Gastrointestinal and Liver Pathophysiology Objectives

Peptic Ulcer Disease

1. Understand the pathophysiologic mechanism and relationship of Helicobacter pylori infection to active chronic gastritis & peptic ulcer disease.

Peptic ulcers are breaks in the lining of the GI tract due to loss of cells from the mucosa, extending through the lamina propria to at least the depth of the muscularis mucosa. They typically arise on a background of inflammation and/or irritation of the mucosa, called active chronic gastritis in the stomach.

One of the leading causes of peptic ulcer disease is infection with Helicobacter pylori, a gram-negative spiral-shaped bacterium that colonizes only gastric-type epithelium. H. pylori can survive in the acidic environment of the stomach because it expresses urease, an enzyme that cleaves urea to produce ammonia and bicarbonate, thus creating an alkaline zone in which the bacterium can thrive. It typically infects the gastric antrum, residing in or under the mucus layer & causing inflammation and peptic ulceration. It can also cause ulcers in the gastric fundus and the duodenum (where it infects gastric-type metaplastic mucosal tissue).

H. pylori causes peptic ulceration by two mechanisms: it does direct damage to the gastric mucosa and also promotes increased secretion of gastric acid, which can overwhelm the normal defense mechanisms of the already-compromised mucosa.

2. Be able to describe the basis for clinical testing of H. pylori infection.

Clinical testing for H. pylori infection is justified because of the organism’s strong association with peptic ulcer disease and gastric cancer.

The basis for most clinical testing for H. pylori infection is the bacterium’s expression of urease, an enzyme that converts urea into ammonia and bicarbonate. When endoscopy is performed, a rapid urease assay can be used to detect H. pylori; a biopsy of antral mucosa is placed in a medium containing urea and a pH indicator, which turns red if the medium is basic and thus contains H. pylori. Similarly, in the carbon-labeled urea breath test, radiolabeled urea is ingested by the patient, who then breathes into a sampling balloon. If radiolabeled carbon dioxide is detected, the presence of H. pylori is confirmed.

Other clinical tests for H. pylori infection (which do not rely on the presence of urea) include direct histological visualization of biopsied tissue, culture of gastric tissue, stool antigen testing, and serologic testing for anti-H. pylori immunoglobulin. Serology is the preferred test if endoscopy is not indicated, but cannot be used to confirm eradication of the organism, as antibody titer remains high for up to a year after the infection has been cleared.

3. Be able to describe the association of H. pylori with gastric cancer.

In gastric cancer, the vast majority of individuals show evidence of past H. pylori infection. The organism is a class I carcinogen and is known to predispose to gastric adenocarcinoma and MALT lymphoma of the stomach. It is unclear if H. pylori eradication decreases the risk of gastric adenocarcinoma, but treatment of active H. pylori infection can lead to regression of MALT lymphoma.

4. Understand the relationship of gastric acid and gastrin to peptic ulcer disease and the mechanisms for gastric protection and acid control.

Secretion of gastric acid is normally tightly regulated to allow for proper digestion of food and elimination of pathogens while preserving the integrity of the gastric mucosa.

Interdigestive (basal) acid secretion occurs continuously at about 15% of the maximal secretory capacity, is regulated primarily by the vagal nerve, and follows a well-defined circadian rhythm with a peak at about 10 PM and a trough at 8 AM. Cephalic acid secretion is initiated by the thought, smell, taste, or chewing and swallowing of food; it appears to be mediated by both the vagus nerve and gastrin. The gastric phase of acid secretion is triggered when food enters the stomach, and is mediated mainly by gastrin, the release of which is triggered by physical (antral distension) and chemical signals. The intestinal phase, which may involve either acid secretion or the inhibition of acid secretion, occurs upon the entry of chyme into the duodenum, and is triggered by duodenal distension and the products of protein digestion; neither vagal input nor gastrin seems to be involved.

Acid is secreted by parietal cells in the gastric oxyntic glands. On stimulation, these cells undergo transformation into a secretory state; a network of tubulovesicles fuse with another and the apical membrane and begin pumping H+ ions into the gastric lumen in exchange for K+ (via the H-K ATPase). The three major stimulants that promote parietal cell activation are acetylcholine, gastrin, and histamine (which appears to have a potentiating effect on the other two stimulatory pathways). Acetylcholine is secreted by postganglionic cholinergic terminals of the vagus nerve, which can also be stimulated by small local reflex loops that are sensitive to gastric distension. Gastrin is produced by G cells in the gastric antrum, and histamine is produced by local mast cells.

In the normal stomach, three mechanisms protect the gastric mucosa from damage: the mucus-bicarbonate barrier, constant epithelial renewal, and prostaglandin secretion. The mucus-bicarbonate barrier consists of an adherent semisolid glycoprotein gel overlaid by soluble mucus, into which bicarbonate is actively secreted to maintain a pH of 7 at the epithelium (despite a luminal pH of 1.5-2). Mucus secretion is stimulated by cholinergic input and some prostaglandins, while bicarbonate secretion is stimulated by vagal input and luminal acid. The epithelium is also constantly renewed (about every 5 days), has extremely strong tight junctions to prevent entry of acid into the mucosa, and can be repaired in a matter of hours after injury. Finally, the gastric mucosa synthesizes prostaglandins which inhibit acid secretion & gastrin production, stimulate mucosal blood flow, promote bicarbonate secretion, and promote gastric epithelial renewal.

The failure of this system in peptic ulcer disease typically involves the disruption of mucosal protective factors (NSAIDs, which inhibit prostaglandin production, and H. pylori, which can directly damage the mucosa and mucus layer) and/or the production of amounts of acid that can overwhelm the protective factors (Zollinger-Ellison syndrome, in which unregulated gastrin production leads to uncontrolled acid secretion, and H. pylori, which can also promote hypersecretion of gastric acid).

5. Be able to describe and differentiate the various etiologies of hypergastrinemia (to include and understanding of the pathophysiology of gastrinoma and retained gastric antrum).

Hypergastrinemia may be due to: Achlorhydia or hypochlorhydia: abnormally absent or reduced gastric acid stimulates

the production of excessive gastrin, and feedback inhibition does not occuro Gastric atrophyo Pernicious anemiao Chronic gastritiso Omeprazole therapyo Vagotomy

Retained gastric antrum: an improperly performed antrectomy & Billroth II gastrectomy procedure, in which the antrum has not been adequately resected. Gastrin producing G-cells in the retained antrum are not exposed to acid from the reconnected stomach and thus sense a paucity of acid and produce high levels of gastrin.

Gastrinoma: a gastrin-secreting tumor that is not subject to feedback inhibition, as in Zollinger-Ellison syndrome. In Zollinger-Ellison, hypergastrinemia is associated with severe peptic ulcer disease, large gastric folds, and diarrhea (due to massive gastric volume output, direct injury to the GI mucosa, and the inactivation of pancreatic lipase by gastric acid)

G-cell hyperplasia: unclear if this actually exists Massive small bowel resection Gastric outlet obstruction Renal failure: gastrin is not cleared from the circulation

6. Understand the relationship of NSAIDs to ulcer disease.

NSAIDs are designed to inhibit the inflammatory enzyme COX-2, but also inhibit the constitutively expressed enzyme COX-1, which is responsible for the synthesis of prostaglandins in the gastric mucosa. Chronic and heavy NSAID use can inhibit prostaglandin production to the extent that gastric mucosal defenses are overwhelmed (decreased mucosal blood flow, impaired epithelial renewal, unrestricted gastrin & acid production), causing peptic ulceration. Patients especially at risk for this complication include the elderly, females, and those with prior peptic ulcer disease. The treatment is withdrawal of NSAIDs, if feasible.

Esophageal & Gastric Motility Disorders and Gastro-Esophageal Reflux Disease

1. Understand the physiological basis for upper GI motor function and dysfunction.

The esophagus consists of two sphincters (the UES and LES) and two muscle regions (the proximal esophagus, composed of skeletal muscle, and the distal esophagus, composed of smooth muscle). The UES and proximal esophagus are involved in the oropharyngeal phase of swallowing, which is controlled directly and extrinsically by the CNS. The distal esophagus and LES, responsible for the esophageal phase of swallowing, are under mixed central & peripheral control, mediated by the brainstem “swallowing center” and intramural nervous plexuses.

Esophageal motor dysfunction occurs when the control mechanisms of the upper and lower esophagus malfunction. This can involve various mechanisms: CNS damage that interferes with the swallowing center (e.g. in stroke), compression of the esophagus by intrinsic or extrinsic masses, structural lesions of the esophagus, and neuromuscular disorders.

Dysfunction of the skeletal muscle region (pharynx, UES, proximal esophagus) causes oropharyngeal dysphagia, which presents with food “sticking” in the cervical region, and often nasopharyngeal regurgitation and/or aspiration. Dysfunction of the smooth muscle region (distal esophagus, LES) causes esophageal dysphagia and is discussed below.

2. Be able to differentiate the two principal types of esophageal motor dysfunction: hypermotility and hypomotility.

Esophageal hypermotility (achalasia, diffuse esophageal spasm, and non-specific spastic disorders) involves a failure of the normal inhibition of contraction in the esophagus. Achalasia is the most severe case, and involves the death of esophageal motor neurons. It presents with dysphagia, regurgitation, and chest pain, caused by a chronically closed LES with resultant esophageal dilatation and failure of peristalsis. Diffuse esophageal spasm and the non-specific spastic disorders, which cause abnormal contractions of the esophagus, typically present with intermittent non-progressive dysphagia and vague substernal chest pain. Most cases involve the dysfunction of inhibitory neurons, but some severe cases involve neuron death.

Esophageal hypomotility involves decreased contraction strength in the esophageal body and/or the LES. The main symptoms (heartburn, pyrosis, dyspepsia) are caused by failure of the LES to close or contract, allowing unrestricted reflux of gastric contents into the esophagus. Some cases are associated with scleroderma or other connective tissue diseases.

3. Recognize the clinical outcome from esophageal motor dysfunction, including presentation, diagnosis, and management approaches.

Disorders of the skeletal muscle region present with oropharyngeal dysphagia and sometimes nasal regurgitation and/or aspiration. Diagnosis involves a modified barium swallow, manometry, and neurological evaluation if indicated. Management involves instruction in “safe swallow” techniques.

Achalasia typically presents with dysphagia and regurgitation, and may also involve chest pain, heartburn, and symptoms of aspiration. It is diagnosed by barium swallow, endoscopy, and/or esophageal manometry, and management is directed at reducing LES basal pressure by pharmacological (calcium channel blockers, Botox, isosorbide dinitrate) or surgical (myotomy, pneumatic dilation) means.

DES and NSSDs typically present with substernal chest pain, and infrequently regurgitation and/or dysphagia. Symptoms are typically intermittent and non-progressive. Treatment is directed at reducing pain and inhibiting gut-brain interaction (e.g. antidepressants).

Esophageal hypomotility presents with symptoms of GERD (heartburn, pyrosis, dyspepsia), and is diagnosed by manometry. Treatment is exclusively directed at managing GERD (e.g. PPIs, H2 antagonists, antacids).

4. Understand the causes of and mechanisms behind abnormal gastric emptying.

Delayed gastric emptying can be caused by mechanical obstruction (e.g. a GI tumor that compresses the pyloric region) or neuromuscular dysfunction. Neuromuscular dysfunction may involve neurogenic mechanisms (e.g. diabetic neuropathy), which damage the nerves controlling gastric emptying, or myogenic mechanisms (e.g. tachygastria and other muscle disorders), which interfere with the production of normal gastric muscle tone. Neuropathic disorders produce a disorganized MMC, while myopathic disorders produce a weak or absent MMC. Disorders that interfere with basal gastric motor tone will delay emptying of both liquids and solids, while disorders that only interfere with distal gastric motor processes will delay emptying of solids while allowing normal passage of liquids.

Rapid gastric emptying is associated with disorders and surgical procedures that reduce receptive relaxation of the proximal stomach (such as vagotomy, diabetic vagal neuropathy) and procedures that prevent normal closure of the pyloric sphincter (such as pyloroplasty and pyloromyotomy, commonly performed in surgery for peptic ulcer disease or esophageal cancer). Rapid gastric emptying may produce the dumping syndrome, in which nutrient-containing liquid (and sometimes solid) meals empty so rapidly into the duodenum that normal digestive and absorptive mechanisms are overwhelmed, producing diarrhea & abdominal pain (early phase) and symptoms of hypoglycemia (late phase) caused by mismatch of glucose absorption and insulin release.

5. Be able to describe rational treatment interventions for abnormal gastric emptying based on pathophysiological mechanisms.

Delayed gastric emptying is initially treated by removing any offending medications and altering the diet to include more liquids & less fat. Prokinetic agents may be used to accelerate gastric empyting but have limited utility due to the rapid development of tachyphylaxis.

Rapid gastric emptying and the dumping syndrome are treated with lifestyle changes (small meals, ingestion of fluids between meals, less carbohydrates & more protein/fat), anticholinergic agents, octreotide (experimental), and in severe cases surgical maneuvers such as jejunum loop interposition or reconstruction of the pylorus.

6. Understand the mechanisms responsible for GERD.

GERD may be produced by three mechanisms: physiological alterations of the LES, hiatal herniation, and impaired esophageal clearance.

Alterations in the LES include relaxation immediately after a swallow (occurs in “normal” patients), intermittent inappropriate relaxations of an LES with normal basal tone, and low LES basal tone. The second alteration (inappropriate relaxation) is the most common LES-related cause of GERD and physiologic reflux.

Hiatal herniation contributes to GERD by creating a reservoir of gastric contents near the LES while the patient is supine, contributing to transient LES relaxations, interfering with distal esophageal clearance, and eliminating the apposition of the LES and diaphragm, which normally produces inspiration-related constriction of the LES.

7. Be able to describe the presentation, treatment, and potential outcomes of GERD.

GERD typically presents with heartburn and postural regurgitation; less common symptoms include chest pain, dysphagia, and odynophagia. “Atypical” GERD can present with esophageal chest pain, bronchopulmonary symptoms due to aspiration (asthma, bronchitis, apnea, pneumonia, fibrosis), or ENT symptoms such as hoarseness, cough, halitosis, and dental enamel loss.

First-line treatment of GERD involves lifestyle modifications (head-of-bed elevation, weight loss, smoking cessation, reduction of meal size, reduction of coffee/fat/chocolate/alcohol, avoidance of eating before bedtime). Pharmacotherapy involves control of intragastric acidity with antacids, H2 antagonists, and/or proton pump inhibitors. Surgical therapy, the final line of treatment, requires reduction of hiatal hernia and Nissen fundoplication.

Intestinal Malabsorption

1. Understand the importance of anatomical factors, particularly those that are rate-limiting in the absorption of carbohydrates and fats.

The stomach produces gastric lipase (which usually contributes to about 10-20% of TG hydrolysis, but is upregulated in neonates and pancreatic insufficiency), mechanically disrupts & emulsifies the meal, regulates normal delivery of nutrients to the small bowel, synthesizes IF (necessary for B12 absorption) and digests cobalamin complexes & binds them to R-complexes.

The small bowel is responsible for some digestion and most nutrient absorption. Anatomical and physiologic differences between the segments of the small bowel are very important in these processes. About 80% of nutrient uptake is usuall completed in the proximal bowel (proximal to Ligament of Treitz). The duodenum alone absorbs iron, folate, and calcium, while the ileum alone absorbs bile salts and vitamin B12-IF. The jejunum is a fairly redundant segment, and its loss is easily accommodated. Carbohydrate digestion in the duodenum involves breakdown of oligosaccharides at the brush border; the rate-limiting step is transport of monosaccharides across the epithelium, except for lactose (hydrolysis by lactase is the rate-limiting step). Fat absorption in the small bowel depends on intraluminal digestion (by pancreatic enzymes), mucosal processing & uptake, and normal postmucosal processing and transport (e.g. by the lymphatic system).

The pancreas produces the enzymes necessary for digestion of nutrients: amylases, proteases, lipases, and nucleases. It also produces the bicarbonate-rich fluid necessary for normal pH maintenance in the duodenum.

The colon reabsorbs fluid and electrolytes, temporarily stores waste products, serves as a major repository for enteric flora, and generates short-chain fatty acids (a major energy source for colonocytes).

2. Understand the pathophysiologic mechanisms for carbohydrate and fat malabsorption.

The most common mechanism for carbohydrate malabsorption is lactose intolerance, which is actually a normal adult phenotype (except in northern Europeans and their descendants). Deficiency or absence of the enzyme lactase, which catalyzes the rate-limiting hydrolysis of lactose, allows the passage of undigested lactose into the colon, where it is broken down by bacteria, producing bloating, gas, and osmotic diarrhea. Damage to the intestinal mucosa by various diseases may produce intolerance in patients who previously tolerated lactose well. Other causes of carbohydrate malabsorption include overconsumption of high fructose corn syrup (which may overwhelm the small bowel’s capacity to absorb fructose), overconsumption of sorbitol, and rare genetic deficiencies of disaccharidases.

Fat malabsorption may be due to maldigestion, impaired fat processing & uptake, and/or disruption of post-mucosal fat delivery. It can cause steatorrhea, diarrhea, weight loss, kidney stones (increased luminal fat chelates calcium, leading to increased absorption of soluble oxalate), and fat-soluble vitamin deficiencies (A night blindness, D osteopenia & tetany, K easy bruising, E rarely any functional defects).

Maldigestion is usually caused by pancreatic insufficiency (chronic pancreatitis, cystic fibrosis, functional insufficiency in Zollinger-Ellison syndrome), in which lipase production, activation, and/or secretion is abnormal, or by bile salt deficiency (biliary obstruction, ileal dysfunction leading to bile salt malabsorption, bacterial overgrowth, etc.). Poor mixing of biliary & pancreatic secretions with food (usually after a gastric surgery) may contribute, as may rapid transit of GI contents (as in hyperthyroidism).

Mucosal disorders may impair fat processing and uptake at the GI epithelium by reducing available surface area (celiac sprue, enteropathy, tropical sprue, resection, radiation/chemotherapy). Rare defects in intracellular lipid metabolism (such as abetalipoproteinemia) may also impair normal fat uptake and/or packaging.

Postmucosal obstruction, typically involving lymphatic obstruction or lymphangiectasia, impairs the transport of absorbed fats to the portal circulation & liver. Causes include congenital malformation, neoplasm, tuberculosis, Whipple’s disease, and trauma.

3. Understand the pathophysiology of bile acid diarrhea.

Bile acid diarrhea is a secretory diarrhea caused by the presence of increased levels of bile acids in the colon, typically due to resection of the ileum (which normally absorbs bile salts). Bacterial metabolites of bile acids are potent secretagogues; they can stimulate massive secretion of fluids & electrolytes by the colon, causing diarrhea without steatorrhea.

4. Understand the tests used to evaluate patients with maldigestion and malabsorption.

Tests for steatorrhea are a common starting point for a malabsorption workup, as fat malabsorption is a common feature of many malabsorption syndromes. Visual inspection of the stool is important, as steatorrhea may cause grossly pale, yellow, sticky, rancid stools. Microscopic inspection with Sudan staining of a stool smear can detect fat in the stool. Staining before the addition of acid suggests the presence of triglycerides and thus pancreatic insufficiency; staining after the addition of acid suggests the presence of free fatty acids. The gold-standard test is chemical detection of fecal fat, which requires 24-hour or 72-hour stool collection, requires hospitalization, is very difficult, and has a long turnaround time.

The D-xylose absorption test is used to assess the absorptive capacity of the proximal small intestine. D-xylose absorption reflects general mucosal absorptive surface area (since it does not require a specific oligosaccharidase or transporter). D-xylose is administered orally and its presence in the urine is assessed over 5 hours. The presence of <5 g in the urine suggests mucosal disease. The test can give a false positive under several conditions (delayed gastric emptying, ascites, bacterial overgrowth in the intestine, NSAID use in the week prior to testing).

The small bowel radiologic series (with barium) is useful for detecting and locating mucosal abnormalities to guide mucosal biopsy, and can also detect anatomic lesions (fistulae and strictures) and other conditions that predispose to bacterial overgrowth. A normal study does not rule out the presence of mucosal lesions, and samples for stool cultures & parasite screens should be obtained beforehand, since barium inhibits the growth or microorganisms.

Peroral biopsy of the small bowel is the key to diagnosis for many mucosal conditions.

Patients with suspected celiac sprue should be instructed to institute a gluten-free diet; failure to respond suggests incomplete removal of gluten or the presence of another GI condition.

Tests for lactose intolerance may involve a trial of withdrawing milk products (not very reliable), a lactose tolerance test, which involves monitoring blood glucose to check for absorption, or a hydrogen breath test, in which breath H2 is measured following ingestion of lactose in water. Many of these tests suffer from poor correlation between symptoms and results indicating lactose maldigestion.

The hydrogen breath test may also be used with lactulose or glucose administration to assess for bacterial overgrowth.

Bacterial culture via endoscopy may be necessary to confirm or rule out bacterial overgrowth.

The Schilling test is a series of procedures done to determine the cause of vitamin B12 deficiency.

In Stage I, an injection of unlabeled B12 is given to saturate all internal B12 binding sites, then oral radioactive B12 is administered and the urine is assessed for radiation. A finding of less than 8-10% of the administered dose in the urine suggests B12 malabsorption.

In Stage II, radiolabeled B12 complexed with intrinsic factor is administered after the initial injection. A normal urine finding suggests pernicious anemia.

In Stage III, the patient is given a course of antibiotics before the test is repeated. A normal urine finding suggests bacterial overgrowth. Web says this is III, coursepack says this is Stage IV. ???

In Stage IV, the patient is given pancreatic enzymes along with the B12. A normal urine finding suggests pancreatic insufficiency. Web says this is IV, coursepack says this is III.

Diarrhea: Pathophysiology and Approach to the Patient

1. Specify the clinical definition of diarrhea.

Diarrhea is defined as a stool volume >200 mL/day or stool weight greater than 200 g/day. Clinical complaints associated with diarrhea may include increase in stool frequency, increase in stool volume, and decrease in stool consistency.

2. Understand the major features of fluid and electrolyte absorption in the small intestine and colon.

Intestinal fluid & electrolyte absorption involves both passive and active transport across a polarized epithelium with tight junctions. Transport is both active and passive, and may involve specialized membrane proteins. Na, K, Cl, and HCO3 are the main ions whose active transport is involved in controlling fluid movement, which follows electrolyte movement.

Solute-coupled sodium absorption is important in the jejunum, especially following a meal. Electroneutral NaCl absorption is relatively more important in the ileum & proximal colon, and involves the secretion of bicarbonate and H+. Electrogenic Na transport plays a more important role in the distal colon.

Most ingested potassium is absorbed in the small intestine via diffusion; active absorption of K+ occurs in the distal colon. The colon is aldosterone-responsive, and can actively secrete K+ in exchange for Na+. Chloride is secreted via special channels throughout the intestine. Bicarbonate secretion is an important cytoprotective mechanism in the duodenum and elsewhere, and may be uncoupled or coupled to Cl cycling.

3. Identify the major pathophysiologic mechanisms of diarrhea.

A simple approach to diarrhea divides pathogenic mechanisms into two categories: enhanced secretion and impaired absorption. A more detailed approach identifies five main categories:

Osmotic diarrhea: defined as diarrhea that stops when the patient fasts and has an osmotic gap >100 on stool analysis. Osmotic diarrhea is caused by the presence in the intestines of poorly absorbed solutes that “drag” water and salt into the lumen. This may be due to ingestion of poorly absorbed solutes (sorbitol, mannitol, lactulose, various salts), deficiencies of nutrient absorption (disaccharidase deficiencies, generalized malabsorption), or other causes.

Secretory diarrhea: caused by enhanced secretion by the proximal GI tract, which overloads the absorptive mechanisms of the colon. Usually involves the production of large volumes of water stool with no osmotic gap, blood, pus, or significant steatorrhea. Causes include infection (acute cases), tumors, celiac sprue, congenital defects, portal hypertension, and Zollinger-Ellison syndrome (chronic cases).

Impaired net colonic absorption of fluid: due to impaired colonic absorption (diffuse colitis, colon resection) or enhanced colonic secretion (fatty acid diarrhea, bile salt diarrhea, villous adenoma).

Motility disorders: rapid transit through the GI tract does not allow for sufficient absorption of fluid/electrolytes (except in scleroderma). Almost always cause chronic diarrhea. Examples include acute stress-related diarrhea, IBS, post-

vagotomy diarrhea, diabetic neuropathy diarrhea, thyrotoxic diarrhea, and scleroderma.

Combined mechanisms: as in celiac sprue and Crohn’s disease, which both produce enhanced secretion and impaired absorption (due to loss of absorptive area in sprue and inflammation in Crohn’s).

4. Define an approach for evaluating the patient with diarrhea.

A careful history is key to the initial approach. Temporal course (acute vs. chronic), associated symptoms (weight loss, fever, abdominal pain, bleeding, etc.), medications (especially laxatives), alcohol use, and the nature of the diarrhea are all important. The patient should be asked about stool size and odor (rancid odor may indicate steatorrhea). It is also important to assess for left-sided diarrhea, characterized by frequent small bowel movements, marked rectal urgency, rectal or LLQ discomfort relieved by bowel movement or flatus, and the presence of bright blood and/or mucus.

Laboratory tests that may be helpful include measurement of stool frequency and volume over 24 hours; assessment for fecal fat, leukocytes, and occult blood; stool culture (acute diarrhea); various other tests, including stool osmotic gap.

5. Discuss the differences between acute and chronic diarrheal illness.

Acute diarrhea has a duration of <2-3 weeks, is usually caused by an infection (cholera, E. coli, C. diff, etc.), is typically self limited, and usually requires only oral rehydration with salt-glucose solutions. Chronic diarrhea has a duration of >3 weeks, a variable course, and a multitude of possible etiologies. It may require treatment of the underlying defect and symptomatic treatment.

Diseases of the Colon

1. Be able to describe the epidemiology, pathogenesis, and clinical presentation of colorectal cancer.

Epidemiology: third most common cause of cancer & cancer-related death in both men and women. Increased risk is associated with hereditary syndromes (FAP, HNPCC), personal history of colorectal cancer or adenomas; first-degree family history of colorectal cancer or adenomas; personal history of ovarian cancer, endometrial cancer, breast cancer, ulcerative colitis.

Pathogenesis: alterations in tumor suppressors and proto-oncogenes in the stem cells of the colonic epithelium lead to the development of adenomas (“polyps”) which acquire further mutations and develop into malignant lesions.

Clinical presentation: may be asymptomatic, or present with iron deficiency anemia, occult GI blood loss, hematochezia, alterations in bowel frequency or stool caliber, or obstructive symptoms. Small lesions are often asymptomatic, so most patients present with advanced disease. Right-sided cancers are more likely to present with

occult stool blood, iron-deficiency anemia, and fatigue; left-side cancers are more likely to present with frank blood in the stool and changes in bowel habits.

2. Understand screening and preventive strategies concerning colorectal cancer.

Since cancers of the colon are usually asymptomatic when small and potentially curable, screening programs for asymptomatic individuals are very clinically important. High-risk individuals (family or personal history of polyps/cancer, personal history of IBD/breast cancer/gynecologic cancer, known familial colorectal cancer syndrome) need earlier, more frequent, more aggressive screening than average-risk individuals (over 50, no family or personal history of colorectal cancer or polyps, no personal history of IBD, breast cancer, or gynecologic cancer).

Colonoscopy is the gold standard; it allows for concurrent screening & treatment of small lesions and screens the entire colon. It is, however, uncomfortable (and requires colonic lavage) and expensive. Sigmoidoscopy uses a flexible scope to examine the distal colon, and is more acceptable to patients. Fecal occult blood testing is inexpensive and easy, but non-specific and susceptible to false positives due to various foods. CT colonography, or “virtual colonoscopy” is expensive, requires colonic lavage, and does not allow for immediate removal of detected lesions, but it does not require sedation. Fecal immunochemical tests are more specific versions of the occult blood test that detect only human globin. Fecal DNA tests detect DNA shed by neoplasms; they are costly and require the collection of an entire bowel movement.

3. Be able to describe the pathophysiology, clinical presentation, and treatment approaches to diverticular disease.

Pathophysiology: diverticula are small balloon-like sacs or pouches of mucosa that herniate through the muscle layers of the colon, and are thought to be caused by low-fiber diets and increased straining during defecation. Most patients with diverticulosis do not suffer clinical problems, but the diverticula may become infected or bleed.

Clinical presentation: o Diverticulitis presents with fever, leukocytosis, and left-sided abdominal pain,

and may progress to perforation. o Diverticular bleed: presents with painless, sudden bright red blood in the

stool. Treatment:

o Diverticulitis: should be diagnosed with CT scan and treated with bowel rest & antibiotics; surgical intervention is reserved for >2 episodes, fistula, abdominal abscess, or free perforation.

o Diverticular bleed: many are self-limiting, but patients who present should be evaluated with an endoscope to exclude other causes; persistent bleeding should be treated with replenishment of fluid & blood products, and surgical intervention (guided by angiography or nuclide scans) may be necessary

4. Be able to describe the pathophysiology, clinical presentation, and treatment approaches to ischemic colitis.

Pathophysiology: ischemic injury to the colon, via low flow states/hypovolemia, arterial thrombosis, increased intraluminal pressure, or injury to the vessels supplying the colon. Ischemia is rarely complete, and distribution of injury is segmental. Localized ischemia typically involves “watershed” areas between blood supplies; diffuse ischemia typically involves the right colon.

Clinical presentation: patients are usually middle-aged or elderly and sick (many have atherosclerosis, heart disease, and/or diabetes), and present with crampy abdominal pain (often LLQ) followed by passage of blood or bloody diarrhea per rectum. Low-grade fever, nausea, anorexia, and peritoneal inflammation may also occur.

Treatment: diagnosis must be established by sigmoidoscopy/and or plain films with barium enema; treatment is supportive (bowel rest, antibiotics, bowel decompression, correction of hypovolemia, avoidance of exacerbating medications e.g. narcotics/NSAIDs/vasoconstrictors) unless peritonitis, perforation, and/or progressive ischemia are directed, in which case surgery is indicated.

5. Be able to describe the pathophysiology and clinical presentation of irritable bowel syndrome.

Pathophysiology: unclear/unknown; thought to involve visceral hypersensitivity, abnormal serotonin signaling in the gut, and/or somatization.

Clinical presentation: abdominal pain, constipation, and/or diarrhea; often associated with anxiety, depression, or severe stress

6. Be able to describe the pathophysiology, clinical presentation, and treatment of microscopic colitis.

Pathophysiology: unclear; two predominant subtypes are lymphocytic (increased numbers of subepithelial mononuclear cells on biopsy) and collagenous (increased collagen deposition & chronic inflammation on biopsy), and it causes diarrhea because of impaired fluid and solute transport.

Clinical presentation: chronic diarrhea, typically in women and without blood, fever, significant weight loss, or lab abnormalities. Some cases may have symptoms more typical of IBD.

Treatment: symptomatic control with anti-diarrheals or bismuth tablets; some patients respond to anti-inflammatories (e.g. 5-ASA) or prednisone.

7. Understand causes of constipation.

Constipation may be caused by obstruction (as in many serious GI disorders, e.g. colon cancer, ileus, Crohn’s, diverticulitis, etc.), colonic dysmotility (primary or secondary, including diabetes, hypothyroidism, electrolyte imbalances, neurologic diseases,

medications), or pelvic floor dysfunction (acquired, usually in women who have had vaginal deliveries).

8. Be able to describe the causes and clinical presentation of acute colonic pseudo-obstruction.

Causes: narcotics, recent surgery with resumption of normal diet, other medications that cause hypomotility, idiopathic

Clinical presentation: abdominal distension, tympany to percussion, absent or hypoactive bowel sounds; gaseous distension & dilated cecum on X-ray

Mucosal Immunology and Inflammatory Bowel Disease

1. Understand the distinctions between the mucosal immune system and the systemic immune system.

The intestinal mucosa has a specialized immune system that operates with a certain degree of independence from the systemic system. Specialized M cells between enterocytes take up antigens from the gut lumen and present them to lymphocytes and dendritic cells in the subepithelial t issue. Activation of these cells can result in proliferation and dissemination of effector lymphocytes to mucosal surfaces in the lungs, oral cavity, gut, and urogenital tract. Gut epithelial cells express special chemokines and adhesion molecules specific for “gut-homing” T cells, and plasma cells in the lamina propria synthesize and release secretory IgA, which is transported into the lumen in the crypts and protects the epithelium from pathogens and toxins.

2. Be able to differentiate the clinical presentation of ulcerative colitis from that of Crohn’s disease.

Both ulcerative colitis and Crohn’s present with diarrhea, abdominal pain, fever, and weight loss, and occur at any age (peak 10-35). Fever, severe pain, and severe weight loss are more common in Crohn’s, but these are usually not useful ways to distinguish between the two.

Ulcerative colitis typically presents with rectal bleeding and rectal involvement in the disease process. It rarely involves anal fissures, anal fistulae, or abdominal masses. Inflammation is mucosal, crypt abscesses are common, and the disease is continuous and confined to the colon.

Crohn’s disease typically presents with anal fissures & fistulae and abdominal mass. It typically does not involves the rectum or present with rectal bleeding. Inflammation is transmural, granulomas & fissures are common, and the disease is discontinuous and may occur anywhere in the GI tract.

3. Understand the pathogenesis of mucosal inflammation in IBD.

The etiology of IBD is still unknown. Genetic factors are known to play a role, especially in Crohn’s. IBD involves prolonged immune activation with infiltration by lymphocytes & macrophages and increased IgG production. Neutrophil infiltration is also involved. The prolonged response eventually causes tissue damage via proteases and reactive oxygen species. Suggested mechanisms for this prolonged immune response are a) an appropriate response to an unknown persistent antigen, and b) an inappropriately prolonged and intense response to a normal dietary or microbial antigen, resulting from an antigen-specific defect in immune regulation. Various factors are known to precipitate or “flare” IBD, including antibiotics, enteric infections, NSAIDs, and smoking cessation (UC only).

4. Be able to describe the current medical therapy for IBD based on our understanding of its pathogenesis.

Current medical therapy for IBD involves anti-inflammatory drugs of various classes, intended to suppress the inappropriately prolonged and intense immune reaction that causes tissue damage in IBD.

Ulcerative colitis is usually treated with 5-ASA compounds, azathioprine, or anti-TNF antibodies (e.g. infliximab). Crohn’s disease is treated with azathioprine or anti-TNF antibodies.

Acute “flares” of either disease require different treatment. Acute UC should be treated with topical 5-ASA or steroids for distal disease, oral 5-ASA or steroids for extensive disease, azathioprine for steroid-dependent disease, and anti-TNF antibodies is azathioprine fails. Trials of oral 5-ASA and steroids are underway. Surgical therapy (colectomy) is required if medical therapy fails. Actue Crohn’s is treated with oral steroids or antibiotics, or azathioprine or anti-TNF antibody for steroid dependent or steroid refractory disease. Surgical therapy is required for failure of medical therapy or complications (obstruction, perforation, bleeding).

Viral Hepatitis

1. Differentiate the salient features of the main hepatotropic viruses (A,B,C,D,E).

Hepatitis A Organism: Non-enveloped RNA virus Epidemiology: Leading cause of acute viral hepatitis worldwide; spread is fecal-oral

& person-person, and related to poor sanitation, bad hygiene, and overcrowding. Water-borne and food-borne outbreaks common.

Risk groups: residents of and travelers to endemic regions, children and caregivers in daycare centers

Pathogenesis: Liver injury is mediated by cellular immune response to infected hepatocytes

Clinical Course: mild to severe illness following incubation of 2-6 weeks: malaise, fatigue, headache, abdominal pain, arthalgias, nausea/vomiting, anorexia, fever;

followed by jaundice, dark urine, pruritus, pale stools. Recovery within 6-12 weeks; fulminant cases very rare (<1/1000)

Chronic Sequelae: no chronic hepatitis, low acute fatality rate, no cirrhosis, no carrier state

Diagnosis: acute = IgM anti-HAV; recovered/latent = IgG anti-HAV; vaccinated = IgG anti-HAV

Treatment: symptomatic; hospitalization rarely required Prevention: HAV vaccine (pre-exposure), immune globulin (post-exposure)

Hepatitis B Organism: double-shelled DNA virus. Outer envelope = HBsAg; inner core = HBcAg Epidemiology: in the US & Europe, disease of adulthood A/W IV drug use,

transfusions, needle-sticks, nosocomial spread, promiscuity. In Africa & Asia, endemic and largely transmitted by maternal-infant or child-child spread

Risk Groups: IV drug users, multiple sexual partners, MSM, infants born to infected mothers, HCW, transfusion recipients

Pathogenesis: immune-mediated (apoptotic, humoral, cellular) Clinical Course: acute form is stereotypical hepatitis with 40-180 day incubation

period; chronic form may be silent or present with fatigue and intermittent exacerbations resembling acute form

Chronic Sequelae: chronic hepatitis (2-10% adults, 90% children <5 y), cirrhosis, low acute fatality rate, carrier state exists

Diagnosis: see below under objective 4 Treatment: interferons, nucleoside analogs, nucleotide analogs to suppress or

eradicate HBV Prevention: HBV vaccine (pre-exposure), HBIg + HBV vaccine (post-exposure)

Hepatitis C Organism: RNA virus Epidemiology: worldwide distribution; recreational injection drug use is the

dominant mode of transmission. Other routes include hemodialysis, high-risk sexual behaviors, sexual & household contacts, HCW.

Risk Groups: injection drug users, transfusion recipients Pathogenesis: unknown; may involve immune-mediated and direct cytopathic injury Clinical Course: acute form has an indolent course with mild or no symptoms after

an 8 week incubation period; fulminant form is extremely rare; chronic form presents with malaise, weakness, fatigue, serious consequences later in the infection (cirrhosis, HCC, lymphoma, membranous glomerulonephritis, vasculitis, etc.)

Chronic Sequelae: very low acute fatality rate, carrier state, high prevalence of chronic hepatitis (70-85%), cirrhosis

Diagnosis: see below under objective 4 Treatment: subcutaneous pegylated interferon and oral ribavirin, 6-12 months Prevention: no vaccine or prophylactic treatment exists

Hepatitis D

Organism: defective RNA virus that must get help from HBV to acquire an envelope and become infective

Epidemiology: occurs worldwide, but prevalence higher in tropical and subtropical areas of Africa & S. America; direct parenteral and sexual routes are the most efficient mode of transmission

Risk Groups: any person infected with hep B, injection drug users Pathogenesis: immune-mediated and direct cytopathic mechanisms Clinical Course: acute and chronic forms similar to other forms of viral hepatitis;

acute form suggests coinfection and rarely becomes chronic, while the chronic form suggests superinfection; both forms can precipitate fulminant hepatitis

Chronic Sequelae: moderate (2-10%) acute fatality rate, carrier state, chronic disease progresses to cirrhosis in 3-5 years in about 40% of patients

Diagnosis: acute = IgM anti-HDV and/or HDV Ag; chronic & recovered/latent = IgG anti-HDV

Treatment: pegylated interferon alfa Prevention: no vaccine is available, but can be prevented by timely administrated of

HBV vaccine as it requires HBV to cause disease

Hepatitis E Organism: non-enveloped RNA virus Epidemiology: primarily in the developing world; primary mode of transmission is

fecal-oral; zoonotic (pigs are reservoir) Risk Groups: residents of and travelers to endemic regions Pathogenesis: appears to involve cytopathic damage & immune-mediated damage Clinical Course: acute form is stereotypical hepatitis with incubation period of 2-8

weeks; course is usually benign with recovery in 2-6 weeks; progression to chronic hepatitis is rare; fulminant hepatitis is very rare

Chronic Sequelae: low acute fatality rate, no carrier state, very little progression to chronic hepatitis, no cirrhosis or HCC

Diagnosis: in the USA, ELISA assays for IgM anti-HEV or HEV-RNA are available only through the CDC and specialty labs in the

Treatment: supportive and symptomatic Prevention: vaccine not available but should be soon

2. Understand the natural history of acute and chronic viral hepatitis.

Acute hepatitis, a major public health problem, usually presents with acute-onset malaise, fatigue, headache, abdominal pain, myalgias, arthalgias, nausea, vomiting, anorexia, and/or fever. These initial symptoms are usually followed by jaundice, dark urine, pale stools, and pruritus. It is usually followed by recovery, although rare cases may result in death.

Fulminant hepatitis is a subtype of acute hepatitis which involves the onset of altered mental status (hepatic encephalopathy) and impaired coagulation within 8 weeks of the initial symptoms of liver disease in an otherwise healthy individual. Other clinical manifestations may include cerebral edema, hypoglycemia, and cardiac/renal/respiratory failure.

Chronic hepatitis is defined arbitrarily as the presence of liver inflammation for at least 6 months. It may culminate in end-stage liver disease (cirrhosis and/or hepatocellular carcinoma) after years to decades of indolent disease.

3. Identify the epidemiological patterns and risk factors for the most common forms of viral hepatitis.

See objective 1.

4. Be familiar with the various diagnostic tests available for viral hepatitis and its interpretation.

Hepatitis A: Acute: IgM anti-HAV+ Chronic: N/A Recovered/Latent: IgG anti-HAV+ Vaccinated: IgG anti-HAV+

Hepatitis B: Acute: IgM anti-HBc+, HBeAg+, HBsAg+, HBV DNA+ Chronic: IgG anti-HBc+, HBeAg+, anti-HBe+/-, HBsAg+, HBV DNA +/- Recovered/Latent: IgG anti-HBc+, HBeAg-, anti-HBe+/-, HBsAg-, HBV DNA -, anti-

HBs+ Vaccinated: anti-HBs+ only

Hepatitis C: Acute: HCV RNA+, anti-HCV Ab in 8-10 wks; all tests possibly negative Chronic: HCV RNA+, anti-HCV Ab+ Recovered/Latent: HCV RNA-/?, anti-HCV Ab+ Vaccinated: N/A

Hepatitis D: Acute: IgM anti-HDV+, HDV Ag+ Chronic: IgG anti-HDV+ Recovered/Latent: IgG anti-HDV+ Vaccinated: N/A

Hepatitis E: Acute: specialty tests available from CDC / research labs Chronic: N/A Recovered/Latent: specialty tests available from CDC / research labs Vaccinated: N/A

Acute and Chronic Pancreatitis

1. Understand the relationship of pancreatic exocrine proteins to the pathophysiology of pancreatitis.

Pancreatitis is thought to be caused by inappropriate activation of pancreatic zymogens (especially proteases) in the pancreas rather than in the lumen. The activation of these zymogens in the pancreas promotes autophagy (the “digestion” of pancreatic tissue), which causes degeneration and inflammation of the pancreas. This in turn leads to the release of more activated enzymes, which are found systemically in patients with acute pancreatitis and are thought to mediate some of the systemic effects (ARDS, pleural effusion, etc.).

2. List the ways that the pancreas protects itself from the harmful effects of digestive enzyme.

Most digestive enzymes are synthesized as zymogens and are not normally activated until they reach the duodenum, where enterokinase activates trypsin.

Intracellular (just-produced) digestive enzymes are segregated in granules, keeping them away from lysosomes and other cellular components.

The activating enzyme, enterokinase, is anatomically segregated from the pancreas.

3. Know the difference between acute and chronic pancreatitis.

Acute pancreatitis is a sudden, generally reversible inflammatory process of the pancreas, with variable involvement of other regional tissues or remote organ systems. Chronic pancreatitis is a chronic, irreversible, irregular scarring of the glandular parenchyma caused by ongoing pancreatic inflammation.

4. Know the common etiologies of acute and chronic pancreatitis.

Acute pancreatitis: Alcohol toxicity Gallstones and other biliary derangements Idiopathic Other (minor causes):

o Traumao Autoimmuneo Hereditaryo Infectiouso Iatrogenico Toxic (e.g. scorpion toxin)o Neoplastico Vascularo Structuralo IBD-relatedo Metabolico Drug-inducedo Iatrogenic

Chronic pancreatitis: Alcohol toxicity

Idiopathic Other (minor causes):

o Hereditary pancreatitiso Cystic fibrosiso Tropical pancreatitis

5. Understand the clinical presentation, diagnosis, and management of chronic and acute pancreatitis.

Acute pancreatitis: Clinical Presentation: steady dull or boring pain in the epigastrium or LUQ, which

may radiate to the back; mild to intense pain on abdominal palpation; other symptoms may include anorexia, nausea, vomiting, fever, dyspnea (rare), coma (rare). Signs include Gray-Turner sign, ascites, hypotension, rebound tenderness, respiratory distress

Diagnosis: serum amylase (faster rise but less specific), serum lipase (slower rise but very specific), physical exam, CT scan and/or EUS showing enlargement/fluid collection

Management: hospitalization, aggressive IV fluid & electrolytes with Hct monitoring, NPO if eating cause worsening pain, antiemetics & narcotic analgesics, antibiotics if infection detected

Chronic pancreatitis: Clinical Presentation: abdominal pain, episodes of acute pancreatitis (~50%), weight

loss, malabsorption, upper GI bleed, diabetes mellitus Diagnosis: plain radiographs (calcification), EUS, CT; exogenous stimulation of

pancreatic secretion with secretin or secretin/CCK, 72-hr fecal fat collection to determine if fat malabsorption is present

Management: analgesics, enzyme replacement (with H2 antagonist or PPI), nutritional support, therapy for DM, drainage of pseudocysts and fluid collections, surgical intervention in extreme cases

6. Know the common complications of acute and chronic pancreatitis and understand the current theories of the pathophysiology behind those complications.

Acute pancreatitis: Local complications related to autodigestion: fluid collection, pseudocyst, pancreatic

necrosis, vascular issues, mass effect Shock: 3rd spacing intravascular hypovolemia and hypotension, capillary leak,

possibly inadequate cardiac response due to vasoactive agents (?) Coagulopathy: destruction of components of the clotting cascade by pancreatic

enzymes Hypocalcemia: decreased responsiveness to PTH and decreased PTH production,

possibly loss of calcium in soaps in areas of fat necrosis Hyperglycemia: destruction of pancreatic islets

Acute renal failure: ATN secondary to shock, possibly direct destruction of renal tissue (?)

Respiratory failure:o Pleural effusions: leak of peripancreatic fluid through the diaphragmo Atelectasis: abdominal distension & paino ARDS: hypotension, activated neutrophils, possibly direct damage by

pancreatic enzymes

Chronic pancreatitis: Pain: possibly secondary to obstruction, irritation, inflammation of pancreas Malabsorption: failure of pancreatic enzyme production (especially lipases) Malnutrition: secondary to malabsorption Diabetes mellitus: destruction of pancreatic islets Pseudocysts & fluid collections Obstruction of the common bile duct: strictures or fibrosis Pancreatic cancer

Bile Formation, Bilirubin Metabolism, Cholestasis

1. Understand the basics of bile formation at the cellular level.

In the liver, hepatocytes take up bile salts, lipids, and other bile components from the hepatic sinusoids. The sinusoidal membrane protein NTCP selectively removes conjugated bile salts from the blood in a sodium-dependent fashion, while OATP mediates sodium-independent uptake of bile salts.

At the canalicular membrane, the hepatocytes pump lipids, toxins, organic solutes, bile salts, and bilirubin into the bile canaliculus. MDR transports solute, lipids, and toxins; cMOAT transports bilirubin; cBST translocates bile salts; and the Cl-HCO3 exchange maintains the bile at an acidic pH.

As bile travels down the canaliculi into the bile ducts, bile duct epithelial cells dilute and modify it, pumping in HCO3 to boost pH and adding water via aquaporins to dilture the bile.

2. Understand the basics of bilirubin metabolism.

Heme (70% from RBCs, 10-30% from hepatic enzymatic turnover, remainder from ineffective erythropoiesis) is converted to bilirubin by enzymes in the endoplasmic reticulum. This “unconjugated” bilirubin, which is lipid-soluble, is transported in plasma tightly bound to albumin, and is taken up by the hepatocytes in the liver.

In the hepatocytes, bilirubin is “conguated” by the enzyme UGT, located in the endoplasmic reticulum, then transported across the canlicular membrane into the bile, and eventually excreted into the duodenum. The intestine cannot absorb conjugated bilirubin; in the

terminal ileum and colon, it is converted to unconjugated bilirubin by bacterial enzymes. The unconjugated bilirubin is then reduced by colonic bacteria to form urobilinogen. Most urobilinogen is excreted with stool, but some is reabsorbed and excreted in the urine.

3. Understand the definition and potential etiologies of cholestasis.

Cholestasis is decreased or absent bile flow. It may be extrahepatic or intrahepatic.

Extrahepatic cholestasis is usually secondary to bile duct obstruction, e.g. by gallstones, tumors, strictures, and extrinsic compression. Compression & bile “backup” cause profound changes in hepatocytes; pumps and proteins that normally localize to the canalicular membrane are redistributed to inhibit the accumulation of toxic bile components in the hepatocyte.

Intrahepatic cholestasis: Cystic fibrosis: CFTR function is impaired, leading to decreased chloride and

bicarbonate secretion in the intrahepatic bile ducts. The change in pH decreases ductular bile flow and may cause precipitation of mucus plugs.

Certain drugs may cause a decrease in the activity of Na/K ATPase, which is necessary to create the sodium gradient that allows for normal bile production

Drugs that interfere with bile acid binding cytosolic proteins and/or microtubule assembly (which is necessary for normal intracellular transport of bile acids in vesicles) can decrease bile flow

Alterations of the canaliculus, e.g. decrease in ATP-dependent transport of organic ions by cMOAT, caused by estrogens

Autoimmune liver diseases; e.g. primary biliary cirrhosis Viral hepatitis Infiltrative disease (e.g. AFLD, NAFLD)

The Biliary Tract

1. Brief review of anatomy & physiology

Bile is synthesized in the liver, where hepatocytes secrete bilirubin, bile salts, lipids, and toxins into the bile canaliculi. It is diluted and refined in the bile ductules, and eventually transported via the hepatic bile ducts into the common hepatic duct. Bile is stored in the gallbladder, from which the cystic duct joins the common hepatic duct to form the common bile duct. The common bile duct joins the pancreatic duct at the ampulla of Vater. Between meals, the gallbladder relaxes and the sphincter of Oddi contracts; during and immediately after meals, the gallbladder contracts and the sphincter relaxes, under the influence of the hormone CCK.

The gallbladder modifies the bile while it is being stored: it concentrates bile by absorbing water and electrolytes, and also secretes mucoprotein (to coat the gallbladder surface) and

acid (to prevent calcium stone formation) into the bile, which consists mainly of a mixture of cholesterol, phospholipids, and bile salts.

2. Gallstones and their complications

Gallstones are a very common clinical problem: more than 20 million Americans have gallstones, although 75-80% of these patients have no symptoms. There is a 2:1 female: male prevalence, risk increases with age, and certain ethnicities have high incidence of gallstones. Gallstones may present with biliary colic and/or acute cholecystitis.

There are three main types of gallstones: cholesterol, black pigment, and brown pigment. Cholesterol stones, the most common in the US, form by cholesterol supersaturation, recur often (35%), and occur preferentially in the gallbladder. Risk factors include age, female sex, obesity, pregnancy, rapid weight loss, and TPN. Black pigment stones are composed of calcium carbonate & calcium bilirubinate and are caused by the overproduction of unconjugated bilirubin; they preferentially occur in the gallbladder and rarely recur. Risks include hemolysis, ileal disease, and cirrhosis. Brown pigment stones, the least common, are caused by bacterial infections of the bile, recur quite often, and preferentially occur in the ducts. Risk factors include bile duct dyskinesia and IgA deficiency.

Gallstone formation requires three principal defects: a) supersaturation of the bile, usually caused by high cholesterol levels or low bile acid levels; b) nucleation, either homogeneous or heterogeneous, which is much more important and involves mucus and bacteria; and c) gallbladder hypomotility or stasis, which may occur in pregnancy, TPN, and starvation or rapid weight loss.

The complications of gallstones include: Biliary colic, a colicky pain usually centered in the RUQ caused by sudden and

temporary obstruction of the cystic duct by a stone. Acute cholecystitis, caused by the impaction of a stone in the cystic duct or neck of

the gallbladder Mirizzi’s syndrome, the obstruction of the common bile duct by a gallstone in the

neck of the gallbladder Choledocholithiasis, the obstruction of the common bile duct by a stone that has

passed through the cystic duct, which can lead to jaundice, ascending cholangitis, and/or acute pancreatitis

Cholecystoduodenal fistula, caused by the erosion of a stone out of the gallbladder into the duodenum, which can lead to Bouveret’s syndrome (the stone becomes lodged in the duodenal bulb, causing vomiting) or gallstone ileus (the stone obstructs the ileocecal valve).

Gallbladder carcinoma

3. CholangiopathiesCholangiopathies may be:

Immune-mediated:

o Primary sclerosing cholangitis: an inflammatory disease of the bile duct of unknown etiology. It is usually diffuse and associated with IBD, can lead to cirrhosis, and predisposes to cholangiocarcinoma. Strictures caused by PSC that involve the extrahepatic bile ducts should be sampled to rule out carcinoma.

o Primary biliary cirrhosis: inflammatory destruction of the interlobular and septal bile ducts, thought to be immune-mediated. Typically presents in middle-aged females, who may be asymptomatic or complain of vague symptoms like fatigue. The hallmark test is positive AMA.

o Chronic GVHD: seen after bone marrow transplantation due to mismatch of minor histocompatibility antigens on cholangiocytes

Infectious: ascending cholangitiso Bacterial: enteral gram-negative bacteria (e.g. E. coli)o Viral: AIDS cholangiopathy, associated with cryptosporidium infectiono Parasitic and fungal infections are very rare causes

Vascular:o Post-surgical injuries: post cholecystectomy bile duct injury, post liver

transplant stricture at anastomosis and/or diffuse ischemia Malignant: cholangiocarcinoma, which presents with painless jaundice Genetic: various genetic defects leading to absence of ducts (Alagille’s), multiple

cysts of the ducts (Caroli’s) or mucus plugging (cystic fibrosis)

4. Diagnostic tests for gallbladder and biliary tract disorders

History & physical: jaundice (especially of sclera), pale stools, dark urine, +/- pain (common in stone disease, not in carcinoma), pruritus

Lab tests: bilirubin (obstruction elevated total & direct), liver transaminases (elevated in acute obstruction), alkaline phosphatase (biliary obstruction, not specific), GGT (more specific test of biliary obstruction)

Transabdominal ultrasound: good for cholecystitis, bile duct disease; not sensitive for common bile duct stones

HIDA scan: uptake and excretion into the bile of a radiolabeled compound; lack of GB filling after 60 minutes suggests cystic duct obstruction and lack of passage into the duodenum suggests CBD obstruction

Cross-sectional imaging: CT (cannot detect cholesterol stones), MRI Endoscopic ultrasound

5. Treatment options for gallbladder and biliary tract disorders

Surgery: cholecystectomyo Standard of care for acute cholecystitis and symptomatic cholelithiasiso Typically laparoscopic

ERCP: combined endoscopic and fluoroscopic procedure that may be used for diagnosis (brush cytology & stricture visualization) or treatment (stone extraction, stenting, treatment of leaks, sphincterectomy)

Percutaneous intervention: for gallbladder decompression and stone removal in patients who are not surgical candidates, or in whom ERCP has been unsuccessful

Medical therapy: ursodiol (synthetic bile acid) for improved bile clearance, cholestyramine (bile acid binding resin) for pruritus of cholestasis

Acute Hepatic Failure

1. Understand the clinical manifestations of acute liver failure.

Acute liver failure is defined as hepatic encephalopathy and an INR >= 1.5 with an illness <26 weeks in duration in the absence of cirrhosis and/or previous history of liver disease.

2. Understand the etiologies and evaluation of patients with acute liver failure.

The most common etiologies of acute liver failure are: Acetaminophen toxicity Idiopathic or indeterminate (especially in children) Non-acetaminophen drug toxicity Hepatitis B Autoimmune hepatitis Ischemic hepatopathy Hepatitis A Wilson’s disease Budd-Chiari syndrome Fatty liver of pregnancy

Evaluation of patients with liver failure involves six main steps Establish that acute liver failure is occurring

o Liver biopsy may be helpful if etiology is unknown Determine etiology

o Requires history and physical, which may be difficult due to altered mental status of hepatic encephalopathy

o Assess acetaminophen level & liver function testso Perform drug screen, viral serology tests, autoimmune serology tests, and

ceruloplasmin level testing.o Hepatic imaging may contribute

Determine hepatic and renal function / severityo Assess INR, serum albumin, serum creatinine, and transaminase levels

Assess need for liver transplanto King’s College criteria for acetaminophen and non-acetaminophen causes

3. Understand the prognostic indicators and treatments for acute liver failure.

In addition to lab levels like pH, INR, creatinine, and bilirubin levels, the etiology of acute liver failure is typically a useful prognostic indicator. ALF caused by acetaminophen,

hepatitis A, ischemia/shock, or pregnancy typically has a good prognosis; ALF caused by drug toxicity, hepatitis B, Wilson’ disease, or an unknown cause has a bad prognosis.

The mangement of acute liver failure involves both etiology-specific and general interventions:

Etiology-specifico Acetaminophen toxicity: administer N-acetylcysteineo Amanita phalloides: administer PCN or silibinino Autoimmune hepatitis: may respond to corticosteroidso Wilson’s disease: may require transplant (?)

Generalo Critical careo Airway protection for high-grade encephalopathyo Manage cerebral edema: elevate head of bed, administer mannitol, possibly

monitor intracranial pressureo Liver transplantation if necessary

Tests of Liver Function and Metabolism

These objectives are not helpful, so here is a summary of liver function tests.

AST & ALTo Liver enzymes found in hepatocyteso ALT is more sensitive for liver cell injury; AST is also found in smooth and

skeletal muscle and RBCso Elevation suggests injury to hepatocytes; degree of elevation does not

correlate with degree of injury, although levels >5000 suggest ischemia or acetaminophen toxicity

o Common causes of elevation: viral hepatitis, autoimmune injury, drug toxicity, Wilson’s disease, hemochromatosis, NAFLD

Alkaline phosphataseo Can be of liver origin, but can also come from bone, placenta, intestineo Elevation can suggest cholestasis

GGTPo More specific test for cholestasis after abnormal alk phos- only found in livero Common causes of elevation: biliary obstruction, PBC, PSC, hepatic

sarcoidosis, drug toxicity Bilirubin

o Elevated levels suggest hemolysis Total bilirubin

o Elevated levels suggest hepatocellular injury and/or biliary obstructionGI Pharamcology I & II

See Google Doc of required drugs

Chronic Hepatocyte Failure I & II

1. Review the definition, causes, and pathophysiology of cirrhosis.

Definition: cirrhosis is a chronic disease of the liver in which diffuse destruction and regeneration of hepatic parenchymal cells have occurred and in which a diffuse increase in connective tissue has resulted in disorganization of the lobular and vascular architecture

Etiologies: cirrhosis is the final pathway of many types of chronic liver injury. Some common causes of chronic liver injury that may result in cirrhosis are:

o Alcohol abuseo Viral hepatitis (B or C)o Cholestatic disorders (PBC, PSC)o Autoimmune liver diseaseo Metabolic disease (Wilson’s, hemochromatosis, alpha-1-antitrypsin

deficiency, NAFLD)o Drugs & toxinso Venous outflow obstruction (Budd-Chiari syndrome)

Pathophysiology: activation of stellate cells during hepatic injury leads to transformation, proliferation, collagen hypersecretion, inflammation, and contraction. These changes, when chronic, lead to the deposition of fibrous bands, distortion of normal liver architecture, “capillarization” of liver sinusoids, and bizarre patterns of hepatocyte death & regeneration. These processes produce the fibrotic, disorganized tissue of advanced cirrhosis, which in turn causes vascular derangement (portal hypertension) and hepatic dysfunction (hypoalbuminemia, clotting abnormalities, hypoglycemia, excretory problems, and failure of detoxification).

2. Review the definition, pathophysiology, and clinical manifestations of portal hypertension.

Definition: portal hypertension is defined as portal vein pressure in excess of the normal 5-10 mmHg, typically assessed via venous catheterization with measurement of the hepatic venous pressure gradient.

Pathophysiology: portal hypertension may be prehepatic, intrahepatic, or posthepatic in nature.

o Prehepatic: portal vein thrombosiso Intrahepatic: cirrhosis, which distorts liver vasculature and decreases the

radius of liver sinusoids, thus raising resistanceo Posthepatic: IVC webs, constrictive pericarditis, severe heart failure, Budd-

Chiari syndrome (thrombosis of the hepatic veins) Clinical Manifestations: hemorrhage from varices, portal gastropathy, splenomegaly

with hypersplenism, acute & chronic hepatic encephalopathy, ascites

3. Understand the management of esophageal varices.

Primary prophylaxis for esophageal varices involves non-selective beta-blockers (which reduce cardiac output & promote unopposed alpha-adrenergic activity in the splanchnic bed, causing vasoconstriction) and/or endoscopic banding of large varices. During episodes of acute bleeding from esophageal varices, endoscopic banding and/or slcerotherapy is used to halt bleeding, and octreotide may be administered to induce splanchnic vasoconstriction. Uncontrollable bleeding may necessitate emergent surgical intervention. Secondary prevention of bleeding typically involves liver transplantation, long-term endoscopic sclerotherapy or band ligation, beta blockade, or TIPSS.

4. Review the definition, potential pathogenesis, and management of portal-systemic encephalopathy.

Definition: portal-systemic encephalopathy is mental state dysfunction occurring as a consequence of liver disease. Specifically, portal-systemic encephalopathy develops due to portal-systemic collaterals that arise from portal hypertension, and develop slowly. A variant form, hepatic encephalopathy associated with acute or fulminant hepatic failure, results from severe inflammatory and/or necrotic liver disease and is associated with the development of cerebral edema.

Pathogenesis: thought to be associated with neurotransmission failure in the brain. There are currently two major theories: ammonia neurotoxicity (portal-systemic shunting allows ammonia derived from bacterial processing of urea and glutamine to bypass the liver’s normal detoxification mechanism and enter the brain, where it is converted to ammonium and exerts direct neurotoxic effects & disrupts the normal metabolism and regulation of glutamate) and GABA overload (gut derived GABA bypasses the liver’s normal detoxification mechanism and enters the brain, causing generalized inhibition of neural activity),

Management: rule out other causes of encephalopathy, seek out and treat precipitating factors (infection, GI bleeding, renal dysfunction, hypovolemia & electrolyte disturbances, drugs, acute liver disease), and commence empirical treatment with lactulose to promote colonic acidification, alter colonic nitrogen metabolism, and promote bowel catharsis. Antibiotics may also be useful (kill colonic bacteria that produce ammonia).

5. Understand the mechanisms of ascites generation in chronic liver disease, and relate these mechanisms to the management of ascites.

Increased portal pressure results in increased lymphatic flow with leakage into the peritoneum. Impaired clearance and increased production of vasodilators (nitrous oxide, endogenous cannabinoids, carbon monoxide) contribute to splanchnic vasodilation, causing fluid pooling and under filling of the arterial circulation (due to decreased effective circulating volume). Hyperdynamic circulation (decreased peripheral resistance) also causes blood pooling, and the neurohormonal & renal response to decreased effective circulating volume promotes increased fluid & salt retention.

Ascites is first managed with bed rest and a low sodium diet, which should reduce fluid retention. If this is not effective, diuretics (usually spironolactone) are used to reduce volume. If ascites is still not corrected, direct large-volume paracentesis with albumin replacement and/or TIPSS (which corrects the vascular backup caused by portal hypertension) are used. The final line treatments are surgical portocaval and/or peritoneovenous shunts and liver transplantation.

6. Understand the pathogenesis, diagnosis, and treatment of spontaneous bacterial peritonitis.

Pathogenesis: portal hypertension leads to intestinal edema and increased permeability, which may predispose to intestinal bacterial overgrowth. Bacterial translocation into the peritoneum causes infection, and the systemic immune response is weakened (liver damage, low protein & complement levels in ascites fluid).

Diagnosis: history & physical (fever, chills, abdominal pain, asymptomatic with unexplained general worsening of condition and/or encephalopathy, ascites, sometimes peritoneal signs), neutrophil count in ascites fluid >250, positive bacterial culture from ascites fluid, may have positive blood culture

Treatment: broad-spectrum antibiotics (e.g. cephalosporins); consider liver transplant due to high recurrence rate

7. Be familiar with the diagnosis of hepatorenal syndrome and the perturbations of normal physiology in chronic liver disease.

Hepatorenal syndrome is a unique form of renal failure seen in patients with liver disease. It is associated with intense vasoconstriction in the renal cortex that results in oliguria and avid sodium retention. The kidneys are histologically normal and the syndrome disappears if the patient receives a liver transplant. The disorder may be caused by the intense extra-splanchnic vasoconstriction caused by reductions in effective arterial volume found in cirrhosis, associated with a failure of systemic & renal vasodilators.

It is important to exclude pre-renal AKI and acute tubular necrosis when diagnosing HRS. Patients with HRS have very low urine sodium values (<10) (unlike patients with ATN) and a normal central venous pressure (unlike patients with pre-renal AKI). The clinician must consider other causes of concurrent renal & hepatic dysfunction, such as shock or CHF, sepsis, acetaminophen & other drug toxicities, autoimmune disease, and PKD.

8. Understand the development of hepatocellular carcinoma as a complication of cirrhosis.

Hepatocellular carcinoma often develops on a background of cirrhosis (inflammation, bizarre cell remodeling & proliferation, etc.), or as a consequence of chronic hepatitis B infection (with or without cirrhosis). Patients who have cirrhosis caused by chronic viral hepatitis, hereditary hemochromatosis, tyrosinemia, or exposure to aflatoxins are at high risk for HCC. Patients with cirrhosis associated with alcoholism, alpha-1-antitrypsin

deficiency, or autoimmune liver disease are at moderate risk for HCC. Patients with Wilson’s disease or PBC are at low risk for HCC.

Nutrition (Combined Objectives from Review Sheet)

1. Understand the differences between digestible vs. non-digestible carbohydrates, and soluble vs. insoluble fiber.

Digestible carbohydrates are those that can be hydrolyzed & absorbed by the human digestive system, and include almost all monosaccharides & disaccharides (with the exception of lactose in many cases) and some polysaccharides (starches like amylase and amylopectin). Humans cannot directly digest & derive energy from non-digestible carbohydrates, which are mainly large polysaccharides like cellulose.

Non-digestible carbohydrates are also known as “fiber,” and the class can be divided into soluble and insoluble categories. Soluble fibers (generally found in plant sources) are soluble in water and can be fermented by colonic bacteria, producing short-chain fatty acids (which can be used as an energy source by colonocytes, among other functions). Soluble fiber is known to bind cholesterol and helps to lower serum cholesterol levels. Insoluble fiber (e.g. cellulose) is not fermented by gut bacteria, and serves mainly to increase stool bulk, soften stool, and decrease stool transit time.

2. Understand the differences between saturated vs. unsaturated fatty acids and know the percentage of total calories that should be ingested from saturated fatty acids.

Saturated fatty acids have no double bonds—their carbons are “saturated” with hydrogen. Unsaturated fatty acids have one or more double bonds, and are healthier than saturated fats. The percentage of total calories ingested from saturated fatty acids should be <10%.

3. Understand the role of history, physical examination, and other factors in nutritional assessment (and review Table 1 p. 267), and the lack of utility of serum markers.

Nutritional history is the first (and perhaps most important) step in any nutritional assessment. It should include an evaluation of any medical, psychiatric, social, or surgical conditions or procedures (including medications) that may cause inadequate nutrient intake, malabsorption, or altered metabolism. The patient should be asked about family history of disease related to poor nutrition (obesity, diabetes, hyperlipidemia) and social factors such as alcohol consumption. An ROS should be performed with special attention to changes in weight & appetite.

The physical exam should include careful inspection of hair, skin, eyes, mouth, teeth, extremities, and fluid status. Temporal muscle wasting, sunken supraclavicular fossae,

and/or decreased adipose stores are important signs of undernutrition. An assessment of body size and/or composition should be performed and BMI calculated.

Serum protein levels and lymphocyte count are not helpful in nutritional assessment, as they are more related to inflammation and injury than malnutrition.

4. Memorize how to calculate BMI and be ready to do so on the exam. Know BMI cutoff points for underweight & obesity.

BMI = weight (in kg) / [height (in m)]2

<18.5 = underweight30+ = obese

5. Know and understand the components of the Harris-Benedict equation (but you don’t have to memorize the formula). 

Total energy expenditure = basal metabolic rate + activity + thermic effect of food

BMR (in kcal/day) = 66.5 + (13.8 x weight in kg) + (5 x height in cm) – (6.76 x age) for menBMR (in kcal/day) = 655 + (9.56 x weight in kg) + (1.85 x height in cm) – (4.68 x age) for women

BMR is multiplied by the Physical Activity Level (PAL) to produce BMR + PAL

Thermic effect of food is added (~6-10% TEE on average)

So components are sex, weight, height, age, physical activity level.

6. Understand how physical activity affects total energy expenditure.

Increased physical activity levels increased total energy expenditure. (Duh?)

7. Nutrition and the life cycle: focus on infant needs (what nutrients are low in breast milk, why does one add cereal at age 4-6 months). What are the common vitamin/mineral deficiencies in the elderly?

Infants have a number of special nutrition requirements. Human milk is the best food for the infant (it provides energy and immunoglobulins), but does not provide enough fluoride, iron, vitamin K, or vitamin D. Breast milk contains iron, but the baby’s iron needs increase rapidly after 4-6 months; it is thus necessary to introduce cereal fortified with iron at 4-6 months of age. Cow’s milk is not recommended until one year of age due to its low iron content, high renal solute load, and association with blood loss via the GI tract.

The elderly also have special nutritional requirements. Food intake is often poor or altered, due to xerostomia, mental status changes, altered dentition, and taste & smell dysfunction.

The elderly also have altered GI motility and poor glucose tolerance & renal function. Constipation is a common problem due to decreased fluid consumption. Psychosocial and economic factors also affect food purchase and preparation. Nutrients of particular concern are calcium, Vitamin D, iron, and B12.

8. Understand the general factors that affect vitamin or mineral deficiency (beginning of lecture). 

General factors and conditions that affect vitamin and/or mineral deficiency include poor appetite (aged & chronically ill patients), alcoholism and other substance abuse, psychiatric disease, fad diets, physician-prescribed diets (e.g. for renal failure and genetic conditions), and malabsorption (gut resection, bowel disease, etc.).

9. Know which of the vitamins are fat-soluble and which are water soluble.

Vitamins A, D, E, and K are fat-soluble.Thiamine, riboflavin, niacin, pantothenic acid, biotin, vitamin B6, vitamin B12, folic acid, and vitamin C are water-soluble.

10. Understand how fat-soluble vitamin deficiency is generated (underlying pathophysiology including pancreatic insufficiency, loss of ileum, etc.)

Fat-soluble vitamin deficiency is typically generated by defects in the absorption, tissue distribution, and handling of fat. These include disorders affecting the pancreas (which decrease lipase production), the intestine (generalized malabsorption), the ileum especially (loss of bile acids, necessary for the digestion of fat), the intestinal lymphatics, and the liver & biliary tree. In addition, disorders affecting the skin, liver, and/or kidneys may impact Vitamin D handling, and many antibiotics can cause Vitamin K defects.

11. Focus on vitamin D deficiency as an example of fat soluble vitamin – vitamin D metabolism, sources, underlying causes of deficiency, and role of supplementation. 

Active vitamin D is found in dairy products, eggs, and fish. Dietary sterols in the skin are converted to an inactive form of vitamin D (D3), which is hydroxylated by the liver to produce 25-OHD3, which is in turn hydroxylated by the kidney to 1,25-(OH)2D3, which is the more potent form. Deficiency of vitamin D can cause rickets in children and osteomalacia in adults. Deficiency is common in patients with conditions that affect bile production and reabsorption (biliary cirrhosis, small-bowel disease or resection), obesity, renal or liver disease, and chronic antiepileptic use.

Serum concentration of 25-OH-D3 (circulating half-life = 15 days) is the best indicator of vitamin D status. Routine vitamin D supplementation has not been shown to reduce fracture risk in otherwise healthy adults. Since breast milk does not contain vitamin D, all children receiving only breast milk should receive vitamin D supplementation. African-American children are at particularly high risk.

12. Review information on vitamin B12 and vitamin C as examples of water-soluble vitamins.

Vitamin B12 is found only in foods of animal origin, especially in liver, kidney, and clams. It is absorbed in a very complex process. It first binds to R-proteins in the saliva, which protect it from the acidic environment of the stomach. The R-B12 complex is degraded by proteases in the duodenum, and B12 later binds to IF (produced by the stomach) and is absorbed in the terminal ileum as a B12-IF complex. B12 is transported in the blood bound to a carrier protein, transcobalamin.

Vitamin B12 is necessary for RBC maturation and maintenance of nerve myelination; its metabolism and use is very interrelated with folate and B6 metabolism. Deficiency (demonstrated by low serum level of cobalamin) should be assessed via the Schilling test to determine the etiology. It produces megaloblastic anemia and peripheral neuropathies, and is commonly seen in pernicious anemia and malabsorption disorders. It is not toxic even at high levels.

Vitamin C is found in large quantities in citrus fruits, and also commonly used as a preservative. It is almost completely absorbed at intakes of 100 mg/day and less, and a body pool of 1500 mg (half-saturation) contains reserves for 30-45 days. Vitamin C is a cofactor for hydroxylation of proline residues, found in high abundance in collagen, so manifestations of vitamin C deficiency center on dysfunctional collagen synthesis. Scurvy involves weakness, irritability, bleeding gums, gingivitis, joint pains, loosening of the teeth, and hemorrhages in the skin, conjunctiva, GI tract, nose, and GU tract. In infants, weight loss and subperiosteal hemorrhages occur, and long bone growth ceases.

Scurvy can be treated by as little as 10 mg vitamin C per day, but there is no evidence for other uses of vitamin C supplementation (e.g. cancer, colds, psychiatric illness). Toxicity occurs at dose of 1 g or more and causes diarrhea, dry mucous membranes, increased oxalate production (and thus kidney stones), and reduced semen production. Patients at risk of renal hypoperfusion (critical illness, recent transplantation) should avoid vitamin C.

13. Understand that deficiency of folate or B12 can result in a macrocytic anemia. Know the clinical symptoms associated with B12 deficiency.

Both folate deficiency and B12 deficiency can result in a macrocytic anemia. To differentiate between folate deficiency and B12 deficiency, check homocysteine and methylmalonic acid. In B12 deficiency, both are elevated; in folate deficiency, only homocysteine is elevated. Clinical symptoms associated with B12 deficiency include megaloblastic anemia and peripheral neuropathy. 14. Understand the dietary challenges of vegetarianism.

A well-planned vegetarian diet can provide adequate nutrition and is often lower in fat and higher in fiber & antioxidants than an omnivorous diet. Those who consume eggs or dairy products should have no significant nutritional problems.

Those who avoid eggs and dairy products as well as meat and fish may have problems with iron (especially women), calcium, zinc, and vitamin B12. A mixture of grains and legumes may be necessary to achieve adequate amounts of all amino acids, and nutritional supplements may be necessary in some cases.

15. Know the likely dietary deficiencies in alcoholics and how these can be clinically manifested.

Alcoholics are commonly deficient in thiamine and folate. Folate deficiency commonly manifests as a progressive megaloblastic anemia, and may cause small-bowel villi atrophy and malabsorption. Thiamine deficiency in alcoholics commonly causes Wernicke’s encephalopathy (ataxia, confusion, short-term amnesia), especially in conjunction with carbohydrate intake.

16. Understand that multivitamins have not been shown to be beneficial in almost all clinical trials for prevention of heart disease and cancer

OK.

17. Know the risks of prescribing antioxidants to people who smoke and the lack of benefit of vitamin E in cardiovascular trials

Vitamin E supplementation has been shown to increase the risk of hemorrhagic stroke, so it should not be prescribed to people at high risk of stroke (e.g. smokers). Other trials showed the generalized antioxidant supplementation in smokers actually increased cardiac and all-cause mortality. Vitamin E supplementation showed little or no benefit in CV trials

18. Know that vitamin D deficiency is almost epidemic and that it takes high doses (50000 IU) for long periods of time to replete stores. 

OK.

19. Know that moderate alcohol intake and a Mediterranean diet in epidemiologic studies have been strongly associated with a reduced risk of cardiovascular disease but that changing dietary habits is very challenging.

OK.

20. Know which factors affect predicted energy expenditure in the harris-benedict equation.

Repeat of #5.

21. Understand the lack of utility of checking plasma protein levels to diagnose protein malnutrition

OK.

22. Understand that while protein is necessary for optimal organ function that oversupply is not beneficial

OK.

23. Know that in general overfeeding is more dangerous than underfeeding

OK.

24. Know the nutritional risk factors (i.e. weight loss) that predict in-hospital mortality

????

25. Understand that nutrition is rarely an acute issue and that waiting for limited periods of time for the clinical situation to become more clear is the best course.

OK.