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931 Cards in this Set
- Front
- Back
What are the signs and symptoms of GI pathology?
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pain
bleeding dysphagia nausea/vomiting diarrhea constipation weight loss jaundice |
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What are the main general mechanisms of GI pathology?
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inflammation
ulceration obstruction dysmotility |
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What are the GI functions of the mouth and oropharynx?
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taste
mechanical preparation of bolus lubrication transport digestion |
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What is dysguesia?
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Taste issues.
Bad taste in mouth etc. |
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What is pyrosis?
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Heartburn
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What is odynophagia?
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Painful swallowing.
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What is dyspepsia?
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Discomfort in the upper abdomen.
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What is the anatomical boundary between the duodenum and jejunum?
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The ligament of Treitz.
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What are borborygmy?
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Growling noises made by the abdomen.
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What symptoms are associated with liver dysfunction?
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fatigue
anorexia pruritus jaundice Diseases that are purely confined to the liver (not the biliary tree) are not typically associated with severe pain. |
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What symptoms are typically associated with biliary tree problems?
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pain
jaundice pruritus |
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What symptoms are typically associated with pancreatic problems?
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pain
diarrhea jaundice |
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What is melena?
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Black, tarry, sticky stool.
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What is hematochezia?
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Fresh red blood in the stool.
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What are considered GI alarm symptoms?
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Weight loss
Blood loss: hematemesis, coffee-grounds emesis, melena, hematochezia Iron-deficiency anemia Dysphagia Nocturnal symptoms (unusual) New-onset GI symptoms after age 45 Jaundice |
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What symptoms are typically associated with esophageal problems?
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Dysphagia
Odynophagia Heartburn (pyrosis) Chest pain |
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At what stage of embryonic development does the GI tract form?
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During fourth week of gestation.
Appears as 4 mm hollow tube. Buccopharyngeal and cloacal membranes rupture during the third and seventh weeks respectively. By end of 2nd trimester, organs well formed and display early function. |
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What parts of the GI tract are considered foregut?
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Esophagus
Stomach Duodenum Liver Gallbladder Pancreas |
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What parts of the GI tract are considered midgut?
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Jejunum
Ileum Ascending colon Transverse colon |
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What parts of the GI tract are considered hind gut?
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Descending colon
Rectosigmoid colon |
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Is there a male:female bias to esophageal atresia with or without tracheoesophageal fistula?
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No
1:3-5000 live births ~50% have other associated anomalies such as: Polyhydraminos in 50% of mothers Cardiovascular-PDA, VSD, ASD Gastrointestinal-imperforate anus, duodenal atresia Skeletal-vertebral anomalies Genitourinary-hypospadias Other-trisomy |
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What is the most common type of tracheoesophageal fistula type malformation?
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Type C
Proximal esophageal atresia with a distal type tracheoesophageal fistula. Accounts for ~85% of cases. Esophageal gap 1 to 2 cm. Distal TEF joins trachea at carina. Diagnosis made by placing nasogastric tube. Cough, choking, aspiration with first feed. |
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What is pure esophageal atresia? (Type A)
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10% of congenital esophageal defects
Absence of gas within the GI tract 20% will have Down’s syndrome If the gap between the esophageal pouches is > 4 cm primary anastomosis is difficult |
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What is an H tracheoesophageal fistula (type E)?
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Looks like an H
3% to 5% of cases Rarely have other anomalies Repeated episodes of pneumonia Esophagus and trachea otherwise normal. |
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How does pyloric stenosis in newborns present?
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1:1000 live births
(more common than atresias) Presents 1 week to 5 months Most frequent surgical disorder of the stomach in babies. Males to females 4-6:1 Family history in ~13%. Non-bilious vomiting. Hypochloremic alkalosis. Pyloric mass on PE. |
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What are some of the possible explanations of the pathogenesis of congenital pyloric stenosis?
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Pyloric muscle hypertrophy from gastric peristalsis against closed pyloric canal.
Hypergastrinemia with hyperacidity Elevations of prostaglandins leading to smooth muscle constriction. |
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How doe duodenal atresia present?
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Bilious vomiting and abdominal distension.
"Double bubble" x-ray Thought to arise from failure of recanalization of duodenal lumina Incidence is 1 in 10,000 50% infants premature. F to M 2:1 Down’s syndrome occurs in up to 30% |
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What does a proximal jejunal atresia look like radiographically?
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Large dilated loops are seen in the upper abdomen with no distal gas.
Impossible to determine which type of atresia is involved without laparotomy. Contrast studies are unnecessary in most cases. |
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What is duplication of the GI tract?
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Typically present later than atresias and stenosis.
(mass effect from a cyst blocking the lumen does not usually happen until later) |
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What is malrotation of the mid gut?
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Failure of midgut to achieve normal position.
Can live normally but predisposes to midgut volvulus. If this happens: Acute bowel obstruction. Bilious vomiting. !Surgical emergency! |
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What is a Meckel's diverticulum?
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Remnant of vitelointestinal duct.
Antimesenteric border of ileum. 2-3% of population. Painless rectal bleeding in children <2 Crampy abdominal pain. |
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What is Hirschsprung's disease?
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Absence of intramural ganglion cells.
1:5000 M>F Associated with Down's 75% Rectosigmoid colon. Aganglionic segment permanently contracted. Delayed passage of meconium. Problems within the first year. Failure to thrive, vomiting, intermittent diarrhea. Abdominal distension. |
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What tests can we use for Hirschsprung's disease?
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Unprepared barium enema
Mucosal suction biopsy Anorectal Manometry (internal sphincter will not relax in Hirschsprung's) |
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Which substances are absorbed by active transport and which are absorbed by diffusion?
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Active transport:
amino acids sugars vitamins Diffusion: water minerals vitamins lipids |
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What are some examples of pathologies of motility?
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Swallowing
GERD vomiting gastroparesia ileus diarrhea constipation |
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What are some examples of pathologies of secretion?
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Ulcer disease
malabsorption diarrhea pernicious anemia |
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What are some examples of pathologies of active transport and diffusion?
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Malabsorbtion and diarrhea can be caused by either.
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What target in the GI system is the sympathetic system able to innervate DIRECTLY?
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Blood vessels
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What are the components of the enteric nervous system (intrinsic)?
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Myenteric Plexus (Auerbach’s)
Submucosal Plexus (Meissner’s) Deep Muscular Plexus |
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What are interstitial cells of Cajal?
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Cells of mesenchymal origin most of which express a c-kit receptor which causes them to develop distinctly from smooth muscle cells.
These cells establish gap junctions with smooth muscle cells and can conduct impulses from nerves. Some can even function as pacemakers and provide continuous depolarization. |
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Where do we find the various interstitial cells of Cajal?
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Associated with the myenteric plexus the ICC-MY (Auerbach)
Associated with the submucosal plexus in the colon Associated with the deep muscular plexus (ICC-DMP) Found within muscle layers (ICC-IM) Found on surface of muscle bundles (ICC-SEP) |
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What neurotransmitters contract GI smooth muscle?
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AcH
Substance P |
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What neurotransmitters relax GI smooth muscle?
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VIP (vasointestinal polypeptide)
Nitric oxide ATP |
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What are the four stages of response to a meal?
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Cephalic
Gastric Intestinal Interdigestive |
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What is the cephalic phase of response to a meal?
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The sight, smell and taste of food as well as mechanical stimulation of the oral cavity participate.
Salivation is stimulated by cholinergic nerves. Vagal reflexes inhibit contractile activity in the proximal stomach [receptive relaxation], stimulate acid secretion by parietal cells in the stomach and secretion of histamine by enterochromaffin-like (ECL) cells. Vagal reflexes to the antrum stimulate secretion of gastrointestinal hormones and also induce a relatively small stimulation of enzyme secretion by the exocrine pancreas. |
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What is the gastric phase of response to a meal?
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Distention of the stomach activates stretch receptors initiating a number of reflexes which alter gastric, intestinal, colonic and pancreatic activities.
Gastric acid secretion is stimulated by vago-vagal reflexes and reflexes mediated by the enteric nerve plexus. If the meal contains protein, protein digestion products produced will stimulate secretion of gastrin further enhancing acid secretion. In addition to stimulating gastric acid secretion, these reflexes stimulate gastrointestinal motility. (increase in the contractile activity of the ileum and relaxation of the ileocecal sphincter [gastroileal reflex] and mass movement in the distal colon [gastrocolic reflex]. Vagal reflexes also cause a relatively small stimulation of enzyme secretion by the exocrine pancreas. |
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What is the intestinal phase of response to a meal?
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Chyme entering the small intestine initiates neural and hormonal mechanisms which alter the activities of the small intestine, pancreas, gallbladder and stomach.
As chyme empties from the stomach into the small intestine mechanical (distention) and chemical signals (osmolarity, pH, breakdown products) stimulate contractile activity and secretion. |
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What is the interdigestive phase of response to a meal?
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The interdigestive phase is the period of fasting after most of the components of the previous meal have been digested and absorbed and the stomach and small intestine are relatively empty.
This phase is characterized by brief periods of intense peristaltic contractions appearing first in the stomach and then in the upper, middle and finally the distal small intestine. These periods of intense contractile activity last for only 5-10 min and are followed by longer relatively quiescent periods. This pattern repeats at intervals of approximately 90 min and has been called the migrating motor complex (MMC). |
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Where do we see tonic rather than phase contraction in the GI tract?
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Sphincters
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What pattern of electrical depolarization in the GI tract?
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There are different slow wave frequencies in every part of the GI tract.
When the waves exceed a certain potential they are coupled with contraction. |
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What are the motility patterns for the various parts of the GI tract?
|
|
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What is the normal slow wave pacemaker rate of the stomach?
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3 cycles per minute
|
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What causes receptive relaxation in the fundus?
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Vagal mediated relaxation.
NO and VIP are the neurotransmitters involved. |
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What sort of noninvasive clinical tests look at the neuromuscular activities of the stomach?
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Scintigraphy:
isotope labelled foods pH/motility capsule: ingested with test foods Electrogastrograms (EGG): myoelectrical activity of the stomach. |
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What do the patterns for liquid and solid phase gastric emptying look like?
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Liquid phase has a faster decline because of more rapid emptying.
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Which stomach neuromuscular dysfunctions are associated with which postprandial symptoms?
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Early satiety:
Poor or excessive accommodation Nausea: Tachygastria or bradygastria Prolonged postprandial fullness: Hypomotility (gastroparesis) RUQ pain: Pylorospasms Nausea, pain, bloating: Hypersensitive stomach |
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What is the differential diagnosis for gastroparesis?
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Obstuctive gastropareis
Ischemic gastroparesis Diabetic gastroparesis (type 1 and 2) Postsurgical gastroparesis (antrectomy, vagotomy, fundectomy, fundoplication) Miscellaneous Causes (CVD, amyloid, MD) Idiopathic gastroparesis (postviral, drug-induced, degenerative or inflammatory processes-smooth muscle, enteric n., interstitial cells of Cajal, ANS) |
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What diet do we recommend for gastroparesis patients?
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|
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What is a neurocrine or paracrine hormone?
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One which affects neighboring cells.
Termed neurocrine if the secreting cell is a neuron. Autocrine hormones affect the secreting cell itself. |
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What is included in the gastrin family of hormones?
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Cholecystokinin
Gastrin Cholecystokinin without a sulfate group will behave just like gastrin. |
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What are the receptors that are acted upon by the gastrin family?
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CCK1 is receptor for gastrin.
CCK2 is receptor for cholecystokinin. Binding is highly concentration dependent. Under physiological concentrations cholecystokinin has no effect on the gastrin receptor. Because gastrin is far more abundant in the circulation, the gastrin effect is predominant. |
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How is gastrin made?
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Preprogastrin is made into progastrin which is a three domain (A,B,C) polypeptide seperated by two diarginyl cleavage sites.
Cleavage of A and C by a signal peptidase leaves progastrin which is then conveted by a prohormone convertase into one of the two active forms of gastrin. These are: Glycine extended gastrin 17+CTFP and Gastrin 17 amide. (glysine extended form or amidated form) Each of these forms acts on different receptors. |
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What stimulates and suppresses gastrin secretion?
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Stimulation:
Presence of protein digestion products. Gastric distention. (various local and central reflexes) Inhibition: Acid (H+ stimulates D-cells to make somatostatin which inhibits gastrin production) |
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What is the main function of gastrin?
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To stimulate production of gastric acid.
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Apart from producing gastrin which directly stimulates parietal cells to make acid, what do gastrin producing cell (G-cells) do when they are activated?
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They activate ECL cells (enterochromatin light cells) which produce histamine.
Histamine binds to type 2 histamine receptors in the parietal cells and further stimulates acid production. Gastrin made by the G-cells also activates D-cells which make somatostatin and this constitutes the negative feedback because somatostatin inhibits parietal cells, G-cells and ECL cells. |
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Which of the two forms of gastrin is the one responsible for stimulating acid production?
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The amidated form
The glysine extended form is mostly important for cell proliferation. |
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What are the effects of cholecystokinin?
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Stimulates bile secretion by promoting the contraction of the gallbladder and the relaxation of the sphincter of odi.
Stimulates the secretion of pancreatic enzymes. Inhibits gastric emptying. Increases the proliferation of pancreatic glandular cells. Synergizes with secretin which promotes pancreatic bicarbonate formation so the presence of both hormones causes a large rise in pancreatic fluid secretion. |
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What are the effects of secretin?
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Stimulates pancreatic fluid bicarbonate secretion.
Stimulates bicarbonate secretion by the liver. Inhibits gastric acid secretion. Promotes pancreatic cell proliferation. |
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What regulates secretin release?
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Duodenal pH
|
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What are incretin hormones?
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Incretin hormones are those that can explain the incretin effect or the difference in insulin response to oral and IV glucose.
In normal subjects the oral response augmentation is three to four fold the IV response. GIP: Gastric Inhibitory Peptide aka Glucose-dependent Insulinotropic Peptide GLP-1: Glucacon Like Peptide 1 Produced in the intestine in response to food ingestion. Broken down by DPP-4 Both GLP-1 and DPP-4 are used in diabetes management. GIP and GLP-1 also inhibit glucagon secretion and decrease gastric emptying. GIP seems to be more important regarding insulin secretion. GLP-1 is a more potent agonist, thus a better candidate as a potential drug. |
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What stimulates GIP release
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Amino acids
Glucose Fatty acids and monoglycerides |
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What stimulates GIP release
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Amino acids
Glucose Fatty acids and monoglycerides |
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What is the main effect of the secretin family hormone, motilin?
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Causes rhythmic contractility during fasting.
Motilin receptors can be activated by erythromycin family antibiotics which can cause diarrhea even without damaging the native flora. |
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What are the secretin family hormones that affect appetite and where are they synthesized?
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PYY:
Synthesized in L cells in colon Ghrelin: Synthesized in X (A-like) endocrine cells in stomach Leptin: Synthesized in adipocytes |
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How does PYY affect appetite?
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Binds the Y2 receptor type
Induces sensation of satiety Secretion of PYY is suppressed by fasting. |
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How does Grehlin affect appetite?
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Binds the GHS-R receptor
Induces sensation of hunger Also has effects on contractility. Secretion stimulated sharply before a meal and suppressed by meal ingestion. |
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How do various food affect GI hormone secretion?
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See table.
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What are the net effects of the various GI hormones?
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See table
|
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What are the GI paracrine hormones?
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Somatostatin
Histamine Nitric Oxide VIP Serotonin Gastrin Releasing Peptide (GRP or Bombesin) |
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What neurotransmitter relaxes sphincters?
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Nitric oxide
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Anatomically speaking, where is the esophagus?
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Posterior organ.
Starts at cricoid cartilage. Perforates diaphragm at T10. |
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What sort of muscles comprise the esophagus?
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Inner layer:
Circular muscle Outer layer: Proximal one-third is lined by striated muscle. Smooth muscle lines the distal two-thirds. |
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What is the lower esophageal sphincter constructed of?
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Inner circular muscle
Diaphragm Upper esophageal sphincter is cricopharyngeal muscle. |
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What innervates esophageal muscles?
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Primarily vagus nerve.
Upper striated portion is controlled primarily by Ach. Lower smooth muscle is controlled by Ach and by nitric oxide. Upper and lower portions are controlled by different parts of the brain. |
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What happens during the pharyngeal phase of swallowing?
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Food reaches the pharynx
Swallowing center activated Cranial nerves 5, 7, 9, 10, & 12 Tongue raises Nasal airway closes Epiglottis closes UES relaxes Pharyngeal muscles contract |
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What happens during the 10 second or more esophageal phase of swallowing?
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Food reaches proximal esophagus
Vagal afferents are activated Peristalsis begins by activation of the intrinsic esophageal nerves (myenteric plexus) LES relaxes Peristalsis proceeds from proximal to distal esophagus. |
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What are symptoms we typically associate with the esophagus?
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Dysphagia
Odynophagia Heartburn (“pyrosis”) Regurgitation Chest Pain (noncardiac) |
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What symptoms are associated with oropharyngeal dysphagia?
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Food sticking in throat
Repetitive swallows Nasal regurgitation Coughing Aspiration |
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What are some possible etiologies of oropharyngeal dysphagia?
|
Structural:
Zenker’s diverticulum, cricopharyngeal bar, webs, tumors CNS: Stroke, tumors, trauma Other neurologic: Parkinson’s, multiple sclerosis, amyotrophic lateral sclerosis Myopathy: Myasthenia gravis, polymyositis, mixed connective tissue disease Picture shows Zenker's diverticulum. |
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What tests are used to evaluate esophageal dysphagia?
|
Barium Esophagram
Esophagoscopy (EGD) Esophageal Manometry |
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What is a Shatzki ring?
|
An esophageal mucosal stricture right above the diaphragm.
|
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What are some cause of esophagitis?
|
GERD
Eosinophilic esophagitis (EoE) Infections Medications: tetracycline, KCl, quinidine, alendronate, 5-FU, daunorubicin, bleo Radiation Caustic ingestion |
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What is eosinophilic esophagitis?
|
Clinical symptoms of esophageal dysfunction – usually solid-food dysphagia and food impactions
> 15 eosinophils/ high-power field Normal 24-hour pH monitoring No response to high-dose PPI therapy. Strong male bias. mean age = 38 50-80 % are atopic – atopic dermatitis, allergic rhinitis, asthma Most likely food allergens, possibly aeroallergens. Can have multiple corrugated rings as pictured. |
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What does eosinophillic esophagitis look like on endoscopy?
|
Concentric rings
Linear furrows White plaques (eosinophilic microabscesses) Food impaction |
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How do we treat eosinophillic esophagitis?
|
Acid suppression
Diet – elimination, elemental Topical steroids – swallowed fluticasone or budesonide Systemic steroids Cromolyn, Montelukast Biologics |
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What are some causes of odynophagia or painful swallowing?
|
Infectious esophagitis:
Fungal (Candida most common) Viral – CMV, HSV Idiopathic Corrosive esophagitis Pill-induced esophagitis |
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What motility disorders can cause esophageal dysphagia?
|
Achalasia and other spastic motor disorders
Diffuse esophageal spasm Nutcracker esophagus Hypertensive LES Scleroderma Other hypocontractile motor disorders |
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What is esophageal achalasia?
|
Failure of LES relaxation + loss of peristalsis in distal esophagus.
Elevated LES pressure: 50 % of cases No sex bias. Relatively uncommon. Loss of NO and VIP vagal transmission causes a change in the balance of tone so that only Ach (contractile) is present. |
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What is globus?
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The sensation of a lump in the throat.
|
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How do we treat esophageal achalasia?
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Nitrates and CCB's.
Botox the muscle. Pneumatic dilation. (risk of perforation) Surgical myotomy (best) |
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What symptoms are associated with GERD?
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Heartburn (pyrosis) 83%
Regurgitation 70% Dysphagia 37% Respiratory symptoms 30% Chest pain 10% Abdominal pain 10% Nausea 8% Belching 7% |
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What are the mechanisms of esophageal reflux?
(Important) |
Transient lower esophageal sphincter relaxations (TLESRs).
A hypotensive lower esophageal sphincter (LES). Anatomic disruption of the gastroesophageal junction, usually associated with a hiatal hernia. |
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Why does hiatal hernia cause GERD?
|
Loss of the diaphragmatic pinch to help close the LES.
LES pressure becomes lowered. The gastric pouch becomes an intrathoracic reservoir. |
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What mechanisms help acid clearance from the esophagus?
|
Swallowing
Salivation Peristalsis Esophageal bicarbonate secretion |
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How do we diagnose GERD?
|
Symptoms
Response to empirical trial of acid suppression therapy (PPI) Endoscopy 24-hour pH monitoring |
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What complications are associated with GERD?
|
Ulcer
Stricture Barrett’s esophagus Adenocarcinoma |
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What is Barrett's esophagus?
|
Defined as a change in the lining of the esophageal mucosa from normal squamous epithelium to columnar with Intestinal metaplasia.
Occurs in 10-15% of patients with chronic GERD. Pre-malignant condition which may eventually lead to dysplasia and adenocarcinoma of the esophagus. Rate of progression of Barrett’s esophagus to cancer is estimated to be 0.5% per year. Factors that promote progression of BE to cancer are unknown. This is a highly aggressive tumor though with a 2-5% 5 year survival. Therefore, all patients with Barrett’s esophagus undergo regular endoscopic surveillance. Experimentally, obliteration of Barrett’s mucosa using PDT may restore squamous epithelium. |
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The goals of GERD treatment are...
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Reduce or eliminate symptoms
Heal esophagitis Prevent complications Improve quality of life |
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What are the treatment options for GERD?
|
Lifestyle modifications
Antacids H2-receptor antagonists Proton pump inhibitors Antireflux surgery Prokinetic agents New endoscopic therapies |
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What are some therapeutic targets for acid inhibition?
|
Histamine blockade
Ach Blockade (anticholinergics) Proton pump inhibition |
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H2 receptor antagonists end in the suffix...
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...tidine
|
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Proton pump inhibitors end in the suffix..
|
...prazole
|
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Which is the better class of drugs in terms of healing and symptom control, H2RA's or PPI's?
|
PPI's
|
|
Picture of functional anatomy of the stomach.
|
|
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What types of cells are found in the oxyntic glands of the gastric body?
|
mucous neck cells
parietal cells chief cells ECL cells |
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What types of cells are found in the pyloric glands of the gastric antrum?
|
mucous cells
G cells |
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What is the function of the hydrochloric acid made by the parietal cells of the stomach?
|
Kills microorganisms
Cleaves pepsinogen to pepsin Activates pepsin at pH < 4 |
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What is the function of intrinsic factor made by the parietal cells of the stomach?
|
binds B12 (cobalamin) which allows absorption in the terminal ileum
|
|
How does B12 absorption work?
|
B12 is liberated from dietary proteins by pepsin/acid
B12 binds to salivary/gastric R factor B12 is cleaved from R factor by pancreatic proteases B12 binds to Intrinsic Factor B12-IF complex binds to ileal receptor |
|
What is pernicious anemia?
|
autoimmune gastritis
antibodies directed against: parietal cells and/or intrinsic factor mucosal damage is greatest in body and fundus gland destruction leads to: achlorhydria and vitamin B12 deficiency gastritis - metaplasia - dysplasia - carcinoma |
|
What is the function of chief cells?
|
They make pepsinogens which are cleaved by HCL to pepsin
pepsin is a proteolytic enzyme |
|
What is the function of ECL's or Enterochromaffin Like Cells?
|
They produce Histamine which stimulates the parietal cell to secrete HCl.
stimulated by gastrin, acetylcholine (vagus) inhibited by somatostatin |
|
What is the function of G-cells?
|
Stimulates ECL cells to release histamine.
Stimulates oxyntic glands to secrete: HCl pepsinogens Trophic effect on: parietal cell mass ECL cell mass Gastrin release stimulated by: gastric distention amino acids Gastrin release inhibited by: somatostatin gastric acid Can be thought of as "go" cells. |
|
What are HCL secretion agonists and antagonists?
|
Agonists:
histamine gastrin acetylcholine Antagonists: somatostatin prostaglandins epidermal growth factor (EGF) |
|
What is the function of D-cells?
|
Produce somatostatin which inhibits histamine release by ECL cells, Gastrin release by G cells and HCL secretion by parietal cells.
stimulated by: acid CCK gastrin inhibited by: acetylcholine (vagus) Can be thought of as "downer" cells |
|
What is the cephalic phase of acid secretion?
|
Elicited by sight, smell, and taste of food.
Entirely mediated by the vagus nerve. Directly stimulates parietal cell Stimulates ECL cells to release histamine. Stimulates antral G cell to release gastrin. Inhibits D cell release of somatostatin. Feedback inhibition: low gastric pH evokes direct inhibition of parietal cells and G cells by inhibitory neural reflexes. |
|
What is the gastric phase of HCL secretion?
|
gastric distention:
mechanoreceptors in the gastric wall initiate vagovagal reflexes. Amino acids and peptides stimulate antral G cells to secrete gastrin. |
|
What is the intestinal phase of acid secretion?
|
acid in duodenum inhibits vagovagal reflex and
releases secretin which inhibits acid secretion through inhibition of g cell gastrin release. Fat and protein in the duodenum release CCK, which inhibits acid secretion through stimulation of D cell somatostatin release. |
|
What elements provide mucosal protection in the stomach?
|
mucus secretion
bicarbonate secretion epithelial barrier mucosal blood flow The pathogenesis of peptic ulcer disease is an ongoing battle between: acid/pepsin vs. mucus/bicarbonate |
|
What are the causes of peptic ulcer disease?
|
Helicobacter Pylori
NSAIDs Stress Gastrinoma |
|
What is helicobacter pylori?
|
small gram negative rod with flagella
colonizes the mucous layer (not invasive) Elaborates urease which produces ammonia and thereby neutralizes acid in the bacterial microenvironment. Strains expressing cagA and vacA genes are the most ulcerogenic and carcinogenic. Induces chronic gastritis through the elaboration of cytotoxins and bacterial lipopolysaccharide. Inflamed gastric mucosa produces less mucus and bicarbonate, hindering mucosal protection. Causes a 6-fold increase in the incidence of gastric cancer. May cause up to 40% of all cases of gastric adenocarcinoma. May cause up to 90% of all cases of MALT (mucosa-associated lymphoid tissue) lymphoma. MALT can be treated with antibiotics. |
|
What tests are used to diagnose H. Pylori?
|
Antibody blood test stays high after cure.
serology urea breath test stool antigen assay biopsy urease test (CLO) histology culture |
|
How do we treat H. Pylori?
(don't need to memorize) |
clarithromycin 500 mg PO bid
amoxacillin 1 gm PO bid omeprazole 20 mg PO bid or clarithromycin 500 mg PO bid metronidazole 500 mg PO bid omeprazole 20 mg PO bid or bismuth subsalicylate 225 mg qid metronidazole 250 mg PO qid tetracycline 250 mg PO qid All regimens include two antibiotics and PPI. |
|
What are the two forms of cycloxygenase?
|
COX-1:
constitutive isoform of COX produces PROSTACYCLIN (cytoprotective in gastric mucosa) COX-2 inducible isoform induced by inflammation, cytokines |
|
What is the effect of prostanglandins on the gastric mucosa?
|
Increase mucosal blood flow
Stimulate the secretion of mucus and bicarbonate Increase mucosal cell restitution Inhibit acid secretion NSAID's therefore: decrease mucosal blood flow decrease mucus production decrease bicarbonate production increase acid and pepsin secretion |
|
What is the advantage of selective COX-2 inhibitor NSAIDs?
|
inhibition of COX-2 results in desired effects of decreased inflammation
inhibition of COX-1 results in undesired effects of gastrointestinal toxicity therefore, a selective COX-2 inhibitor could theoretically provide all the benefit of an NSAID without the adverse effects. Examples include the expensive colxicib (celebrex) and the cheaper diclofenac. |
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How does EXTREME stress such as is seen in trauma, burns, head injuries and ventilator patients contribute to peptic ulcers?
|
alpha-adrenergic mediated decrease in mucosal blood flow.
|
|
What is Gastrinoma (Zollinger-Ellison syndrome) ?
|
Endocrine tumors of the duodenum or pancreas (rarely stomach,liver, spleen)
1/3 patients have MEN-1 Dramatic gastrin production: drives acid production by parietal cells. increases parietal cell and ECL cell mass. 90% of patients have PUD 50% of patients have diarrhea Diagnosis is based on serum gastrin level (must differentiate from pernicious anemia though) Tumor localization: endoscopic ultrasound, octreotide (radiolabelled somatostatin) scan, CT scan Surgical resection is the only curative therapy > 50% are locally invasive or metastatic at dx PPI therapy provides best symptom palliation. |
|
What are the complications of peptic ulcer disease?
|
pain
bleeding perforation gastric outlet obstruction |
|
What interventions are available to reduce acid production in PUD?
|
Acetylcholine:
anticholinergics vagatomy Histamine: H2 receptor antagonists Gastrin: antrectomy proton pump inhibitors |
|
What mucosal protection interventions are available for PUD?
|
Misoprostol (Cytotec) 200 mcg qid:
a synthetic prostaglandin E1 analog which increases mucus and bicarbonate production and also inhibits acid production. Sucralfate (Carafate) 1 gm qid: adheres to ulcer base, forming a protective barrier. Also inhibits pepsin activity. Neither are very well tolerated and have largely been replaced with PPI therapy. |
|
What are the four main etiologies of the acute abdomen?
|
Inflammation
(ie abscess, perforation) Ischemia/ Necrosis Obstruction / Distention Bleeding: Intraperitoneal Intraluminal |
|
What do we mean by visceral abdominal pain?
|
Deep, Dull, crampy pain
Caused by: Stretch Ischemia Contraction against obstruction |
|
What do we mean by parietal abdominal pain?
|
Sharp, focal, intense, constant pain.
Caused by: Trauma to peritoneum Infection / inflammation Irritants |
|
What is the definition of referred abdominal pain?
|
Sensation of pain in a somatic distribution (dermatome or myotome) derived from the same spinal cord segments as the inflamed peritoneum (visceral or parietal).
Example: Small bowel pain perceived as diffuse discomfort in T10-12 dermatomes of back and anterior abdominal wall. |
|
Where is phrenic irritation often referred to?
|
The shoulder
|
|
What is the best first course of action for acute abdominal pain?
|
Fluids.
Resuscitate while you think. |
|
What descriptions of pain obtained from history can help focus the diagnosis of the acute abdomen?
|
Episodic pain:
obstruction Steadily progressive pain: Ischemia, Peritoneal inflammation Colicky, changing to steady pain: Intestinal strangulation Sudden relief of pain: Relief of obstruction or perforation Colicky pain is waxing and waning, comes in waves, sharp and severe. |
|
Instantaneous onset of acute abdominal pain pain makes us think about...
|
Perforation of hollow viscus
or Rupture of solid organ Examples: Duodenal perforation, cecal perforation; splenic or hepatic rupture |
|
Abdominal pain with a rapid onset but not instantaneous makes us think about...
|
Hollow organ obstruction
Inflammatory process Toxic or metabolic Examples: SBO, ureteral colic, sickle cell, porphyria, peritoneal blood, leaking perforation |
|
Gradual onset "acute" abdominal pain makes us think about...
|
Chronic (non surgical) processes
or Progressive inflammation Examples: Appendicitis (can be rapid onset pain too though), cholecystitis, PID |
|
What is the utility of auscultation in evaluating the acute abdomen?
|
Chest auscultation to rule out pneumonia
Early bowel sounds variable Perforation may lead to loss of bowel sounds (ileus) Stethoscope to distract during palpation Silent abdomen is a cause for concern. |
|
How do we palpate the acute abdomen?
|
Start gently in quadrant opposite pain if localized.
Note rigidity will not relax with expiration. Test rebound, tenderness last. |
|
What labs are important to obtain in evaluating the acute abdomen?
|
CBC
Electrolytes, liver function Amylase/lipase Urinalysis (kidney) Serum BHCG for pregnancy (not an option) |
|
What is the differential for acute abdominal pain?
|
Most common:
Appendicitis Small bowel obstruction Acute cholecystitis Acute pancreatitis Diverticulitis Pelvic inflammatory disease Peptic ulcer disease |
|
What are some female sources of acute abdomen?
|
Operative:
Ruptured ectopic pregnancy Ruptured cysts Non operative PID / Salpingitis Endometriosis Mittelsmerz Tubovarian abscess |
|
What are some non-surgical intra-abdominal causes of abdominal pain?
|
Primary peritonitis
Porphyria, sickle cell crisis, polyserositis, uremia, DKA Neutropenic colitis Rectus hematoma Addison’s crisis |
|
What are some non-surgical extra-abdominal causes of abdominal pain?
|
Pneumonia, pleural inflammation
PE, MI, pericarditis, esophagitis Toxins Herpes zoster |
|
How good is our diagnostic history and physical in evaluating acute abdomens?
|
47-76% accuracy
|
|
What is the standard imaging technique for acute abdomen management?
|
Abdominal CT
|
|
What is a target sign on abdominal CT?
|
Concentric rings seen in the appendix indicative of inflammation.
|
|
What is an alvarado score?
|
A score out of 10 for diagnosis of appendicitis.
Migration of pain=1 Anorexia=1 Nausea-vomiting=1 Tenderness in right iliac fossa=2 Rebound pain=1 Raised temperature (>37.3°C)=1 Leukocyte count >10´109/l =2 Neutrophils >75%=1 |
|
What are the most common acute abdomen diagnoses in geriatric patients?
|
Diverticulitis 18%
Bowel Obstruction 18% Nephrolithiasis 10% Gallbladder disease 10% |
|
What are some causes of bowel obstruction?
|
Adhesions from prior surgery or peritonitis
Hernia (more common in less developed countries) Anatomic Colonic obstruction Mass Volvulus |
|
What are the three different types of hernias?
|
Inguinal
Umbilical Incisional |
|
Who has the highest rate of esophageal squamous cell cancer in the U.S?
|
AA males
High rates in Asia, Africa and Iran |
|
What are the risk factors for squamous cell esophageal cancer?
|
Alcohol and tobacco (synergistic):
Hard liquor is worse Alcoholics- Selenium deficiency HPV |
|
What are risk factors for esophageal adenocarcinoma?
|
Caucasian 5X greater than African-American; (Caucasian males 8X)
Obesity GERD (Barrett's metaplasia) but 50% have no hx of symptomatic reflux disease. !Unrelated to alcohol! |
|
What is the absolute risk of Barrett's esophagus turning into cancer?
|
~0.5-0.8%
This represents a 30-60 fold increase over the general population though. |
|
Which of the two esophageal cancer has a higher risk of metastasis?
|
Squamous cell carcinoma
|
|
What are the two most common symptoms of esophageal cancer?
|
Dysphagia (90%)
Odynophagia (50%) SCC is aggressive. Vocal cord paralysis, hoarseness Hematemesis from tumor ulceration. Majority have advanced disease on presentation. (T1-T4 with T4=bad) Can have hypercalcemia, hypoalbuminemia and anemia. |
|
What imaging do we use for esophageal cancer?
|
Barium swallow vs EGD , EUS (ultrasound), PET
|
|
5-yr survival rate in patients with esophageal cancer amenable to surgery is...
|
only 5-20%
|
|
Which countries have the highest rates of gastric cancers?
|
Japan
Costa Rica China Men more than women. |
|
What are two of the risk factors for stomach cancer?
|
Benign gastric ulcer disease (2-3x risk)
H.Pylori infection |
|
How do we diagnose gastric cancer?
|
Biopsy endoscopy
Barium studies |
|
How do we treat gastric cancer?
|
Surgery remains the only curative procedure for advanced cancer.
|
|
What is gastric carcinoid?
|
Account for 2% of all gastrointestinal carcinoids and 0.3% of all gastric neoplasms.
Pts usually asymptomatic Arise from gastrointestinal neuroendocrine cells mostly ECL origin. Syndrome does not occur unless there is hepatic involvement Risk factors include pernicious anemia and chronic atrophic gastritis (25%). Hypergastrinemia resulting in ECL cell hyperplasia. No increased risk with proton pump inhibitors Non-metastatic, 5-yr survival 95%. Metastatic 5-yr 50% |
|
What are gastrointestinal stromal tumors or GIST?
|
mesenchymal tumors in the GI tract
Indolent, slow-growing tumors that are usually asymptomatic until very large. GI bleeding, dyspepsia or obstructive sx’s. Most have gain of function c-kit mutations and respond to Gleevec (imafinib) or other mesylate- tyrosine kinase inhibitors. Called malignant if spread into regional lymph nodes, or with distant mets (liver, lung, peritoneal) |
|
Gastric MALT is strongly associated with...
|
H. pylori
Can treat with antibiotics |
|
Small bowel lymphomas are associated with...
|
Celiac sprue
Immunocompromised states Most common small bowel cancers are metastatic such as melanomas, small cell lung cancer etc. |
|
Charcot's triad is
|
Jaundice
RUQ pain fever |
|
How do we define diarrhea?
|
Increase in the volume & frequency of bowel movements as well as a change in the consistency of the stools.
OR Passage of 3 or more stools per day that conform to the shape of their container. |
|
How are infectious diarrheas transmitted?
|
Acute infectious diarrhea is a very common illness, esp. in the young.
On average, persons in developed countries will experience 1-2 episodes per yr, whereas in developing countries, the average will be 3 or more episodes per yr. Almost all infections are acquired via a fecal-oral route, usually by ingestion of contaminated food or water. Overcrowding, inadequate public sanitation, & poor personal hygiene are all major risk factors. |
|
What are the infectious agents that most commonly cause diarrhea?
|
Potential microbial causes are quite varied and tend to be age & setting dependent.
In the US and other temperate developed countries, viruses (rotaviruses, noroviruses) are the predominant etiologic agents. Enterotoxigenic E. coli (ETEC) are the most frequent bacterial cause of noninflammatory (watery) diarrhea. Salmonella & Campylobacter are the primary bacteria causing inflammatory diarrhea. Parasitic infections can also cause diarrhea. |
|
What are the two major pathophysiological mechanisms of infectious diarrhea?
|
Excess excretion of fluid into intestinal lumen (noninflammatory):
Role of enterotoxins Destruction of ileal &/or colonic mucosa (inflammatory): cytotoxins or invasion of enterocytes |
|
What enteric infections are considered luminal?
|
V. Cholera
E. Coli (heat labile or stable toxins) Staph food poisioning Rotavirus Noroviruses Giardia Cryptosporidium |
|
What enteric infections are considered mucosal?
|
Shigella
C. Jejuni Salmonella Invasive E.Coli E. Hystolytica |
|
What enteric infections are considered systemic?
|
S. Typhi
Yersinia C. Fetus |
|
What is the difference between inflammatory and non-inflammatory diarrhea?
|
Overall, noninflammatory (watery or secretory) diarrhea, which is most often mediated via enterotoxins, is estimated to account for ~90% of all cases of diarrhea.
That syndrome is characterized by watery stools that may be of large volume (>1L/d) without blood, fecal WBCs, severe abdominal pain, or significant fever. Usual causative organisms would be viruses, ETEC, V. cholerae, & selected parasites. Inflammatory diarrhea (dysentery) accounts for 5-10% of the total cases of diarrhea & is characterized by frequent, small-volume, mucoid or bloody stools with associated tenesmus, severe abd pain, fever (T>101.3), & fecal WBCs. Salmonella, Shigella, & Campylobacter are prototypical causative organisms. |
|
What factors predispose to enteric infections?
|
Immune “immaturity” (younger age)
Poor personal hygiene (eg. lack of handwashing) Reduced gastric acidity (from age, surgery, or medications such as PPIs) Altered enteric microflora (induced by prior antibiotic therapy) |
|
What signs and symptoms are associated with infectious diarrhea?
|
(Symptoms)
Systemic: Malaise Myalgias Fever Upper GI: Nausea, vomiting Lower GI: Cramping, diarrhea, tenesmus (Signs) Systemic: Fever Signs of dehydration Rash Abdominal: Hyperactive BS Tenderness/ guarding Distention; NO rebound Rectal: Tenderness Guaiac + stool The presence of severe abdominal pain, tenesmus, & significant fever (T>101.3) all suggest infection due to a pathogen that causes inflammatory disease (ie, Salmonella, Shigella, etc). |
|
Recent travel to underdeveloped countries makes us think of...
|
Enterotoxigenic E. coli, Salmonella,
Shigella, Campylobacter, Giardia, Entamoeba |
|
Recent Mountains/camping expereinces makes us think of...
|
Giardia
|
|
Recent antibiotic use makes us think of...
|
Clostridium difficile
|
|
People who engage in anal sex or anal-oral contact are susceptible to..
|
With enteritis: Shigella,
Giardia, Entamoeba, Campylobacter With proctitis: Neisseria gonorrheae, HSV, Chlamydia, Campylobacter, Treponema pallidum |
|
HIV patients GI systems are susceptible to...
|
Cryptosporidia
Candida |
|
Children in day care centers are susceptible to...
|
Giardia, Campylobacter, Shigella,
Rotavirus |
|
Dairy products can lead to infection with...
|
Salmonella, Yersinia, Campylobacter
|
|
Poultry is associated with...
|
Campylobacter infections.
|
|
Seafood ingestion is associated with...
|
V. parahemolyticus,
noroviruses |
|
What are the typical incubation periods associated with various infectious gastroenterites?
|
<2hrs.:
None 2-8 hours: S. Aureus toxin B. Cereus toxin 8-14 hours: C. Perfringens B. Cereus >14 hours: V. Cholera E. Coli toxin Shigella Invasive E.Coli V. parahemolyticus Y. enterocolitica Salmonella If onset of symptoms is within 8 hrs of ingestion of the putatively tainted foodstuff, disease is almost certainly due to a preformed toxin. |
|
Which enteric infections have leukocytes in the stool?
|
Salmonella spp.
Shigella spp. Invasive E. coli Campylobacter Yersinia Non-cholera vibrios and Antibiotic associated infections. |
|
Which enteric infections do not have leukocytes in the stool?
|
E. Coli
V. Cholera "Food poisoning" Viruses Parasites |
|
Which agents are detected by routine stool culture?
|
Salmonella Entamoeba
Shigella Giardia Campylobacter By special request: Vibrio parahaemolyticus C. difficile Rotaviruses Enterohemorrhagic E. coli Yersinia Only in specialty labs: Enterotoxigenic E. coli Clostridium perfringens Invasive E. coli Noroviruses |
|
Stool cultures should be reserved for patients with ....
|
Inflammatory diarrhea
Increased risk for severe or complicated infections. Illness which has public health implications. Persistent diarrhea. |
|
Should we use antimotility agents in infectious diarrhea?
|
We prefer not to because this increases the interaction time between the bugs and the mucosa.
|
|
Most episodes of infectious diarrhea are caused by...
|
viruses
|
|
Summarize the management of infectious diarrhea?
|
Aggressive rehydration is the critical intervention in persons with diarrhea.
Empiric antibiotic therapy should be considered only in those patients with a high probability of infection due to an enteroinvasive pathogen (ie, inflammatory diarrhea). In patients with proven infection, therapy is clearly warranted for shigellosis, cholera, traveler’s diarrhea, amebiasis, giardiasis, & Cyclospora. Always assess the public health implications of infection. |
|
How do we diagnose amebiasis?
|
Intestinal:
3 stool exams (90% sensitive) for cysts or trophozoites esp. w/ RBC Stool antigen detection (differentiates from E. dispar) most with positive serum serologies by day 7. Titers remain positive for years, despite treatment (IHA) Extraintestinal: clinical picture, + serologies, “anchovy paste” aspirate Note: aspiration of amebic cysts free of WBCs since amebae are cytolytic. |
|
How do we treat amebiasis?
|
Invasive disease:
metronidazole (Flagyl) Affects only trophozoites, NOT cysts Intestinal cysts: paromomycin, iodoquinol Need to treat with these drugs subsequently to eliminate the cyst shedding state. NO therapy needed for E. dispar, or other commensals (E. hartmanni, E. polecki, E. ginigivalis, etc.) only E. hystolitica |
|
How do we diagnose giardiasis?
|
Microscopic exam of stool for cysts, trophozoites
“gold standard” Identifies 50-70% of infections with 1 stool, 90%+ with 3 stools Fecal suspension ELISA for antigen > 90% sensitive (applies to amebiasis too) Microscopic exam of duodenal fluid (Entero-Test or string test), duodenal aspirate, tissue |
|
How do we treat giardiasis?
|
Metronidazole
Divided doses x 7 days Quinacrine |
|
How does cryptosporidium infection present?
|
7-10 day incubation period
Diarrhea, crampy abdominal pain Varies from intermittent, scant to continuous, watery, voluminous (up to 17L/day) Self-limited in immunocompetent Can be devastating in immunocompromised, particularly AIDS patients. Dx: Microscopic (modified Acid Fast Stain) ELISA stool antigen detection NO treatment. |
|
What are some of the less common intestinal parasites?
|
Isospora belli
Cyclospora Microsporidia |
|
What are the major intestinal helminths?
|
Ascaris
Enterobius Hookworm: Necator americanus Ancylostoma duodenale Strongyloides |
|
What is the pathogenesis of ascariasis?
|
Asymptomatic infection common in light infections. (vast majority)
Larval migratory phase: host reactions Pneumonitis: hypersensitivity reaction as parasite migrates through. Cough, wheezing, sob, fever, chills, malaise Adult worms cause vague crampy abdominal pain. Intestinal obstruction (1/500 infected persons/year) Aberrant migration can occur into bile ducts, appendix Causes fever, local pain If in bile duct jaundice, pancreatitis, hepatitis. Diagnosis through stool examination: Ova or adult parasites. Easy to do because of large number of ova per adult female. |
|
How do we treat ascariasis?
|
Mebendazole
Albendazole Pyrantel pamoate |
|
How do we treat enterobius or pinworm infection?
|
Mebendazole 1 dose or
Pyrantel pamoate 1 dose Repeat dose at 2 weeks May need to treat close contacts/family members |
|
What are the non-specific and barrier immune mechanisms of the GI system?
|
Gastric Acid:
Increases infectious dose Mucin : Binds normal flora and antimicrobial compounds. Some pathogens can bind mucin though. Tight junctions Paneth cell products: Defensins, Lysozymes, Phospholipases, DNAases, Trypsin |
|
In neutropenic patients, treatment with Anti-gm positives/fungals causes...
|
more gm (-) infection
Anti- gm negatives causes more fungal infection. |
|
By what mechanisms do native flora protect the gut?
|
Competition
TLR conditioning Antibiotic-depleted epithelium becomes MUCH more sensitive. |
|
What are M-cells and what is their function?
|
Tight junctions exclude most antigens from direct access to submucosal antigen presenting cells
M cells are specialized cells that ‘sample’ the environmental antigens Derived from the same precursor cell as epithelial cells Concentrated over Peyer’s Patches |
|
What is the role of gut dendritic cells?
|
Reside in the submucosa
‘Fed’ antigens by M cells Present antigens to T cells in the Peyer’s patch region as immature DCs Can be a mechanism of tolerance If activated by other stimuli (eg. TLR stimulation, T cell products) DCs migrate to local lymph nodes and present antigen as matured DCs. |
|
In what order do B-cells class switch
|
IgM
IgD IgG IgE IgA (most common defective switch) class switch requires T cell help. |
|
The most common cause of severe transfusion reaction after clerical error is...
|
anti-IgA antibodies
|
|
What is thought to be the mechanism of crohn's disease?
|
Leaky barrier causes direct activation of T-cells without M-cell presentation and this causes production of interleukins, TNF and cytokines..
|
|
What are some examples of systemic illness triggered by gut immunity?
|
Extra-intestinal manifestations of IBD.
Post-diarrheal Guillian-Barre Syndrome (C. jejuni is predominant organism) Yersinial arthritic syndromes Pyoderma gangrenosum post gastric/jejunal bypass (gets better if the bypass is reversed or taken down) Graft vs. Host Disease in BMT patients. |
|
What aspects of immune health do the antigens of normal intestinal flora like bacteroides fragilis influence?
|
Th1/Th2/Treg/Th17 balance
Thymic health/development |
|
What are some G- rods that commonly cause systemic illness/diarrhea?
|
Salmonella species
Shigella E. coli (ETEC, EPEC) Campylobacter Yersinia |
|
What are some risk factors for salmonella infection?
|
Achlorhydria greatly increases risk of infection
PPIs and advanced age risk factors Most common sources in food supply: Chicken Eggs Most common non-food sources: Reptiles Treatment: fluoroquinolones, cephalosporins, others |
|
What are the risk factors for C. difficile colitis?
|
Major risk factor is antibiotic therapy.
Leads to loss of normal flora and overgrowth of Clostridium difficile Can be febrile with high WBC and very fulminant disease (even toxic megacolon) Can also be clinically well with just troublesome diarrhea or even asymptomatic carrier status. Diagnosis: gold standard is sigmoidoscopy (pseudomembranes; toxin assay most common) Treatment: oral metronidazole for mild disease oral vancomycin for more serious disease Both po vancomycin AND IV metronidazole for life-threatening illness. |
|
What is celiac disease or gluten enteropathy?
|
Gluten allergy which leads to local immune response in the small bowel.
T cells and IgA to tissue transglutaminase. Produces inflammatory cytokines and metalloproteinases which lead to villus atrophy and malabsorption syndrome. Improves with avoidance of gluten (wheat) More common in patients with IgA deficiency, siblings (HLA DQ2 and DQ8 increase risk), other autoimmune diseases. |
|
Recent evidence has suggested that colon cancer may be linked to infection with...
|
Enterotoxigenic Bacteroides fragilis
A substrain of fragilis that causes inflammatory diarrhea w/out much fever/systemic symptoms. It is very toxic to colonic epithelium and disrupts tight junctions Can chronically colonize thereafter and lead to chronic inflammation and eventually colon cancer because of the immune response of Th17 cells through the Stat3 pathway. |
|
What are the layers of the gut wall from the lumen outwards?
|
Mucosa:
Epithelium and lamina propria Muscularis mucosa Submucosa Muscularis externa: Two or three layers of smooth muscle Serosa/adventitita |
|
The inner lumen of the esophagus is lined with....
|
stratified squamous epithelium
glands in submucosa for lubrication |
|
The outermost layer of the esophagus is made of...
|
Esophagus is not free as it courses through the thoracic cavity (embedded in connective tissue); thus outer tunic is adventitia, not a serosa.
|
|
The last representation of striated muscle we see in the GI tract is in the...
|
Proximal esophagus
|
|
How does the upper esophageal sphincter work?
|
It pulls the larynx forward when we swallow.
Normally upper and lower sphincters closed except during swallowing to prevent entry of air from the oral cavity or reflux of stomach contents. |
|
What substances are absorbed in the stomach?
|
Small amounts certain lipid-soluble compounds.
(including aspirin and other NSAIDs) Ethanol |
|
What cell types are found in the stomach?
|
Non-secretory:
Stem cells (throughout GI tract) Secretory Mucus: Surface mucous cells Mucous neck cells Acid and Intrinsic Factor: Parietal cells (oxyntic cells) Enzymes: Chief cells (peptic cells) Peptides: (endocrine/paracrine factors) Enteroendocrine cells (found throughout GI tract) |
|
What is the role of the surface mucous cells in the stomach?
|
Each contains mucinogen granules forming “mucous cup” apically; when released the mucinogen forms viscous coat that adheres to epithelial surface.
Provides mechanical protection and, because of high bicarbonate concentration, protects epithelium from acidic gastric juice. |
|
What is the role of mucous neck cells in the stomach?
|
Shorter than surface cells, located among groups of parietal cells in neck region of gastric glands.
Contain less mucinogen and no prominent mucous cup. Produce more soluble mucous, under the control of vagal stimulation. |
|
How does epithelial renewal occur in the stomach?
|
Dividing stem cells primarily in isthmus region of gastric glands.
Most new cells become surface cells (live 3-5 days). Other cell types have longer lifespans (up to 150-200 days for parietal cells) but all are replaced from the stem cells. |
|
What are stomach chief cells?
|
Protein secreting cells
Abundant rER basally, so basophilic. Eosinophilic apically due to presence of secretory (zymogen) granules containing enzyme precursors. Secrete pepsinogen (converted to pepsin on contact with gastric juice) and a weak lipase. |
|
What do parietal cells in the stomach look like?
|
oval shape
eosinophilic cytoplasm “fried egg” appearance with prominent central nucleus “secrete” HCL Key player is H+/K+ ATPase ("proton pump“) in cannalicular membrane. When the cells are actively secreting they form cannaliculi and surface microvilli to increase the surface area of the apical region. |
|
How does acid production occur in parietal cells?
|
Dissociation water yields hydrogen ions
Hydroxyl ions formed and rapidly combine with carbon dioxide to form bicarbonate (catalyzed by carbonic anhydrase) Bicarbonate transported out of the basolateral membrane in exchange for chloride Chloride and potassium ions transported from cytoplasm into the lumen of the cannaliculi by passive conductance channels. Hydrogen ions pumped out of the cell and into the lumen in exchange for potassium through the action of the proton pump (ATPase); potassium is thus recycled back into the cytoplasm. Accumulation of osmotically-active hydrogen ions in the cannaliculus generates osmotic gradient across membrane; get outward diffusion H2O. Acid production dependent on ATP; large numbers mitochondria account for eosinophilia of parietal cells. |
|
Where, in terms of anatomy, do the enteroendocrine cells secrete various hormones?
|
|
|
What epithelial cells comprise normal small intestine mucosa?
|
Columnar epithelium.
|
|
What cells secrete mucous in the small intestine?
|
Goblet cells.
|
|
What are IEL's?
|
Intra-epithelial lymphocytes in the small intestine.
Usually below 10/100 epithelial cells. |
|
Brunner's glands are unique to...
|
The duodenum.
|
|
What structures are unique to the ileum?
|
Peyer’s patches
|
|
What is the normal villous-crypt ratio in the small bowel?
|
3-5:1
|
|
What is celiac disease (non-tropical sprue)?
|
An immune mediated disorder in genetically susceptible hosts with damage to SI mucosa & malabsorption due to certain types of HLA expression.
Atrophy of villi with associated compensatory crypt hyperplasia produces a flattened avillous surface so that small bowel looks like large intestine. Plasma cells and numerous intraepithelial lymphocytes can also be seen. Worldwide in distribution but occurs mostly in European whites. Clinical onset anytime from infancy to late adulthood. Abdominal pain, diarrhea, steatorrhea, dermatitis herpetiformis, fatigue. 2 or more genes involved: class I HLA-B8 & class II HLA-DR3 & DQW2 Exposure to gliadin results in humoral & cell mediated injury Possible relationship to prior infection with adenovirus I2 E1B viral protein homologous with gliadin possibly resulting in cross reactivity Serum endomysial and tissue transglutaminase autoantibodies. |
|
What is refractory sprue? (not on test)
|
Sprue with absent or incomplete clinical response to gluten free diet.
Abnormalities in T cells in many patients with loss of CD4 & CD8 & with monoclonal rearrangements in TCR gamma gene ? Early T cell lymphoma Some develop collagenous sprue |
|
Pyramidal or triangular structures which are eosinophillic (pink) attached to the luminal surface are indicative of..
|
Giardiasis.
May look normal in low magnification. |
|
What is the epidemiology of Crohns disease?
|
An idiopathic chronic inflammatory disorder involving any part of the GIT
Worldwide distribution More common in western nations In US, incidence is rising; 8/100,000 Genetic susceptibility Most often presents in 2nd decade 2nd smaller peak in 8th decade. |
|
What is the pathology of Crohn's disease?
|
Thickened wall with firm, stiff consistency due to fibrosis, muscular hypertrophy & fat wrapping
Strictures Fistulas In early or mild disease, mucosa has aphthous ulcers With progression, fissures or wide based longitudinal ulcers; cobblestone mucosa Skip areas |
|
In Crohn's resection section what do things we look for are?
|
Transmural chronic inflammation
Fibrosis Non-casseating granulomas Increase in plasma cell in the lamina propria. |
|
The histopathology of Crohn's disease includes...
|
Transmural chronic inflammation with lymphoid nodules (string of beads)
Fibrosis Muscular & neuronal hypertrophy Basilar plasmacytosis PMNs in LP & epithelium (cryptitis) Ulcers, including fissures Pseudopyloric metaplasia Non-necrotizing granulomas (biopsies 30%; resections 60%) Vasculitis Variability in changes |
|
What do mean by osmolality?
|
Osmoles of solute per kg of solvent (depends on the number of particles in solution)
Luminal contents of the intestine are isotonic compared with plasma (~290 mOsmols/kg) |
|
What structural features of the intestine make it ideally suited for absorption?
|
Small intestinal surface area
is amplified by the circular folds, villi, & microvilli. Absorption is also facilitated by movement of the villi. This stirs the chyme immediately adjacent to the mucosa and presents new surfaces for absorption. Movement of the villi is regulated by local nervous reflexes and hormonal mechanisms. Extension of the microvilli is regulated to facilitate absorption by increasing surface area. The intestinal mucosal surface area is under trophic influences linked to the presence of food in the GI tract. |
|
Hoe does intestinal blood flow change after a meal?
|
At Rest:
~ 10-15% of Cardiac output (75%-> mucosa, 5%->submucosa, 20%->muscularis externa) After a Meal: Blood flow increases 30-130% (especially to the mucosa) as a result of increased CO and shunting of blood from other layers. Postprandial blood flow to intestine ~ 1-2 L/min |
|
Cells in the vilus tip are primarily absorptive whereas cells in the crypts are primarily secretory, how do they mature and what are the differences?
|
Cells migrate up the vilus and mature as they travel up.
After a certain point they express brush border hydrolases. Cells at the tip of the vilus apoptose and slough into the lumen. |
|
Even though the colon is the most efficient at water absorption it only absorbs about 1.3L of the ~9L the duodenum sees. Why?
|
~5.5L absorbed by the jejunum
~2L absorbed by the ileum So only about 1.5L are available for resorption in the large bowel. ~200cc/24hours of water are excreted with the feces which leaves 1.3L.. |
|
What is the cellular mechanism of intestinal water absorption?
|
Water absorption is passive and dependent on absorption
of ions (principally Na+ & Cl-) and solutes (sugars, amino acids) Water movement may be transcellular (through the cell) or paracellular (through the tight junctions between cells) Water moves bidirectionally to keep the luminal contents isotonic with plasma Passive solute permeability and water absorption decreases caudally. (Highest permeability in duodenum/jejunum) |
|
How are various ions absorbed and secreted in the small and large intestine?
|
|
|
Test of choice for abdominal pain and fever is .....
|
CT
|
|
Test of choice for abdominal bleeding per rectum is...
|
colonoscopy
|
|
Where are lacteals located?
|
In the center of an intestinal villus.
|
|
How does ion absorption occur in the jejunum?
|
Tight junctions are leaky
Na+ absorption is highest in Jejunum; Most (~85%) of Na+ absorption is active Na+ is actively absorbed by Na+ dependent nutrient transporters (glucose, amino acids) Na+ is also absorbed via Na+/H+ exchange (NHE3) Na+ is moved across the basolateral membrane by the Na+/K+-ATPase K+ moves passively (moves down its concentration gradient secondary to H2O movement) Cl- moves paracellularly down its electrical gradient (follows the Na+) H+ secretion acidifies the lumen, reacts with HCO3- to release CO2 and water. CO2 can then diffuse across the epithelial cell barrier into the blood Intracellular HCO3- crosses basolateral surface Result: Net NaCl, KCl, and NaHCO3 absorption. |
|
How does ion absorption occur in the colon?
|
Tight junctions are tighter
Na+ is moved against a large electrochemical gradient because a lot of it has already been absorbed in the small intestine. Little Na+/solute cotransport (short chain fatty acids; right colon) Na+ is absorbed by the Na+ channels ENaC (electrogenic Na absorption) Na+ is moved across the basolateral membrane by the Na+/K+-ATPase K+ is moves down its electrochemical gradient into the lumen via channels (but can also be absorbed by the apical H/K-ATPase) Cl- is absorbed via Cl-/HCO3- exchange (DRA) and exits through Cl channel protein. Cl- is also absorbed paracellularly HCO3- is secreted via Cl-/HCO3- exchange. |
|
Why are infants with prolonged diarrhea particularly susceptible to hypokalemia?
|
Most K+ absorption in the small intestine is driven by water absorption, that increases the
lumenal K+ concentration. Hence, significant K+ loss may occur in diarrhea, leading to decreased extracellular levels and life-threatening consequences such as cardiac arrhythmias. |
|
What are the basic principles behind GI water absorption?
|
Water movement in the intestine is passive & dependent
upon transport of electrolytes and other solutes Water movement may be transcellular or paracellular (through the tight junctions between cells) Water moves bidirectionally to keep the luminal contents isotonic with plasma. Ions (& solutes) are transported via transcellular and paracellular pathways into the lateral spaces, where a “standing osmotic gradient” is established for the passive movement of water. |
|
What compounds that are released by enteric neurons stimulate net secretion of electrolytes and water?
|
Acetylcholine
Nitric oxide Serotonin VIP Substance P |
|
What compounds that are released by enteroendocrine cells in the mucosa or submucosa stimulate net secretion of electrolytes and water?
|
Histamine
Calcitonin Guanylin Bradykinin Platlet-activating factor Prostaglandins Leukotrienes Arachidonic acid Adenosine |
|
What compounds that are released by enteric neurons promote net absorption of electrolytes and water?
|
Norepinephrine
Neuropeptide Y Opioids |
|
What compounds that are released by enteric neurons stimulate net secretion of electrolytes and water?
|
Somatostatin
|
|
What hormones stimulate net secretion of electrolytes and water?
|
Prostaglandins
Atrial natriuretic peptide Gastrin Motilin Bombesin GIP |
|
What lumenal factors stimulate net secretion of electrolytes and water?
|
Bile salts
Long-chain fatty acids |
|
What hormones promote net absorption of electrolytes and water?
|
Epinephrine
Enkephalins Aldosterone Glucocorticoids Angiotensin II Peptide YY Prolactin Growth hormone |
|
What lumenal factors promote net absorption of electrolytes and water?
|
Short chain fatty acids
|
|
Clinically we divide diarrhea into 3 main categories. What are they?
|
Osmotic Diarrhea -
Poorly absorbed, low molecular weight aqueous solutes create an osmotic force that quickly pulls water (and ions) into the intestinal lumen (in order to maintain an intra-luminal osmolality equal to that of body fluids). Shows an abnormal Osmotic Gap (disappears with fasting) Causes: Lactase deficiency (lactose), foods and supplements (sorbitol,lactulose, Mg++) Secretory Diarrhea: Caused by overstimulation of the intestinal tract’s secretory capacity. Driving force is always either net secretion of Cl- or HCO3-, or inhibition of net Na+ absorption. Shows a normal Osmotic Gap. Causes: bacterial enterotoxins, neuroendocrine tumors (overproduce pro-secretory hormones), inflammatory mediators, dihydroxy bile acids, hydroxylated fatty acids, drugs. Complex Diarrhea – Most clinically significant diarrheas are complex, with multiple pathophysiologic mechanisms involving consideration of paracrine, immune, neural, and endocrine modulators. |
|
What is an osmotic gap?
|
We look at the pattern of stool electrolytes.
290-2x(Conc.Na+K) (290 is the assumed osmolarity of blood plasma) An Osmotic Gap < 50 mOsm is considered normal and can be found with secretory diarrhea. Osmotic Gap > 50 mOsm indicates osmotic diarrhea |
|
What are the principal driving forces behind water absorption and secretion in the intestine?
|
Na+ flux is the principle driving force for intestinal water absorption.
Cl- flux is the principle driving force for intestinal water secretion. Net water and electrolyte transport across the intestinal mucosa represents the differences between the lumen to blood (absorption) and blood to lumen(secretion) fluxes. These flux differences normally favor water absorption. Epithelial cells near the villus tip are active in net absorption Crypt epithelium usually functions as net secretors of ions and water |
|
What is the mechanism for cholera diarrhea?
|
Cholera toxin A chain
irreversibly activates adenylate cyclase, increases cAMP, and activates Cl- secretion via CFTR Na+ passively follows Cl- Water passively follows the Cl- and Na+ flux Cholera toxin also inhibits non-nutrient Na+ and Cl- absorption by villus tip cells Cholera patients may produce up to 20 L/day of watery stool |
|
How do we treat cholera diarrhea?
|
Treated with oral rehydration therapy:
Administration of a solution of glucose & salt increases driving force for water absorption by increasing Na/glucose uptake. Newer formulas are hypo-osmolar and include amylase-resistant starch (rice starch) to enhance colonic short chain fatty acid and water absorption. |
|
What is the mechanism of constipation in the elderly?
|
Colonic CFTR expression (Cl- secretion) declines with age (major player in water secretion)
Colonic ENaC expression (Na+ absorption) is maintained with age (major player in water absorption) This sets up a potential imbalance between intestinal water absorption and secretion where the stool becomes excessively desiccated. Drugs that activate ClC2 chloride channels may be useful. |
|
What are some drugs that can be used against diarrhea?
|
Opiates:
(u receptor agonists, antiperistaltic) Diphenoxylate Loperamide Codeine Morphine Tincture of opium Alpha adrenergic agonist: Clonidine Somatostatin analog: Octreotide (carcinoid syndrome) Bile acid biding resin: Cholestyramine Fiber supplements: Psyllium Calcium polycarbophil Bismuth subsalicylate (Pepto-Bismol). |
|
What contrast materials are naturally found in the GI tract?
|
GAS=Black
CALCIUM=White FAT=Gray |
|
The normal bowel gas x-ray pattern in a normal patient laying supine is..
|
Gas mostly in the colon.
Small bowel should look pretty empty. Reversal of this normal gas pattern can suggest obstruction. |
|
Dilation of both the colon AND the small bowel on plain film can suggest...
|
Adynamic ileus.
However, it can also be an obstructive neoplastic lesion in the sigmoid colon or rectum but there is no good way to tell. |
|
If we see the outer borders of the bowel clearly, this is an indication of...
|
Pneumoperitonium.
|
|
What plain film views are best for discerning free gas in the abdomen?
|
Left lateral Decubitus or upright film
The single most sensitive test for seeing gas in the abdomen though is CT. |
|
When we are looking at the liver, how do we tell the difference between gas in the venous system and gas in the biliary tree?
|
Go with the flow.
If the gas goes all the way out to the periphery, portal system. Usually dead bowel. |
|
Calcification of the border of the gallbladder sometimes called porcelain gall bladder should rouse connotations of...
|
Gall bladder carcinoma.
|
|
The reason we can see the edge of organs is....
|
Fat
|
|
Calcification in the adrenal glans can be indicative of...
|
Addison's disease
or TB |
|
Chilean shepherds with champagne looking abdominal films have...
|
Echinococcal disease
|
|
An extremely dilated transverse colon can be a sign of ...
|
Toxic megacolon in ulcerative colitis patients.
|
|
Winking owl sign in a vertebral body can represent...
|
Metastasis
|
|
What cavity is the pancreas in?
|
It is retroperitoneal.
|
|
What types of glands are pancreatic acini?
|
Exocrine.
|
|
What types of glands are the 1,000,000 or so islets of langerhans in the pancreas?
|
Endocrine
Alpha cells make glucagon Beta cells make insulin |
|
What is the significance of pancreatic stellate cells?
|
As in the liver, they are responsible for fibrosis.
|
|
What is acute pancreatitis?
|
An acute inflammatory process of the pancreas which by definition has the potential to return to normal.
|
|
What is chronic pancreatitis?
|
An irreversible chronic inflammatory process characterized by fibrosis and loss of endocrine and exocrine elements of gland.
|
|
Can a patient go straight from normal to chronic pancreatitis without recovery?
|
Yes, a patient experiencing significant (>30%) pancreatic necrosis may lose sufficient pancreatic tissue to become endocrine ± exocrine insufficent, and have pancreatic scarring.
|
|
What pH is protective for the pancreas?
|
Alkaline
|
|
How does the pancreas protect itself?
|
Highly toxic enzymes (e.g. trypsin) are contained and when possible secreted in inactive (pro) forms.
Low extracellular ionized calcium. Alpha-1antitrypsin. Alkaline pH. |
|
What happens when pancreatic acinar cells experience blockage of secretion?
|
Fusion of lysosome and Zymogen granules.
Inflammation Third space losses/fluid accumulation. Fat necrosis Pancreatic and peripancreatic necrosis. |
|
What are the guidelines regarding volume replenishment in acute pancreatits?
|
6-8L in the first 24 hours.
It is a common mistake to underestimate the volume of fluid replacement required by these patients. 100 cc/hr is inadequate! If the patient can tolerate a 1-2 liter fluid bolus, give it, followed by 300 or 400cc/hr Patients with predicted severe acute pancreatitis should have their urine output carefully monitored. Aim for at least 50cc/hr, and 100cc/hr or more is better If you let the kidneys die, other systems quickly follow…. |
|
What systemic complications often result from severe pancreatitis?
|
Renal failure
Respiratory failure (ARDS) Coagulopathy (DIC) Encephalopathy Hypocalemia (tetany) Used to be considered a manifestation of systemic spread of pancreatic enzymes and local inflammatory factors. Now known to result from the effects of inflammatory cytokines (Interleukins, NO, and TNF-alpha). |
|
For the most part, what accounts for the local effects of pancreatitis?
|
largely due to pancreatic
enzymes, especially TRYPSIN |
|
What is the definition of SIRS?
|
HR > 90/min
Body temp < 36 or > 38 deg C RR > 20/min or PaO2 < 60 WBC < 4 or > 12,000/cc3 |
|
How does acute pancreatitis typically present?
|
Abdominal pain and tenderness.
Nausea and vomiting. Fever. Tachycardia. Elevated WBC, serum amylase and serum lipase. |
|
What are the causes of acute pancreatitis?
|
Gallstones (90%+ in US) 90%
“Alcohol” (acute-on-chronic) 10% Drugs Trauma Structural (P divisum, tumors) Autoimmune Genetic |
|
Which of the two enzyme tests is more specific for pancreatitis?
|
Serum lipase.
Serum amylase has a bigger differential. |
|
In the USA, 90-95% of acute pancreatitis attacks are related to ...
|
gallstones or “sludge” (microlithiasis)
|
|
How long does someone have to be a drinker to have episodes of acute pancreatitis?
|
It takes 10-20+ years of abuse for the pancreas to respond by episodes of acute pancreatitis.
|
|
What drugs cause acute pancreatitis?
|
>300 drugs reported to cause AP
Most pancreatitis related to drugs is idiosyncratic, not dose-related Culprits include thiazide and loop diuretics, steroids, certain antibiotics (e.g. tetracycline, sulfonamides), valproic acid, anti-metabolites, many drugs used for HIV. (this is seldomly tested) |
|
What are the main metabolic causes of pancreatitis?
|
Hypercalcemia:
Almost always due to hyperparathyroidism. Increasing incidence of milk-alkali syndrome from use of Ca-containing antacids. Hypertriglyceridemia Usually >1,000 mg/dl with lipemic serum Often other physical signs of hyperlipidemia (arcus, xanthelasma) |
|
What physical problems can cause pancreatitis?
|
Congenital pancreatic divisum
Neoplasms. |
|
What do we know about autoimmune pancreatitis?
|
Probably more common than we think.
Association with Sicca Syndrome, primary sclerosing cholangitis (PSC), autoimmune hepatitis, SLE, and maybe RA. Bulky pancreas, irregular pancreatic duct on imaging. 1/3-1/2 have elevated IgG4. May respond to systemic steroids. |
|
Can Gila monster venom cause pancreatitis?
|
No, this is an urban legend.
Brown recluse and a variety of other venoms can though. |
|
About 80% of pancreatitis is said to be mild, this is also known as...
|
Edematous or Interstitial pancreatitis
Mortality is <1% |
|
The 20% of pancreatitis cases that are deemed severe fall into two categories. What are they?
|
Sterile Necrosis:
10% mortality Infected Necrosis: ~25% mortality |
|
What do patients with pancreatitis die of?
|
Early: Metabolic death
Late: Infection |
|
What are the three common scoring systems for pancreatitis?
|
Ranson’s Score – outdated
Balthazar Score – based on CT findings of necrosis, fluid collections, etc. APACHE-II (or III) Score Both the current scoring systems require 24 hours to obtain data. |
|
What causes Chronic Pancreatitis?
|
ALCOHOL! (60-70%)
GENETIC (familial, sporadic) (20%) CHRONIC UNRELIEVED CAUSES OF ACUTE PANCREATITIS (gallstones, hyperlipidemia, hypercalcemia, maybe A1-AT deficiency, pancreas divisum, autoimmune, etc) (10-20%) |
|
What are the patterns of Chronic Pancreatitis?
|
Asymptomatic
Recurrent acute attacks Chronic pain alone |
|
What are the complications of chronic pancreatitis?
|
Pain.
Recurrent attacks of pancreatitis. Exocrine insufficiency (steatorrhea). Endocrine insufficiency (DM) Fluid collections secondary to pancreatic ductal disruption (e.g. pseudocysts, ascites) Strictures of adjacent structures (e.g. duodenum, bile duct, colon) Life-threatening bleeding from pseudoaneurysms of the splenic and related arteries in pseudocyst patients. |
|
What is the gender bias of IBS?
|
3:1
Most common in ages 15-34. |
|
How does IBS affect quality of life?
|
Physical functioning, bodily pain, general health, mental health, emotions, social functioning, vitality
Several studies report that IBS increases the rate of absenteeism |
|
What is the annual health care cost of IBS?
|
>20 Billion in both direct and indirect expenditures
|
|
What are the rome 3 diagnostic criteria for IBS?
|
Abdominal pain 3 days/month in the last 12 weeks that is continuous or recurrent
Associated with >2 of the following: Improvement with defecation, change in stool frequency, change in stool form Onset >6 months prior to diagnosis Supportive symptoms include: Abnormal stool frequency (<3bm/week; > 3bm/day) Abnormal stool form (lumpy, hard, loose, watery) Straining with defecation Urgency, incomplete evacuation Bloating, passing mucous |
|
What is the bristol stool scale?
|
Type 1 - Separate hard lumps like nuts (difficult to pass)
Type 2 - Sausage shaped but lumpy Type 3 - Like a sausage but with cracks on surface Type 4 - Like a sausage or snake, smooth and soft Type 5 - Soft blobs with clear-cut edges (passed easily) Type 6 - Fluffy pieces with ragged edges, a mushy stool Type 7 - Watery, no solid pieces (entirely liquid) |
|
What are some possible pathophysiologic mechanisms for IBS?
|
Neuromuscular dysfunction
Abnormal Brain- GI tract interactions Immune activations Genetic Influence Psychological Distress Intestinal Flora Disturbances |
|
What neurotransmitter is thought to play a role in the neurogenic defects of IBS?
|
Serotonin (5-hydroxytryptamine, 5-HT)
Released by mucosal enterochromaffin cells with noxious stimulation. Activates peristalsis- abnormalities cause increased/decreased transit Activates sensory pathways that mediate pain. |
|
What organisms are associated with post infectious IBS?
|
salmonella, shigella and Campylobacter
6-27% of pts develop PI-IBS after E. coli or C. jejuni |
|
What is the role of psychological distress in IBS?
|
Psychological stress exacerbates gastrointestinal symptoms
Psychosocial disturbance affects illness experience and behavior (sexual and physical abuse) IBS can lead to impaired health related quality of life. |
|
Is there evidence of genetic linkage in IBS?
|
Yes, somewhat.
|
|
How do we diagnose IBS in practice?
|
Extensive diagnostic testing is not required unless there are red flag symptoms.
(weight loss, fevers, blood in stool, anemia, etc.) Consider: CBC, ESR, CRP, Metabolic profile, stool cx, stool O&P, WBC and c-difficile toxin Celiac antibodies (total serum IgA and tissue transglutaminase antibodies) Flexible sigmoidoscopy or colonoscopy for red flag symptoms. |
|
How do we treat IBS?
|
Provide reassurance/education
Treat according to predominant symptom Assess response to therapy in 4-6 weeks. |
|
What pharmacological agents are available for IBS?
|
Bulking agents:
(psyllium) Stimulant Laxatives: bisacodyl, senna Osmotic laxatives: Magnesium Salts Sodium phosphate Lactulose Sorbitol Polyethylene Glycol |
|
What is lubiprostone?
|
Approved for chronic functional constipation .
Increases intestinal fluid secretion by stimulating a specific intestinal chloride channel (ClC2) in apical membrane No change in electrolyte concentrations in the serum hence safe for chronic use. |
|
What does Loperamide (immodium) do?
|
Slows transit time through colon
Increasing resorption of intestinal water |
|
What does Diphenoxylate w/ atropine (Lamotil) do?
|
Reduces transit time
Reduces intestinal muscle spasms Anticholinergic activity |
|
How do low dose antidepressants help in IBS?
|
Reduce the intensity of pain signals going from the gut to the brain.
|
|
What medications can reduce the pain and bloating associated with IBS?
|
Antispasmodics (dicyclomine, hyoscyamine) relieve abdominal pain by inhibiting smooth muscle contraction
5HT3 antagonists 5HT4 agonists Anti-depressants: TCA and SSRI's Antibiotics Probiotics |
|
What drug that was previously approved for WOMEN with IBS was taken off the market?
|
Alosetron- 5 HT3 antagonist- targets serotonin receptors in the gut. reduced visceral pain, slowed colonic transit
Side Effect: constipation; ischemic colitis Recently reintroduced after 12 week multicenter, randomized placebo study. Lowest dose most effective (0.5-1.0mg) with less risk of severe constipation. Approved only for women with severe IBS-D. |
|
What is Tegaserod Maleate?
|
5HT4 agonist
Stimulates intestinal motility via cholinergic transmission. Augments the peristaltic reflex Enhances intestinal secretion Reduces visceral hypersensitivity Removed from the U.S. market because of increased risk of serious cardiovascular adverse effects. |
|
Is there evidence that probiotics are effective in IBS?
|
Yes.
But so far only Bifidobacterium infantis 35624 |
|
What is ulcerative colitis?
|
A recurrent acute chronic inflammatory disorder with extensive ulcers of the colon and involvement of extracolonic sites.
1:10,000 No sex bias familial clustering Starts in rectum and extends proximally. Coalescing ulcers and progressive mucosal sloughing. Pseudopolyps. Acutely, neutrophils , cryptitis and crypt abscesses that coalesce to undermine mucosa. Marked goblet cell depletion. Chronically, branched and irregular glands. Increased plasma cells in the lamina propria (basilar plasmocytosis) and eosinophils. Unlike Crohn's disease, must include the colon and is mucosal based rather than transmural. Increases risk of adenocarcinoma of the colon. |
|
What percentage of Crohn's has colonic involvement? (granulomatous colitis)
|
~40%
|
|
What are the main pathological differences between granulomatous colitis (Crohn's) and ulcerative colitis?
|
Crohn's is segmental whereas UC is continuous.
Crohn's is predominantly right sided, UC is primarily left sided. Crohn's has rectal sparing in about 50% of cases.UC ALWAYS involves the rectum. Crohn's has minimal mucosal atrophy and regeneration with preserved mucin. Crohn's has TRANSMURAL lymphoid aggregates, non-casseating granulomas, edema and fissures (ulcers). |
|
What are the pathological characteristics of diverticular disease?
|
Hypertophy of taenia coli and circular muscle with flask shaped sacs of mucosa and submucosa protruding along the sides of the taenia.
Sigmoid involvement in 99% (44% exclusively) Descending colon in ~30% Entire colon in ~16% Complications include: Inflammation Pericolic abscess Hemorrhage |
|
What is a hyperplastic polyp?
|
Usually asymptomatic
Present in 30% of all colons Usually multiple. <5mm Normal looking but elongated crypts. Can be either penduculated (with a stalk) or sessile (no stalk). In cross section the polyp lumen has a star fish appearance. |
|
What is a juvenile polyp?
|
Found in children.
Completely benign. Most common in rectum. Pedunculated, focally ulcerated, smooth surface round polyp. Numerous cysts. |
|
What are colonic adenomas?
|
Most common true benign epithelial neoplasms in the colon.
Sharply circumscribed elevations of dysplastic premalignant epithelium. Pedunculated or sessile. Hyperchromasia.High N/C ratio. |
|
Why are adenomas important?
|
2/3 of adenocarcinomas arise from adenomas.
Size, histology and degree of dysplasia are all predictors of how it will develop. Over 2cm are very worrisome. Less than 1 cm= less than 1% risk. |
|
What is the 5 year survival of colonic carcinoma?
|
~45%
|
|
What are the two major gross appearances of colonic carcinoma?
|
Polypoid mass on the right side of the colon.
Circumferential napkin ring stricture on the left side. |
|
What is the worst variant of colonic carcinoma?
|
Mucinous aka colloid adenocarcinoma.
Worse prognosis than classic gland forming adenocarcinoma. |
|
What is the inheritance pattern for familial adenomatosis polyposis?
|
Autosomal dominant.
|
|
What is Lynch Syndrome (HNPCRC)
|
AD inheritance of colorectal carcinoma with young age at diagnosis, right sided predominance, & multiplicity
Associated with Kidd (18q 11-12) 8 times more common than FAP May be associated with “Flat” adenomas |
|
What are the two genetic pathways at play in colon cancer?
|
Suppressor Pathway:
Genetic changes in APC, beta-catenin, & TCF4-80% sporadic colon cancers FAP Mutator Pathway: Multiple genetic changes in DNA mismatch repair gene systemResults in microsatellite instability10-20% sporadic cancers- Many cases of CUC cancers |
|
What is the standard physiological response to blood loss?
|
Peripheral vasoconstriction
(cold, clammy skin) Diminished cardiac output (compensatory tachycardia and hypotension) Oliguria Orthostatic Hypotension (> 25-30% blood loss) Signs of shock (> 50% blood loss) |
|
How do we describe hematemesis?
|
Bright red (active hemorrhage)
Bright red with clots (mixture of active hemorrhage and older, clotted blood) “coffee grounds” (older blood that has completely clotted) |
|
What is melena?
|
Black, tarry, sticky, pungent stool.
Digested blood that has passed through the GI tract |
|
What is hematochezia?
|
Passing of bloody stools
Usually a mixture of bright red (or maroon) blood and clots. Usually lower GI bleed but !!upper GI bleeding can result in hematochezia!! |
|
What is the most common cause of upper GI bleeding?
|
Ulcerative or Erosive Disease (55%)
Peptic ulcer disease Esophagitis Pill induced (usually esophageal) |
|
What is a Dieulafoy’s lesion?
|
AV malformation characterized by a bleeding vessel with no surrounding ulcer.
|
|
Gastric Antral Vascular Ectasia (GAVE) is often termed....
|
“watermelon stomach”
|
|
What are Mallory-Weiss tears?
|
Tear of gastric and esophageal mucosa at the GEJ, usually after retching.
|
|
What is the most common cause of lower GI bleeding?
|
Diverticulosis (~33%)
Prevalence increases with age, 30% at age 60, 65% at age 85. Left>>right, though right sided disease accounts for the majority of bleeding. |
|
What is angiodysdplasia?
|
A rare cause of lower GI bleed (~8%).
Dilated tortuous submucosal vessels (usually veins) which can rupture. More common in elderly, and those with multiple medical problems. |
|
When does post polypectomy bleeding usually occur?
|
Can be immediate or delayed
(up to 10 days) |
|
What do hemotchezia and melena tell us about the location of a GI bleed?
|
Hematemesis and/or melena are usually signs of an upper GI bleed.
Hematochezia is usually a sign of lower GI bleeding. However, massive upper GI bleed can also cause this. |
|
What does NG tube aspirate tell us about an upper GI bleed?
|
Aspiration of bright red blood = active bleeding
Aspiration of clots and coffee grounds = bleeding may have stopped Aspiration of bile = may not be an upper GI bleed Duodenal bleeding may have a false negative NG lavage (if no blood refluxes into the stomach). Do not check gastroccult. It will almost always be positive due to the trauma of the NG tube being placed. |
|
What is unique about how we manage GI bleeds with regard to transfusion?
|
Transfuse blood based on hemodynamic status, not hematocrit initially.
After equilibration keep hematocrit > 30 in patients with vascular disease, >20 for others. Correct coagulapathy (fresh frozen plasma to keep INR < 1.5)) and thrombocytopenia (platelets if needed to >50,000) |
|
When do we start high dose PPI's in suspected upper GI bleeding?
|
As early as possible.
Decrease rebleeding rate Decrease hospital stay Decrease transfusion requirements Block gastric proton pumps (H-K-ATPase) in parietal cells and quickly (in high dose IV form) increase gastric pH. Allow more effective clotting in a more neutral pH Improved mucosal healing in a more neutral pH |
|
Apart from high dose PPI's, what other medical therapies should be initiated in upper GI bleeding?
|
Promotility agents (erythromycin IV) to increase gastric motility and improve visualization during upper endoscopy.
If it is a lower GI bleed, begin colon preparation with a orally administered polyethylene glycol (PEG) based saline lavage (e.g. Golytely). Check and treat H. pylori in patients with PUD. Usually with serum IgG. |
|
On endoscopy, what are considered high risk upper GI bleeding lesions?
|
Ulcers:
Actively bleeding Non-bleeding visible vessels Adherent clots Oozing without visible vessel Variceal hemorrhage |
|
On endoscopy, what are considered lower risk upper GI bleeding lesions?
|
Ulcers:
Pigmented spot Clean based Most other etiologies of upper GI bleeding are at low risk for rebleeding, assuming they are appropriately treated (e.g. Dieulafoy’s lesion, Mallory Weiss tears) |
|
What is endoscopic injection therapy?
|
Usually epinephrine
Effective in immediate hemostasis, but high risk of rebleeding |
|
What is the danger of using endoscopic thermal contact coagulation probes?
|
Can lead to perforation if used in thin walled organs (right colon).
|
|
What is endoscopic noncontact thermal therapy?
|
Argon Plasma Coagulation (APC)
Thermal energy is delivered via ionized argon gas. Coagulation is superficial. The probe does not touch the mucosa. Ideal for treating angiodysplasia, especially in the colon, and GAVE . |
|
How do we define endoscopic failure?
|
Recurrent hemorrhage after initial stabilization
(with up to two attempts at obtaining endoscopic hemostasis) Hemodynamic instability despite vigorous resuscitation (more than a three unit transfusion) Shock associated with recurrent hemorrhage Continued slow bleeding with a transfusion requirement exceeding three units per day. |
|
What options are there for GI bleeding intervention other than endoscopy?
|
Angiography with embolization:
Particularly effective in lower GI bleeding when the source cannot be identified endoscopically. Carries risk of infection, bleeding, damage to vessels, mucosal ischemia and necrosis (if not selective) Surgery: Usually reserved for endoscopic and/or angiographic failures Can entail oversewing (ligation) of the vessel, resection, vagotomy (decrease acid secretion). |
|
What is occult GI bleeding?
|
The initial presentation of a positive fecal occult blood test (FOBT) result and/or iron-deficiency anemia (IDA), when there is no evidence of visible blood loss to the patient or physician.
|
|
What are the possible etiologies of occult GI bleeding?
|
GI cancers (upper and lower)
Ulcers Esophagitis Angiodysplasia IBD Hemorrhoids And all other causes of GI bleeding |
|
How does fecal occult blood testing work?
|
Guiac (a natural compound found in certain trees) contains phenol which turns to a blue quinone mediated by a peroxidase (found in heme) in the presence of hydrogen peroxide.
Stool placed on one side of the card, the card is turned over and hydrogen peroxide is placed over the stool. Blue = positive test No color change = negative test |
|
What are the problems with fecal occult blood testing?
|
High false positive rate:
Must avoid NSAIDs and other irritant drugs Avoid red meat, turnips, and horseradish (all have peroxidase activity) Stool obtained from digital exams can be heme positive from trauma. Low sensitivity: Many lesions bleed intermittently and may be missed (though the test can detect as little at 10-20 cc of blood loss/day) Vitamin C can lead to a false negative test Poor public acceptance rate |
|
What is obscure GI bleeding?
|
Bleeding from the GI tract that persists or recurs without an obvious etiology after upper endoscopy, colonoscopy, and radiologic evaluation of the small bowel (such as by small bowel follow-through or enteroclysis).
2 subcategories: Obscure-overt – clinically evident GI bleeding (e.g. hematemesis, melena, hematochezia) Obscure-occult – clinically absent GI bleeding |
|
What are the etiologies of obscure GI bleeding?
|
Missed lesion on EGD or colonoscopy
Angiodysplasia Small bowel tumors NSAID enteropathy Meckel’s diverticulum Cameron’s lesion Dieulafoy lesion GAVE Hereditary hemorrhagic telangiectasia Celiac Sprue Crohn’s disease |
|
What areas of the world have the highest rates of colon cancer?
|
Highest incidence in North America, Australia, and Western and Northern Europe.
10 times higher incidence than Africa and Asia Thought to be due to genetics, diet, and environment. |
|
What are the major evidence based risks for colon cancer?
|
Age
Family history (20-25%) Inflammatory bowel disease |
|
What are the key genes identified as involved in the pathogenesis of colon cancer?
|
K-ras:
most frequent mutation of the ras oncogene in CRC this mutation effectively leaves the growth switch ON. Adenomatous Polyposis Coli (APC) gene: The most important tumor suppressor gene in CRC mutation of this gene leaves cell growth unchecked p53 gene: “the guardian of the genome” produces a DNA-binding protein that activates transcription of growth inhibitory genes. Mutation of this tumor suppressor gene can result in uncontrolled cell division. |
|
What is the difference in the pathogenesis of sporadic and inherited colon cancer at the level of the genome?
|
Sporadic colon cancer:
Results from stepwise occurrence of multiple somatic mutations APC – MMR – K-ras – p53 Inherited Colon Cancer Syndromes: Result from single germline mutations. FAP: APC gene HNPCC: MMR gene |
|
How does sporadic colon cancer develop?
|
APC – MMR – K-ras – p53
|
|
What are the variant forms of Familial Adenomatous Polyposis (FAP)?
|
Gardner’s Syndrome
Turcot’s Syndrome |
|
What are some alternative names for Hereditary Nonpolyposis Colorectal Cancer ?
|
HNPCC
Lynch Syndrome |
|
Give an example of a familial colon cancer syndrome that is not HNPCC or FAP.
|
Peutz-Jeghers Syndrome
|
|
So what exactly is FAP?
|
Autosomal dominant trait
germline mutation of the APC gene located on chromosome 5q21-q22 1/3 of cases represent new mutations (no family history) represents less than 1% of the total CRC risk clinical manifestations: more than 100 colorectal polyps polyps begin to develop in 2nd decade Average CRC diagnosis at age 39 compared with age 65 in the average US population. 100% will have colon cancer by age 45. Duodenal ampullary carcinoma. Variants of the disease include: Gardner’s Syndrome associated with extra-gastrointestinal tumors such as osteomas (bone tumors, mostly of skull and mandible) cutaneous tumors (fibromas, lipomas, epidermal cysts) desmoid tumors (most commonly in the abdomen) Turcot’s Syndrome: associated with brain tumors such as medulloblastoma and glioma. |
|
How do we manage FAP?
|
Phenotype identified endoscopically
Treatment: Total proctocolectomy Ileostomy Ileal-Pouch-Anal Anastamosis (IPAA) Timing depends on size and histology of polyps. Many can wait until completion of high school. |
|
What exactly is Hereditary Nonpolypsis Colorectal Cancer orLynch Syndrome?
|
Autosomal dominant germline mutations in DNA mismatch repair (MMR) genes.
more rapid adenoma-carcinoma sequence. average age of colon cancer diagnosis is age 48 60% lifetime risk of colon cancer predominance for the right side of the colon. synchronous and metachronous cancers are common: uterus (also ovary, stomach, small bowel, bile ducts, ureter) 80% overall cancer risk (colon + extra-colonic) Strongly consider colectomy with this diagnosis. Rectum can often be preserved. |
|
What exactly is Peutz-Jeghers Syndrome?
|
autosomal dominant
characterized by multiple pigmented spots on the lips and buccal mucosa. Associated with hamartomas: small bowel colon stomach Typically present in third decade with: intussusception obstruction bleeding Adenomatous change occurring in hamartomas, leading to the adenoma-carcinoma sequence. 15 fold increased risk of cancer in: colon stomach small intestine pancreas breast ovary lung |
|
What are the most common presentations of colorectal cancer?
|
40% abdominal pain
40% rectal bleeding or melena 40% change in bowel habit 20% weakness 10% anemia alone 5% weight loss Right colon lesions tend to present with blood loss. Left colon lesions tend to present with pain, altered BM. Patients presenting with pain have a worse prognosis. |
|
What are the best tests for the diagnosis of colon cancer?
|
Colonoscopy -
The best test to diagnose CRC. The best sensitivity and specificity. Allows biopsy of any lesions found. Detects any synchronous cancers and removal of any synchronous benign polyps. Barium Enema: 50% sensitivity Fallen out of favor. CT (routine): Poor sensitivity for intraluminal lesions. Main utility is to detect metastases (liver, lymph nodes) CT colonography: Sensitivity of up to 90% for CRC positive results require colonoscopy for biopsy. |
|
How do we stage colon cancer?
|
Stage 0-IV are based on TNM system with IV having the worst prognosis.
Tis: carcinoma in situ T1: invades submucosa T2: invades muscularis propria T3: invades through MP into subserosa T4: directly invades other organs, peritoneal space N0: no lymph node mets N1: mets in 1-3 regional nodes N2: mets in 4 or more regional nodes M0: no distant mets M1: distant mets |
|
How do we treat colon cancer?
|
Endoscopic polypectomy:
for Tis - T1, well-differentiated cancer in pedunculated polyps Surgical resection: for cure- 5 cm margins and regional lymphadenectomy required for flat polyps, T2 lesions, or if poorly differentiated. for palliation- of obstruction or bleeding. Chemotherapy for Stage III and IV disease: FOLFOX (FOLinic acid, Flourouracil, OXalipitin) Rectal Cancer: radiation and chemotherapy (5-FU) for Stage II and III |
|
What is pretty unique about colon cancer from a treatment standpoint?
|
Resection of mets can actually influence 5 year survival substantially.
Stage four disease with good functional status actually does better with Chemo than most other cancers. |
|
Average-risk screening for colon cancer begins at age 50 and can be done by...
|
Fecal occult blood testing q 1 year.
Flexible Sigmoidoscopy (FS) q 5 years. CT Colonography (CTC) q 5 years. Colonoscopy q 10 years. A positive test by any method gets a colonoscopy. |
|
What cancers are screened for in the U.S?
|
Cervical cancer.
Breast cancer. Colon cancer. |
|
How should a patient with a 1st degree relative with CRC age < 60 be screened?
|
Start at age 40, or ten years younger than the index patient, whichever comes first.
q 5 years |
|
How often should a patient with a personal history of colon adenoma
be screened for CRC? |
3-5 years
Use 3 year interval if > 1 cm, more than 2 polyps, villous, or high grade dysplasia |
|
How often should a patient with a personal history of colon cancer be screened for CRC?
|
1, 3, and 5 year interval
Then every 5 years thereafter; Looking for missed lesions and metachronous lesions. |
|
How often should a patient with a personal history of ulcerative colitis be screened for CRC?
|
Once a year.
Start after 8-10 years of pancolitis. |
|
How often should a patient with a personal history of colon adenoma
be screened for CRC? |
3-5 years
Use 3 year interval if > 1 cm, more than 2 polyps, villous, or high grade dysplasia |
|
How often should a patient with a personal history of colon cancer be screened for CRC?
|
1, 3, and 5 year interval
Then every 5 years thereafter; Looking for missed lesions and metachronous lesions. |
|
How often should a patient with a personal history of ulcerative colitis be screened for CRC?
|
Once a year.
Start after 8-10 years of pancolitis. |
|
What is the differential on bloody diarrhea in a young healthy person?
|
Infectious colitis
Inflammatory Bowel Disease Unlikely: ischemic colitis or malignancy |
|
Fecal culture usually reports...
|
salmonella,
shigella, campylobacter, yersinia, E. coli 0157 |
|
What ethnicity has the highest incidence of IBD in descending order?
|
Ashkenazi jews
Non-jewish caucasians African americans |
|
When is the peak age of IBD diagnosis?
|
20
Second much smaller peak again at around 60. |
|
How can ulcerative colitis be broken down into three sub categories based on distribution?
|
Ulcerative proctitis
Distal Ulcerative Colitis (left sided) Extensive Ulcerative Colitis (pancolitis) |
|
Bloody diarrhea in IBD is typically indicative of...
|
Colon involvement
|
|
Perianal disease is associated with...
|
Crohn's disease
|
|
What pattern does IBD follow?
|
Relapsing remitting.
|
|
What are some of the perianal complications of Crohn's?
|
Perianal fistulae and abscess.
|
|
What are some of the extraintestinal manifestations of IBD?
|
Skin disorders:
Erythema nodosum Pyoderma gangrenosum Joint disorders: Peripheral arthritis (> in large joints, no nodules and seronegative) Sacroiliitis Ankylosing spondylitis Ocular disorders: Iritis Uveitis (treat aggressively) Episcleritis Hepatobiliary: Gall stones Sclerosing Cholangitis Cholangiocarcinoma Renal: Renal stones Amyloidosis Other: Apthous stomatitis |
|
What are some IBD therapies?
|
Aminosalicylates:
5-ASA Steroids: Prednisone, budesonide Immunomodulators: Azathioprine/6-MP, methotrexate Biologics Anti-TNF therapy: Infliximab, adalimumab, certolizumab Surgery |
|
5-ASA drugs are approved for use in ulcerative colitis. Are they approved for Crohn's disease?
|
No.
But we often try them because they are very safe. |
|
Why is the steroid budesonide particularly well suited to Crohn's disease?
|
It is delayed release and releases in the small bowel where it is most needed.
Metabolized in the liver quickly which amounts to lower serum levels and systemic effects. VERY expensive drug though. |
|
How is Azathiprine related to 6-mercaptopurine (6-MP) ?
|
It is it's prodrug.
|
|
What infection is a patient on ant TNF therapy susceptible to?
|
TB
Also coccidiomycosis and histoplasmosis. |
|
How do we treat ulcerative colitis?
|
First line therapy is 5-ASA:
Oral and or rectal Steroids: Short course for bad flares Immunomodulators: Use for steroid-dependent UC Biologics: Failure of standard therapy |
|
How do we treat mild to moderate Crohn's disease?
|
Oral aminosalicylates
Budesonide |
|
What is the only drug that is technically FDA approved for mild to moderate Crohn's disease.
|
Budesonide
|
|
How do we treat fulminant ulcerative colitis?
|
IV steroids
IV infliximab IV cyclosporine Surgery |
|
How do we treat Moderate-Severe active Crohn's disease?
|
Prednisone:
short course only Immunomodulators: Azathioprine/6-MP Methotrexate Anti-TNF Therapy: Infliximab Certolizumab adalimumab |
|
What are the indications for surgery in ulcerative colitis patients?
|
Exsanguinating hemmorage
Toxicity and/or perforation Suspected cancer Significant dysplasia Growth retardation Sytemic complications Intractibility |
|
What are indications for surgery in Crohn's disease?
|
Failure to respond to medical therapy
Complication management: Strictures Fistulae Perforations Perianal disease Cancer or precursors |
|
If we see cysts in the pancreas of someone who has never had acute or chronic pancreatitis, we assume that they have...
|
Pancreatic cancer.
There is no reason they should have pseudocysts. |
|
What is another term for neuroendocrine lesions of the pancreas?
|
Islet cell neoplasms.
|
|
How do liver conditions affect the risk of hepatocellular carcinoma?
|
Any chronic liver disease increases the risk.
HepB (biggest risk worldwide) Hemochromatosis. Fatty liver (NASH). Hep C (biggest risk in U.S) HepA is acute so it does not increase the risk. HCC is the third leading cause of cancer death. Very common in asia and subsaharan Africa. HCC often unresponsive to treatment (serafonib) |
|
How do the risk factors affect the clinical course of hepatocellular carcinoma in various geographical regions?
|
Endemic regions (Asia/Africa): HBV carriers from infancy; HCC often occurs in persons ages 20-40
Western societies: Cirrhosis precedes HCC in 80-90%; risk factors include ethanol, HCV, HBV, any chronic liver disease such as hemochromatosis. |
|
What are the clinical features of hepatocellular carcinoma?
|
Often masked by cirrhosis; weight loss, malaise, abdominal pain/fullness, hepatomegaly
Serum alpha-fetoprotein: elevated in 50-70% cases (also elevated in chronic hepatitis, liver necrosis, cirrhosis, gonadal germ cell tumors) Imaging: Ultrasound, CT, MRI, angiography if surgical resection is considered Treatment: Complete surgical excision (before lung and nodal metastases) is only hope of cure 5 year survival all HCC: 5% (dismal) |
|
What screening tests do we use for hepatocellular carcinoma?
|
Imaging studies:
Ultrasound* Computed tomography No significant differences between spiral CT and MRI. Blood tests: Alpha-fetoprotein* (not all that sensitive or specific but still used) US screening strategy is q 6-12 months and AFP q 6 months is the most commonly used strategy in Asia and U.S. Rationale for 6-month screening interval: Median doubling time = 6 mo |
|
What is the most common presentation of hepatobiliary malignancies?
|
JAUNDICE!!!
|
|
What are the risk factors for gallbladder cancer?
|
Female sex
Age > 50 years Gallstones > 40 years (mostly cholesterol). High risk populations such as Native Indians, Chile Chronic cholecystitis Calcified GB (porcelain GB) Fat, Fertile, Forty, Female |
|
How do we treat gallbladder cancer?
|
Surgery:
Only chance for cure. Prophylactic cholecystectomy for asymptomatic gallstones not recommended, even if > 40 yrs Chemotherapy and Radiation: Poor response Palliation: ERCP for jaundice / pruritus Overall mean survival of 6 months 5%, 5-year survival Invasion usually local (contiguous spread) Palliative management If detected incidentally at time of cholecystectomy, then may survive long-term. |
|
What are the risk factors for cholangiocarcinoma?
|
Primary sclerosing cholangitis (PSC)-seen in IBD. (narrowing of the intra and extrahepatic ducts)
Basically anything that causes inflammation in the bile duct. |
|
What type of tumor is cholangiocarcinoma (aka klatzkin tumor if it is in the hilum)?
|
Adenocarcinoma (90%),
|
|
What is the typical presentation of cholangiocarcinoma?
|
Cholestasis:
Jaundice, pruritus, weight loss Hepatomegaly: ascites RUQ mass (late) Cholangitis is rare in cholangiocarcinoma and is usually caused by stones not tumors. |
|
How do we diagnose cholangiocarcinoma?
|
Labs:
Cholestatic obstructive LFTs Elevated serum CA19-9 (>100 U/ml) in 55-65% US: Dilated intrahepatic or extrahepatic duct; no mass detected CT: Dilated intra or extrahepatic ducts; usually difficult to identify mass lesion ERCP: Detect level of stricture Brush cytology (sensitivity 50-55%) Stenting for palliation or bridge to surgery. |
|
What are the risk factors for ampullary carcinoma?
|
Familial Polyposis
Ampullary adenoma |
|
How does ampullary carcinoma usually present?
|
Cholestatic jaundice
Pruritus Intermittent bleeding Cholangitis Pancreatitis Obstructive LFTs |
|
How do we treat ampullary carcinoma?
|
Important to distinguish from pancreatic cancer or cholangiocarcinoma
Surgical resection possible in 75% Pancreatoduodenectomy (Whipple’s) |
|
When will jaundice occur with pancreatic cancer?
|
Usually if the tumor is in the head of the pancreas.
|
|
Recent onset of diabetes or anorexia gets us thinking about...
|
Pancreatic cancer.
|
|
What is Courvoisier’s sign?
|
Palpable distended GB often associated with pancreatic cancer.
|
|
What are the CT resectability criteria for pancreatic cancer?
(not crucial for step 1) |
No extrapancreatic disease.
Unobstructed SMV-PV confluence. No tumor extension into Celiac or SMA. Clear fat plane between around Celiac and SMA. CT has 80% predictability using these criteria Despite this, 5 year survival <20% and median survival 15-17 months |
|
What are the cystic neoplasms of the pancreas?
|
Serous Cystadenoma (benign cyst):
Elderly women (>60); asymptomatic Large lesions; multiloculated , multicystic(honeycomb) Malignant transformation is rare. Intraductal Papillary Mucinous Neoplasm: Premalignant, seen in elderly men, pancreatic duct obstruction Mucinous Cystadenoma /carcinoma: 40-60 years of age. Unilobular or multilobular cyst containing mucin. Should be resected. Excellent prognosis if resected prior to carcinoma. |
|
What do we want to know about Pancreatic Neuroendocrine Tumors (Islet Cell neoplasms)?
|
Functional vs Non-functional
All endocrine tumors appear similar histologically. Immunos/peroxidase to distinguish subtype and biochemical data. Malignancy based on the presence of local invasion, spread to regional LN, or liver/distant mets. Inuslinoma, VIPoma,gastrinoma, glucagonoma, somatistatinoma. |
|
Relative to benign salivary gland tumors, salivary gland malignancies have a tendency to...
|
Grow more rapidly
To infiltrate superficial and deep tissues and thus be fixed; benign tumors are movable masses. Invade nerves producing, pain , parasthesias and CNVIII paralysis. |
|
In descending order, what are the most common salivary gland tumors?
|
Parotid (~80%):
Most often benign 9/2 Submandibular (~15%): About 1/3 are malignant Minor (~5%): About half are malignant. |
|
What are the two most common types of benign salivary gland tumors?
|
Pleomorphic Adenoma aka Benign mixed tumor. Well defined and encapsulated with collagen.
Warthin’s Tumor: Almost exclusively found in the parotid gland. Most common salivary glad tumor in elderly men. Most common tumor that shows up with a bilateral presentation. |
|
On gross pathology we can differentiate Warthin's tumors from pleomorphic adenoma bcause..
|
Pleomorphic adenoma has a solid glistening appearance.
Warthin's is cavitary with uneven polypoid projections.It also feels softer. |
|
What are the most common malignant tumors of the salivary glands?
|
Mucoepidermoid CA
Adenoid Cystic CA Polymorphous Low Grade CA Lymphoma |
|
Why is there bilateral parotid enlargement (Mikulicz’s) associated with Sjogren's syndrome?
|
Infiltration of lymphocytes.
Sometimes the minor salivary glands are biopsied in the lip looking for periductal lymphoid infiltrates. |
|
The inner mucosa of the esophagus is comprised of...
|
Nonkeratinizing stratified squamous epithelium;
Glandular epithelium in distal 1-2 cm |
|
What is the histological change that occurs in Barrett's esophagus ?
|
Epithelium goes from squamous to intestinal glandular in type.
|
|
The vast majority of carcinoma of the esophagus is...
|
Squamous cell carcinoma
|
|
What is the pathologist's diagnostic feature of eosinophillic esophagitis?
|
>20 eosinophils/HPF in mucosa
|
|
The overall 5 year survival of esophageal cancer (SCC + AC) is...
|
30%
|
|
What puts you at greater risk for esophageal SCC?
|
Food & water rich in nitrates & nitrosamines,
alcohol, tobacco, vitamin deficiencies, achalasia, Plummer-Vinson syndrome, erosive esophagitis with strictures, HPV, black men |
|
What is an increased risk for esophageal adenocarcinoma?
|
Barrett's Esophagus, (especially with high grade dysplasia which has a 50-66% risk)
White men |
|
What are acute stress ulcers?
|
Shallow ulcers.
Often multiple. Associated with hypotension. |
|
What are the different types of chronic gastritis?
|
Nonatrophic (H.pylori)
Multifocal atrophic Autoimmune Lymphocytic Viral (systemic, CMV) Granulomatous Reactive |
|
What type of organism is H. Pylori?
|
Gram negative spiral rod
Strong affinity for gastric surface epithelium Congregates near tight junctions & in mucus Produces urease, ammonia, acetaldehyde, phospholipases, toxins VacA & cagA, platelet activating factor Most common in developing countries. Occurs in children but less common in the U.S. |
|
What diseases are associated with H. Pylori infection?
|
Nonatrophic gastritis
Multifocal atrophic gastritis Peptic ulcers Gastric adenocarcinoma Gastric lymphoma Prevalence of nonulcer dyspepsia is similar with & without infection. |
|
What are the pathological changes of chronic non-atrophic gastritis?
|
Lymphoid follicles/nodules.
Expansion of Lamina propria by plasma cells Neutrophils in Lamina propria & epithelium of surface & pits. Erosions |
|
What is multifocal atrophic gastritis?
|
Multiple areas of chronic gastritis with marked glandular atrophy & intestinal metaplasia in fundus & antrum.
H.pylori infection acquired early in life. |
|
What is autoimmune gastritis?
|
Corpus restricted atrophic gastritis (not in the antrum) with serum anti-parietal cell & anti-IF antibodies, & IF deficiency, with or without pernicious anemia.
Iron deficiency anemia also common Risk factor for adenomas, adenocarcinoma, endocrine tumors Idiopathic |
|
Where are peptic ulcers most common?
|
Duodenum (~75%)
|
|
What are the two main types of gastric adenocarcinomas?
|
Intestinal (more common):
Mean age 55 3:1 M:F ratio H. Pylori association Polypoid gross appearance Gland forming histology Diffuse (more agressive): Mean age 45 1:1 M:F ratio Infiltrative gross appearance Signet ring cell histology |
|
What does partial gastrectomy do to gastric adenocarcinoma risk?
|
Increases it.
Stump carcinomas. |
|
Early gastric carcinoma is defined as...
|
Gastric adenocarcinoma confined to the mucosa and/or submucosa.
Prognosis is obviously better before the lymp nodes are involved. |
|
The most common site for extranodal non-hodgkins lymphoma is...
|
The gastrointestinal tract.
Stomach is primary site in 60-65% of GI NHLs Accounts for 5% gastric cancers Small intestine is primary site 20-35% Accounts for 25% of all small intestine cancers. The trend continues distally. Predisposing factors include H. pylori infection, celiac disease, CIBD, immune deficiency states. |
|
What are the different types of gastric lymphomas?
|
DLBC
Marginal Zone (MALToma): Associated with H.Pylori Burkitt's Mantle cell Follicular |
|
What are the histological features of gastric MALTomas?
|
Composed of small-medium sized tumor cells with slightly irregular nuclei & clear cytoplasm
Usually confined to mucosa & submucosa as diffuse infiltrate Lymphoepithelial lesions Colonized benign follicles Plasmacytoid features |
|
What are GI stromal tumors?
|
Most patients middle aged on older
M:F 1:1 65% in stomach; 30% in SI No known risk factors Interstitial cells of Cajal: pacemaker cells between autonomic nerves & smooth muscle Challenge of predicting behavior differs by location. Gleevec (c-Kit; CKD 117) |
|
What are predictors of malignancy in gastric stromal tumors?
|
Size >5 cm
MF count >5/50 hpf Invasion of LP Tumor cell necrosis Dense cellularity |
|
What are the normal changes that occur in hepatocytes with age?
|
Hepatocyte size varies more greatly.
Binucleation or multinucleation can occasionally be seen. |
|
What is chronic hepatitis?
|
A syndrome of hepatocyte necrosis and inflammation with varied etiology histologic, symptomatic and lab abnormailities.
Lasts longer than 6 months. |
|
What are the etiologies of chronic hepatitis?
|
Chronic hepatitis B
Chronic hepatitis D Chronic hepatitis C Autoimmune hepatitis Drugs Metabolic disorders Hep B and C most common. |
|
What are piecemeal and bridging necrosis in chronic hepatitis?
|
Piecemeal necrosis:
Periportal necrosis of hepatocytes and inflammation with disruption of the limiting plate and isolation individual cells. (most charcteristic of autoimmune hepatitis) Bridging necrosis: Zones of necrosis and inflammation extending from portal tracts to connect adjacent and/or central areas. |
|
The extent or severity of damage in the liver is referred to as..
|
Grading.
Grade 1: Inflammation restricted to portal tracts. No infiltration of liver parenchyma. Grade 2: Some infiltration of lobular parenchyma. Piecemeal necrosis at limiting plate. Grade 3: More inflammation than grade 2. Somewhat subjective. Grade 4: Bridging necrosis. Mononuclear cells replace hepatocytes. |
|
What are the normal changes that occur in hepatocytes with age?
|
Hepatocyte size varies more greatly.
Binucleation or multinucleation can occasionally be seen. |
|
What is chronic hepatitis?
|
A syndrome of hepatocyte necrosis and inflammation with varied etiology histologic, symptomatic and lab abnormailities.
Lasts longer than 6 months. |
|
What are the etiologies of chronic hepatitis?
|
Chronic hepatitis B
Chronic hepatitis D Chronic hepatitis C Autoimmune hepatitis Drugs Metabolic disorders Hep B and C most common. |
|
What are piecemeal and bridging necrosis in chronic hepatitis?
|
Piecemeal necrosis:
Periportal necrosis of hepatocytes and inflammation with disruption of the limiting plate and isolation individual cells. (most charcteristic of autoimmune hepatitis) Bridging necrosis: Zones of necrosis and inflammation extending from portal tracts to connect adjacent and/or central areas. |
|
The extent or severity of damage in the liver is referred to as..
|
Grading.
Grade 1: Inflammation restricted to portal tracts. No infiltration of liver parenchyma. Grade 2: Some infiltration of lobular parenchyma. Piecemeal necrosis at limiting plate. Grade 3: More inflammation than grade 2. Somewhat subjective. Grade 4: Bridging necrosis. Mononuclear cells replace hepatocytes. |
|
In the context of chronic hepatitis, staging refers to....
|
The amount and distribution of collagen containing connective tissue and fibrosis.
Often requires trichrome stain to evaluate. Stage 1: Little or no increase in fibrosis. Stage 2: Slight increase in connective tissue away from the portal tracts towards the central veins. Stage 3: Strand or bands connecting portal tracts to portal tracts or portal tracts to central veins or both. Stage 4: Cirrhosis. Hepatocytes form round nodules AND circumferential bands of collagen. |
|
A dead heaptocyte that is brilliantly eosinophillic with a very pale nucleus is reffered to as...
|
Acidophil body
|
|
The characteristic appearance of liver tissue in hepatitis C is....
|
Clear little round wholes from nodular enlargement of the portal tracts.
Not diagnostic but highly characteristic. |
|
What are the main categories of alcoholic liver disease?
|
Fatty liver
Central (perivascular) necrosis Alcoholic hepatitis (Steatonecrosis) Cirrhosis |
|
Trichrome stains are designed to highlight...
|
Collagen
|
|
Hyaline in swollen cells is highly characteristic of...
|
Alcoholic hepatitis.
Not commonly seen but highly characteristic. There is also: hepatocyte necrosis centrilobular ballooning Neutrophillic infiltrates Fatty change Perivenular and sinusoidal fibrosis |
|
What exactly is cirrhosis?
|
Requires two microscopic features.
Nodules,Thick cell plates AND Bands of fibrosis that completely encircle the regenerative nodules. Involves the entire liver parenchyma. Can be classified based on nodule size: Micronodular Macronodular Mixed Can also be classified by etiology. |
|
What are the causes of cirrhosis in descending order of incidence?
|
Alcoholic liver disease (~65%)
Viral hepatitis Biliary diseases Hemochromatosis Cryptogenic or idiopathic. |
|
What is autoimmune hepatitis?
|
Chronic, genetically predisposed (HLA8,DR,DR4) liver disorder.
More comon in women (85%), with autoantibodies & a good response to immunosupression. Defect in suppresor T cells Antibodies vs hepatocytic surface. Type 1 (adults): ANA & ASMA (antic nuclear antibody and anti smooth muscle antibody) Type IIa (pediatrics) : ALKM (anti liver kidney microsomal antibody) |
|
What are the pathological findings of autoimmune hepatitis?
|
Gross:
normal-shriveled-cirrhotic Chronic inflammation: portal & periportal lymphocytes & prominent plasma cells Piecemeal necrosis Scattered acidophil bodies Sinsusoidal fibrosis |
|
What is primary biliary cirrhosis or PBC?
|
Chronic nonsuppurative duct destruction with progressive cholestasis & cirrhosis.
Attack on the bile ducts is probably autoimmune. Antimitochondrial autoantibody is definining; directed at E2 of pyruvate dehydrogenase 90% women Onset typically 40-60 yrs. Rare entity in children. Gross: slightly enlarged & bile stained to green cirrhosis Destructive cholangitis of interlobular & septal ducts Damage to duct BM, intraductal lymphocytes & plasma cells, epithelial cell damage & regeneration. Florid duct lesion (rare but characteristic): granulomatous &/or severe lymphocytic infiltrates Lobules generally normal |
|
What is alpha-1-antitrypsin deficiency?
|
Autosomal recessive (codominant) disorder with low serum A1AT levels
A1AT is major protease inhibitor, especially of neutrophilic enzymes, eg. elastase ~75 forms of A1AT; most are normal PiS: low serum levels; no disease PiZ: 10% normal levels; most common form with disease Emphysema Liver effects: Cytoplasmic inclusions in periportal hepatocytes 10-20% affected have cholestatic hepatitis of infancy with ductal and hepatocytic cholestasis & portal lymphocytic infiltrates 20% cirrhosis in mid life 2-3% Hepatocellular carcinoma |
|
The portal vein is derived from a confluence of the...
|
splenic vein and superior mesenteric vein.
~75% of blood flow to the liver comes from the portal vein |
|
What tests truly measure liver function?
|
Protein Synthesis:
Albumin PT / INR Total protein SPEP/Globulins T-bilirubin Cholesterol |
|
What tests are indicators of hepatobiliary disease?
|
Aminotransferases:
AST ALT Lactate dehydrogenase Alkaline phosphatase GGT 5’ Nucleotidase |
|
What are the three major functions of the liver?
|
Powerplant (gluconeogenesis):
Glucose Fatty acids (Also produces bile to absorb fats) Manufacturing plant: Proteins involved in transport Proteins involved in coagulation (vitamin K dependant factors II, VII, IX and X) Waste management plant: RBC breakdown. |
|
What are AST and ALT?
|
Intracellular aminotransferring enzymes in the process of gluconeogenesis.
Aspartate Aminotransferase (AST) (Aspartic acid ->Oxaloacetic acid) Alanine Aminotransferase (ALT) (Alanine->Pyruvic acid) AST is both cytosolic and a mitochondrial isoenzyme ALT is a cytosolic enzyme Present in large quantities in hepatocytes. "Leak” in serum secondary to hepatocyte injury / death. Elevation in many forms of liver disease. Highest in those with severe hepatocyte necrosis. AST is NOT specific to the liver and is found in muscle too. |
|
What are the relative levels of AST and ALT in liver disease?
|
ALT should be relatively higher.
If not, consider extrahepatic etiology. |
|
Does degree of AST and ALT level correlate with prognosis?
|
No.
Also correlates poorly with extent of necrosis. But serial measurements can be of value eg. Fulminant hepatitis Rapid AST & ALT fall with rising bilirubin and PT can mean poor prognosis. |
|
How does the degree of elevation of AST and ALT help in forming a differential diagnosis?
|
< 500 IU can be many disorders but
>2000 IU has a relatively limited differential. >2000IU: Drugs or toxins, viruses or ischemia |
|
What are some causes of acute or toxin induced hepatitis?
|
Acetaminophen
Halothane Amanita mushrooms CCl4 Very High Levels ( > 2000 IU/L) of aminotransferases. |
|
How does the time course over which aminotransferases rise to >2000IU/L help us diagnostically?
|
Ischemia is the most rapid.
Viral/drug elevations can take weeks to months. |
|
AST/ALT ratio > 2:1 suggests...
|
Alcoholic Hepatitis
>3:1 is even more specific Mainly reflects low ALT level Alcohol-related deficiency of pyridoxine. CAUTION, In these patients: AST & ALT should be < 300 IU/L If AST > 500 IU/L we have to rule out a co-existing cause such as: Acetaminophen toxicity Viral hepatitis |
|
How do we identify alcoholic liver disease?
|
The history is the key – 60 grams/day
Alcoholic cirrhosis is associated with: Gynecomastia, parotid hypertrophy, dupuytren’s contracture of the palmar fascia. Alcoholic hepatitis: RUQ pain anorexia fever jaundice RUQ tender hepatomegaly Abnormal LFTs leukocytosis Treatment for alcoholic hepatitis: Abstinence Nutrition Consider prednisolone or pentoxifylline |
|
LDH elevation occurs in...
|
Liver, acute & chronic
Muscle injury Skeletal Cardiac Hemolysis CVA Kidney infarction Very non-specific and therefore rarely useful in addition to aminotransferases. Occasionally helpful in diagnosing Ischemic hepatitis (massive elevation) or malignant infiltration (sustained elevation). |
|
What are alkaline phosphatases?
|
Group of enzymes that function best at pH 9.
Located mostly on the cannalicular membrane in hepatocytes and on the luminar membranes of bile duct epithelium. Also seen in bone and placenta (high in pregnancy or bone disease like paget's) Normal levels of these are age dependent. |
|
Transaminase means the same thing as...
|
Aminotransferase
|
|
What enzymes are found on the cannalicular membrane but NOT in bone?
|
We order these with a high alk. phos.
to detemine bone or liver origin. GGT or 5' nucleotidase. If one of these is also high, liver problem. If it's not, bone is a more likely cause for the elevated Alk. Phos. GGT is inducible by EtOH & drugs |
|
What affects albumin levels?
|
Liver synthesizes 10 g/day
Liver disease=decreased synthesis However, Serum ½ life is ~ 20 days so no change in acute liver injury and not useful to follow progress. Levels also influenced by: Nutritional status Volume status Vascular integrity Increased catabolism Urinary losses |
|
What does prothrombin time (PT/INR) tell us about liver function?
|
Coagulation factors are synthesized in the liver but not factor VIII (vascular endo / reticuloendo)
Liver disease can cause increased INR in one of two ways: Synthetic: Acute or chronic liver failure Cholestatic: Biliary obstruction The two can be distinguished with a therapeutic dose of vitamin K. If the INR corrects, the liver is fine. Keep in mind a prolonged INR can also mean: Vitamin K deficiency (malabsorption, malnutrition, antibiotics) Warfarin (Coumadin) DIC |
|
What are the fat soluble vitamins?
|
A,D,E,K
|
|
What are the best scoring systems for liver function?
|
Chil-pugh criteria
and MELD score for liver transplant priority. MELD is based on bilirubin INR and creatinine. Child-pugh also takes into account albumin, ascites and encephalopathy. |
|
High can billirubin result from...
|
Overproduction of billrubin
(hemolysis or a big hematoma getting resorbed) Liver dysfunction A specific liver enzyme deficiency. An excretion problem like a bile duct obstruction. |
|
Wher does UDP glucoronyl transferase conjugate biilrubin carried by ligandin after it is delivered to the liver by albumin?
|
The rough ER of the hepatocyte.
|
|
Where does conjugated billirubin exit the hepatocyte?
|
Into the cannliculus
|
|
A normal billirubin level is ~...
|
1.2
Neurotoxic at about 20-25 Phototherapy for physiological jaundice of the newborn is initiated at about 12. |
|
What is breast milk jaundice?
|
Breast milk contains an enzyme called beta glucoronidase which can deconjugate billirubin.
When this happens we stop the breastfeeding for a while until serum levels resolve. |
|
What is Gilbert's syndrome?
|
An inherited autosomal disorder which affects up to 10% of caucasians.
Characterized by a low UDP glucoronyl transferase activity level. Exacerbated by fasting or recurrent illness. |
|
Typically we start seeing jaundice with an unconjugated billirubin of about...
|
3
|
|
What do we see in the urine of a patient with Gilbert's syndrome?
|
Billirubin is not seen in the urine because it is highly bound to albumin.
|
|
What is Criggler Najjar syndrome?
|
Autosomal recessive.
Another defect in UDP glucoronyl transferase. In type II Criggler Najjar syndrome, the enzyme is inducible with phenobarbitol. |
|
What is Dubin Johnson syndrome?
|
UDP glucoronyl transferase is fine but the transport proteins of the cannalicular membrane are dysfunctional.
Mixed hyperbillirubinemia. |
|
In pure billirubin metabolism disorders, AST, ALT and Alk. Phos. should be...
|
Normal.
High indirect billirubin and normal to high direct billirubin. Particularly with Gilbert's. |
|
Hepatocellular disorders with high billirubin are characterized by very high...
|
AST/ALT
|
|
Cholestatic disorders with high billirubin are characterized by very high...
|
Alk. Phos.(ALP)
|
|
Why does transfusion cause hyperbillirubinemia?
|
RBC's lyse in the bag and during the transfusion.
|
|
Which diseases cause a predominantly hepatocellular lab picture?
(primarily AST and ALT abnormalities on a blood test) |
Viral hepatitis (A,B,C,D,E)
Alcohol Medication-induced liver disease Ischemic liver injury Nonalcoholic Steatohepatitis (NASH) Autoimmune hepatitis Hemochromatosis Wilson’s disease Alpha-1 Antitrypsin Deficiency Acute Fatty Liver of Pregnancy |
|
Which conditions create a cholestatic picture on labs?
(primarily Alk. Phos.) |
Extrahepatic bile duct obstruction
(Choledocholithiasis, Pancreas cancer, cholangiocarcinoma) Primary sclerosing cholangitis Primary biliary cirrhosis Intrahepatic cholestasis (Medication-induced, TPN, sepsis, post-op Intrahepatic cholestasis of pregnancy) Infiltrative disorders (Sarcoid, amyloid, infection, neoplasm) |
|
Spider angiomata (blanchable spider veins) on the skin can be an indication of...
|
Cirrhosis
|
|
Why can Cirrhosis cause splenomegaly?
|
Portal hypertension.
|
|
What is the algorithm for managing a jaundiced patient?
|
|
|
What are the three major forms of inherited liver disease?
|
Hemochromatosis
Wilson's disease Alpha 1 antitrypsin disease |
|
What is the leading cause of inherited Cirrhosis in children?
|
Alpha 1 antitrypsin disease
Hemochromatosis is most prevalent in adults because it manifests later. |
|
How much iron is stored in the liver?
|
Body content of iron ~ 4 g;
~ 1 g is stored in hepatocytes |
|
About what % of the iron we ingest do we actually absorb?
|
~10%
|
|
How is iron absorbed?
|
DMT1 – Absorbs iron from gut
Iron is stored bound to ferritin Iron is pumped into blood via Ferroportin Ceruloplasmin converts Fe2+ ->Fe3+ In blood, iron is transported bound to transferrin Transferrin receptor 1 (liver & other tissues) clears the iron-Transferrin complex. Iron is stored in hepatocytes bound to ferritin. Iron from phagocytosed red cells is stored in macrophages. Amount of iron in circulation is controlled by the expression of Ferroportin. |
|
What is the acts as the iron sensor in the body?
|
The hepatocyte
Sensor is made of HFE, transferrin receptor-2 and hemojuvilin. If there is excess iron, these iron sensors increase expression of the HAMP gene and secretion of its gene product (Hepcidin). Hepcidin bind to and inhibits Ferroportin activity and expression. The effect is that Intestinal iron absorption is blocked; iron stays stored bound to ferritin in macrophages and iron homeostasis is restored. |
|
What is hemochromatosis?
|
Autosomal dominant
Early and progressive expansion of the plasma iron storage compartment. Progressive parenchymal iron deposition. Nonimpaired erythropoiesis. Responds to phlebotomy. Defective Hepcidin synthesis or activity. Most common defect is in hepatocyte iron sensing due to bad HFE protein. |
|
In hemochromatosis, where is the excess iron coming from?
|
More is absorbed in the GI tract AND more is liberated from destruction of RBC's
|
|
Where are the main parenchymal sites iron deposits in hemochromatosis causing symptoms?
|
liver
heart pancreas endocrine glands |
|
What mutations in the HF gene cause hemochromatosis?
|
2 major mutations:
Cysteine 282->tyrosine (C282Y) Histidine 63->aspartic acid (H63D) C282Y: homozygosity produces major clinical manifestations. Highly prevalent in individuals of Northern European descent, rare in Arica and Asia; frequency of C282Y homozygotes is ~1/250 for Anglo-Celic-Nordic population. |
|
When do clinical manifestations of hemochromatosis usually become evident agewise?
|
Typically seen in males in their 40’s-50’s and females in their 60’s
(curve is shifted in women as a result of iron loss due to menses & childbirth) |
|
What are some of the clinical manifestations of hemochromatosis?
|
Liver:
Abnormal liver function tests Cirrhosis Hepatocellular carcinoma Cardiac: Cardiomyopathy Arrhythmias Joint: Arthropathy Endocrine: Diabetes mellitus Testicular atrophy Pituitary (gonadotropin insufficiency) Other: Skin bronzing Weakness or lethargy Impotence in men Other findings include: Hepatomegaly, splenomegaly, & other complications of chronic liver disease such as ascites, edema, and jaundice. Serum aminotransferase elevations are usually mild. |
|
The what is the classic diagnostic triad of hemochromatosis and other iron overload disease?
|
cirrhosis, diabetes, and skin pigmentation (“bronzed diabetes”)
rare now due to increased awareness of HH. Earlier diagnosis and treatment. |
|
What x-ray finding suggests hemochromatosis?
|
Arthropathy
(iron accumulation in joint tissues) Changes in the 2nd and 3rd metacarpophalangeal joints most common. |
|
What x-ray finding suggests hemochromatosis?
|
Arthropathy
(iron accumulation in joint tissues) Changes in the 2nd and 3rd metacarpophalangeal joints most common. |
|
What is increased in a hemachromatosis patient's labs?
|
Fe increased
Transferrin saturation increased Ferritin is increased TIBC will be decreased. |
|
On a hemochromatosis liver biopsy with prussian blue stain, which cells do NOT contain iron?
|
The resident macrophages
(kupffer cells) |
|
Why is liver biopsy important in hemochromatosis?
|
Important to document if cirrhosis is present since this affects the prognosis.
Patients treated before development of cirrhosis have a normal life expectancy. |
|
How do we treat hemochromatosis?
|
Perform phlebotomy of 500 mL (1 unit) of whole blood weekly
until hematocrit value drops below 37%. ( 1 unit ~ 200-250 mg iron) The iron-chelating drug deferoxamine can be used in those patients who cannot tolerate phlebotomy. Monitoring: Check transferrin saturation and ferritin levels at 2- to 3-month intervals to monitor response (optional). Maintenance Once iron stores are depleted (serum ferritin <50 ng/mL; transferrin saturation <50%), proceed to maintenance phlebotomy of 1 unit of whole blood every 2 to 3 months. Aim to keep transferrin saturation <50%; if successful, ferritin should remain <50 ng/mL.. |
|
What symptoms of hemochromatosis are reversible?
|
Reversible:
Cardiac dysfunction, glucose intolerance, hepatomegaly, skin pigmentation. Irreversible: Cirrhosis, arthropathy, hypogonadism, risk of hepatocellular carcinoma. |
|
What is Wilson's disease?
|
Rare inherited metabolic, copper accumulation in liver and brain
Prevalence ~ 1:30,000 (carrier state 1: 90) Autosomal recessive disease caused by mutation in ATP7B gene (> 300 mutations) Defective biliary excretion of copper; copper overload affects multiple organs. Commonly presents with liver or neurological symptoms Variable age of onset for symptoms (usually 6 - 40 years of age) Undiagnosed and untreated is generally fatal by age 30 Early diagnosis and treatment can yield almost complete recovery with normal life Treated with chelating agents or zinc (rarely with liver transplant) |
|
What enzymes is copper an essential cofactor for?
|
Cytochrome-c oxidase,
superoxide dismutase, Catechol oxidase, Protein-lysine 6-oxidase, Ceruloplasmin, Dopamine-α-monooxygenase |
|
What are good dietary sources of copper?
|
oysters, liver, crab, shrimp, cod, yeast, olives, hazelnuts, whole wheat bread, peas
|
|
Copper is transported in the blood primarily by...
|
ceruloplasmin (>95%),
albumin (<5%) We absorb about 50% of what copper we ingest. Major site of storage is lever. Excreted in the bile (major) and urine (minor). |
|
So the actual defects of wilson's disease are...
|
Inability to mobilize copper for incorporation into ceruloplasmin.
Inability to mobilize copper to the bile cannaliculus for secretion into bile. Deposition of copper in various tissues thus occurs. |
|
What are the typical initial presentations of Wilson's disease?
|
40% liver disease
35% neurological 15% psychiatric 10% endocrine, renal cardiac, hematological |
|
What are the manifestations of Wilson's disease?
|
Liver:
Abnormal liver function tests Acute hepatitis Acute hepatic failure Liver disease with hemolysis Chronic hepatitis Cryptogenic cirrhosis CNS: Parkinson-like disorders with dystonia and tremors Psychiatric disorders Eye: Kayser-Fleischer rings Sunflower cataracts Kidney: Fanconi syndrome with hypouricemia Bone: Osteopenia Joint Arthropathy |
|
How do we diagnose Wilson's disease?
|
Measure serum ceruloplasmin
(< 20 mg/dL) Measure serum free copper (> 25 mcg/dL)* Measure 24 h urinary Copper excretion (> 40 mcg) Slit lamp exam (Kayser-Fleischer rings) Liver biopsy for histology or quantitative copper measurements. Serum free copper = total copper – [serum ceruloplasmin (in mg/dL) x 3] |
|
How do we treat Wilson's disease?
|
Chelation (Penicillamine or trientine) plus pyridoxine
Zinc Avoid high copper foods Liver transplantation* (*with acute liver failure or end-stage liver disease) Monitoring: Kayser-Fleischer rings Urinary copper excretion Serum free copper levels (non-ceruloplasmin-bound) Results: Prevents disease when begun early Improves liver and CNS disease Prolongs life |
|
What is alpha 1 antitrypsin deficincy?
|
Common inherited metabolic disease causing lung + liver disease
Most common genetic cause of liver disease in children Prevalence of deficiency allele combinations ~ 1:490 (North America); Severe deficiency ~1:3500 live births (more common in Caucasians; rarely found in African Americans or Asians) Autosomal recessive disease Caused by mutations in α1-antitrypsin gene (SERPINA1) α1-AT binds and inactivates neutrophil elastase and other serine proteases; Α1-AT is the major serine protease inhibitor in blood α1-AT alleles are also called Protease inhibitor (Pi) alleles. Most common Pi alleles associated with disease: PiS, PiZ |
|
What happens when when serum α1-AT drops below ~ 11 µM?
|
Risk of pulmonary emphysema rises.
Serum α1-AT levels do not strictly correlate with risk of liver disease. Disease phenotype is defined by the serum levels and alleles Liver disease is associated with PiZ allele (lysine to glutamic acid at AA342) |
|
By what mechanisms does alpha 1 antitrypsin disease cause COPD and liver disease?
|
Absence of α1-AT is the primary mechanism for premature development of pulmonary emphysema or COPD in affected patients.
Liver disease is caused by accumulation of misfolded α1-AT protein. (Z isoform) |
|
In (α1-AT) disease, the bad genotype to have is...
|
PiZZ
|
|
How do we treat α1-Antitrypsin (α1-AT) Disease?
|
No specific therapy is currently available (avoid alcohol, smoking, weight gain and obesity)
Treatment of complications of liver and lung disease Hepatocellular carcinoma surveillance. Transplantation (cures the liver and lung disease) α1-AT infusions (treats the lung disease - emphysema) Family screening |
|
What is the diagnostic algorithm for alpha 1 antitrypsin disease?
|
|
|
What type of virus is hepatitis A?
|
ssRNA picornavirus (hepatovirus)
|
|
The majority of chronic viral hepatitis is caused by...
|
HCV
|
|
What explains the outbreak nature of HAV?
|
It is shed in stool long before antibody titers are positive.
Young kids don't get jaundice and thus continue attending school, daycare etc. Very Few <6 get jaundice About half from 6-14 get jaundice Majority >14 get jaundice. |
|
What are the clinical sequelae of hepatitis A?
|
Acute hepatits can be come:
Cholestatic hepatitis Relapsing hepatitis Protracted hepatitis Fulminant hepatitis (pt. can die) |
|
Is the vaccine for Hep. A effective?
|
Yes
|
|
What kind of virus is hepatitis B?
|
DNA virus of the hepadnavirus family.
Multiple serotypes. Reverse transcription in liver and other tissues. |
|
How long after infection with HBV do you start seeing surface antigen?
|
~1 month
Increased ALT is earlier indicator. Jaundice usually does not appear until about 8 weeks. |
|
How do we make a diagnosis of HBV?
|
+ surface antigen
AND +Anti core (Anti HBc) |
|
What do the various results on HBV serology mean?
|
Acute HBV:
HBSAg + and HBcAb IgM + Resolved HBV: HBcAb IgG+ and HBSAb+ Chronic HBV: HBSAg+ and HBCAb IgG+ HBV vaccinated: HbSAb + only |
|
Who is at greatest risk with the carrier state of HBV?
|
Neonates.
Risks diminishes with age. |
|
Who is at greatest risk of HBV through sexual contact?
|
Heterosexuals
|
|
How prevalent is HBV in asian populations?
|
VERY.
50 % of HBV infected persons are infected from maternal perinatal transmission /early childhood family exposure. About 1 in 4 Asians are infected 2/3 Asian men are asymptomatic and unaware they are infected. Lifetime risk of liver cancer if infected is 1 in 4. Screening asymptomatic Asians for HBV is essential. This is a highly cost-effective and necessary strategy Prolonged immunotolerance phase, prolonged immune clearance phase A Chinese study indicates that 20% of infected persons < age 25 have advanced fibrosis. Liver cancer is listed about # 9 on priority list, but HBV is still not on the WHO list for priority concern which is almost criminal. |
|
How are acute and chronic HBV different in terms of transplant?
|
Acute results are much better because of no immune tolerance
|
|
The goal of HBV treatment is to...
|
Prevent cirrhosis.
Prevent hepatocellular carcinoma. |
|
How do we treat HBV?
|
Prolonged administration of nucleoside analogues is mainstay.
Currently available and approved are: lamivudine, adefovir, telbivudine, tenofovir, entecavir. Pegylated interferon sometimes used at initiation of treatment. Must be managed by an expert, as drug resistance is emerging threat and guidelines constantly changing. Current guidelines available: AASLD, EASL, APASL. Generally these are updated yearly. |
|
How does one acquire hepatitis D infection?
|
Coinfection:
Simultaneous introduction oh HBV and HDV Superinfection: Introduction of HDV into HBsAg + host. |
|
What type of virus is hepatitis C?
|
ssRNA
|
|
How do we test for HCV?
|
RNA shows up much earlier (day 12) than antibodies (day70) so we usually test for that.
Only about 15 % will be symptomatic. Viral RNA will not be present until after 10-24 days. All will seroconvert to anti-HCV positivity, but there is a 70 day delay. |
|
What is the main mode of transmission of HCV?
|
IV drug use.
|
|
What is the natural history of acute HCV?
|
15 % will spontaneously resolve
15% of remaining chronic HCV patients will develop Cirrhosis. 25% of those with chronic HCV will go on to HCC, transplant and or death. |
|
How do we treat HCV?
|
Peg Interferon Alpha + Ribavirin
|
|
What type of virus is hepatitis E?
|
RNA
|
|
How is hepatitis E transmitted?
|
Fecal-oral
Water borne Food born Mollusk associated |
|
Which patients with hepatitis E are at increased risk of fulminant hepatitis and consequently death..
|
Pregnant women
|
|
How do we diagnose autoimmune hepatitis?
|
Hypergammaglobulinemia (IgG)
Female gender most common Autoantibodies: Positive: ANA, ASMA, anti-LKMNegative: AMA, HLA DR3 or DR4 Negative for markers for viral hepatitis Positive response to treatment |
|
How do we treat autoimmune hepatitis?
|
Prednisone alone, prednisone & azathioprine, and azathioprine alone are effective in improving 2-year survival.
Prednisone with azathioprine preferred. Relapse rate is 50 - 86 % if treatment is stopped. Typically, patients remain on therapy indefinitely, with prednisone taper. Excellent prognosis. |
|
What is primary billiary cirrhosis?
|
50-60 % asymptomatic at Dx
9:1 Female-male ratio Peak onset 5th decade, rare < 25 years age Organ-specific autoimmune attack Highest incidence, Northern Europe. Range 40-400/million population 1/6 have an affected family member Fatigue 21 %, Pruritus 19 %, RUQ discomfort 10 %, Fatigue severity unrelated to severity of liver disease. Majority of asymptomatic patients develop symptoms by 4 years; 1/3 stay asymptomatic for years. |
|
How do we diagnose primary billiary cirrhosis?
|
Detectable AMA (antimitochondrial antibody) in serum
LFT changes, with primarily SAP elevation All 3 above:definite Dx; 2/3 above:probable Dx IgM elevation typical, even when AMA negative; course the same if AMA neg. AMA positivity > chance of later PBC Physical exam: Normal if asymptomatic Melanin skin pigment, excoriations, spiders. Xanthelasma in 5-10 %; tendon xanthomas rare. Hepatomegaly in 70 % Splenomegaly, ascites, late Typical liver biopsy includes granulomas. |
|
How do we treat primary billiary cirrhosis?
|
Ursodiol at 13-15 mg/kg is mainstay of therapy
Liver transplantation for treatment failures |
|
What is sclerosing Cholangitis
|
A chronic progressive disease, characterized by inflammation, fibrosis, and stricturing, of the medium intrahepatic and large extrahepatic bile ducts.
Etiology remains unknown, but proposed mechanisms include portal bacteremia, toxic bile acid metabolites (more lithocholic acid B/C of increased 7-alpha dehdroxylation of cheno by bacteria), toxin production by enteric bacteria, chronic viral infections, ischemic vascular damage, and altered genetic immunoregulation. |
|
What other disease is primary sclerosing cholangitis associated with
|
Overwhelming majority of PSC patients have IBD. Ulcerative colitis > Crohn’s disease.
Estimates 75-90 % As worldwide incidence of Crohn’s increases, PSC seen more commonly with Crohn’s PSC may have temporal discordance with PSC (PSC can develop decades after colectomy; UC can develop after liver transplant) |
|
What clinical findings are typical of primary sclerosing cholangitis?
|
Most are asymptomatic at Dx
Fatigue, pruritus Fever indicates secondary bacterial cholangitis Persistent jaundice with advanced disease Cholestatic liver enzymes, with primarily SAP elevation Increased gamma globulins (30%, with IgM 40-50%); + pANCA (30-80%); + DRw52A in widely varying %; AMA universally negative 70% of affected patients are men |
|
How do we diagnose primary sclerosing cholangitis?
|
Multifocal stricturing of intrahepatic +/- extrahepatic bile ducts.
Most have extrahepatic bile ducts involved. ERCP and MRCP are comparable. Pancreatic duct involvement in 10% Liver biopsy confusing and rarely diagnostic; most helpful in small duct PSC (pericholangitis) |
|
What is the natural history of primary sclerosing cholangitis?
|
Generally a progressive disease, with median survival 10-12 years
Survival worse if symptomatic at Dx Mortality risk increased with jaundice, advanced fibrosis on Bx, splenomegaly, age, and Mayo risk score Transplant alters survival, obviously Despite “general” progression, some cases spontaneously remit and are not progressive |
|
Summarize a good way to discern between autoimmune hepatitis, primary billiary cirrhosis and primary sclerosing cholangitis.
|
|
|
Which autoimmune liver disease carries substantial risk of cholangiocarcinoma?
|
Primary sclerosing cholangitis.
|
|
What is Non-Alcoholic Steatohepatitis (NASH)?
|
Most common liver disease.
More common in women (75%) Associated with Obesity DM II, Hyperlipidemia (TG and/or cholesterol) Diagnosis: AST/ALT < 1, exclude other causes, U/S, liver bx Treatment: no proven therapy treat associated conditions |
|
How do we define fulminant hepatic failure?
|
Rapid development of hepatic dysfunction.
No prior history of liver disease. Hepatic encephalopathy. |
|
How much acetominophen is toxic?
|
Danger dosages (70 kg patient)
Toxicity possible > 10 gm Severe toxicity certain > 25 gm Lower doses potentially hepatotoxic in: Chronic alcoholics Malnutrition or fasting Dilantin, Tegretol, phenobarbital, INH, rifampin NOT in acute EtOH ingestion NOT in non-alcoholic chronic liver disease. |
|
What is the pathogenesis of acetominophen toxicity?
|
Day 1:
Nausea, vomiting, malaise, or asymptomatic Day 2 – 3: Initial symptoms resolve AST and ALT begin to rise by 36 hours RUQ pain, tender enlarged liver on exam Day 4 AST and ALT peak > 3000 Liver dysfunction: INR, encephalopathy, jaundice Acute renal failure (ATN) |
|
How do we treat acetominophen toxicity?
|
Activated charcoal if < 4 hours from ingestion.
Administer as a single dose 1 mg/kg PO or NG Does not adversely effect NAC efficacy N-Acetylcysteine (NAC): 140 mg/kg loading dose PO or NG 70 mg/kg q 4 hours PO or NG X 17 doses Continue longer until INR < 2.0 and improved OK to DC if acetaminophen levels undetectable and normal AST at 36 hours. |
|
What are the etiologies of portal hypertension?
|
Prehepatic:
Portal Vein Thrombosis Intrahepatic: Presinusoidal-schistosomiasis. Sinusoidal-Cirrhosis and infiltrative disorders. Postsinusoidal-Veno-Occlusive Disease Posthepatic: Budd-Chiari Syndrome (clots in the hepatic vein), Right Heart Failure, Constrictive Pericarditis |
|
What clinical clues suggest cirrhosis?
|
Physical Examination:
Jaundice Hepatomegaly !Splenomegaly! !Ascites! Edema Spider angiomata Palmar erythema Gynecomastia Asterixis Laboratory Tests: !Thrombocytopenia! Hypoalbuminemia Prolonged PT Hyperbilirubinemia Imaging: Nodular liver Splenomegaly Ascites Large collaterals At the end of the day, cirrhosis is a biopsy diagnosis. |
|
How do we measure portal hypertension?
|
We don't.
There is no non-invasive way to do this. |
|
What are the three major complications of portal hypertension?
|
GI bleeding
Ascites: Spontaneous Bacterial Peritonitis Hepatorenal Syndrome Encephalopathy |
|
In portal hypertension, the increased pressure is not only as a result of increased resistance in the liver but also because of ....
|
Increased splanchnic blood flow.
|
|
Esophageal varices in portal hypertension are fed primarily by which vessels?
|
The coronary vein coming off the portal vein on the lesser curvature of the stomach.
AND The short gastric coming off the splenic vein on the greater curvature. |
|
What causes GI bleeding in the setting of portal hypertension?
|
esophageal varices (most common)
gastric varices portal hypertensive gastropathy much less common: rectal stomal anastomotic |
|
What is a normal portal vein pressure?
|
5 – 10 mm Hg
Portal Vein Pressure Necessary For Variceal Hemorrhage is > 12 mm Hg |
|
How can we treat portal hypertension?
|
Beta blockers to decrease cardiac output.
Portocaval shunt, TIPS Medication for dealing with splanchnic vasodilation. Esophageal variceal band ligation. Acute therapy: Octreotide Endoscopic therapy Minnesota tube TIPS Prevention (Primary vs. Secondary): Beta-blocker Endoscopic therapy TIPS |
|
What are the most important primary prevention guidelines for esophageal varices hemmorage?
|
Screening EGD for the diagnosis of esophageal and gastric varices is recommended when the dx of cirrhosis is made.
If varices are large, nonselective B-blockers (like propranolol and natolol) or esophagela variceal band ligation are recommended for prevention of EVH. |
|
What is TIPS?
|
Low resistance tunnel through the liver.
Portocaval shunt done non-surgically with a stent. Secondary prevention of esophageal variceal hemmorage. |
|
How do we treat an acute GI bleed in cirrhosis?
|
Avoid vigorous volume resuscitation with saline.
Transfuse pRBC to maintain Hb of 8 gm/dl. Octreotide should be given in all cases of suspected EVH and continued for 3-5 days if EVH is confirmed by EGD. Antibiotics should be given for 7 days.(norfloxacin and ciprofloxacin) EGD should be performed within 12 hours, and if EVH confirmed, EVL (ligation) should be performed. TIPS is indicated when octreotide and EVL fail to control EVH. Balloon tamponade should be used as a temporizing measure for uncontrollable bleeding until EVL or TIPS can be done. |
|
What is considered secondary prevention for EVH?
|
Patients who survive acute variceal hemorrhage should receive therapy to prevent recurrent EVH.
Combinations of nonselective B-blockers plus EVL is the best option for secondary prophylaxis of EVH. |
|
In descending order, what are the causes of ascites?
|
Chronic liver disease (by far)
Malignancy Heart failure TB Miscellaneous |
|
What exactly is ascites?
|
Accumulation of fluid in the peritoneal space
500 cc before clinically evident Differential diagnosis: Portal Hypertension Malignant ascites, nephrotic syndrome, TB SAAG = Serum albumin – Ascites albumin (> 1.1 in portal hypertension) |
|
What portal vein pressure is required for ascites?
|
> 12 mm Hg
|
|
What are the two main mechanisms of ascites?
|
Increased hydrostatic pressure from portal hypertension with decreased oncotic pressure from decreased albumin.
AND Activation of the renin-angiotensin system for Na and water retention. |
|
How do we make a physical diagnosis of ascites?
|
flank dullness
shifting dullness fluid wave These correlate best with the gold standard (ultrasound), but 1500 cc needs to be present. Ultrasound can detect as little as 100 cc of ascites. Ascites is unlikely in the absence of lower extremity edema. Always remember to check neck veins in any patient with new-onset ascites. |
|
How do we treat ascites?
|
2 gram Na diet
(most important part) 1000 cc fluid restriction only if Na<130 Avoid NSAID Lasix 40 mg/d (160 mg/d max) Spironolactone 100 mg/d (400 mg/d max) Large Volume Therapeutic Paracentesis: Consider IV albumin if removing > 5 liters to protect kidneys TIPS |
|
What is spontaneous bacterial pertitonitis?
|
A complication of ascites that is pretty much unique to cirrhotic ascites. Very rarely seen in malignant or cardiac ascites.
Ascitic fluid infection without an evident intraabdominal surgically treatable source. Bacterial translocation: Bacteria traverse colon wall and colonize lymphatics. Small lymphatic vessels rupture into ascites. Bacteria move from lymphatics into systemic circulation. Diagnosis based on ascites fluid culture and ascites fluid PMN > 250 cells/mm3 |
|
What organisms cause SBP?
|
E. Coli (vast majority)
Klebsiella S. pneumo Alpha hemolytic strep Group D strep Other strep Enterobacteriacae Others |
|
How do we treat SBP?
|
Patients with ascites PMN>250 should receive cefotaxime.
All patients with suspected SBP should also receive IV albumin to save kidneys. Mortality is 20-50%. |
|
How do we prevent SBP?
|
All cirrhotic patients with GI bleeding should be given antibiotics for 7 days.
norfloxacin or ciprofloxacin. Patients who have survived an episode of SBP should receive long-term prophylaxis with daily norfloxacin or trimethoprim/sulfamethoxazole (bactrim). |
|
What is hepatorenal syndrome?
|
Advanced chronic or acute liver failure with portal hypertension
Serum Cr > 1.5 or 24 hour CrCl < 40 Absence of shock, infection, massive GIB, massive renal fluid loss, nephrotoxic drugs No sustained improvement in renal function with 1 mg/kg of IV albumin for 2 days Less than 500 mg/dl proteinuria and no u/s evidence of obstruction or parenchymal dz |
|
What are the pulmonary complications of portal hypertension?
|
Hepatopulmonary syndrome:
Increased A-a gradient Liver disease Evidence of IPVDs ; intrapulmonary vascular dilations (shunts) Platypnea Portopulmonary syndrome: Pulmonary Hypertension in the setting of Portal Hypertension Patients present with DOE, syncope, chest pain Contraindication for liver transplant. Hepatic Hydrothorax |
|
What is hepatic hydrothorax?
|
Pleural effusion of >500 cc in patients with cirrhosis and no underlying cardiac or pulmonary disease.
Likely cause is passage of ascites fluid through small defects in the diaphragm. Because of negative intrathoracic pressure, most patients have only mild ascites. Usually unilateral right-sided effusion (85%) Typical symptoms: dyspnea, cough |
|
How doe treat hepatic hydrothorax?
|
Just like ascites.
2 gram Na diet 1000 cc fluid restriction only if Na<130 Avoid NSAID Lasix 40 mg/d (160 mg/d max) Spironolactone 100 mg/d (400 mg/d max) Large Volume Therapeutic Thoracentesis (Consider IV albumin if removing > 5 liters) TIPS |
|
What is Hepatic Encephalopathy (HE)or Portosystemic Encephalopathy (PSE)?
|
A syndrome of reversible brain dysfunction in the setting of significant liver disease
Pathogenesis likely multifactorial Endogenous toxins: ammonia Inhibitory neurotransmitters: GABA Decreased hepatic clearance of ammonia due to liver dysfunction, portosystemic shunts. Dx: History- sleep disturbance (insomnia/hypersomnia) lethargy, somnolence, confusion, coma. Exam- asterixis (liver flap), hyperreflexia, fetor hepaticus (ammonia breath smell) Laboratory- BMP, drug screen, ammonia CT head |
|
How do we treat hepatic encephalopathy?
|
Lactulose is the treatment of choice, dosed to achieve 2-3 soft bowel movements daily. Can be used in enema form.
Antibiotics: rifaximin, metronidazole, or neomycin Correct precipitating factors. Consider safety issues like driving |
|
What should we do for cirrhosis patients in terms of hepatocellular carcinoma?
|
Patients at high risk for HCC should be entered into a surveillance program.
Ultrasound every 6-12 months. |
|
How much bile does the liver make a day?
|
0.5L -1L
|
|
What is the pH of bile?
|
~8
Isotonic with plasma. |
|
What kind of control is the release of bile under?
|
Chemical -
Bile salts stimulate hepatic bile flow Neural - Gall bladder contraction is controlled partially by nervous (vagal) stimulation. Hormonal - Cholecystokinin (CCK) released by the duodenal mucosa strongly induces gall bladder contraction Fibroblast Growth Factor 19 (FGF19) stimulates gallbladder filling. |
|
What sort of substances are excreted in bile?
|
cholesterol, bilirubin, steroid hormone conjugates, metal cations (iron and copper), drug conjugates
|
|
By % weight, what makes up bile?
|
Water 82 %
Bile salts 12 % Phospholipid 4 % Cholesterol 1 % Other 1 % |
|
What are the major functions of bile salts?
|
Induce bile flow and biliary lipid secretion
Aid in fat solubilization and absorption (Essential for cholesterol and fat-soluble vitamin absorption) Major route for cholesterol elimination (Regulation of cholesterol metabolism) Anti-bacterial actions in the gut (Prevention of small bowel bacterial overgrowth) Prevent formation of Gallstones and kidney oxalate stones Act as hormones to regulate lipid and glucose metabolism |
|
Bile is actually an admixture of three secretions. What are they?
|
Hepatocyte Bile salt-dependent
Hepatocyte Bile salt-independent Ductular secretion Most bile flow is bile salt dependent though which means that bile salts are secreted as free ions and provide the osmotic pull for H20 and electrolytes to move into the canalicular space. |
|
Why is it important that bile salts are amphipaths?
|
Above their critical micelle concentration, bile salts form micelles that “solubilize” and carry fat-soluble substances such as
cholesterol, fat-soluble vitamins (A, D, E, K), long chain fatty acids The solubility of cholesterol in bile is 2 million-fold greater than its solubility in water |
|
What problem does bile solve in the intestine?
|
Unstirred water layer (100-500 µm) acts a diffusion barrier for hydrophobic molecules.
This reduces their effective concentration at the plasma membrane. Bile salts form mixed micelles with cholesterol to increase its aqueous solubility. This increases the rate of cholesterol absorption > 100-fold. |
|
How are bile salts synthesized?
|
Bile salts are synthesized from
cholesterol in the liver. Bile salts are synthesized first as steroid acids. The primary bile salts synthesized by the liver are: Cholic acid 3 OH groups More hydrophilic AND Chenodeoxycholic acid 2 OH groups More hydrophobic ~ 40% of total cholesterol removal occurs via its conversion to bile salts. |
|
What is the function of bile salts in antimicrobial defense?
|
Proximal Intestine:
Direct bacteriostatic actions of bile salt/fatty acid mixed micelles. Distal intestine: Bile salts act as a hormone to induce expression of anti-microbial factors by binding to the FXR receptor. |
|
How do bile salts prevent enteric hyperoxaluria and formation of kidney oxalate stones?
|
Oxalate in food (such as spinach, rhubarb, swiss chard, mixed nuts) usually precipitates as calcium oxalate in the intestinal lumen and is lost in the stool.
In the absence of bile salts, long chain fatty acids stay in the lumen of the intestine and compete with oxalate for the available calcium. This blocks calcium oxalate formation and allows more dietary oxalate to be absorbed and ultimately excreted by the kidney. This ‘enteric’ hyperoxaluria can lead to formation of calcium oxalate kidney stones. Enteric hyperoxaluria should be considered in patients with: any form of chronic diarrhea inflammatory bowel disease pancreatic insufficiency primary biliary cirrhosis short bowel syndrome after bariatric surgery |
|
What are the concentrations of bile salts in the various compartments?
|
Gallbladder 50-200 mM
Small Intestine 5 - 10 mM Portal Blood ~0.02 mM Peripheral Blood < 0.01 mM |
|
What are the general properties of bile salt circulation?
|
Total bile salt pool 3 - 5 g
Cycles 2-3 times per meal 6-10X/day Intestinal reabsorption 20-30 g/day Bile salt loss < 400 mg/day Intestinal (Ileal) absorption of bile salts is > 95% efficient. |
|
Which four categories can disorders of bile salt synthesis and cycling be divided into?
|
1.
Primary Defects in Bile Salt Formation (synthesis and conjugation) 2. Primary Defects in Membrane Transport (uptake and secretion) 3. Disturbances involving Bacterial Transformation (deconjugation & dehydroxylation) 4. Disturbances in Movement Through or Between Organs (bile salt circulation) |
|
How do primary Defects in Bile Salt Formation (synthesis and conjugation typically present?
|
Rare congenital disorders.
Most commonly present as cholestasis or hepatitis. 3α-hydroxy-C27-steroid dehydrogenase deficiency: Neonatal Hepatitis Bile acid conjugation defect: Neonatal cholestasis, fat-soluble vitamin deficiency. Cerebrotendinous xanthomatosis (CTX) : Progressive neurological dysfunction. |
|
What are some examples of Primary Defects in Membrane Transport (bile uptake and secretion)?
|
Rare congenital disorders.
Progressive Familial Intrahepatic Cholestasis Types 1, 2, 3: Caused by mutations in hepatic canalicular transporters for bile salts and phospholipids. Primary Bile Acid Malabsorption: Caused by mutation in the ileal bile acid transporter. |
|
What are Disorders of Bile Salt Synthesis and Cycling involving bacterial transformation (increased deconjugation and dehydroxylation)?
|
Small Intestinal Bacterial Overgrowth
Common cause of chronic diarrhea Increases bile salt deconjugation and dehydroxylation. Deconjugated secondary bile salts (deoxycholic acid, lithocholic acid) are less soluble than conjugated primary bile salts. These bile acids will precipitate from solution and be excreted in the feces. The soluble bile salt concentration needs to stay above ~ 2 millimolar in order to efficiently absorb fats and fat-soluble vitamins. Small intestinal bacterial overgrowth -> increased bile salt loss & fat malabsorption (steatorrhea). |
|
Conditions associated with bacterial overgrowth include....
|
Blind loop (Billroth II gastrectomy, end-to-side anastomosis)
Small intestinal diverticulosis Small intestinal stricture (Crohn's disease) Diabetes Idiopathic intestinal pseudo-obstruction Scleroderma Acid-lowering medications Atrophic gastritis Vagotomy Gastrocolic or enterocolic fistula Resection of ileocecal valve Celiac sprue Chronic pancreatitis Chronic renal failure Cirrhosis Old age Rheumatoid arthritis Radiation enteritis |
|
What conditions cause disturbance sin bile salt circulation?
|
Biliary obstruction
(stones in biliary tract or gallbladder; biliary tract carcinoma) Biliary Fistula (after biliary trauma) and Gallstone ileus Cholecystectomy (only small effect on bile salt metabolism) Cholestasis: Primary Biliary Cirrhosis, Primary Sclerosing Cholangitis, drug induced cholestasis, intrahepatic cholestasis of pregnancy, biliary atresia. Ileal Resection (particularly > 100 cm of small bowel) Short Bowel Syndrome Crohn’s disease (Inflammatory Bowel Disease) |
|
What is cholesterol saturation index?
|
Ratio of molar % of cholesterol in bile to maximum micellar solubility of cholesterol.
If CSI > 1.0 - Cholesterol precipitates out of solution and forms crystals. Bile salts prevent gallstone formation by: Solubilizing cholesterol in mixed micelles Binding Ca++ to prevent formation of calcium bilirubinate, or calcium salts of phosphate, carbonate, or palmitate (insoluble precipitates) (calcium bile salts stay soluble) |
|
What three factors contribute to the formation of goal stones?
|
Hypomotility
Super saturation Nucleation |
|
What are the requisites of optimal nutrition?
|
Access and ingestion
Digestion and absorption Metabolic utilization |
|
How many amino acids are essential?
|
10
|
|
What are the essential fatty acids?
|
Linoleic acid (18:2)
alpha linolenic acid (18:3) |
|
How much is a calorie in clinical nutrition?
|
1000 "physics" calories
hence the capital C or kcal designation |
|
How much energy does each nutrient provide/ gram?
|
CH 4
Prot 4 Fat 9 EtoH 7 |
|
What is the average USA diet comprised of?
|
Carbs 45%
Protein 20% Fat 35% |
|
Glycogen is stored in ...
|
Liver and muscle
|
|
What accounts for the amount of energy we need?
|
Resting energy expenditure ~60%
Thermic effect of food is ~10% Activity energy expenditure is ~30% |
|
Which organs contribute substantially to resting energy expenditure?
|
Liver 29%
Brain 19% Muscle 18% heart 10% Kidney 7% |
|
Resting energy expenditure is dependent upon...
|
fat free mass
|
|
Energy balance in broad terms is....
|
Intake-TEE (total energy expenditure)
TEE= Activity Energy Expenditure (AEE) + Thermic Effect of Food (TEF) + Resting Energy Expenditure (REE) REE= The sum of basal metabolic energy expenditure and sedentary activities REE is proportional to Fat Free Mass, (because fat is metabolically inert) |
|
Intake may be determined indirectly and directly by...
|
Indirectly:
Dietary recall Food diaries Directly: Prepared controlled portions In a research ward |
|
How do we measure TEE (totoal energy expenditure)?
|
Double labeled water
TEE calculated from isotopic clearance Direct calorimetry. TEE determined directly as heat production. Indirect calorimetry. Respiratory quotient. Most useful. |
|
How do we estimate total energy expenditure?
|
harris benedict formulas:
(♀) = 655 + 9.5WKg + 1.9Hcm - 4.7A (♂) = 66 + 13.8WKg + 5.0Hcm - 6.8A Uses weight height and activity. Doesn't work if really skinny or really fat. |
|
To maintain positive N balance we need...
|
Adequate amino acids
AND Ample caloric intake |
|
The most common primary neoplasm of the liver is...
|
Hepatocellular carcinoma.
Associated with Cirrhosis Less common in the U.S than africa and asia. Strongest correlation with viral hepatitis and hemochromatosis. Male predominance (~85%) Elevated AFP in most. Survival in U.S median 6 months. Cells resemble hepatocytes in a sheet like pattern but with a larger nucleus an therefore increased N/C ratio. Sometimes trabeculae. |
|
What is the most common neoplasm of the liver?
|
Most are adenocarciomas, often arising in LI, lung, breast, & pancreas;
others include other lung cancers, sarcomas, & melanomas In a series of 8455 autopsies of cancer patients, 39% had liver metastases; of these, only 6% were solitary. |
|
What is the most common pancreatic cancer?
|
Adenocarcinoma of the ductal system aka ductal carcinoma
~90% of all true neoplasms of the pancreas. Risk factors: tobacco and high fat diet Patients usually have advanced disease at presentation. Weight loss and abdominal pain most common presentations. 90% of patients are noresectable. 5 year survival 1%. Median survival six months. False positive by biopsy is very rare. |
|
What are the genetics of ductal carcinoma?
|
!Mutations in codon 12 of K-ras oncogene in nearly 100%; occurs early!
Abnormalities in p16 in most; mutations or hypermethylation of promoter. DPC4 (Smad4) mutations in 55% TP53 mutations in 50% |
|
Ductal carcinoma is often preceded by...
|
Pancreatic intraductal neoplasia.
(PanIN) Spectrum of premalignant changes in ductal epithelium, with mucinous metaplasia the earliest & CIS the most developed. Although most resected organs with ductal carcinoma have PanIN, natural hx is unknown Most have genetic abnormalities of ductal CA, especially K-ras mutations. International grading system: 1A: mucinous metaplasia 1B: tufting & nuclear stratification 2: greater proliferation & loss of polarity with mild-moderate cytologic atypia 3: greater nuclear irregularities & mitotic figures |
|
Abdominal pain that radiates towards the back is characterize of...
|
Ductal carcinoma of the pancreas.
|
|
What are the characteristics of islet cell tumors?
|
There really are not any because manifestations are so diverse.
Sometimes secretion of hormones Non-functional mass Minority have multiple tumors. !!not possible to tell benign from malignant under the microscope!! |
|
What are Intraductal Papillary-Mucinous Neoplasms of the pancreas?
|
5% of pancreatic tumors;
80% in head 7th-8th decade; nonspecific symptoms Localized or multicentric Endoscopy: mucin extrusion Radiology: duct ectasia (dilation) Carcinogenesis different from that of ductal CA (some overlap) Intraductal neoplasia: benign to malignant cytology, papillae & mucin Assciated Invasive carcinoma in 35%;ductal or colloid types but with far better prognosis than ductal carcinoma. Surgery; 75% 5 yr survival |
|
What are Intraductal Papillary-Mucinous Neoplasms of the pancreas?
|
5% of pancreatic tumors;
80% in head 7th-8th decade; nonspecific symptoms Localized or multicentric Endoscopy: mucin extrusion Radiology: duct ectasia (dilation) Carcinogenesis different from that of ductal CA (some overlap) Intraductal neoplasia: benign to malignant cytology, papillae & mucin Assciated Invasive carcinoma in 35%;ductal or colloid types but with far better prognosis than ductal carcinoma. Surgery; 75% 5 yr survival |
|
At what stage does the liver develop?
|
Liver appears during 4th week of gestation as diverticulum arising from duodenum.
Cranial portion forms parenchymal tissue and bile ducts, Caudal portion forms gallbladder and cystic duct. |
|
How do we define pathological jaundice?
|
Conjugated fraction comprises more than approximately 20% of total.
|
|
What are the extrahepatic causes of cholestasis in children?
|
Biliary Atresia.
Choledochal cyst. Spontaneous perforation of the bile duct. |
|
What is billiary atresia?
|
Progressive disease characterized by dynamic fibroobliteration of the bile ducts. (inflammatory process)
Occurs in a range of 1 in 8000 to 25000 live births In some cases associated malformations occur Embryonic or fetal type: Approximately 34% of cases. More commonly associated with other abnormalities Perinatal type: Approximately 66% of cases. Later onset of jaundice. Theories: Ductal plate abnormality Failure of recanalization Infantile obstructive cholangiopathy Ischemic insults Abnormal bile acid metabolism Immunologic dysfunction Jaundice often not apparent until 3 to 5 weeks of life. Acholic (bile pigment) stools present. Liver firm and enlarged. Elevated alkaline phosphatase. |
|
What form of cholestasis in children is associated with giant cell hepatitis?
|
Idiopathic
|
|
What are choledochal cysts?
|
Cystic dilation of billiary tree.
Leads to cholestasis. Predisposes to infection. Very rare. 1/3 diagnosed before 1 year. More common in females. Increased risk of carcinoma. |
|
How does the pancreas develop?
|
Originates as dorsal bud and two ventral buds
The left ventral bud atrophies Rotation of stomach and duodenum with elongation carries right ventral bud posteriorly Fusion of right ventral with dorsal bud completes head and uncinate process |
|
What is annular pancreas?
|
Hypertrophy of normal pancreatic tissue
Fusion of heterotopic pancreatic rests Failure of left ventral bud atrophy Failure of free rotation of right ventral bud |
|
How does annual pancreas present?
|
Symptoms may present at any age. Approximately 50% in pediatric age
Vomiting (mostly billious) Peptic ulceration Abdominal pain Jaundice Associated with other congenital defects |
|
How do we diagnose annular pancreas?
|
Evidence of duodenal obstruction on plain abdominal film(double bubble effect)
Sonographic evidence Barium studies demonstrating duodenal filling defect ERCP and laparotomy |
|
How do we manage annular pancreas?
|
Surgical intervention mandatory in cases with obstruction.
Recommended approach is a bypass operation, preferably duodenoduodenostomy. |
|
What is ectopic pancreas?
|
Presence of pancreatic tissue lacking anatomic and vascular continuity with the main body of pancreas.
70-90% occurs in the upper GI tract mostly in gastric antrum. Usually incidental finding. |
|
What is Pancreas Divisum?
|
Refers to abnormality resulting from incomplete fusion of dorsal and ventral pancreatic ductal systems.
Dorsal duct functions as main drainage system but opens into smaller accessory papilla. Development of pancreatitis. |
|
What is common channel syndrome?
|
Anomalous junctions of common bile duct and main pancreatic duct.
The presence of a long common channel with pancreaticobiliary junction located outside of duodenal wall associated with pancreatitis and choledochal cyst. Reflux of pancreatic juice. |
|
What is the bile binding resin Colesevalam used for?
|
Type 2 diabetes (insulin resistance)
Off label use: Bile salt malabsorption-associated diarrhea Cholestasis-associated pruritus. |
|
UDCA (ursadiol) is a bile salt used to treat....
|
Primary billiary cirrhosis
Gall bladder stones |
|
CDCA (chenodiol) is a bile salt used to treat...
|
Cerebrotendinous xanthomatosis
|
|
Cholestyramine can be used to treat...
|
Hypercholestrolemia
|
|
With what bile salts do we treat inborn errors of bile synthesis?
|
CDCA-CA-UDCA mixtures
Life saving and curative |
|
What is the difference between Cholelithiasis and Choledocholithiasis?
|
Cholelithiasis=GB stones
Causes Biliary Colic and Acute !Cholecystitis! Choledocholithiasis=CBD stones Causes Biliary Colic and Acute !Cholangitis! |
|
Cholelithiasis is...
|
Gallbladder stones
|
|
Cholecystitis is...
|
GB infection/inflammation
|
|
Choledocholithiasis is...
|
Common bile duct stones
|
|
Cholangitis is..
|
Common bile duct infection/inflammation
|
|
What types of stones can cause cholelithiasis?
|
Cholesterol (> 50% cholesterol) = 80%
Brown pigment: (Calcium Bilirubinate & Palmitate) ->INFECTION secondary to biliary sepsis Black pigment (Calcium Carbonate & Phosphate) ->Hemolysis (Sickle Cell Disease) cirrhosis/alcoholism |
|
What are risk factors for gall stones?
|
Obesity (>30% over IBW)
Female gender Ethnicity: Native American Hispanic Total parenteral nutrition Rapid weight loss Pregnancy Age (>40) (fat, fertile, forty) |
|
What effects do stones in various parts of the gallbladder have?
|
Cystic duct=cholecystitis
Infundibulum (neck)= Billiary colic Gall bladder body =asymptomatic (also fundus) |
|
How does cholelithiasis/biliary colic typically present?
|
Rarely symptomatic
85% asymptomatic Stone impacts cystic duct temporarily blocking it Classic symptoms: RUQ Radiates to back or shoulder 1-2 hours post prandial Fatty meals classic Pain crescendos then plateaus and slowly subsides. Can be associated with nausea and vomiting. |
|
What are the diagnostic options for biliary colic?
|
Abdominal ultrasound
Computed Tomography Nuclear study Ultrasound is test of choice for suspected cholelithiasis. Sensitivity >90% Specificity >90% CT: High specificity but poor sensitivity |
|
What nuclear study is available for cholelithiasis?
|
Hepatobiliary Scintigraphy.
Good to detect cystic duct obstruction ->Acute cholecystitis. NOT GOOD for detecting GB stones. |
|
What is acute cholecystitis?
|
Gallbladder wall inflammation with fever, leukocytosis, and acute RUQ pain.
Prolonged or recurrent cystic duct obstruction leading to GB wall inflammation. Not completely understood Minimal AST/ALT elevation, T Bili slightly elevated. Normal amylase/lipase Classic Murphy’s sign (Palpation of the RUQ upon inspiration induces pain) |
|
How do we diagnose acute cholecystitis?
|
clinical features
Ultrasonography: 88% sensitive, 80% specific Nuclear studies: 97% sensitive 90% specific for cystic duct obstruction CT: Typically required only if complicated cholecystitis is suspected. |
|
How do biliary colic and acute cholecystitis differ in management strategy?
|
Biliary colic:
Elective surgery Acute Cholecystitis: Early surgery (Dx can be made on clinical features alone and does not require imaging) |
|
What are the symptoms of choledocolithiasis?
|
Symptoms similar to biliary colic
Typically associated with elevations of liver function tests in association with pain Increased T.bilirubin, alkaline phosphatase, AST/ALT |
|
How well do Ultrasound and CT do at detecting choledocholithiasis?
|
Ultrasound:
Sensitivity 20-50% Specificity >90% CT: Sensitivity 30-70% Specificity >90% |
|
What are the sequelae of choledocholithiasis?
|
Ascending cholangitis
Obstructive jaundice Pancreatitis |
|
Charcot's triad is suggestive of...
|
Acute cholangitis
RUQ / epigastric pain Jaundice (Cholestatic picture with increased AST/ALT) Fever EMERGENCY. Antibiotics +ERCP (endoscopic retrograde cholangiopancreatography) |
|
Pancreatitis occurs when a stone becomes wedged in ...
|
The distal common bile duct
|
|
What is biliary pancreatitis?
|
Features of pancreatitis clinically.
Classically pain that radiates to the back with nausea, vomiting, anorexia May have mixed cholestatic/hepatic liver enzyme pattern. Elevations in WBC, amylase, lipase Endoscopic emergency if biliary obstruction is evident. Elevated total bilirubin= ERCP Can form pseudocysts. |
|
Post cholecystectomy pain, fever, WBC, elevations in AST/ALT, Bili may be...
|
Bile duct injury
|
|
Hypoechoic & Anechoic areas on ultrasound appear...
|
Black
Isoechoic appears gray. Hyperechoic appears white. |
|
On CT hyperdensity (bone) appears...
|
White
|
|
Hyperintensity on MRI appears...
|
Bright.
|
|
What is a hepatic abscess?
|
Localized collection of pus in liver due to destruction of hepatic parenchyma.
Pathology: Pyogenic 88% Amebic 10% Fungal 2% Most commonly following diverticulitis or appendicitis Differential diagnosis: Metastasis High fever and white count suggest abscess rather than mets. Radiologic finding : Coalescing cystic liver lesions with surrounding edema. |
|
What is a hepatic hemangioma?
|
Benign tumor composed of multiple vascular channels.
Most common benign tumor of liver Differential diagnosis: Peripheral cholangiocarcinoma Hypervascular metastasis Focal echogenic lesion with increased through transmission on ultrasound. !!Focal lesion with peripheral nodular enhancement on CT!! Filling in of contrast in delayed images (follows blood flow) |
|
In the arterial phase of hepatocellular carcinoma, it appears on imaging as..
|
Homogenously enhancing lesion
|
|
What are the most common sources of liver metastases?
|
Colon
Stomach Pancreas Breast and Lung |
|
What biliary stones can be virtually invisible on CT?
|
Non-calcified stones.
|
|
The most sensitive radiological test for stones in the bile duct is... (Choledocholithiasis)
|
MRCP
|
|
Double barrel or parallel channel sign is an indication of...
|
Intrahepatic biliary ductal dilatation
|
|
What are the complications of acute cholecystitis?
|
Gangrenous or emphysematous cholecystitis
Abscess formation Perforation |
|
What are the ultrasound findings of acute cholecystits?
|
Diffusely thickened gallbladder wall
Impacted gall stone Sonographic Murphy’s sign Pericholecystic fluid Increased doppler flow in the gallbladder wall |
|
What is the ultrasound finding of gallbladder carcinoma?
|
Irregular mixed echogenic lesion in GB
|
|
What would we use contrast enhanced CT for in the setting of acute pancreatitis?
|
Grading
Complications: Pseudocyst formation, Infected necrosis Pseduoaneurysm formation, Venous thrombosis |
|
What radiologic findings do we expect in chronic pancreatitis?
|
Multiple !!calcifications!! in the pancreas within an atrophic pancreas with dilated irregular pancreatic duct.
|
|
What radiologic findings do we expect in acute pancreatitis?
|
Unenhancing pancreas suggestive of pancreatic necrosis with peripancreatic inflammatory fluid tracking along the left anterior para-renal space
|
|
What do pancreatic pseudocysts generally look like on CT?
|
Unilocular cystic lesion in the tail of the pancreas.
|
|
What does pancreatic head adenocarcinoma look like on ultrasound?
|
Ill defined hypoechoic lesion in the head of pancreas with dilated intra and extrahepatic bile duct dilation
This is called double duct sign. |
|
When do we order ultrasound?
|
Useful:
Right upper quadrant pain –Initial test Cholelithiasis, cholecystitis Bile duct dilatation Assessment of vasculature: Portal vein, TIPS (Transjugular intrahepatic portosystemic shunt) Budd Chiari Not very useful: To visualize distal CBD Pancreatitis, pancreatic neoplasm |
|
When do we order CT scan?
|
Most useful:
Hepatic, Gall bladder and pancreatic neoplasm localizing and staging Pancreatitis – severity index, pancreatic calcification Cholecystitis complications Emphysematous and gangrenous cholecystitis, perforation or abscess formation Pre liver resection |
|
When do we order MRI?
|
Most Useful:
Best modality for lesion characterization in liver and pancreas MRCP CBD stones, Intra or extrahepatic bile duct path. Cholangiocarcinoma Better lesion detection compared to CT: Before liver resection, screening for HCC in cirrhosis. |
|
Average thermic effect of food per meal for a 70Kg person is ~
|
TEE of “average” mixed meal ~200C
Dietary Fat ->Body Fat ~ 60 Dietary Glucose-> Glycogen~ 140 Diet Protein-> Muscle Protein ~480 |
|
What are some important caveats about nitrogen balance?
|
Positive N balance:
Needs adequate caloric intake, regardless of the amount of dietary protein intake. Cannot be “forced” by intake of large amounts of protein or amino acids alone. Negative N balance: In catabolic stress can be decreased (“protein sparing”) by giving enough glucose to turn off gluconeogenesis and enough amino acids to spare muscle protein. |
|
What is the clinical impact of protein/calorie malnutrition?
|
Delayed post-surgical wound healing
Delayed recovery from severe trauma Increased mortality in severe burns Impaired immune response Increased toxicity of chemotherapy Growth failure in pediatric patients |
|
Where is lactase found?
|
At the brush border
|
|
What are the various sites of diestion of macromolecues?
|
Some molecules like glucose do not need digestion.
Proteins are broken down intraluminally. Lactose is broken down by lactase found in the brush border. Some smaller peptides are digested intracellularly. Any combination of the above. |
|
Where are the major enzymes made?
|
Mouth & stomach:
amylase, gastric lipase (mild lipase), pepsin Pancreatic enzymes: lipase, proteases, DNAase Enterocyte enzymes: brush border & secreted |
|
Galactose and hence lactose is only made by...
|
Mammals
|
|
What enzymes break glycosidic bonds besides lactase and sucrase?
|
Glucoamylase:
breaks starch 1:4 links Alpha-dextrinase (isomaltase): breaks starch 1:6 links |
|
What are the two main monosaccharide sugar transporters?
|
SGLT1:
Glucose and galactose transporter GLUT5: Fructose transporter |
|
What is lactase persistence?
|
Lactase persistence is an autosomal dominant trait. LCT on chromosome 2.
Lactase is a 150,000 Kd beta-disaccharidase which appears in high levels in brush border shortly after birth. Levels fall with weaning in all mammals and by the end of adolescence in most human populations. In some populations there is a high frequency of persistence of high lactase levels into adulthood. As we go from North to South and West to East the allele becomes less frequent. |
|
By what processes are glucose and galactose transported across each membrane?
|
Luminal membrane:
Secondary active transport (Na+ related) From cell to interstitial space: Facilitated diffusion. |
|
What are the classes of amino acids?
(not on exam) |
Polar:
Gly, Ala, Ser, Thr, Asn, Asp Aromatic: Phe, Tyr, Trp Charged: Glu-, Asp-, Lys+, Arg+, His+ Branched chain: Val, Leu, Ile Cyclic: Pro Sulfur containing: Met, Cys |
|
How are proteins digested and absorbed?
|
Luminal Digestion - stomach
Gastric pepsin (the only acidic peptidase) Luminal Digestion – small intestine Pancreatic peptidases Enterocyte peptidases Brush Border Digestion Aminopeptidase: di- and tri-peptides -> single AA Amino-oligopeptidase: oligopeptides-> 2,3 AA Dipeptidyl-aminopeptidase -> removes Ala, Pro Transporters: amino acid specific |
|
How are protease precursors activated to proteases?
|
Cleavage of the "safety" fuse of trypsinogen by enterokinase.
Trypsin activates the rest. |
|
How does absorption efficiency vary amongst the lipids?
|
Triglycerides, phospholipids: 95%
Cholesterol: 50% |
|
How are lipids digested and absorbed?
|
Luminal Digestion - stomach:
Gastric and lingual lipases release some FA’s Stomach mixing forms emulsion particles. Luminal Digestion - small intestine: Pancreatic lipase releases large amounts of fatty acids Hydrolysis products form mixed micelles Brush Border - passive diffusion Intracellular Events: Re-esterification to TG Chylomicron assembly and secretion. |
|
What is the importance of gastric emulsification in lipid absorption?
|
Lingual and gastric lipase hydrolyze dietary fats, liberating FA’s, mono- and di-glycerides, which serve as emulsifying agents.
This increases absorption efficiency substantially. (from ~50% to ~95%) |
|
What does the lipase/co-lipase system do ?
|
Breaks the fatty acyl bond from the chain and liberates monoglycerides and free fatty acids.
Lipids can then be solubilized in mixed micelles with bile that has hydroxyl groups on it. |
|
What happens to micelles in the lumen?
|
They diffuse across the unstirred water layer and then by diffusion or transport move into the cytosol of the cell.
|
|
What absorption processes are highly regional?
|
Carbohydrates are absorbed almost entirely in the duodenum and jejunum because of the high efficiency.
Protein, fat, water and sodium are also absorbed in the duodenum but again can happen anywhere in the small bowel. Bile salts and vitamin B12 are absorbed only in the terminal ileum. (problem in crohn's surgery) Iron is absorbed only in the duodenum and upper jejunum. (can be a problem in GI surgery) |
|
Vitamins cannot be synthesized but they are crucial for...
|
DNA and protein synthesis
Enzyme and transporter function Many other metabolic processes |
|
What are the water soluble vitamins?
|
Thiamine (B1)
Riboflavin (B2) Niacin (B3) Pyridoxine (B6) Folic Acid (B9) Cobalamin (B12) Ascorbate (C) Biotin Pantothenic Acid |
|
What are the fat soluble vitamins?
|
Retinol (A)
Calciferol (D)* Tocopherol (E) Menaquinones (K)* D and K are semi vitamins. We can synthesize very small amounts of D (not enough though). We can use some of the K from gut bacteria. Any condition that affects gut bacteria can thus be problematic for clotting factors. |
|
What molecules are considered macro minerals?
|
Sodium (Na)
Potassium (K) Calcium (Ca) Magnesium (Mg) Iron (Fe) Chloride (Cl) Phosphorus (PO4) Sulfur (SO4) |
|
What molecules are considered trace minerals?
|
Chromium (Cr)
Cobalt (Co) Copper (Cu) Iodine (I) Manganese (Mn) Molybdenum (Mo) Selenium (Se) Zinc (Zn) |
|
What is the importance of vitamin C?
|
Cofactor for collagen biosynthesis
Facilitates iron absorption Role in activation of folate VERY powerful aqueous phase antioxidant. Can detoxify molecules by scavenging free electrons and ultimately becoming 2,3-diketo-1-gluconic acid. |
|
Scurvy or vitamin C deficiency is characterized by ...
|
Severe periodontal disease
Cutaneous hemorrhage Poor wound healing Populations at risk include: Cigarette smokers Severe malnutrition, cachexia High doses of vitamin C may cause mild diarrhea and kidney stones in susceptible patients. |
|
Who is at risk for folate deficiency?
|
Severe Malabsorption
Drug and food antagonists Poor diet in the elderly Pregnant women should have HIGH levels to prevent neural tube defects. Toxicity is not possible. |
|
Vitamin A,D,E and K absorption is dependent upon...
|
The presence and efficient absorption of dietary fat.
They are: Solubilized by bile in mixed micelles. Transported into enterocytes, packaged along with fat into chylomicrons, and secreted into lymph. Taken up by the liver in chylomicron remnants. Re-secreted into plasma on transport proteins. Some things to keep in mind: Fat soluble vitamins can be stored Fat soluble vitamins in excess can be toxic. The body can synthesize vitamins D and K but not in sufficient amounts. |
|
What is the importance of folic acid?
|
Cofactor in methyl transfer reactions.
Synthesis of DNA, glutathione, hormones, phospholipids, and neurotransmitters. |
|
Two retinol molecules bound together are a ....
|
Beta carotene
|
|
What is the importance of vitamin A?
|
Visual pigment synthesis
Maintains ocular structures Epithelial cell function Bone growth & development Reproduction Vitamin A sources: Eggs Meat Dairy products Beta carotene sources: Green leafy and intensely colored fruits and vegetables. |
|
What does vitamin A deficiency do to the eyes?
|
Keratomalacia
|
|
What skin lesion is associated with vitamin A deficiency?
|
Hyperkeratosis
|
|
What populations are at risk for vitamin A deficiency?
|
Fat malabsorption syndromes
Poor diet in the elderly Some 3rd world countries |
|
What are the pharmacologic uses for vitamin A?
|
Analogs are used topically for acne and other skin disorders. Profoundly teratogenic though.
Beta-Carotene Trial: Study was halted due to increased cancers in the treatment group. Dietary supplements used with caution because of the potential for serious toxicity. Toxicity: Hypervitaminosis A syndrome Hepatotoxicity (polar explorers eating polar bear liver) Teratogenic effects |
|
How does vitamin A deficiency present?
|
Night blindness
|
|
Apart form our skin and sunlight, where do we get vitamin D?
|
Cheese
Butter Margarine Fortified milk Fish Fortified cereals |
|
What is the importance of vitamin D?
|
It increases intestinal calcium absorption by receptor gene upregulation.
Liver or kidney disease can cause functional Vitamin D depletion even with normal absorption. |
|
What is vitamin D deficiency?
|
Ricketts & Osteoporosis
Populations at risk include: Fat malabsorption syndromes The elderly and homebound Severe kidney disease |
|
What is Vitamin D used for pharmacologically?
|
Used to treat hypocalcemia after parathyroidectomy
Used as an adjunct in treating osteopenia and osteoporosis Used as a dietary supplement in combination with Ca++ supplements for “bone health”. Toxicity: Hypercalcemia, weakness Kidney stones |
|
What is the importance of vitamin E and where do we get it?
|
Membrane antioxidant
Corn, nuts, olives, green leafy vegetables, vegetable oils. |
|
What does vitamin E deficiency do?
|
Hemolytic anemia
Very rare: seen only with very severe fat malabsorption. Populations at risk for mild deficiency: Cystic fibrosis Severe pancreatic insufficiency Short bowel syndromes Total Parenteral Nutrition Genetic abnormalities |
|
What are the pharmacological uses of vitamin E?
|
Prevents pulmonary oxygen toxicity in premature infants?
No activity in Parkinson’s disease, atherosclerosis, and cancer prevention studies Widespread use as antioxidant dietary supplement. Little evidence of efficacy May function as a pro-oxidant? Toxicity: Generally safe High doses may cause diarrhea and clotting abnormalities |
|
When vitamin becomes oxidized, it can regenerated by..
|
Vitamin C
|
|
Where do we get vitamin K?
|
Cabbage, cauliflower, spinach and other green leafy veggies.
Cereals. Bacteria. |
|
What does vitamin K deficiency do?
|
Bruisability and Bleeding
Populations at risk: Fat malabsorption syndromes Patients on chronic antibiotics Short bowel syndromes |
|
What are the pharmacological uses of vitamin K?
|
Acute reversal of coumarin induced anticoagulation.
Stabilization of anticoagulation in patients taking coumarin Rx. Toxicity: Generally safe. Excess does NOT induce hypercoagulable state. NOTE!!: Be very careful with giving antibiotics to patients on coumadin. |
|
What is the outcome of calcium deficiency?
|
Osteoporosis.
Absorption aided by vitamin D. Populations at risk: Women, esp. post-menopause Fat malabsorption syndromes Short bowel syndromes Chronic steroid use Pharmacologic uses: Prevention of Osteoporosis Treatment of Osteoporosis Antacid for Rx of GERD Bile salt diarrhea Oxalate kidney stones Side effect is constipation. Toxicity: Safe |
|
How do we define malabsorption?
|
Impaired absorption of individual or multiple nutrients caused by the pathologic disruption of the normal physiological processes of digestion and intestinal transport.
|
|
What are the symptoms of malabsorption?
|
General Symptoms:
Diarrhea Steatorrhea Weight Loss > 10% Bloating, gassiness, flatulence Specific Symptoms: Peripheral edema Pica; symptoms of anemia Neuropathy Night blindness Accelerated osteoporosis |
|
Which symptoms are associated with which specific malabsorptions?
|
Weight Loss: Total Calories
Diarrhea: CHO, Protein, Fat Steatorrhea: Fat Bloating, flatulence: Sugars Edema: Protein Pica, Sx of anemia: Iron, vitamin B12, folate Neuropathy: Vitamin B12 Night blindness: Vitamin A Osteoporosis: Vitamin D, Calcium |
|
What are the causes of malabsorption?
|
Disaccharide Malabsorption:
Lactase Deficiency (common) Fructose Intolerance (uncommon) Sucrase Deficiency (rare) Maldigestion (selective fat malabsorption): Gastric resection or bypass Bile salt deficiency - ileal resection/disease, SIBO Pancreatic Insufficiency Global Malabsorption (CHO, protein, fat): Short Bowel Syndrome Mucosal Disease - Crohn's, Celiac, Whipple's, amyloidosis, lymphoma, radiation enteritis. |
|
What history clues can suggest malabsorption?
|
GI Surgery:
Ulcer operations (esp. vagotomy & antrectomy) Gastric resection or bypass Cholecystectomy Small bowel resection (esp. terminal ileum) Right colon resection (esp. ileo-cecal valve) Pancreatitis or Hx of heavy EtOH abuse Abdominal or pelvic irradiation Collagen vascular disease |
|
What is lactose intolerance?
|
Most common cause of chronic diarrhea in USA.
Primary: Absent lactase persistence SNP Highest incidence in persons of Asian, Native-American, and African-American ancestry Secondary: Aging Post-infectious (enterovirus) Chemotherapy Celiac disease, Tropical Sprue, Giardiasis Bacterial Overgrowth Rapid transit syndromes Dx: Presumptive Trial of a low-lactose or lactose-free diet(may give a false negative result) !!Lactose-Hydrogen Breath Test!! Tx: Dietary lactose restriction Lactase-treated milk (Lactaid®, DairyEase®) Lactase enzyme supplements |
|
How does the H2 breath test work?
|
Large amount of loactose is given orally.
If lactase deficient, lactose is not absorbed and metabolized by bacteria which make H2 and methane. S pike in H2 or methane therefore suggests lactose intolerance. |
|
What are sucrose deficiency and dietary fructose intolerance?
|
Sucrase Deficiency
Very rare autosomal recessive disorder Sx: diarrhea appearing in early infancy. Typically right after weaning, Dx: sucrose hydrogen breath test Rx: lifelong sucrose free diet Dietary Fructose Intolerance: Mild dysfunction of the GLUT 5 transporter Sx: diarrhea with ingestion of fruit and products containing high fructose corn syrup Dx: fructose hydrogen breath test Rx: dietary fructose restriction |
|
What can cause selective fat malabsorption?
|
Gastric resection or dysmotility (gastroparesis)
Bile Salt Malabsorption or deficiency (bacterial overgrowth, TI resection, cholecystectomy) Pancreatic insufficiency: chronic pancreatitis Mucosal Diseases |
|
How do we test for steatorhoea?
|
Stool Sudan Fat Stain
Can quantify with dietary fat absorption test over three days. !!>7g/day in stool=malabsorption!! (seldom used any more) |
|
Maldigestion due to bacterial overgrowth can occur because of....
|
Hypomotility
(DM, scleroderma, visceral myopathy) Achlorhydria (gastrectomy, atrophic gastritis) Jejunal diverticulosis Ileo-cecal valve resection Bile salt deconjugation->bile salt malabsorption ->decreased bile salt pool ->fat malabsorption Chronic mucosal inflammation Dx: Suspicion Jejunal aspiration for quantitative culture(gold standard, but not widely available) 14C-Glycocholate Breath Test Glucose-Hydrogen Breath Test Tx: Oral systemic or non-absorbable antibiotics. Usually requires chronic treatment Antibiotic rotation to prevent resistance. |
|
What can we see on a glucose hydrogen breath test that is diagnostic of bacterial overgrowth maldigestion?
|
An early intestinal peak and a late colonic peak.
|
|
What causes maldigestion due to pancreatic insufficiency?
|
Chronic pancreatitis (common)
Pancreatic cancer with duct obstruction (rare) ZE Syndrome - lipase denaturation (rare) Steatorrhea occurs when the secretion of pancreatic lipase falls to < 10% of normal Disease also destroys alpha and beta cells, resulting in decreased insulin and glucagon secretion Brittle diabetes appears in advanced disease |
|
What is the classic imaging picture of chronic pancreatitis?
|
Duct Dilation and Calcification
|
|
How do we diagnose maldigestion due to pancreatic insufficiency?
|
Presumption
Stimulated pancreatic secretion analysis Pancreatic imaging by CT, EUS, ERCP Tx: Pancreatic enzyme supplements containing at least 30,000 units of lipase at each meal. Enteric coated tablets PPIs, H2 blockers, or NaHCO3 keep gastric pH > 5 to prevent enzyme denaturation Reduced fat diet |
|
What causes global malabsorption?
|
Small Bowel Mucosal Diseases.
Celiac disease (upper small bowel) Crohn’s disease (terminal ileum) Whipple’s disease (duodenum, jejunum) Intestinal lymphoma Chronic giardiasis Other rare disorders: Tropical sprue Eosinophilic gastroenteritis Abetalipoproteinemia Amyloidosis Lymphangectasia |
|
What is the algorithm for diagnosing the cause of malabsorption?
|
|
|
What is included in a diet history?
|
Review usual pattern of food intake:
24 hour diet recall Food frequency questionnaires Food diaries Food intolerance or allergies Use of supplements Specific dietary Rx Dining out; fast food |
|
What sorts of symptoms may emerge in a diet history?
|
Appetite - Increased or Decreased?
Steatorrhea (malabsorption) Rash (B vitamin or essential FA deficiency) Night blindness (vitamin A deficiency) Easy bruising (vitamin K deficiency) Pica (iron deficiency) Sore tongue (iron or B vitamin deficiency) Edema (depleted visceral protein stores) |
|
What is included in a weight history?
|
Current Weight and BMI
Ideal Body Weight: Calculated Estimated (post-adolescent weight) % Ideal Body Weight Recent Change in Weight % Usual Body Weight Rate of Weight Loss Maximum Lifetime Weight Desired Weight |
|
How do we calculate BMI?
|
BMI = weight (kg) / height (m2)
1 Kg = 2.20 lbs 1 inch = 2.54 cm Overweight=25-30 |
|
How do we calculate ideal body weight?
|
Metropolitan Life Tables
NHANES I and NHANES II Survey Data The Hamwi method: ♀ 100 lbs for 5 ft + 5 lbs for each inch over 5 ft ♂ 106 lbs for 5 ft + 6 lbs for each inch over 5 ft |
|
How do we interpret % ideal body weight?
|
Severe malnutrition < 70 %
100-110% appropriate Severe obesity >200% |
|
How do we interpret rate of weight loss?
|
One week:
1-2% significant >2% severe One month: 5% significant >5% severe 6 months: 10% significant >10% severe |
|
What is the best measure of body fat distribution?
|
Waist/hip ratio
The higher the ratio the higher the risk of disease. |
|
Uveitis can be a sign of....
|
Vitamin A deficiency
|
|
What is Cheilosis?
|
Cracks at the corner of the mouth.
Failure of the bodies repair system. |
|
What is glossitis?
|
Beefy red tongue
Smooth if severe. |
|
What is adiposity?
|
% body fat.
This can be done by: Underwater weighing Bioelectric impedance Anthropometry: Skin fold thickness measured by calipers. Arm muscle area (determined from triceps skinfold and arm circumference) DEXA Scan CT and MRI scanning |
|
How do we interpret % body fat?
|
Malnourished:
<10% women <2% men Obese: >32% women >25% men |
|
At what % body fat does ammenorrhea usually begin?
|
10-14%
|
|
What are good rules of thumb for energy intake in kcal/kg?
|
Weight Loss 20 - 25
Weight Maintenance 25 - 30 Illness, Fever 30 - 40 Burns, Severe Trauma 40 - 50 |
|
What are our protein requirements in g/kg/day?
|
Normal 0.8 - 1.0
Moderate Stress 1.0 - 2.0 Severe Stress 2.0 - 2.5 Disease Specific 0.4 - 3.0 |
|
How do we determine protein status?
|
Visceral proteins:
Albumin - half-life = 18-21 days Transferrin - half-life = 7-10 days Prealbumin - half-life = 2-3 days Nitrogen balance: Requires 24 hr urine collection and a 24 hr dietary protein count Lean body mass |
|
How do we interpret serum visceral protein levels?
|
Albumin (g/dl):
5.5 – 3.5 normal < 2.0 severe depletion Prealbumin (g/dl): 40 – 14 normal <5 severe depletion Transferrin (mg/dl): 375 – 200 normal <100 severe depletion |
|
Appetite stimuli can be either...
|
Orexigenic:
stimuli that increase appetite Anorexic: stimuli that decrease appetite |
|
Why does too much fat interfere with reproduction?
|
Fat is metabolically active.
Adipocyte interleukins and inflammatory cytokines inhibit ovulation and implantation |
|
How does the appetite control system in the brain work?
|
Two classes of neurons in the arcuate nucleus (ARC) respond to GI hormonal signals:
NPY-AgRP neurons secrete orexigenic peptides- Neuropeptide Y Agouti-related peptide POMC neurons secrete the anorexic peptide: alpha-melanocyte stimulating hormone These neurons project to the PVN, and from there to the NTS in the brainstem The balance between NPY-AgRP:POMC neuron activity regulates appetite, hunger, and satiety. |
|
What is Grehlin?
|
28 AA peptide
Strongly orexigenic Increases gastric motility Plasma levels oscillate and peak before meals Secretion decreased by food Conversely CCK is an anorexic signal. |
|
What is leptin?
|
16 kDa protein.
Mutated in the ob/ob mouse Plasma levels proportional to BMI and body fat mass Long-term appetite regulator Leptin does not directly regulate hunger and satiety |
|
What happens with high leptin, high insulin , low grehlin? (the well fed state)
|
POMC neurons are excited
NPY/AgRP neurons are inhibited Decreases food intake behaviours |
|
What happens with low leptin, low insulin , high grehlin? (the starved state)
|
NPY/AgRP neurons are excited
POMC neurons are inhibited Increases food intake behaviors. |
|
When we plot BMR and appetite curves, the point where they intersect is considered the...
|
Setpoint of adiposity.
Shape of the curve is determined by genetics. |
|
What is the caloric content of fat?
|
~9 kcal/gm
|
|
In terms of % body fat, what is obesity?
|
>32% for women
>25% for men |
|
Why do we use BMI?
|
In healthy populations BMI correlates well with adiposity.
easy to compute Shortcoming: very muscular individuals may have a high BMI and low adiposity, but still be classified as obese |
|
Obesity is a strong predictor of diseases such as diabetes, hypertension, coronary artery disease, fatty liver, cancer, hyperlipidemia, osteoarthritis. How do we grade it in terms of BMI?
|
Grade I: obesity 30 - 35
Grade II: severe obesity 35 - 40 Grade III: extreme obesity >40 |
|
What is the cutoff waist/hip ratio that predisposes someone to increased risk of disease?
|
> 0.95 in men
> 0.80 in women Increases risk of: Atherosclerosis Cancer Type 2 Diabetes Infertility Osteoarthritis Sleep apnea Increased ABDOMINAL fat is also associated with the Metabolic Syndrome: Insulin resistance Glucose intolerance Dyslipidemia Hypertension |
|
What is an example of a monogenic obesity disorder?
|
Leptin deficiency
|
|
What is an example of a population with polygenic susceptibility to obesity?
|
Pima Indians
|
|
What is the relationship between frequency of eating out at a restaurant and %body fat?
|
Linear
|
|
Alcohol has an energy content of..
|
7Kcal/g
|
|
Energy density of food is most highly correlated with...
|
Water content.
Volume is the main determinant of the amount of food that is consumed at each meal. Food fat content is a 2º correlate Thus: Food Energy Density will determine the number of calories eaten at each meal |
|
The water content of adipose tissue is approximately...
|
20%
|
|
What are some easy weight loss actions?
|
Don’t Drink Your Calories !
Discontinue sodas, sugared beverages, flavored lattes and coffee drinks Reduce consumption of alcohol Water is the best beverage Eliminate high-fat, high-calorie snacks Eat fresh fruits, nuts, low fat cheese sticks Read labels at the store Choose foods with a lower fat content, higher protein, and higher fiber content Increase activities of daily living Take the stairs, park in the far lot, walk! |
|
What is the recommended nutrient content of a Weight-Reducing Diet?
|
55% or more of daily calories from carbohydrates,
15% from protein, 30% or less from fat. In addition, specific recommendations are made regarding the composition of fat ingestion: total energy intake should be comprised of 8%-10% calories from saturated fat, 10% or less calories from polyunsaturated fats, and 15% or less calories from monounsaturated fats. Daily cholesterol intake should not exceed 300 mg/d, and daily fiber intake should be between 20-30 g/d. |
|
What is orlistat?
|
Orlistat is a competitive inhibitor of gastric and pancreatic lipase
Orlistat inhibits intra-luminal fat digestion and absorptionUndigested fat passes into the colon and is excreted in the stool Combined with a moderate dietary fat reduction (<30%), Orlistat can result in modest (2-5 kg) weight loss. Side effects: Steatorrhea - Gas, bloating, cramping - Increased number of BMs - Fecal incontinence - Decreased absorption of fat soluble vitamins. |
|
What is sibutramine?
|
Sibutramine blocks neuronal monoamine (serotonin, norepinephrine, dopamine) reuptake.
Basically speed. dry mouth, constipation, and insomnia |
|
What is a Roux-en-Y Gastric Bypass?
|
Clinical improvement or resolution in:
60% to 100% of patients with DM 60% to 70% of patients with HBP 85% of patients with sleep apnea 60% to 100% of patients with lipids 90%+ of patients with NASH Side Effects and Complications: Bloating, diarrhea, nausea, vomiting Vitamin B12 deficiency Iron deficiency anemia Osteoporosis Hypoproteinemia and edema Anastomotic stenosis; internal hernias. |
|
What are some specific dieatry treatments for disease?
|
Phenylketonuria :
Decrease phenylalanine Maple Syrup Urine: Decrease branched chain AA Glycogen storage disease: (+) nocturnal starch (uncooked) Hereditary fructose intolerance: Decrease sucrose and fructose Galactosemia: (-) milk/dairy products Sitosterolemia: Decrease plant sterols Adrenoleukodystrophy: Decrease VLCT, Increase C18:1+C22:1 Abetalipoproteinemia: Decrease Fat, Increase MCT, Increase vitamins A & E |
|
What is abetalipoproteinemia?
|
Rare autosomal recessive disorder
Neonatal diarrhea, steatorrhea Failure to thrive & poor growth Very low plasma TG and cholesterol Absence of chylomicrons, VLDL, LDL, and immunologically detectable apo B No post-prandial rise in triglycerides Pre-chylomicrons absent in the golgi Slice mutation in the MTP gene Hemolytic anemia Retinal degeneration Progressive neurologic dysfunction because of fat soluble vitamin deficiency. |
|
How do we treat abetalipoproteinemia?
|
Very low-fat, high carb, high protein diet.
Supplementation with MCT (medium chain triglycerides) Pharmacologic doses of surfactant solubilized vitamin A and vitamin E. All clinical features can be prevented. |
|
What sort of diet is recommended in renal failure?
|
!Low protein!
Watch Sodium and potassium |
|
What sort of diet is recommended for constipation?
|
Increased soluble fiber.
|
|
What sort of diet is recommended post gastrectomy?
|
((+) Iron, Vitamin B12)
Multiple small, frequent meals Moderate dietary fat restriction Oral iron supplementation Ferrous sulfate (FeSO4) 300 mg PO qD !Parenteral! vitamin B12 Cyanocobalamin 1 mg IM every month. |
|
What clinical features do we expect in post-gastrectomy patients?
|
Early satiety
Dumping syndrome Iron malabsorption: Iron deficiency anemia Vitamin B12 malabsorption: Macrocytic anemia Peripheral neuropathy |
|
Why does achlohydia lead to iron malabsorption?
|
non-heme iron (from plants) remains in the ferric (Fe+3) form which is poorly absorbed in the duodenum.
|
|
What is necessary for B12 absorption?
|
R factor made in salivary glands.
IF made by parietal cells must be bound for recognition of the transport protein in the terminal ileum. |
|
What diet is recommended for seizure disorders?
|
ketogenic diet
|
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What diet is beneficial for parkinson's?
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Time shift protein intake to help L-dopa absorption.
Protein after lunch. |
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What dietary modification is useful for GERD patients?
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Decreased xanthines (Coffee, tea)
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What dietary modification is useful for Irritable bowel syndrome patients?
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Decreased stachyose (beans, onions)
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What diet is useful for patients with kidney stones?
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Decreased oxalate
Increased calcium |
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What is enteric hyperoxaluria?
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Bile salt malabsorption secondary to disease or resection of the terminal ileum:
Bile salt malabsorption Decreased Bile salt pool Fat Malabsorption This creates a problem with calcium absorption which leads to increased intestinal oxalate absorption: Increased urine oxalate concentration. Recurrent calcium oxalate kidney stones. Dietary calcium supplementation provides enough calcium to bind to FA’s, BA’s, !!and!! oxalate |
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What is the dietary treatment for enteric hyperoxaluria?
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Supplemental Calcium
(1 gm CaCO3 qid) High fluid intake (>2 liters/day) Low oxalate diet (no root vegetables, tea, cocoa, peanuts, bran, and no rhubarb) Moderate fat restriction |
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What do we currently think helps prevent atherosclerosis?
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Increased vitamins B6, B12, C, E, folate CoQ, flavinols, isoflavones
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What do we currently think helps prevent cancer?
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Increased caroteinoids, glucosinolates, Se
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What do we think helps prevent breast cancer?
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Decreased fat
Increased isoflavones |
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What do we currently think helps prevent prostate cancer?
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Increased isoflavones, lycopenes, vit E
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What do we currently think helps prevent colon cancer?
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Decreased fat
Increased calcium, Viatmin C, E and folate. |
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What are three examples of functional food components?
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Phytosterols (plant sterols)
beta-sitosterol, stigmasterol, campesterol Decrease cholesterol absorption and therefore plasma LDL Omega-3 Fatty Acids: ALA (18:3), EPA (20:5), DHA (22:6) Decrease TG, anti-inflammatory, brain development Soy Isoflavones: genistein, diadzein, coumestrol Prevent heart disease, osteoporosis, cancer ? |
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What are some characteristics of cholesterol?
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Important component of cell membranes
Only animals make cholesterol Cholesterol is inefficiently absorbed by the human intestine (~50% efficiency) There is very wide person-to-person variability in absorption efficiency Dietary cholesterol can raise LDL levels, but its impact on LDL is also variable |
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What two transporters is cholesterol absorption dependent upon?
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NPC1L1:
nondiscriminatory sterol absorber that imports into the enterocyte ABCG5/G8: Discriminatory transporter that throws some sterols back into the intestinal lumen. Much more efficient for plant sterols (phytosterols). |
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What are phytosterols?
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Plants make Phytosterols (plant sterols):
beta-sitosterol, stigmasterol, campesterol, avenasterol, brassicasterol, and stanols Unlike cholesterol, phytosterols are poorly absorbed by the intestine (<1% efficiency) It has been known since the 1950’s that phytosterols inhibit cholesterol absorption Only recently has the full mechanism of the phytosterol effect been elucidated. |
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What is an example of a phytosterol functional food?
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Plant Stanol Margarines
Over 40 placebo controlled trials reported Can achieve up to 14% lowering of plasma LDL when used alone as “monotherapy” Could produce up to a 30 mg/dl reduction in LDL when used to replace butter in the diet Can produce up to a 10% additional LDL lowering when taken along with a statin Palatable, safe, no effect on fat-soluble vits. Comes in lower calorie (“lite”) versions. |
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What are omega 3 fatty acids?
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Highly unsaturated
( 3 or more double bonds) alpha-Linolenic acid (18:3) (ALA): Essential fatty acid – must obtain from the diet. Precursor for longer omega 3 fatty acids Eicosapentaenoic acid (20:5) (EPA): Precursor for prostanoid synthesis Docosahexaenoic acid (22:6) (DHA): Major component of structural phospholipids in the brain (30%) and in the retina (50%) Maternal intake during pregnancy may affect neonatal retinal and brain development. |
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What are omega 6 fatty acids?
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Linoleic acid (18:2) (LA) :
Essential fatty acid - must obtain from the diet Precursor for arachidonic acid synthesis Gamma-Linolenic acid (18:3) (GLA): Non-essential precursor for prostanoid synthesis Arachidonic acid (20:4) (AA): Substrate for the synthesis of prostaglandins, leukotrienes, and other bioactive prostanoids |
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What does the omega terminology denote?
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How many carbons from the beginning of the hydrocarbon chain the first double bond appears.
Mammals cannot add double bonds further out than omega 9. |
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What is the importance of EPA and DHA made from omega 3 alpha linolenic acid in contrast to the arachidonic acid made from other fatty acids?
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They alter the balance of inflammatory prostanoids so that there are less of them by inhibiting the release of arachidonic acid and it subsequent products.
They also form prostaglandins that are far less inflammatory and vasoconstricting. |
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So what is the net effect of omega 3 dietary supplementation?
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CV:
Lower plasma triglycerides Lower blood pressure Anti-arrhythmic effect Reduce platelet aggregation Reduce sudden death after MI Psychiatric: Reduce incidence/severity of depression May reduce aggressive behavior |
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What are some newer tentative possible benefits of omega 3 fats?
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Anti-Inflammatory Activity:
Rheumatoid Arthritis Asthma Inflammatory bowel disease Psoriasis Neuro-Behavioral Disorders: Neonatal visual/neural development Benefit in ADHD and Autism ? Benefit in memory disorders ? |
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Where do we find omega 3 in food?
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Oily fish like salmon and anchovies.
(only fish have the longer more efficacious variety) Flaxseed and canola oil. |
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What are the shortcomings of fish as a source of omega 3?
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Wild caught fish may contain unsafe levels of methyl mercury or other toxic environmental pollutants (e.g., PCB's)
Farmed fish may have much lower levels of EPA/DHA than wild fish Concentrated fish oil supplements can leave a fishy taste and fishy breath. Solution: Hens fed flax meal (a rich source of ALA) produce eggs with an 8-fold higher DHA content. |
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What is the supposed benefit of eating soy?
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Soy contains estrogen-like phytochemicals with E2 receptor agonist-antagonist activity
The soy hypothesis: Soy isoflavones, by their estrogen receptor agonist-antagonist action, protect against ASCVD and estrogen-sensitive disorders. Addition of soy and/or soy isoflavones to the Western diet can lower the risk of ASCVD and estrogen-sensitive disorders. |
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In practice, what is the benefit of soy?
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Alternative protein substitutes
Lower cost than animal source protein Lower fat content than most meats A "Green" Food Consume fewer resources and less energy to produce than animal protein Expand the vegetarian repertoire |
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In summary, what do we know about current functional foods?
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Stanol fortified margarines effectively lower plasma LDL levels alone or in combination with diet and statins
Omega-3 eggs can increase the daily intake of DHA and EPA and might help modulate inflammatory diseases Soy products may have a small effect on plasma LDL levels and hot flashes, but evidence for other actions is weak |
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What are some of the currently popular fad diets?
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Atkins
South Beach Zone Sugar Busters Protein Power Blood Type n-Day Miracle Cabbage Soup |
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What are the main types of fad diets?
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Very-low carbohydrate (<10%) (ketogenic)
Low carbohydrate, high protein (>20%) Very-low fat (<10%), high carbohydrate Very low calorie, rapid weight loss Specific nutrient or category elimination Highly regimented / prescribed foods |
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What is the principle underlying the atkins diet?
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Diets containing higher amounts of protein and moderate amounts of fat may be more satiating than low fat/high carb diets.
Insulin & PG levels “normalized” by “optimum” 40/30/30 nutrient ratio. |
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What is the south beach diet?
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Description:
Three-phase high protein, low glycemic index carbs, low sat. fat diet Premise: Insulin and glucose intolerance normalized by eliminating high GI carbs Advantages: Weight loss by mild caloric restriction; wide range of food choices Disadvantages: Weigh loss decreases in phase II Proof: May have initial superior weight loss efficacy, but not beyond 6 months |
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The ornish and an pritikin diet's are both examples of...
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Very-Low Fat (<10%)
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What is the ornish diet?
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Description:
Ultra low fat, vege based Premise: Diet can reduce plasma cholesterol Advantages: Weight loss; exercise and stress reduction are part of the program Disadvantages: Requires very strong motivation; vege menus not for everyone Proof: Weight loss, improved lipids, and reversal of CAD shown in several studies |
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What is the right for your type diet?
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Description:
Meat, grain, and/or dairy elimination based on ABO blood type Premise: ABO type identifies archetypical diet; eating “wrong” foods causes harm Advantages: Personalization of one’s diet Disadvantages: Book filled with pseudo-science, half-truths, and misinformation Proof: NY Times Best-seller |
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What is nutrigenomics?
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The study of how foods interacts with our genome:
How dietary chemicals alter gene expression How genetic differences (gene variants) affect the metabolic and physiologic response to food How diet-regulated genes may play a role in the incidence, progression, or severity of chronic disease How dietary interventions based on knowledge of genotype (i.e., "personalized nutrition") can be used to prevent, mitigate or cure chronic disease |
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How many SNP's are in the human genome?
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>10^6
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What is an allele?
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A variant gene with a frequency of greater than 1% in a population.
Not all SNPs are alleles Not all alleles are SNPs |
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Where is the lactase persistence gene located?
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Mapped to a SNP (C/T-13910) upstream of the lactase gene on chromosome 2
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Prevalence of Lactase Persistence is highest in...
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Northwestern europe. (low sunlight)
Helps in calcium absorption in lieu of vitamin D. |
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What are the genetics of taste?
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Ability to sense different tastes is mediated by five families of lingual taste receptors.
T2R is the bitter receptor. There is a very wide individual variation in the ability to perceive bitter tastes. Taster trait (T+) is Mendelian dominant: Homozygous (TT) – Supertaster (ST) Heterozygous (Tt) – Taster (T) Homozygous (tt) – Non-Taster (NT) Trait caused by polymorphisms in theT2R family of G-protein coupled receptors ~ 35% of USA population are non-tasters Nausea susceptibility is also highly variable: ~50% of the population has decreased susceptibility. Non-tasters display a higher maximum nausea than Tasters or Super-tasters Non-tasters also display a more rapid and higher magnitude rise in mean nausea scores over 16 minutes than Tasters The traits may have therefore coevolved. |
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What happens to Lipoprotein Metabolism During Lactation?
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Villus hypertrophy during the last trimester.
Prolactin shuts off peripheral lipid deposition. If the fat goes to the liver, mom gets it. If it goes to the breast, baby gets it. |
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What is the Apo A-IV-S Allele?
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S-allele frequency = 20-25% worldwide
Associated with Increased Post-prandial chylomicron clearance Increased BMI and increased Adiposity. More rapid chylomicron clearance may increase the flux of dietary fat into milk. The S-allele may have evolved to confer a neonatal nutritional advantage. |
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What is the thrifty gene hypothesis?
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Proposed in 1962 by geneticist James Neel
Postulates that certain genes evolved to maximize metabolic efficiency and nutrient storage In ancient times, thrifty genes would have conferred a selective advantage during periods of famine. However, in abundant times, thrifty genes predispose carriers to diseases caused by dietary excess Ethnic groups with a history of food scarcity will have undergone greater evolutionary pressure, and may harbor more thrifty genes than other populations. |