toilet bowel," floating stools in the toilet caused by air trapped in steatorrheic stools,) foul-smelling stools, vitamin deficiencies. 3. Name the four type of diarrhea based on stool characteristics. • Types: watery, fatty, inflammatory, exudative, or "functional" (we have no idea). o __Watery diarrhea__: • __Osmotic__ diarrhea: lactose intolerance, sorbitol from chewing gum, high-fructose diets, osmotic laxatives, etc. Caused by the presence of poorly absorbed intestinal osmoles; this brings water into the intestinal lumen. § __To make sure__: measure stool sodium + potassium, multiply by 2, and subtract from 290; if the difference is over 50, that's osmotic diarrhea. • Non-osmotic ("__secretory__") watery diarrhea: bacterial toxins, neuroendocrine tumors (rare), bile salt malabsorption, stimulant laxatives, disordered motility or regulation (diabetic neuropathy, Crohn's/UC, post-vagotomy). § Note also that means that if you're taking bile acid resins for hypercholesterolemia, you'll likely wind up with watery diarrhea. o __Fatty diarrhea__: • Caused by fat malabsorption due to Whipple's (recall it's a lymphatic disease and fat is mainly absorbed through the lacteals), celiac, bacterial overgrowth, etc. Can also have a problem with lipolysis (eg. from pancreatitis). • Note that you use a "Sudan stain" to stain the fat globules in stool to diagnose. o __Inflammatory/Exudative__: • As due to IBD, toxin-producing or invasive bacterial infection, parasite infection, or ischemic colitis. • Look for __white cells in the stool__. These are absent in certain infections (cholera, toxin-producing E. coli and S. aureus, Giardia), but present in others (Shigella, Campylobacter, invasive E. coli)-- not enormously sensitive but presumably fairly specific. 4. Given a patient with symptoms relating to the colon, recognize obstruction, pseudo-obstruction and constipation. • [this one got a little confusing.] • __Constipation__: decreased frequency or ease of defecation, generally caused by either colonic inertia or outlet obstruction. Test by ingesting X-ray-detectable solid material. If it's diffused throughout the colon after a time, that's inertia (nothing's much moving). If they're all clustered down by the rectum, that's outlet obstruction. • __Obstruction__: can be either benign or malignant. Get an X-ray or CT; usually see air and blockage in a distended colon. • The distinction between constipative outlet obstruction and obstruction per se seems to be that outlet obstruction is, you know, at the outlet and nowhere else. Obstruction per se is in the colon itself. • Pseudoobstruction: looks like obstruction on X-ray or CT (distended colon, full of air), but no blockage is found. 5. Given a patient with symptoms of colitis, be able to determine whether ischemic colitis, ulcerative colitis or Crohn’s disease is most likely. • __Ischemic__ colitis: classically it's older people with CV disease, but it also occurs in young athletes, particularly runners (not enough fluid intake). • __Ulcerative__ colitis: look for __mucosal__ involvement in the colon (**always** rectal involvement). __Never involved in the small bowel__. Fairly obvious on colonoscopy. • Note that you can get megacolon and/or perforation with ulcerative colitis. We're not sure why. • Also look for bloody diarrhea and urgency (latter due to rectal involvement). • __Crohn's disease__: look for __transmural__ involvement in the colon and ileum (often anal involvement as well)-- can be purely colonic, in which case it's often tough to distinguish from ulcerative colitis. • Crohn's tends to have a lot more __pain__ associated with it. Also look for the string sign on barium swallow. • As might be expected from the string sign, __obstruction__ is a big problem with Crohn's, particularly in the small intestine. Also, as mentioned, fistula formation from one GI segment to another due to transmural involvement. Note that you can also get fistulas out into the skin, usually out through surgical scars or through the umbilicus. • __Perianal__ fistulas and/or abscesses (anal involvement) is more common with Crohn's. Also recall that granulomas and lymphoid aggregates only show up in Crohn's.  • [Note that Crohn's always recurs after surgery, possibly because of the process of the surgery itself.] 6. Given a patient with inflammatory bowel disease, recognize the extra-colonic manifestations. • __Ulcerative colitis__: fever, malaise, non-inflammatory necrosis in the skin of extremities, fatty liver, uveitis, etc. Complete list is on his slide 17. • __Crohn's__: peripheral arthritis, gallstones, renal stones. • Generally peripheral arthritis shows up in large joints, not distal small ones. • Presentation says arthritis is common to __both__ of them (internet search backs this up), notes only mention it for Crohn's.
 * [Localization of absorption, good for boards:]
 * Iron absorption: mainly in duodenum, some in jejeunum.
 * Folate absorption: in jejeunum.
 * B12 absorption: in specialized cells of terminal ileum.
 * Vitamins ADEK: absorbed along with fat, mainly in the proximal jejeunum.
 * Problems with malabsorption of each:
 * A: xerophthalmia (dry eyes)
 * D: bone mineralization defects, osteomalacia
 * E: progressive neuronal dysfunction
 * K: clotting dysfunction
 * [Recall that bile salts that form micelles stick around in the lumen of the duodenum; after fat's been absorbed in the proximal 2/3 of the jejeunum, the bile salts get reabsorbed in the terminal ileum (thus in Crohn's, ulcerative colitis, etc, you get not only B12 deficiency but also can't reabsorb your bile salts and thus get watery diarrhea) and are stored again in the liver.]
 * [Note that fecal incontinence is often caused by trauma to the anal canal or diabetes/other neuropathies. Just in case you were wondering.]
 * [Note the distinction between **IBD** - Crohn's or UC - and **IBS** (irritable bowel syndrome), which is a __functional__ diagnosis of abdominal pain and bloating, generally in young, otherwise healthy people without blood in the stool, fever, or a high white count. GI docs can get cranky about this.]

[No longer an LO: List the five major tests used in the evaluation of patients with fat malabsorption. For each test, describe: the indications, the physiology of the test and the results of the test in six specific disease categories.] • Note bacterial overgrowth can cause fat (and B12 and ADEK) malabsorption. Note that with overgrowth, you'll have normal folate levels (due to bacterial production). • Celiac sprue or celiac disease: villous blunting, inflammatory cells in lamina propria. • Serologic tests: anti-endomysial antibodies, anti-tissue transglutaminases, anti-gliadin IgA and IgG. • Best diagnostic tool: biopsy. • Tropical sprue: looks histologically identical to celiac disease, but caused by bacterial toxins/colonization, generally after travel (need history). • Classic presentation: megaloblastic anemia from B12 deficiency. • Whipple's disease: Gram-positive //T. whippelii// infection. • Clinical presentation: fever, joint pain, neurological symptoms. • Diagnosis made by small intestine biopsy (look at PAS stain for macrophages). • Mesenteric ischemia: caused __acutely__ by emboli, __chronically__ by 2 of 3 major vessels occluded (2 of celiac, superior mesentery, or inferior mesentery), often by atherosclerosis. • Clinical: post-prandial abdominal pain, weight loss (due to sitophobia: fear of eating). • Look for other signs of CV involvement or get an angiogram. • Tends to happen at the recto-sigmoid or splenic flexure areas (watersheds). • Small intestinal tumors: very rare that you get primary tumors in this region. Can present with symptoms of obstruction. Check with barium swallow.

Treatments for Lower GI Disorders
Tuesday, October 21, 2008 8:00 AM **Treatments for Lower GI Disorders, 10/21/08:**

[From "Upper GI Pharmacology," continued:] 6. PROKINETIC AGENTS: Describe the site and mechanism of action and list the side effects of: cisapride, metoclopramide. • __Cisapride__: 5-HT4 agonist to activate cholinergic motor neurons. • Note 5-HT3 agonists do the same thing. • Side effects: at high levels, act like class III antiarrhythmics (block potassium channels), lengthening the QT interval and predisposing to torsades de pointes. • __Metoclopramide__: D2 receptor antagonist to inhibit D2's inhibition of cholinergic motor neurons. • Side effects in CNS: D2 blockade causes increased direct-pathway tone (involuntary movement/tremor). • MoA: Both of these __facilitate ACh release__ and __cause smooth muscle contraction__ in the GI tract. • [Other things you can use for this: erythromycin (increases ACh release), neostigmine (decreases ACh breakdown), bethanochol (ACh receptor agonist).] 7. ANTIEMETIC AGENTS: Describe the site and mechanism of action and the relative efficacy and list the side effects of: antihistamines (dimenhydrinate) metoclopramide, ondansetron, and phenothiazines (prochlorperazine). • Background: there's a vomiting center in the medulla. • The __chemoreceptor trigger zone__ (CTZ), outside the blood brain barrier, frequently mediates plasma drug effects on the vomiting center. • __Receptors on CTZ__: M1 receptors, D2 receptors, 5-HT3 receptors. • __Ondansetron__ blocks the 5-HT3 receptors on the CTZ. Mainly used to prevent vomiting coming out from general anesthesia (stage II). Also blocks the opioid receptors (see below). § It can be expensive but it's well tolerated. • __Phenothiazines and metoclopramide__ block the D2 receptors on the CTZ. § At higher doses, can get tortacollis and other antidopaminergic effects; treat with antimuscarinics (benztropine). • Note opioids have their own receptors in the BBB, but can also affect the D2 receptors on the CTZ. • Note that there are muscarinic and histamine receptors in the cerebellum (not in the CTZ) that affect the vomiting center as well. • __First-generation antihistamines__ like __dimenhydrinate__ block both M and H1 receptors here. • [Scopolamine (muscarinic antagonist) blocks the M receptors here.]

1. LAXATIVES: Describe the mechanism of action of each class, drawbacks to use, guidelines for use [psyllium seed, dioctyl sodium sulfosuccinate, mineral oil, MgSO4, bisacodyl]. • __Bulk-forming (psyllium seed)__: put bulk in colon, indirectly stimulate peristalsis. May take 1-3 days but safe for chronic use. • __Osmotic (MgSO4)__: increase osmolality of GI lumen, drawing water out. This swells and distends the colon, indirectly promoting motility. Safe for chronic use. Note can also be used as a purgative before surgery. • __Wetting agents (mineral oil)__: lubricate the colon (which is just nothing I ever thought I'd be writing). Dioctyl sodium sulfosuccinate (aka docasate) acts as a surfactant to make foamy bubbles in and around the stool (this keeps getting better and better). • __Stimulants/irritants (bisacodyl, senna)__: __directly__ increase motility and ion secretion. Most effective (15-60 minutes with a suppository). Tend to be overused. At regular doses, can be used chronically. Often prescribed with opioids. 2. ANTI-DIARRHEALS: Describe the mechanism of action and explain the rationale for and guidelines for use [opiates / anticholinergics, kaolin / pectin, polycarbophil]. • Opioid: __loperamide__ (Imodium). Slows GI intestinal motility, secretion, and absorption by direct agonist action on mu and delta opioid receptors in the GI tract. Most effective drug of those listed here. Note that this has some anti-secretory activity against cholera toxin; can also be used in traveler's diarrhea, but discontinue if no improvement after 48 hours. • __Kaopectate__: adsorbents to reduce fluidity. Note they can also absorb nutrients and drugs. Note also that they have scant effect on the actual fluid volume excreted. • __Polycarbophil__: treats both constipation (pulls in water to itself, prevents fecal desiccation) and diarrhea (pulls in water to itself, absorbs some excess from lumen). Again, doesn't do much to prevent the fluid loss. • [Remember you're worried about electrolyte loss, not just fluid, particularly in kids.] 3. DRUGS FOR IBS: Describe the site and mechanism of action and the relative efficacy and list the side effects of: tegaserod and alosetron. • Treatments for IBS: • IBS is kind of funny (not ha-ha funny, uh-oh funny) in that it can come in either diarrheic or constipated flavors. • For pain: use tricyclic antidepressants (NE/5-HT action, but note that the antimuscarinic effects will worsen constipation) and SSRIs. • For constipation, if present: use 5-HT4 agonist (__tegaserod__, like cisapride). • For diarrhea, if present: use 5-HT3 antagonist (__alosetron__). • Note both of the latter are restricted use in women due to dangerous side effects (ischemic colitis, cardiac problems); they don't seem to work as well in men. • They're both used mainly for refractory symptoms.

Exocrine Pancreas and Salivary Gland Physiology
Tuesday, October 21, 2008 8:56 AM **Exocrine Pancreas and Salivary Gland Physiology, 10/21/08:**

[Contents of saliva: mucins, amylase and lingual lipase, sodium bicarbonate, IgA, lactoferrin.]

1. Contrast the plasma and saliva concentrations of Na+, Cl-, and HCO3- at low secretion rates and at high secretion rates and the principal cell types involved in each secretion rate. • At the time the saliva is excreted by the acinus (primary secretion), it's isotonic to plasma/physiological saline solution: • Na+ = 140 mM  • K+ = 4 mM   • HCO3- = 25 mM   • Cl- = 100 mM   • As the primary secretions travel through the intercalated ducts that connect it to the mouth, the duct cells modify the secretion. The longer the secretions are in the ducts (ie. the lower the secretion rate is), the more they're modified. • Salivary duct cells: remove Na+ and Cl-, add in K+ and HCO3-. Note that __salivary duct cell membrane are water-impermeable__ (the secretions can be and are diluted, making them hypotonic). This is different from pancreatic duct cells; see below. • __Low secretion rates in the salivary glands__: the secretions sit in the salivary ducts long enough for the ducts to modify them extensively. The bicarb levels are very high; the chloride levels are very low. The sodium levels are low. The solution is **very hypotonic**. • Na+ = 60 mM  • K+ = 15 mM   • HCO3- = 60 mM   • Cl- = 60 mM   • __High secretion rates in the salivary glands__: the secretions aren't in the salivary ducts long enough to be extensively modified by the duct. The bicarb levels are slightly high; the chloride levels are slightly low. The sodium levels are mildly depressed. The solution is **slightly hypotonic**. • Na+ = 120 mM  • K+ = 10 mM   • HCO3- = 30 mM   • Cl- = 80 mM


 * [Common secretion mechanisms in both salivary and pancreatic acinar cells:]
 * There's your standard Na-K ATPase pumps in the basolaterial membrane (2 K in, 3 Na out).
 * These establish the sodium gradient that's used to power co-transporters to take in Na+ and K+. Chloride follows the influx of positive ions into the cell and flows out the apical side through numerous passive channels in the apical membrane.
 * Sodium and water follow the chloride paracellularly through the not-so-tight junctions between the acinar cells.
 * Note you have muscarinic (M3) receptors in the blood; upon activation, intracellular calcium rises, which increases the rate of insertion of Cl- channels in the apical membrane (which in turn increases the rate of sodium and water secretion).
 * The specifics change depending on where you're at (eg. pancreatic acinar cells are stimulated by cholecystokinin). But that's the common idea.
 * Enzymes in both types of acinar cell are stored in vesicles (amylase, mucin, IgA for salivary, zymogens etc. for pancreatic); the signal for exocytosis of these vesicles is the M3 muscarinic receptor for both, as well as CCK and secretin for the pancreatic cells. Effectively you get increased Ca++ or cAMP content that changes the cytoskeletal configuration to release vesicle.

2. Describe three types of stimuli that increase salivary secretion. • Sympathetic and parasympathetic input both increase salivary secretion (parasympathetic input moreso). I have no idea what else she's talking about. If you do, post it. Note that First Aid only describes the two. 3. Describe the components of the saliva important in oral hygiene. • At pH less than 7, the calcium in the teeth begins to become leached out; the HCO3- is therefore important to preserve the pH above that level. • For more on dental caries, see "Oral Healthcare Issues In Clinical Practice." • __IgA__ is obviously antibiotic. • __Lactoferrin__ chelates iron and prevents its use by bacteria. 4. List the major ionic and peptide/protein components secreted by the pancreas. Contrast the plasma and pancreatic concentrations of Na+, Cl-, and HCO3- at low secretion rates and at high secretion rates and the principal cell types involved in each secretion rate. • Again, the primary fluid excreted by the pancreas (right after secretion) is isotonic to saline. And again, this fluid is modified by the duct cells that lead out from the acinus. • Main difference between pancreatic and salivary ducts: the duct cells in the pancreas do __not__ form an impermeable barrier to water (recall that the salivary duct cells do). • __Pancreatic secretions__: • Ok. A couple things to consider here. • One: you have two secretory components, one in the acinus and one in the ducts. The one in the acinus secretes isotonic saline solution with lots of digestive enzymes. The one in the ducts secretes lots of bicarb and swaps it out for chloride. § If you have predominantly the first type of secretion, the pancreatic juices are going to be bicarb-low. If you have predominantly the second type of secretion, the juices are going to be bicarb-high. § At "high flow rates" the second secretion is going to dominate. At "low flow rates" the first secretion is going to dominate. • Two: there are evidently some other duct cells that do the reverse of the first type (swap out bicarb for chloride). At low flow rates, the bicarb gradually decreases as the secretions have more time to sit around in the duct. • Sheep picture in the pancreas: high-flow-rates-equals-high-bicarb. Low-flow-rates-equals-low-bicarb. Baa. • Details on pancreatic duct cells (bicarb-secreting): • There's a HCO3- (out)/Cl- (in) exchanger in the apical membrane to get the process rolling. • Chloride then leaks out CFTR channels in the apical membrane to be able to activate the exchanger again and pump out more HCO3-. § Note that CFTR channels are the ones that are nonfunctional in **cystic fibrosis**; this erases the substrate for the HCO3-/Cl- exchanger, which doesn't pump HCO3- into the lumen any more. This screws up the whole shebang and you don't have adequate water secretion into the pancreas. § In CF, the zymogens get stuck in the ducts (not enough water to move them along); they can't act on their targets in the duodenum, and the patient gets malabsorption. • Once again, you have the 3 Na/2 K ATPase pumps in the basal membrane. • The Na gradient that these establish drive the following: • Co-transporter for Na+ and HCO3- (NBC transporter) in the basal membrane (bring in HCO3- to be pumped out by the apical exchanger). • (Note you also get CO2 diffusion from the bloodstream-- this combines with H2O to form bicarb and protons. The protons are pumped out by:) • Na+/H+ exchangers to bring in Na+ and pump out H+ (to facilitate the carbonic-anhydrase-mediated synthesis of bicarb and protons from water and CO2). • Finally, you have a HCO3-/Na+ co-transporter (NBCn1) in the basal surface. • __Low secretion rates in the pancreas__: Secretion is **isotonic**. Bicarb levels are low, chloride levels are high. Sodium levels are relatively normal to saline. • __High secretion rates in the pancreas__: Secretion is **isotonic**. Bicarb levels are high, chloride levels are low. Sodium levels are relatively normal to saline. 5. Describe the mechanism by which pancreatic zymogens are activated in the small intestine. • Trypsin is cleaved and activated by enterokinases (which should actually be called enteropeptidases, as they have peptide cleavage action); it in turn cleaves and activates all the other zymogens (as well as any leftover trypsinogen not cleaved by enterokinase). • Note that if even a small amount of these zymogens are activated in the pancreas, it can set off a chain reaction in which the active enzymes activate other enzymes, which activate others, etc; they all chew the hell out of the pancreas (acute pancreatitis). I'm not sure exactly how this works (what gets it started?) but it seems to be a major player in causing cell injury in acute pancreatitis. 6. Describe the mechanisms by which chyme from the stomach is neutralized in the duodenum. • Mainly it's the HCO3- in pancreatic secretions. Note the neutral/alkaline pH in the duodenum is necessary for the pancreatic zymogens to function.
 * [Reviewing the distinctions between high and low flow rates and relative bicarb concentrations in saliva and pancreatic fluid is probably a good idea.]

Pathology of the Gall Bladder and Exocrine Pancreas
Wednesday, October 22, 2008 7:53 AM **Pathology of the Gall Bladder and Exocrine Pancreas, 10/22/08:**

1. List the clinical factors that increase risk for cholelithiasis. What are the major types of gallstones and what are the clinical implications of each type? What procedures can help establish the diagnosis of cholelithiasis, and under what conditions will one procedure not be informative? • __Cholelithiasis__: gall bladder stones. Form when the concentration of material (cholesterol or bilirubin) exceeds the solubilizing capacity of the bile. Etiology: • (1) Supersaturation of cholesterol • (2) Hypomotility of bile • (3) Crystallization around calcium salts or proteins (nucleation) • [Note "__cholesterolosis__:" excess cholesterol is absorbed into the wall of the gall bladder and phagocytized by macrophages instead of forming stones. Sort of an atherosclerosis of the gall bladder?] • __Factors__: age (older is worse), gender (female is worse), weight (more is worse), cholesterol levels (more is worse), family history (any is worse). Also increased incidence among Native Americans. • __Types of gallstones__: • Cholesterol stones (most common; not many are radio-opaque) • Pigment stones (composed of calcium salts of unconjugated bilirubin-- as due to __hemolytic anemias__ or __alcoholic cirrhosis__. Most are radio-opaque). • (note: don't confuse these with kidney stones, which are a whole different beast. Not that, you know, I ever asked my preceptor about struvite gall bladder stones or anything. 'Cause that would be stupid.) • __Procedures__: • X-rays-- these only pick up stones with a lot of calcium salt (radio-opaque-- very dense) and don't detect others well (radiolucent-- not as dense). • Abdominal ultrasound (picks up all stones) • Oral cholecystogram (essentially an iodine swallow that gets excreted into the bile, followed by an X-ray; picks up all stones) 2. List at least three important complications of cholelithiasis. • Stones can obstruct the __cystic duct__ (usually associated with __cholecystitis__, leading to an infection and/or perforation of the gall bladder) or the __common bile duct__ (__choledocholithiasis__, often leading to an infection of the biliary tree called __cholangitis__). • Stones can block the pancreatic duct and trigger acute pancreatitis. • Stones can erode through the wall of the gall bladder and form a fistula with the small bowel. Uncommon. 3. Compare and contrast the macroscopic (visible appearance) and microscopic features of acute and chronic cholecystitis. • __Acute cholecystitis__ (usually caused by a stone obstructing the cystic duct): • Upper quadrant pain, fever, nausea, vomiting. • When there's common bile duct involvement, look for an increase in serum alkaline phosphatase. • Grossly: swelling and edema in the wall of the gall bladder, sometimes hemorrhage. • Histologically: § Infiltration of PMNs and lymphocytes. § Damage to the mucosa from the breakdown products of bile. § Can also get pus and necrosis (cholangitis), usually due to a secondary bacterial infection. § Can see thickening of the muscularis propria. § [Recall that there is no muscularis mucosa in the gall bladder.] • Note that the cystic artery is an end artery, so any compromise in it (as per swelling due to obstruction) can cause gall bladder ischemia and coagulative necrosis. • __Chronic cholecystitis__ (usually caused by a string of subclinical acute episodes): • Nearly all patients have cholelithiasis. • Grossly: marked thickening and fibrosis of the wall of the gall bladder due to repeated bouts of inflammation. • Histologically: § There's lots of connective tissue from fibrosis, as well as an infiltrate of lymphocytes and plasma cells. No PMNs (it's not acute). § May be a thickening of muscularis propria. § Can also see mucosal outpouches ("Rokitansky-Aschoff sinuses") coming deep into the wall from the lumen. 4. Describe the histopathologic features of gallbladder cancer. • __Gall bladder cancer__: Adenocarcinoma, associated with gallstones and parasitic infection. Highly infiltrative growth pattern; frequently goes into the liver or nearby lymph nodes. Often picked up late; very poor prognosis. • Like pancreatic cancer (see below), it can produce a lot of scar/connective tissue. • It can also fill up the lumen of the gall bladder. 5. Compare and contrast the histopathologic and clinical features of acute and chronic pancreatitis. • __Acute pancreatitis__: • Associated with alcoholism and gallstones (lodged in pancreatic duct), as well as cystic fibrosis and a host of other less common problems. • Clinically (from Wiki), see pain radiating to the back, nausea/vomiting, sometimes fever and chills, possibly hypovolemic shock from hemorrhage, and steatorrhea. Not uncommonly fatal. • Acute pancreatitis is where you see **fat necrosis**. Acute injury to pancreatic cells causes them to release lipases; the lipases break down surrounding fat and membranes to liberate free fatty acid; FFAs form insoluble calcium soaps, making those fatty lumps you see at autopsy. • Histopathologically, see PMN infiltrate laced throughout thin layers of fat. • __Chronic pancreatitis__: • Associated with repeated bouts of acute pancreatitis due to alcoholism or cystic fibrosis. • Clinically, malabsorption and malnutrition develop due to pancreatic insufficiency; often a considerable amount of pain accompanies it. • See atrophy and scarring of the duct and destruction of the acinar tissue. • Histopathologically, see broad swaths of scar tissue and lymphocyte infiltrate. Note the **islets are intact** (chronic pancreatitis doesn't generally produce diabetes). 6. Describe a pancreatic pseudocyst and know the clinical settings where a pseudocyst sometimes occurs • __Pseudocyst__: a cyst-like pouch within the pancreas, usually filled with necrotic debris and blood. Not a true "cyst" since it does not contain an epithelium. • These can become infected and lead to peritonitis. Dr. Peterson's oft-repeated refrain: drain any pus. • Often occur secondary to trauma. 7. Know the two common types of pancreatic neoplasms. Compare and contrast the clinical syndromes and microscopic appearance of each type of lesion. • __Pancreatic adenocarcinoma__: weak associations with smoking, chronic pancreatitis, and obesity. Associated with BRCA mutations and family history. • Clinically, usually present at a late stage, with widespread disease (weight loss and metastasis). Can also present with back pain (cancer invades nerves) or painless jaundice (blockage of the common bile duct). • **Trousseau Syndrome**: In about 10% of pancreatic cancer patients, see a __hypercoagulable state__ (due to increased mucins in the bloodstream? Common to all mucinous adenocarcinomas.). • Microscopically, the adenocarcinomas make a lot of connective tissue and malignant glands that expand out to fill the pancreas and invade the small bowel. • __Islet cell tumors__: • Associated with Multiple Endocrine Neoplasia, type I (MEN1, Wermer's syndrome). • Usually __beta-cell__ tumors; usually benign. May produce a lot of insulin; thus patients often present with hypoglycemia. • If gastrin-producing tumors, can see Zollinger-Ellison syndrome (high gastrin levels in serum, parietal hyperplasia, ulcers in duodenum); they are more often malignant. • Microscopically, cells look like carcinoid tumors (glandular organization) with spherical, glassy nuclei.
 * [Boards note: bile acids are formed from cholesterol in the liver; they're linked to taurine or glycine to form bile salts, which are more capable of foaming up to form micelles. The excretion of about 5% of secreted bile salts in the stool is the body's main/only mechanism for eliminating cholesterol.]
 * (this makes the bile acid binding resins from CVPR make a little more sense- you're stripping the body of its bile salts, which means it has to mobilize its stored cholesterol to make more, which helps with hypercholesterolemia.)
 * [Note that "bile" isn't just bile salts; contains water, bicarb, bile salts, phospholipids, protein (lecithin, etc), cholesterol, and bilirubin.]

Pathophysiology of the Gall Bladder and Exocrine Pancreas
Wednesday, October 22, 2008 9:02 AM **Pathophysiology of the Gall Bladder and Exocrine Pancreas, 10/22/08:**

1. Understand the primary manifestations of acute pancreatitis. • Acute and severe abdominal pain, nausea, and vomiting. See elevated pancreatic enzymes (amylase and lipase) in the serum. Note that acute pancreatitis is self-limiting. • Two types of acute pancreatitis: necrotizing and interstitial (interstitial is more common and less severe). Use a CT to differentiate, at least according to the notes (Dr. Peterson is skeptical about utility). • Note you can get systemic manifestations: ARDS, renal failure. Also see hypocalcemia (since Ca++ is bound in lipid soaps), hyperglycemia, and acidosis. 2. Understand the primary manifestations of chronic pancreatitis. • Chronic inflammation and abdominal pain, often with malabsorption and steatorrhea. Often see weight loss, malabsorption (so look for bleeding disorders due to lack of vitamin K), and diarrhea. 3. Understand the pathophysiology of gallstone formation. • Most pathological stones are cholesterol stones (and most of those aren't radio-opaque). • Occur due to: • (1) __Cholesterol hypersecretion__ (eg. obesity, genetic, rapid weight loss, age: too much cholesterol) • (2) __Bile acid hyposecretion__ (eg. in ileal diseases like Crohn's: too little bile) • (3) Both. • Recall: stasis plus a supersaturating concentration of cholesterol in the bile plus "nucleation" (the seed around which the stone crystallizes) forms stones. • Note: generally don't take out asymptomatic gallstones. 4. Understand the pathophysiology of acute cholecystitis. • Caused by cystic duct obstruction from a gallstone. • If there's cholangitis (infection of the biliary tree secondary to bile duct obstruction, check the blood's white count), always drain the pus to avoid or ameliorate secondary bacterial infections. • Liver function tests are generally elevated; total bilirubin is usually normal. Can have elevated alkaline phosphatase if the stone's in the common bile duct).  • Look for a positive Murphy's sign.

Colorectal Cancer
Thursday, October 23, 2008 7:53 AM **Colorectal Cancer, 10/22/08:**

1. Recognize the magnitude of the CRC (colorectal cancer) problem. • It's big. Says here that it's the second most common cause of cancer death in both men and women. We've been taught elsewhere, and Internet searching seems to support, that it's actually third, behind lung and breast/prostate, in any given individual. • Dr. Ahnen on this: it's the second most common cause of cancer death in COMBINED men and women. Evidently the stats are meant for hermaphrodites. • CRC is in relative decline among women, but the rates are pretty steady (and higher) among men. 2. Understand the mechanisms of pathophysiologic consequences of CRC. • Strong risk factors: age, country of birth, genetics (familial adenomatous polyposis, hereditary non-polyposis colon cancer), long-standing ulcerative colitis. • Note that there's a strong correlation between family history and colon cancer risk-- get it more often, get it younger. • "Country of origin" influence seems to have a lot to do with diet-- immigrants from one country to another have children whose cancer risk is the same as the indigenous population. • About two-thirds of all colon cancers occur in the descending colon. • __Adenomas__ (not adenocarcinomas) in the colon rarely cause any functional complications except __bleeding__-- thus one of the main screens for benign tumors is blood in the stool. • Note that adenomas are sort of "cancer in waiting" (like carcincoma in situ is like "lazy cancer")-- they are dysplastic, just not to the point where they're verging on invasion or metastasis. • Adenocarcinomas have a variety of other presentations (eg. can perforate the bowel or grow into surrounding structures), but they also very commonly bleed. • Note that unexplained weight loss seems to be only infrequently associated with colorectal cancer. • __Right-sided__ colorectal cancers: bleeding is occult and not easily visible since the stool is liquid at this point in the colon. • This means they generally aren't caught until they've grown to a larger size. • Note also that since the stool is liquid, the tumor isn't going to perceptibly obstruct flow until it's extremely large. • __Left-sided__ colorectal cancers: more obvious bleeding: blood on the surface of brown stool (stool is more solid by the time it's descending). • These are more likely to cause a change in bowel habits (constipation, obstruction) and can sometimes be felt on rectal exam; therefore they're caught more frequently at an early stage. • More on left vs. right at the bottom of the next lecture's LOs. • Look for tubular vs. villous patterns of dysplasia: tubular is sort of standard glandular approach, villous pushes out in 'fingers' into the lumen. (again, next lecture has more.) 3. Understand how pathophysiology has modulated the clinical approach-prevention/treatment of CRC. • Fecal occult blood tests: large adenomas and adenocarcinomas bleed intermittently. Goljan says blood in the stool in a person over 50 is colorectal cancer (or adenoma) unless proven otherwise. • Can also look for the cells that adenocarcinomas shed in the lumen-- stool DNA testing is beginning to be used. • The dominant screening form in the US is regular colonoscopies-- visualize, remove adenomas and polyps. • It's also possible to use CT colonography instead of colonoscopy. 4. Understand that the molecular basis of CRC is not uniform and that this impacts the pathophysiology of the disease. • It's not uniform. • 3 molecular driving forces for developing colorectal cancer (more on all of these in the next lecture): • __Microsatellite-stable__: § Chromosomal instability pathway • Most sporadic cancers and FAP cancers (about 80% of all CRCs). Most mutations in oncogenes or tumor suppressor genes fall into this category. § Defective DNA pathway • Failure of DNA mismatch repair: when due to a germ line problem, accounts for HNPCC cases. § Microsatellite-stable cancers look like fairly typical adenocarcinomas. • __Microsatellite-unstable__: § Epigenetic mutation pathway • Due to post-translational modifications of DNA. • What we're talking about here is altered DNA methylation (recall that DNA methylation is a normal inactivation mechanism), primarily of CpG islands (CG repeats). A hypermethylation of these islands results in underexpression of certain genes (CpG islands are often located in promoter regions). Hypomethylation of other regions can result in their overexpression. General principle: when you screw with repressor-promoter patterns, you tend to get cancer. This seems to be responsible for about 15% of all colorectal cancers. • Note that just because it's not directly genetic doesn't mean the tendency to create inappropriate methylation patterns can't be hereditary. § Microsatellite unstable cancers tend to show __serrated__ edges and have __high__ levels of mucin production, as opposed to typical adenocarcinomas (low levels of mucin production). § They also don't respond as well to adjuvant chemotherapy. Despite this, they tend to have a better prognosis than microsatellite-stable cancers. § Note also that they're more frequently located in the ascending, rather than the descending, colon.

Polyps and Colon Carcinoma
Thursday, October 23, 2008 9:01 AM **Polyps and Colon Carcinoma, 10/22/08:**

1. Describe and compare the three major types of GI polyps. • [Note a piece of basic vernacular: polyps can either be __sessile__ (lying flat along the mucosal surface) or __pedunculated__ (attached to the mucosa by a thin stalk).] • **Hyperplastic** polyps: • Very common in middle aged or older adults, particularly in the left (descending) colon. • Grossly: small, smooth, yellow, raised spots. • Histologically: crypt cells are normal, and columnar cells are normal with normal mucin production. Proliferative activity is limited to the basal mucosa, as per normal tissue. The only thing odd about them is that the __lumen of the crypt is dilated and looks serrated or cross-like__. • Note that there is more or less no risk of progression of cancer from most hyperplastic polyps, except in rare isolated cases or in some rare familial conditions that cause giant hyperplastic polyposis (can progress to adenomas). • **Neoplastic** (adenomatous) polyps: • Most common clinically significant polyp. • Three varieties, in order of frequency: tubular, tubulovillous, and villous. § Common histological theme: hyperplastic columnar, mucin-producing epithelium on a fibrous, vascularized stalk. • __Tubular__ adenomas look like trees: a poofy ball on top of a thin stalk. Ok, more like trees drawn by artistically challenged 3-year-olds (or me in present day). • __Villous__ adenomas are more embedded in the surface of the mucosal wall and send out folds or fingers into the lumen. • __Tubulovillous__ adenomas are sort of the bastard children of both types. § Most of these polyps are benign; malignancy takes years to develop. The bigger the polyp, the larger the risk of developing malignancy. • Look for dysplastic changes and __glands present in the stalk__ as signs of cancer development and invasion. § Villous (less than 1%) are at highest risk for progression (they're right there next to the submucosa). • Theme here: the overwhelming majority of colon cancers progressed from a pre-existing polyp. Resect the polyps, save the world. • **Hamartomatous** polyps: • Very slight risk of progression, but generally benign. • Recall that a hamartoma is essentially a tissue construction project with misplaced blueprints-- it's composed all of normal tissue elements, but they're all disorganized and growing haphazardly. There's no dysplasia to speak of. § When they arise in the mesenchymal tissue of the submucosa, they can push the mucosa out into the lumen of the colon. Note that this submucosal growth can include fat, connective tissue, or nervous/vascular tissue (vascular tissue bleeds easily). § When they arise in the mucosa itself, they can be either __juvenile__ or __Peutz-Jeghers__ polyps. The former is a significant etiology for __GI bleeding in children__; the latter has submucosa and smooth muscle proliferation in addition to mucosal proliferation, and carries an __increased risk of malignancy__ in the pancreas and other locations (Peutz-Jegher syndrome; see below). 2. Understand the key genetic changes that underlie progression from a benign adenomatous polyp to frank carcinoma in "sporadic" cases of cancer. • Adenomatous polyps progress to cancer due to an expansion of a stem cell that has inactivating mutations in both APC genes (chromosome 5q). • [Take-home for boards: APC = main tumor suppressor gene in colon cancer.] 3. Discuss which genetic syndromes carry an increased risk to develop GI carcinomas at a young age. • __Familial adenomatous polyposis__ (FAP): inherited inactivation mutation in one APC gene Results in thousands of colonic polyps; typically progresses to colon cancer inside 10-15 years. • Note different mutations in the APC gene (it's a big gene with systemic effects) can cause fibromatosis or malignant brain tumors. • __Hereditary non-polyposis colon cancer__ (HNPCC, also called Lynch syndrome): mutations in the DNA mismatch repair pathway. Doesn't show the overabundance of polyps that FAP does, but the polyps that are there tend to progress to cancer. • __MYH polyposis__: mutations in the DNA base excision pathway for taking out mispaired guanine bases. • Some hereditary epigenetic modification syndromes, as mentioned in the last lecture. 4. Discuss and describe hamartomatous polyps and which genetic syndrome carries a propensity to develop hamartomatous polyps in the GI tract. • Mainly described above. • Serine/threonine kinase 11 (STK11) mutations can cause __Peutz-Jeghers syndrome__ (P-J hamartomas, plus increased risk of pancreatic, breast, lung, ovary, uterus cancers). 5. Describe the major histologic features of colon cancer, including the common patterns of growth seen in right-sided versus left sided lesions and how this affects the way these cancers present clinically. • Histologically, colon cancer usually looks like medium- to well-differentiated adenocarcinoma (possible exception for microsatellite-unstable cancers). • Cancers on the right: • Tend to present __late__ (as mentioned in the last lecture, the stool is fluid at that point and the colon has significant expansile ability, so obstruction isn't obvious). • Tend to be exophytic (masses growing out into the lumen). • Cancers on the left: • Tend to present __earlier__ (again as mentioned, it's easier to pick up obstruction when the stool is more solid). • Tend to be circumferential (sort of colonic stenosis). • Tend to metastasize to the liver, sometimes also to the lungs.

Oral Healthcare Issues In Clinical Practice
Friday, October 24, 2008 10:33 AM **Oral Healthcare Issues In Clinical Practice, 10/24/08:**

[Starred with "**" are the points he heavily suggested would be testable material.]**

• **Periodontal ligament: binds tooth root to alveolar bone. This is what you want to watch out for during various oral infections to prevent tooth loss.** • //Streptococcus mutans//: breaks down sucrose to lactic acid. Mouth + Strep. mutans + sucrose = acids --> caries. § Technically, Wiki notes that S. mutans can break down fructose, lactose, and glucose to acid as well, but says that only in sucrose metabolism is one other byproduct produced: a sticky residue that adheres the acid to the tooth surface, which seems to be necessary for tooth decay. Thus sucrose metabolism by these bacteria is necessary to actually cause caries. § That said, lots of (say) glucose in the diet (or in the blood-- see below under diabetics) probably doesn't help. • Acid causes demineralization of teeth-- long periods between sucrose ingestion or regular teeth brushing helps clean off sucrose/acid and allow teeth to remineralize again. • First sign of caries: white spots on teeth (demineralization). Apply fluoride. • Caries can go into the soft tissues and cause facial cellulitis. • Oral cancer: increased risk with EtOH and smoking. • If there's chronic inflammation in the oral cavity, the resultant inflammatory mediators (TNF-alpha, IL-1) can circulate systemically and get up to distant mischief. • Chronic periodontitis: when the inflammation gets between the gum and the tooth, it starts attacking the periodontal ligament. • Diabetes: poor glycemic control = higher risk of periodontitis. • Obesity: promotes inflammatory mediator release = higher risk of periodontitis. • Dry mouth, caused by a variety of drugs, can lead to higher rates of periodontitis, as do chemo drugs or anything else that suppresses the immune system. • Periodontitis-derived inflammatory response is associated with coronary artery disease. • Periodontitis is also associated with higher rates of preecclampsia. • **Most common chronic disease of childhood: dental caries.**
 * 1. Describe normal child and adult oral anatomy. **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **"Neglected sites:" lateral tongue, under tongue, behind lips, floor of mouth.
 * • By age 3, child should have a full set of 20 teeth. By age 18-20, adults should have 32 teeth (8 + wisdoms). **
 * 2. Understand how oral and systemic health are inter-related (caries, periodontal disease, cancer). **
 * • It works both ways: oral affects systemic, systemic affects oral. **
 * • Caries: pain, poor eating/nutrition, impaired speech development, etc. **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **Note cavities are caused by an infectious, transmissible disease:
 * 3. Encourage medical and dental collaboration. **
 * • Or the dentists will come for you in the night. **

**Functional Histology of the Liver**

 * Monday, October 27, 2008 **

Functional Histology of the Liver, 10/27/08:
 * 7:42 AM **


 * [Functions of liver:] **
 * • Bile production (emulsify fats); stores iron, glucose, and vitamins; synthesizes albumin and other plasma proteins; does metabolite exchange in blood; detoxifies blood in smooth endoplasmic reticulum (note SER hypertrophy on ingestion of toxins) and traps NH3 and other wastes for excretion. **
 * 1. Be able to discuss (in a very general sense) the digestion/absorption of lipids and the role of bile in the emulsification of fats. Why do we need bile? **
 * • Ok. Dr. Michaels explains this a little differently from Dr. Grichtchenko. Here, the bile salts form micelles immediately (before pancreatic lipase/colipase administration); the lipases and colipases get into the micelles and break the triglycerides up into smaller molecules that the cells can absorb. Then the bile salt micelles transport the smaller molecules to the cell membrane. **
 * • Note that triglycerides get into the caval system without going through the hepatic portal circulation (go through the lymphatics). **
 * • Note also that while the cholesterol and bilirubin in bile are largely excreted in the stool, the bile salts are reabsorbed in the terminal ileum. **
 * • We need bile, in any case, because we can't absorb fat without it, and also because it's our only way of excreting cholesterol. **
 * 2. Review the blood supply to the liver. Explain the statements: 1) the liver has a double blood supply and 2) the liver is an exocrine and an endocrine gland. What is the major exocrine role of the liver? Endocrine role (general)? **
 * • Right hepatic artery supplies right lobe. Left hepatic artery supplies left, caudate, and quadrate lobes. **
 * • No anastamosis between left and right hepatic arteries (independent blood supplies). **
 * • Exocrine role: bile (stored in gall bladder, released upon ingestion of fats; contains bile salts, bilirubin, cholesterol, water, ions, and IgA)-- secreted by the liver but doesn't go into the blood. **
 * • How this storage thing works: when you're not eating fatty foods, a sphincter (specifically the Sphincter of Oddi) down by the Ampulla of Vater contracts to prevent bile from flowing into the duodenum; it backflows up into the gall bladder. **
 * • Endocrine role: albumin, clotting factors, lipoproteins and glycoproteins, etc. Essentially, everything made in the liver that goes into the blood. **
 * 3. Discuss the morphological boundaries and the functional significance of a hepatic (classic) lobule, a portal lobule and an acinar lobule. Be able to describe how blood, bile and lymph flows in a lobule. **
 * • Not to speak ill of Our Medical Forefathers, but this terminology sucks balls. Bear with me, I'm going to try and figure it out. Shout-out to Dr. Michaels for shoring me up with this. **
 * • Structural organization of the liver: parallel chains of linked hepatocytes make up a hexagonal 'block' of liver tissue. This 'block' is called a **lobule **and is the smallest functional unit of the liver. It is surrounded by six hepatic triads running parallel to it at each 'point' of the hexagon.**
 * • The hepatic artery (containing well-oxygenated blood with few nutrients) and the portal vein (containing poorly-oxygenated blood rich in nutrients) drain blood towards the center of each lobule through **sinusoids **(tracts running to the center flanked by hepatocytes). At the center of each lobule there's a** central vein **that eventually drains to the caval system.**
 * • The bile ducts are being drained out into by small __bile canaliculi__ that run between adjacent hepatocytes. **
 * • Okay. Having described the structural organization, there are now three ways of conceiving of this organization, depending on what you're interested in tracking. Unfortunately, someone decided to name the conceptual organizations by the same name as the structural organizations, ie. "lobules." Here we go: **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1.5in; text-indent: -0.25in; vertical-align: middle;">• **Classic lobules**: A "classic lobule" seems to be equivalent to a structural "lobule;" you're looking at one lobule structure, all of the blood flow into it, and all of the bile flow out of it. It's used mainly when you want to think about big-picture blood flow and drainage.**
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1.5in; text-indent: -0.25in; vertical-align: middle;">• **Portal lobules**: Here, you're looking at bile secretion. The "portal lobule" looks at all the bile canaliculi that drain into a bile duct in a given hepatic triad. This corresponds roughly to a triangularly-shaped area between three central veins, with the bile duct in question in the middle.**
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1.5in; text-indent: -0.25in; vertical-align: middle;">• **Acinar lobules**: Used for looking at areas of relative perfusion. Dr. Michaels says this is the most clinically relevant way of thinking about it. They're diamond-shaped territories between two central veins (the long axis of the diamond) and two adjacent hepatic triads (the short axis of the diamond). There are three zones in each structural lobule corresponding to the extent of oxygen and nutrient perfusion from those triads:**
 * § Zone I: closest to blood supply (on the outside of the lobules, farthest from the central vein). This is where hepatitis virus damage tends to cluster (first tissue exposed). **
 * § Zone II: intermediate distance from blood supply. **
 * § Zone III: farthest from blood supply (nearest to the central vein). **
 * § Note that not only are these zone III cells most vulnerable to ischemia, they also tend to be most vulnerable to blood-borne toxins (less capacity to detoxify). Main 2 toxins: EtOH and acetaminophen (and its metabolites). **
 * § This is a relatively significant concept for boards and whatnot. **
 * • If you're looking at a lobule histologically, the large vessels seen are almost always the portal venules. Just FYI. **
 * 4. Be able to discuss the functional and structural specializations of hepatocytes, sinusoidal endothelial cells, Kupffer cells, stellate cells, the space of Disse and bile canaliculi. **
 * • Hepatocytes: big, polygonal cells, situated between sinusoids on either side. Can be multinucleated, possibly because the liver's stem cell capacity is fairly astounding. **
 * • Polarity of hepatocytes is weird. **
 * § __Apical__ surface of a hepatocyte is the surface that faces the bile canaliculi that lie between adjacent hepatocytes. **
 * § __Basolateral__ surface is the surface that faces blood in sinusoids on both sides. Lots of microvilli on these surfaces. **
 * • Note that a given hepatocyte has two basolateral surfaces-- maximizing its contact with the blood in the surrounding sinusoids. See note, below, about the liver being kind of a massive capillary bed. **
 * • Essentially the hepatocytes modify incoming blood from sinusoids - take oxygen and nutrients from it, do toxin/metabolite exchange with it - and then allow the blood to keep going down the sinusoids to the central vein. Kind of like capillary beds. **
 * • Sinusoids: have a discontinuous endothelium with big gaps in it. **
 * § If you consider the liver - minus the biliary function - as one big capillary bed doing oxygen exchange and detox/endocrine functions, these are the actual capillaries carrying the blood through the gas- and metabolite-exchange portion of the bed. **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1.5in; text-indent: -0.25in; vertical-align: middle;">• **Space of Disse**: Space between the endothelium of the sinusoids and the basement membrane on the basal side of the hepatocytes. Unrelated to the fabled city of Hell in Dante. If you don't know it, go get some culture. Can't study the liver without culture.**
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1.5in; text-indent: -0.25in; vertical-align: middle;">• **Kupffer cells**: macrophages that live within the walls of the sinusoid endothelium.**
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1.5in; text-indent: -0.25in; vertical-align: middle;">• **Stellate cells**: fat and fat-soluble vitamin storage cells of liver. Live between the hepatocyte and the sinusoid endothelium (in the space of Disse). With damage to those cells, they start acting like fibroblasts and produce fibrosis and scarring.**
 * • Bile canaliculi: as mentioned, formed by the plasma membrane of two adjacent hepatocytes. These drain out into canals of Hering and from there out into the bile ductules. **

**Pediatric Liver Disease**

 * Monday, October 27, 2008 **

Pediatric Liver Disease, 10/27/08:
 * 8:56 AM **


 * [Note that as per notice from Megan Tripp-Addison and Laura Friedlander, our right honorable course reps, the LOs for this lecture were changed.] **


 * 1. Review common anatomic abnormalities of the hepatobiliary system **
 * • Total hepatic agenesis (incompatible with life) **
 * • Hepatic lobe agenesis (usually asymptomatic) **
 * • Situs inversus totalis (mirror image of normal anatomic arrangement) **
 * • Asplenia/polysplenia (midline, symmetrical liver lobes) **
 * • Omphalocele and diaphramatic hernia can shift hepatic location and mess with its vascular supply. **
 * • Choledochal cyst: ductal dilation and biliary stasis in and above the common bile duct. **
 * • Most present before 10 years with jaundice and upper quadrant pain, can see a RUQ mass as well. **
 * • Can get infection, gallstones, pancreatitis if obstruction of pancreatic duct, etc. **
 * 2. Discuss the differential diagnosis of neonatal cholestasis, with focus on biliary atresia **
 * • DDx: **
 * • Physiological jaundice (harmless; largely due to immature bilirubin conjugation system) **
 * • Infection **
 * • Medication **
 * • TPN (total parenteral nutrition, as given to prematurely born infants) **
 * • Obstruction/biliary atresia **
 * • Metabolic disease **
 * • Hereditary hyperbilirubinemia **
 * • Idiopathic neonatal hepatitis **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **Biliary atresia**:**
 * • 1 in 8,000; obstruction of extrahepatic biliary tree. **
 * • More common form: acquired perinatally; biliary tree undergoes fibrosis and closure __after birth__. Shows normal at birth, but develops cholestasis; progressive hyperbilirubinemia (can't excrete it). No compelling evidence for any one etiology, but viral heads the list of maybes. **
 * • Rarer form: embryonic/fetal. Shows immediate jaundice after birth due to abnormal development of biliary tree __in utero__. **
 * 3. Review common metabolic storage diseases that involve the liver **
 * • Most common are the disorders of iron (hemochromatosis) and copper (Wilson's disease) storage. Tend to present in adult life. More in "Non-Viral Liver Disease." **
 * • Also see glycogen and lysosomal storage disorders. Not extensively discussed here. **
 * 4. Discuss hepatic involvement in common genetic diseases including alpha-1-antitrypsin deficiency and cystic fibrosis **
 * • __Alpha-1 antitrypsin disease__: AR disorder characterized by a misfolded protein (which is involved in neutralizing endopeptidases secreted by, among other things, neutrophils.) Results in excessive damage from inflammatory reactions. In this setting, we're concerned about accumulation of the (toxic) misfolded protein in the liver, not the response to inflammation (that's significant in the lungs, where it's what gives you pan-acinar, early-onset emphysema). Can result in cirrhosis. **
 * • __Cystic fibrosis__: the liver really isn't the first thing you worry about in CF, but as patients live longer it starts to be more of a problem. Pathology: focal cirrhosis causing loci of fibrosis. Grossly it looks like massive bulbules growing out of the liver (kind of the opposite of adult-onset polycystic kidney disease). **
 * 5. Review the most common hepatic neoplasms in the pediatric population, with focus on hepatoblastoma **
 * • Benign: hamartomas, teratomas, hepatocellular adenomas, hyperplasias. **
 * • Malignant: hepatoblastomas (mainly under 5 years) hepatocellular carcinomas (mainly over 5 years, mainly adults) **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **Hepatoblastoma**:**
 * • 27% of pediatric liver tumors, about half of all malignant pediatric liver tumors. **
 * • 2:1 male:female incidence **
 * • No association with underlying disease. **
 * • Tends to present with anorexia, weight loss, nausea/vomiting, pain, RUQ abdominal mass. **
 * • See __elevation of serum alpha-fetoprotein__ (also elevated in hepatocellular carcinomas). **
 * • Genetics: activation of Wnt/beta-catenin pathway; link with FAP (similar mechanism) and Beckwith-Wiedemann Syndrome (overgrowth disorder with abdominal wall defects). **
 * • Histology: can be epithelial, mesenchymal, or mixed. Tend to be very large and not resectable until it's shrunken with chemotherapy. **
 * • Overall survival is 65-70%. **


 * Some other stuff he covered that's not in the new LOs: **
 * • Idiopathic neonatal hepatitis: diagnosis of exclusion but fairly common (25-40%). Some familial patterns but mostly sporadic. Sporadic form has a better prognosis. Most cases spontaneously resolve but can also see chronic liver damage or death. **
 * • See multinucleated giant cells in liver (common liver disease finding). **
 * • <span style="font-family: Verdana,sans-serif; font-size: 10pt;">Hereditary hyperbilirubinemias: unconjugated vs. conjugated. **
 * • Unconjugated hyperbilirubinemia: generally a lack of conjugation enzymes. Note that unconjugated bilirubin is neurotoxic to neonates (incomplete BBB). **
 * § Crigler-Najjar Syndrome: decreased (AD) or no (AR) function in glucuronidation enzyme. **
 * § Gilbert's syndrome: slightly reduced function of the same enzyme; only really clinically significant during periods of systemic stress. __This is extremely common__ (5-10% of population). **
 * • Conjugated hyperbilirubinemia: defects in transporter proteins such that the conjugated product can't be excreted properly. **
 * § Dubin-Johnson syndrome: defect in excretion of conjugated product due to a mutation in MRP; generally significant during systemic stress. **
 * § Rotor Syndrome: defects in hepatocellular uptake/excretion of bile pigments. **
 * • Reye syndrome: currently rare; used to be a main cause of encephalopathy in children. Caused by use of aspirin in viral febrile illnesses. Mitochondrial injury in liver leads to microvesicular (smaller than the nucleus) __fatty degeneration of organs__, particularly the liver. (note microvesicular fat storage tends to be indicative of metabolic storage diseases; macrovesicular fat storage tends to be indicative of dietary etiology.) **

**Viral and Non-Viral Liver Disease**

 * Monday, October 27, 2008 **

Viral and Non-Viral Liver Disease, 8/27/08:
 * 9:43 AM **


 * [Lots of material here. If you're really pressed for time, check out his "review slides" at the end of each powerpoint presentation for things he seemed to think were particularly important.] **


 * 1. Describe the pattern of histological findings that is referred to as “acute hepatitis”. List the two principal recognized etiologies for this disorder in order of their likelihood. State the most common factor associated with each etiology. **
 * • Acute hepatitis: liver damage within 6 months of symptoms (chronic is after 6 months). Generally due to drugs or hepatitis A/B virus. Most common cause of drug-induced __acute__ hepatitis: acetaminophen. Hep A transmitted fecal-oral; hep B transmitted through blood/body fluids. **
 * • Histologically: __apoptotic bodies__ (shrunken, apoptosing hepatocytes); also diffuse, mixed inflammation. **
 * • Hyperacute subtype: fulminant hepatic failure (liver damage within 4 weeks of onset); most of these cases are due to acetaminophen overdose. See "bridging necrosis" between adjacent central veins. **
 * 2. List the five most important hepatotropic viruses and indicate their mode of transmission and clinical behavior. What histological pattern is associated with each? Which viruses are most likely to cause chronic hepatitis, acute hepatic failure and cirrhosis? **
 * • Last point first: **
 * • Acute hepatitis only: __A and E__ (both in the word acute) **
 * • Chronic hepatitis only: __C__ (for chronic) **
 * • Both acute and chronic: __B and D__ (D needs B, see below; no clever mnemonic) **
 * • Cirrhosis follows chronic disease. Note cirrhosis and the chronic fibrosis it suggests can lead to hepatocarcinoma. **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **Hepatitis A**: most common in US.**
 * • Single-stranded RNA, non-enveloped virus. Does not cause chronic hepatitis; acute only. **
 * • Acquired through fecal-oral route. **
 * • Has an incubation of about 4 weeks; acute disease occurs 1-2 months after exposure. **
 * • Histologically: see above (acute hepatitis). **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **Hepatitis B**: next most common in US.**
 * • Circular DNA virus (can integrate into host genome). Can cause chronic, acute, and/or fulminant hepatitis. **
 * • Acquired through blood and/or other body fluids (is an STD). Can be acquired by fetus in utero from infected mother. **
 * • In chronic infection, the blood markers (antigens) remain detectable for years. Watch out for cirrhosis and hepatocellular carcinoma development. **
 * • Histologically: see "ground glass" hepatocytes (crystalline viral particles) in which the organelles have been pushed to the rim of the cytoplasm in acute hepatitis B episodes, but not in chronic. Also see "sanded" or finely stippled nuclei (inclusion and expansion of viral DNA). **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **Hepatitis C**:**
 * • Single-stranded RNA virus. __High genetic variability__, facilitating escape from antibodies. **
 * • I assume you all know this already, but there's vaccines for Hep A/B and none for C. **
 * • Almost never causes acute hepatitis. **
 * • Repeated bouts of viral mutation and escape from immune control, and the corresponding inflammatory responses, are characteristic and cause chronic fibrotic injury. **
 * • Acquired through blood/body fluids; mainly drug use and sexual exposure. Can also be transferred to fetus from mother. **
 * • Histologically, look for lymphoid infiltrates in portal tracts, fatty liver, and lesions in the bile ducts. Also chronic inflammation and fibrosis, as expected. **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **Hepatitis D**: circular RNA. Infection is completely dependent on co-hepatitis B infection, and potentiates it-- increases inflammation, fibrosis, and rate of progression.**
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **Hepatitis E**: similar to hepatitis A, but water-borne and more aggressive; causes acute and not chronic hepatitis. Note it's a major risk of fulminant liver failure in pregnant women.**
 * • [Note hepatitis G is not associated with disease, inhibits HIV replication, and may be protective against other forms of hepatitis.] **


 * ** [Not in the LOs but he did put some emphasis on it: __end-stage liver disease__: coagulopathy, hypoalbuminemia, hyperbilirubinemia, encephalopathy, hepatorenal syndromes (kidney ischemia and failure secondary to liver failure), skin changes, portal hypertension.]
 * Portal hypertension: ascites (fluid in peritoneal cavity), engorgement of portal-systemic shunts (esophageal varices, paraumbilical veins), and splenomegaly.
 * Biopsy descriptions: __Grade__ = degree of inflammation. __Stage__ = degree of fibrosis.
 * 3. Name several non-viral causes of chronic liver disease that show a "chronic hepatitis pattern" similar to viral hepatitides. How are these diseases differentiated from viral disease histologically and serologically? **
 * 3. Name several non-viral causes of chronic liver disease that show a "chronic hepatitis pattern" similar to viral hepatitides. How are these diseases differentiated from viral disease histologically and serologically? **


 * • Autoimmune hepatitis: **
 * • Can present with jaundice and fever. **
 * • Usually shows up in women 15-40 years of age. **
 * • Diagnose by serum autoantibodies and plasma cell infiltrates on biopsy. Treat with steroids. **
 * • Metabolic liver diseases (see below). **


 * ** [Note: for the rest of the lecture, he largely goes off two tables at the end of his notes. Knowing them might be useful.] **
 * 4. Based on Table 1, describe the pattern of histologic findings associated with the diagnosis of alcoholic liver disease/ steatohepatitis. Name the histologic findings (if any) that indicate the etiology of the disease. List the clinical features associated with nonalcoholic steatohepatitis. **


 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **Steatohepatitis **(most is alcohol-induced):**
 * • Histologically, frequently indistinguishable from many other things (steatosis, inflammation, fibrosis, damage to hepatocytes, etc). **
 * • PMNs dominate infiltrate in acute __alcohol__-induced steatohepatitis. **
 * • In __alcoholic__ steatohepatitis, look for "ropy" pink deposits (__Mallory hyaline__) and fibrosis extending out into the sinusoids. **
 * • [Steatosis: the triglycerides in hepatocytes are not only not broken down by beta-oxidation, but not exported as VLDL either. Alcohol inhibits both pathways.] **
 * • Factors associated with non-alcoholic steatohepatitis: obesity, diabetes mellitus, hypertriglyceridemia, amiodarone use, and chemotherapy. **
 * • Note distinction: "fatty liver" is steatosis alone, where steatohepatitis also includes damage to the hepatocytes. **
 * 5. Based on Table 1, describe the pattern of histologic findings associated with chronic biliary injury. List the two most important diseases that show this pattern. Name the histologic findings (if any) that differentiate these two entities. State the non-tissue based diagnostic modalities that may influence the interpretation of the biopsy. **
 * • Basic problem: obstruction of the biliary tree causes a buildup of bile salts and copper; these seem to destroy nearby hepatocytes. **
 * • Two diseases associated with it: primary biliary cirrhosis (autoimmune destruction of bile ducts) and sclerosing cholangitis (fibrosis-mediated, circumferential stricture of bile ducts). **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **Primary biliary cirrhosis**:**
 * • 95% of patients have __anti-mitochondrial antibodies__, most have other autoimmune diseases. **
 * • Note __no risk of cancer__ and insidious onset (itching before jaundice). **
 * • Histologically, see "florid duct lesions:" bile ducts surrounded by __granulomatous inflammation__. **
 * • Like most autoimmune conditions, more common in __women__. **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **Sclerosing cholangitis**:**
 * • Two thirds of SC patients also have inflammatory bowel disease. **
 * • Clinically, see progressive fatigue, itching, and jaundice. **
 * • Histologically: see "__onion skin fibrosis__" buildup around bile ducts, gradually causing strictures in bile ducts. **
 * • Radiology is important: get an endoscopy or MRI study to confirm strictures. **
 * • See __increased risk of cancer__. **
 * • More common in __men__. **
 * • Note this can be caused (secondary SC) by pretty much anything that causes chronic obstruction in the biliary tree. **
 * 6. Based on Table 1, define chronic hepatitis. List the histochemical stains that are used for diagnosis of the two most important diseases of iron or copper accumulation in the liver. Describe the genetic basis of these disorders and the relationship to the usefulness of genetic testing. What associated clinical findings accompany each of these diseases? **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **Hemochromatosis **(iron buildup):**
 * • Hereditary form: AR-inherited, fairly common in white people. Doesn't mention much about genetic testing, but I would imagine it can be useful for picking up the severe mutations. **
 * • Present in middle age; classically show up with __liver disease__, __diabetes__, and __heart failure__, due to accumulation of iron in liver, pancreas, and pacemaking heart tissue respectively. **
 * • Acquired form: from repeated bouts of transfusions or hemolysis. **
 * • Histologically, can see brown pigment (iron) inside hepatocytes. Note difference from brown pigment inside //macrophages// due to overuse of cascara laxatives (melanosis coli). **
 * • Note accumulation of iron in the liver begins closest to portal vein (Zone I). **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **Wilson's Disease **(copper buildup):**
 * • AR-inherited mutation in copper excretion protein; rare. __Hard to do genetic testing__ (many mutations). **
 * • Tends to present in childhood with neurologic symptoms (copper in lenticulate nucleus, leads to Parkinsonian syndrome), Kayser-Fleischer rings (copper-colored rings around the iris). Sometimes "bronze diabetes"-- copper in pancreas and skin. **
 * • Can get steatohepatitis and fibrosis. **
 * • Copper staining shows this up. **
 * 7. Based on Table 1, name a genetic cause of chronic liver injury that is associated with lung disease. Describe the genetic diagnosis of individuals at risk for this disorder. What histologic finding is commonly seen in patients with this disease? What is the histochemical stain that shows this finding most clearly? **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **Alpha-1 Antitrypsin Deficiency**:**
 * • AR- inheritance; most severe form is PiZZ form (< 10% normal alpha-1 AT levels). **
 * • Note alpha-1 AT is made in the liver (liver transplant cures the deficiency). **
 * • Mutant form of alpha-1 AT gets stuck in the liver, causing injury and cirrhosis in about 1 in 10 PiZZ patients. **
 * • __PAS-diastase__ stain picks up alpha-1 AT-heavy hepatocytes (cytoplasmic inclusions). Affects mainly Zone I hepatocytes. **
 * 8. List three benign tumors and three malignant tumors that arise in the liver (i.e. not metastatic disease). Describe the histologic findings that would allow their differentiation. What clinical or history features are useful in suggesting particular diagnoses? **
 * • Benign: **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1.5in; text-indent: -0.25in; vertical-align: middle;">• **Focal nodular hyperplasia**: actually a vascular malformation. Acquired. Causes local hepatocyte hyperplasia. Histologically, look for thick-walled vessels with __non-trabecular proliferation__ of hepatocytes around them. Excised.**
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1.5in; text-indent: -0.25in; vertical-align: middle;">• **Hepatocellular adenoma**: steroid-induced disease, usually associated with oral contraceptives in women or anabolic steroid use in men. Histologically, no portal triads, central veins, or sinusoids; just solid hepatocytes packed cheek to jowl. Excised.**
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1.5in; text-indent: -0.25in; vertical-align: middle;">• **Hemangioma**: most common benign tumor of the liver. An incidental finding.**
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1.5in; text-indent: -0.25in; vertical-align: middle;">• **Biliary adenoma/cyst**: about what you'd expect. Watch out for biliary cysts as a sign of autosomal dominant polycystic kidney disease.**
 * • Malignant: **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1.5in; text-indent: -0.25in; vertical-align: middle;">• **Hepatocellular carcinoma**: most common liver cancer; __number one cause of cancer death worldwide__. Usually arises at advanced age from cirrhotic liver, but can also present at a younger age associated with hepatitis B. Note incidence is increasing in the US. Histologically, normal trabecular framework is destroyed (may be glandular patterns). Can infiltrate into either the blood or the lymphatics.**
 * <span style="font-family: Wingdings; font-size: 10pt; margin-left: 2in; text-indent: -0.25in; vertical-align: middle;">§ **Fibrolamellar **variant of HCC: better-prognosis, younger-presenting HCC with large amounts of collagen banding.**
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1.5in; text-indent: -0.25in; vertical-align: middle;">• **Cholangiocarcinoma**: adenocarcinoma of the biliary tree; typically not associated with cirrhosis. Histologically, disordered glandular formation with dysplasia.**
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1.5in; text-indent: -0.25in; vertical-align: middle;">• **Angiosarcoma**: rare, mainly occurs in elderly patients with exposure to discontinued radiation contrast dye.**

**Liver Function Tests**

 * Tuesday, October 28, 2008 **

Liver Function Tests, 10/28/08:
 * 7:43 AM **


 * [From his notes: "Serum liver chemistry tests are often referred to as liver function tests (LFTs). This is a misnomer in that most of these tests do not actually assess liver function." He prefers "liver chemistry tests." That said-- everyone is going to call them LFTs.] **


 * 1. Understand common liver chemistry tests and their clinical implications when abnormal: **
 * • __AST/ALT__: reflect hepatocellular damage. **
 * • ALT is only expressed in the liver; AST is also expressed in the heart, muscle, and blood. ALT is cytosolic, while AST is also in mitochondria. **
 * • __Alkaline phosphatase__: reflects cholestasis, infiltrative disease, or biliary obstruction **
 * • Present pretty much everywhere; generated in response to obstruction (thus also infiltrative disease, cancer, etc). **
 * • Also elevated in bone disease and pregnancy. **
 * • Can get tests that are more specific for liver-generated alk-phos (__GGT test__, 5'-nucleotidase test). **
 * • __Bilirubin__: reflects cholestasis, impaired conjugation, or biliary obstruction **
 * • (see #3 below) **
 * • Can also look at __albumin__ levels (production is in the liver) and __prothrombin time__ (to test production of liver-produced clotting factors). **
 * • Note elevated prothrombin time can be due to vitamin K deficiency or malabsorption as well; administer __sub-q vitamin K__ to look for normalization. **
 * 2. Characterize patterns of liver chemistry test abnormalities: **
 * • Two general patterns of liver dysfunction: **
 * • Hepatocellular: predominantly AST/ALT elevation **
 * • Cholestatic: predominantly alk-phos elevation **
 * 3. Understand bilirubin metabolism and causes of jaundice: **
 * • Normal heme degradation product; insoluble in water until it's conjugated. **
 * • Unconjugated = indirect bilirubin; conjugated = direct bilirubin. **
 * • Mnemonic he mentioned: __un__conjugated and __in__direct both have a prefix. **
 * • Basically once you take the iron out of heme and pop one or two things off it, you have bilirubin. It gets picked up out of the blood in the liver sinusoids by the hepatocytes, conjugated by __UDP glucuronyl transferase__ (UDP-GT) in their SER, then secreted by active transport into the bile canaliculi. **
 * • High levels of unconjugated bilirubin indicate that the problem is occurring before the bilirubin gets to the liver-- ie. hemolytic anemia. **
 * • High levels of conjugated bilirubin indicate that the problem is occurring somewhere in the biliary tree or liver-- ie. a biliary obstruction. **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **Gilbert's disease**: inherited problem with UDP-GT gene. Can't conjugate bilirubin well, so __unconjugated bilirubin builds up in a stressed, fasting or febrile state__, or any other situation in which there's increased heme breakdown. Very common but also very mild.**
 * • __Crigler-Najaar Syndrome__: no UDP-GT enzyme at all, presents at birth with severe jaundice. Technically there are two variants of this, one with slight enzyme activity. **
 * • __Dubin-Johnson Syndrome__: defect not in UDP-GT, but in active transport of conjugated bilirubin into the bile canaliculus; benign condition, no therapy required. **
 * 4. Review abnormal liver chemistry test algorithms: **
 * • __Elevated AST/ALT__ (<5x nml): **
 * • AST:ALT ratio < 1 = normal; AST:ALT ratio > 1 is usually cirrhosis; AST:ALT ratio > 2 is suggestive of alcoholic liver disease. **
 * • Differential is pretty big and includes both hepatic and non-hepatic disorders. **
 * • Algorithm: **
 * § Take history and physical. **
 * § Check medications, discontinue if necessary. **
 * § Look at alk. phos, bilirubin, INR, albumin, iron studies, viral serologies. **
 * § If everything is negative and the patient is asymptomatic, try lifestyle modifications, check again in 3-6 months. **
 * § If everything is negative and the patient is symptomatic, get more specific tests: ultrasound, autoimmune serology tests, alpha-1 antitrypsin tests. **
 * • __Elevated alk phos__: **
 * • Differential is even bigger, and is notable for having more non-hepatic sources (more extrahepatic sources of alkaline phosphatase). **
 * • Algorithm: **
 * § Take history and physical. **
 * § Check other liver chemistries: **
 * • If the AST/ALT is normal, get a GGT test. **
 * • If the GGT is normal, it's not from a hepatobiliary source. **
 * • If the GGT is abnormal, get a right upper quadrant ultrasound to look for biliary duct dilation. **
 * • If the AST/ALT is abnormal, get a RUQ ultrasound. **
 * • If the ultrasound is positive for dilation, get either an endoscopy or an MRI to check it out. **
 * • If it's not, get an AMA (anti-mitochondrial antibody) test. **
 * • If it's positive, it's __primary biliary cirrhosis__ (see "Non-Viral Liver Disease"). **
 * • If not, get biopsy or endoscopy/MRI. **
 * • __Jaundice__: **
 * • Algorithm: **
 * § Take history and physical. **
 * § Get liver chemistries: **
 * • If it's the unconjugated bilirubin that's high, but the AST/ALT and alk-phos are normal, it's probably Gilbert's syndrome, but look for hemolysis. **
 * • If it's the conjugated bilirubin that's high, and the AST/ALT and alk-phos are abnormal, get a RUQ ultrasound to look for biliary duct dilation. **
 * • If it's present, get an endoscopy/MRI. **
 * • If not, get various more specific tests (AMA, etc). **
 * 5. Review abnormal liver chemistry tests cases. **
 * • As per Powerpoint. **

**Ethics: Liver Transplantation**

 * Wednesday, October 29, 2008 **

Ethics: Liver Transplantation, 10/29/08:
 * 8:00 AM **


 * 1. Discuss the decision to undergo LDLT (Living Donor Liver Transplantation) with both donor and recipient. **
 * 2. Define the indications for liver transplantation, and LDLT in particular. **
 * • __MELD score__: survival statistic that predicts 3-month survival; based on creatinine, bilirubin, and INR. The lower, the better. Higher MELD score takes priority for transplants. **
 * 3. Discuss the ethical issues surrounding transplantation, especially in patients with substance abuse issues or with a marginal outcome. **
 * 3. Discuss the ethical issues surrounding transplantation, especially in patients with substance abuse issues or with a marginal outcome. **

**Chronic Liver Disease**

 * Thursday, October 30, 2008 **

Chronic Liver Disease, 10/30/08:
 * 7:50 AM **


 * 1. Be able to identify physical exam and laboratory and radiological findings suggestive of cirrhosis. **
 * • Histologically: regenerative nodules surrounded by fibrous tissue. **
 * • Clinically: can be compensated (no complications) or uncompensated (complications). Complications in question: __variceal hemorrhage__, __ascites__, __encephalopathy__, __jaundice__. **
 * • Presentation: look for abovementioned complications, as well as: **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1.5in; text-indent: -0.25in; vertical-align: middle;">• **Physical exam**: jaundice, spider angiomatas, white nails/clubbing, edema, scleral icterus, enlarged liver, purpura, palmar erythema, umbilical hernia, gynecomastia, etc.**
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1.5in; text-indent: -0.25in; vertical-align: middle;">• **Labs**: chronically elevated AST and ALT and/or elevated alkaline phosphatase. Also low albumin, prolonged PT time, high bilirubin, and low platelet counts.**
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1.5in; text-indent: -0.25in; vertical-align: middle;">• **Imaging**: nodular liver, caudate hypertrophy (caudate drains directly into the IVC, and therefore can have better drainage), ascites, splenomegaly (blood backs up into the spleen), enlarged venous collaterals (caput medusae, esophageals), hepatocellular carcinoma.**
 * • Note cirrhosis is a common endpoint for lots of different disorders-- most of the serious pathologies we've talked about wind up here. Note also that hepatitis C and alcohol abuse account for about half of all liver transplantation in the States. **
 * • Side note on cirrhosis and carcinoma: generally, HCC arises from pre-existing cirrhosis. But notice that chronic hepatitis B, before it progresses to cirrhosis, can cause HCC in the absence of cirrhotic changes. **
 * • A liver biopsy is not necessary to make the diagnosis if you see chronic liver disease and cirrhotic complications, a CT scan showing cirrhotic findings, or characteristic physical findings. **
 * 2. Understand mechanisms of portal hypertension and role in formation of varices and development of ascites and hepatorenal syndrome. **
 * • Initially: increase in intrahepatic vascular resistance. In cirrhosis, this takes place __in the sinusoids__ (as opposed to, say, Budd-Chiari syndrome, in which the vascular clot forms in the outgoing hepatic vein). **
 * • In cirrhosis, the increased resistance is due to both structural factors (increased fibrosis and nodular development) and hemodynamic factors (reduction in nitric oxide production in the endothelium). **
 * • Next, the increase in intrahepatic vascular resistance means that more blood gets pushed back into the splanchnic circulation. The increased pressure in the splanchnics causes increased NO production in the splanchnic endothelium, which causes a dilation of its lumen, which increases the volume of blood the splanchnics take in, which increases the amount of blood trying to get into the liver, which further increases the portal hypertension. **
 * • __Portal hypertension boiled down__: P = Q x R. Increased resistance (fibrosis, lack of NO in portal system) plus increased flow (from splanchnics) equals a very high pressure (portal hypertension). **
 * • [Measuring portal hypertension: you measure it by sticking a balloon up in the hepatic venous system, inflating it, and measuring the pressure drop when you decrease it. Normal portal pressure is less than 6 and the pressure drop is around 3-4; in cirrhosis you can get a pressure drop of 15+. The measurements are different in other causes of portal hypertension (pre-hepatic portal occlusion, for example, will have more or less normal measurements)-- there's a summary slide in his Powerpoint if you're interested.] **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **Varices**: recall that, by LaPlace's Law, the wall tension in a vessel goes up with the diameter of the vessel. By shunting lots of blood into the paraumbilical and esophageal veins, you dilate the hell out of them, increasing wall tension and risk of rupture.**
 * • Transjugular intrahepatic portal shunt (TIPS): go in through the jugular vein, create a large shunt from the portal to the hepatic vein. **
 * • Notice that by putting in a shunt, you're bypassing the physiological effects of the liver on blood-- can develop hepatic encephalopathy, etc. **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **Ascites**: Cirrhosis is by far the most common cause of ascites.**
 * • Develops from an increase in nitric oxide production in the splanchnic circulation, as mentioned above-- the resultant relaxed endothelium allows fluid to escape out into the surrounding space. **
 * • Vicious cycle: **
 * § This creates a low arterial volume state. **
 * § That kicks off the RAA system, sympathetic system, etc to compensate (which means you wind up with sodium and water retention). **
 * § This leads to further stretch in the splanchnics, leading to more NO production. **
 * § The increased splanchnic NO leads to more ascites. **
 * • Note that refractory ascites can lead to hepatorenal syndrome (see below). **
 * • Dr. Burton is really keen on diagnostic paracentesis on new-onset ascites patients. **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **Hepatorenal syndrome**: can show up in advanced cirrhosis:**
 * • A disease of increased renal vascular resistance, connected to the abovementioned ascites cycle. **
 * • Increased volume in the splanchnic circulation leads to increase NO production and vasodilation/ascites with resultant low arterial volumes. This activates sympathetic mechanisms that promote renal vasoconstriction. **
 * • The increased renal vasoconstriction drops the GFR fairly drastically. **
 * • Note that there are __no significant histological changes in the kidney__. **
 * • The kidney is capable of working but it's not in the right environment to do so. After transplanting out the kidney into someone else or transplanting a new liver into the cirrhotic patient, the kidney will work fine. **
 * • This can be rapid (type 1) or progressive (type 2). **
 * • Note lots of things can make this worse: NSAIDs, infections or vasodilators, diarrhea or hemorrhage, diuretics, etc. **
 * • Note also that __ascites__ is universal in hepatorenal syndrome; if they don't have ascites, they almost certainly don't have HRS. They also tend to have water retention out of proportion to their sodium retention (thus __hyponatremia__). **
 * • [Nice little summary slide of cirrhosis and how it leads to ascites, HRS, and hyponatremia in his Powerpoint.] **
 * 3. Understand the role of the serum-to-ascites albumin gradient in evaluating the etiology of ascites. **
 * • (indisputably on the test, as per Dr. B.) **
 * • SAAG: Serum albumin minus ascites albumin, obtained at the same time. **
 * • Correlates well with sinusoidal pressure; __a SAAG of greater than 1.1 is consistent with portal hypertension__. **
 * • Look for total protein in the ascitic fluid to check the cause of the ascites: **
 * • Low protein (< 2. 5) = sinusoidal hypertension **
 * • High protein (> 2.5) = cardiac ascites or veno-occlusive disease. **
 * • A SAAG less than 1.1 is often diagnostic of malignancy or tuberculosis instead of portal hypertension. **


 * ** [Note that ascites is a risk factor for developing spontaneous bacterial peritonitis-- bacteria get out into the peritoneum with the fluid. SBP, in turn, puts patients at increased risk for HRS.] **
 * 4. Identify precipitating factors for development of hepatic encephalopathy. **


 * • Recall that the leading etiological contender of hepatic encephalopathy is ammonia (also recall that astrocytes are the only CNS cells that metabolize ammonia). **
 * • On increasing the ammonia load, as in cirrhosis, astrocytes go a little nutty and start overexpressing BDZ receptors, activating neurosteroids that kick up GABA-ergic tone. **
 * • In brief, it looks like varying levels of increased GABA-ergic tone: mild confusion, limited attention span, and messed up sleep all the way to somnolence, disorientation, aphasia, and coma. Check out table 6 in his notes for further details on progression of HE. **
 * • Largely a clinical diagnosis; liver disease + confusion is usually hepatic encephalopathy. **
 * • Precipitating factors: **
 * • Largely has to do with bacteria metabolism of protein to ammonia: **
 * § High ingested protein load **
 * § GI bleeding (high protein levels in colon) **
 * § Constipation (bacteria has lots of time to digest) **
 * • Also infection and over-diuresis. **
 * • As mentioned, placement of a TIPS can also precipitate HE. **

**Energy Balance and Physical Activity**

 * Tuesday, November 04, 2008 **

Energy Balance and Physical Activity, 11/4/08:
 * 7:48 AM **


 * [Don't forget we have a dietary self-monitoring exercise due on November 26th.] **

• Note part of this can be used in unconscious movement (shifting posture, etc)-- it's not all from walking around and jogging (or climbing mountains, you unnatural, unnatural people). • The unconscious movement energy expenditure is called __NEAT__-- non-exercise activity thermogenesis. Don't you love cutesy acronyms? 'Cause they make me want to rip the heads off bunnies. • Note that part of all energy expenditures is made up of heat 'waste'-- the second law of thermodynamics being what it is. Note also that that 'waste' is what makes us warm-blooded creatures and is essential for life-- without waste we can't live. Comfort yourself with that fact next time you're curled on the floor in a drunken heap. 3. Describe the relationship between energy expenditure and body weight. • Two possible points he's referencing with this. • (1) With greater body mass, the __total__ energy expenditure generally goes up, partly because of increased __resting__ metabolic rate and partly because they expend more energy to do the same mechanical work than a leaner person (moving more mass)-- thus __EEPA__ goes up for the same degree of movement. TEF seems to be about the same. • (2) Changes in TEF and RMR don't seem to correlate much with changes in body weight. Activity energy expenditure, on the other hand, is strongly correlated with them-- exercise-related or not. § Specifically, active energy expenditure is correlated with an increase in fat-free body mass. Exercise induces oxidation of fat. 4. List the methods available to measure energy intake and energy expenditure. Describe the reliability and accuracy of these measures. • Intake: Not a lot of good ways to measure this (most people under-report food intake by 20-40%). If a person isn't gaining or losing weight, then their energy intake must, by definition, be equal to their total energy expenditure (which can be directly measured, see below). • Expenditure: • RMR can be measured by indirect calorimetry (measures respiratory gas composition and flow to estimate VO2 and VCO2, providing an estimate of the rate of energy consumption of a fasting person at rest). § Can also estimate RMR from age, sex, height, weight, and (if known) lean body mass or fat-free mass. • TEF can be measured sort of the same way that RMR is measured: take a RMR of a fasting patient, then take the same measure (indirect calorimetry) in the same patient following a test meal, then measure the difference. • EEPA is measured by subtracting RMR and TEF from the total energy expenditure (TEE). • TEE is measured by the "doubly labeled water" method (use double-labeled H2O and track CO2 production over a period of time to measure overall metabolism). 5. Estimate the pool sizes of stored fuels (fat, carbohydrate and protein) within the body. • Fat stores comprise the largest fuel store (120,000 kcal or 13 kilograms in most people). • Carbohydrate stores are next (3,000 kcal, 750 grams), mainly in glycogen in muscle and liver. • Protein isn't generally used as a store except in starvation situations, in which muscle protein will be broken down to make glucose. 6. List the hierarchy of fuels for oxidation and discuss how this affects weight gain. • Since there's no fuel storage for protein, dietary protein is preferentially oxidized over carbohydrates and fat. • Similarly, between carbohydrates and fat, carbohydrates will be preferentially oxidized, since there's a lower capacity to store them. • Theme here: the body prefers to store what it stores well (fat > carbohydrates > proteins). It prefers to oxidize (ie. utilize for energy) what it can't store well (proteins > carbohydrates > fat). • What this means: if your food intake is balanced and, in total, is more than your total energy expenditure, you're going to get fat-- you'll preferentially utilize the overabundant proteins and carbs for energy and store the fat in adipose tissue.
 * 1. Estimate the accuracy of energy balance in “normal” people. **
 * • Roughly a 0.3% imbalance between energy intake and energy expenditure, in the direction of intake. You'll probably gain, on average, about a pound every year. That would mean that I'll weigh about 250 pounds when I'm 75. That's depressing. I'm going to have some chocolate. Freakin' self-reinforcing cycle. **
 * 2. List the components of the energy balance equation including components of energy expenditure. **
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **Resting Metabolic Rate **(RMR): energy cost involved in maintaining heartbeat, brain/liver/kidney activity, body temperature, Na/K pumps, etc. Comprises 75% energy expenditure in resting people. Classically this is called "basal metabolic rate."**
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **Thermic Effect of Food **(TEF): energy cost involved in digesting and distributing ingested nutrients. Comprises 8% energy expenditure in most people.**
 * <span style="font-family: Symbol; font-size: 10pt; margin-left: 1in; text-indent: -0.25in; vertical-align: middle;">• **Energy Expenditure of Physical Activity **(EEPA): fairly self-explanatory. Comprises up to 30-40% of energy expenditure in highly active or exercising people, less in sedentary individuals.