Boards and Beyond: Gastroenterology A Companion Book to the Boards and Beyond Website Jason Ryan, MD, MPH Version Date: 11-1-2016
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Table of Contents Gastrointestinal Gastrointestinal Embryology Gastrointestinal Gastrointestinal Anatomy GI Blood Supply Gastrointestinal Gastrointestinal Tract Liver, Gallbladder, Gallbladder, Pancreas Salivary Glands Hernias Bile Bilirubin Gastrointestinal Gastrointestinal Secretions Gastrointestinal Gastroint estinal Hormones Exocrine Pancreas Esophageal Disorders Liver Disease
1 7 9 13 17 20 25 30 34 40 43 49 53 59
Cirrhosis Liver Tumors Wilson’s & Hemochromatosis Hemochromatosis Gallstones Biliary Disorders Gastric Disorders Malabsorption Acute Pancreatitis Chronic Pancreatitis & Cancer Intestinal Disorders Inflammatory Inflammator y Bowel Disease Colon Cancer Carcinoid Tumors Gastrointestinal Gastrointestinal Pharmacology
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63 68 71 75 80 83 91 98 104 107 113 118 124 126
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GI Embryology •
Gastrointestinal Embryology
•
Endoderm GI tract •
GI tract epithelium, epithelium, glands
•
Many organs bud off: liver, liver, pancreas, pancreas, trachea
Mesoderm Surroundingstructures •
Stroma (GI tract connective connective tissue)
•
Muscles
•
Peritoneum
•
Spleen
Jason Ryan, MD, MPH
Portions of GI Tract •
•
•
Mesentery
Foregut •
Celiac trunk
•
Mouth to Ampulla of Vater
•
•
•
Midgut •
SMA
•
Ampulla of Vater to transverse transverse colon
•
•
Hindgut •
IMA
•
Transverse colon to rectum
Mesentery •
•
Gut moves away posterior posterior wall in development
•
Dorsal mesentery mesentery grows between gut and posterior wall
•
Covers most abdominal abdominal structures
Ventral mesentery •
Only exists bottom esophagus, stomach, stomach, upper duodenum
•
Derived from septum septum transversum (mesenchyme tissue)
•
Liver grows into this mesentery
•
In adult: lesser omentum and falciform ligament
Enclosed by mesentery
Retroperitoneal organs •
Covered by peritoneum peritoneum only on anterior anterior wall
•
Lie against posterior abdominal wall
Mesentery
Dorsalmesentery Dorsal mesentery •
Double layer of pe ritoneum Suspends abdominal organs from cavity walls Intraperitonealorgans
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•
Mesogastrium
•
Mesoduodenum
•
Mesocolon
Omentum
Foregut Development Development
Latin: “apron” •
•
Greateromentum
•
•
Hangs from greater greater curvature of stomach
•
Covers intestines
•
Formed from mesogastrium
•
•
•
Lesser omentum
•
•
Between stomach and liver
•
Formed from ventral mesentery
Lung “buds” off from foregut “Respiratory diverticulum”; “lung bud”
Tracheoesophageal septumdivides septum dividesdiverticulum Matures into separate trachea and esophagus Abnormal septum development pathology •
Esophageal atresia (closed esophagus)
•
Occurs when septum deviates posteriorly
Esophageal Atresia
Esophageal Atresia
Clinical Features
Clinical Features
•
Esophagealatresia •
•
•
Esophagus does not connect connect to stomach
•
Polyhydramnios (baby cannot swallow fluid)
•
Drooling, choking, vomiting (accumulation secretions)
•
Cannot pass NG tube into stomach
•
•
Gastric distension (air ( air in stomach on CXR)
•
Reflux aspiration pneumonia
•
•
Sometimes residual dysmotility
•
GERD
respiratory distress
Omphalocele
Herniation
•
•
Fistula esophagus trachea
Midgut Development Development •
Treatment:surgicalrepair Prognosis:
About 6th week of development
•
Abdomen temporarily becomes too small Intestines “herniate” through umbilical cord •
“Physiologic herniation”
•
Visible on fetal ultrasound!
Persistence of normal herniation = omphalocele omphalocele •
Intestines covered by membrane outside body
•
“Simple omphalocele”
•
Liver does not herniate
•
If lateral embryonic folds fail liver in omphalocele
•
Key features:
Reduction of hernia occurs by 12th week
•
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Liver-containing omphalocele
•
Covered by peritoneum
•
Through umbilical cord
Omphalocele
Gastroschisis
•
Normal GI function
•
Extrusion of bowel through abdominal wall
•
Many genetic defects defects
•
Exact mechanism unclear unclear
•
•
Trisomy 21 (Down ( Down syndrome) syndrome )
•
Trisomy 18 (Edwards syndrome)
•
Trisomy 13
•
•
•
Many associatedconditions conditions •
•
Usually on right side of umbilical cord
Not covered by peritoneum
Congenital heart defects (up to to 50% babies)
•
Orofacial clefts
•
Neural tube defects
Abdominal Wall Defects
Gastroschisis •
Poor GI function
•
Few associated defects
•
Probably involves incomplete incomplete closure of abdominal wall
Paraumbilicalabdominal Paraumbilicalabdominal wall defect
Often associated associated with atresia, atresia, stenosis
•
If GI function restored, restored, good prognosis
•
Rarely associated associated with Down, other congenital congenital disease
Treatment for both: Surgical reduction/closure reduction/closure
Midgut Development Development
Malrotation
Rotation •
•
•
•
•
During physiologic herniation, bowel rotates
•
Midgut rotates around SMA Continues after return to abdomen Results in normal positioning of small bowel, colon •
Cecum in right lower quadrant
•
Obstruction •
Cecum in mid-upper abdomen
•
Peritoneal tissue (Ladd bands)
•
Duodenal obstruction
Volvulus •
Small bowel twists twists around SMA
•
Vascular compromise
•
Vomiting, sepsis (bowel necrosis)
ischemia obstruction
•
Abdominal distention, blood in stool
•
Treatment: surgery
Left sided colon •
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Anatomic variant
Meckel’s Diverticulum
Vitelline Duct Pathology •
In early development, midgut open to yolk sac •
•
By week 5, connection with yolk sac narrows •
•
•
Does not become become enclosed like other portions of gut
•
Persistent remnant of vitelline duct
•
Diverticulum of small bowel (ileum) •
•
Meckel’s diverticulum (most common)
•
Cysts, polyps
Meckel’s Diverticulum
“True diverticulum”
•
Contains all layers of bowel: bowel : mucosa, submucosa, muscular
•
Most diverticulum only mucosa/submucosa
•
Usually defect (hole) in muscular layer
•
•
Often contains stomach tissue •
“Ectopic gastric tissue”
•
Origin unclear
•
Sometimes pancreatic tissue also
•
Usually no symptoms Can present any age but 50% <10 years Often incidental discovery •
Other imaging
•
Abdominal surgery for other reason
Ectopic gastric tissue may secrete acid •
•
Meckel’s Diverticulum •
“Outpouching,” “Bulging”
Normally, vitelline duct disappears by week 9 Persistence congenitalanomalies
•
•
Most common congenital GI abnormality abnormality
“Yolk stalk,” “vitelline duct,” “omphalomesenteric duct”
Meckel’s Diverticulum •
•
Ulceration
•
Pain
•
Bleeding
Potential cause of obstruction, diverticu diverticulitis litis
Meckel’s Diverticulum
Rule of 2’s:
•
Diagnosis
•
2 percent of population
•
Technetium scan
•
Male-to-female ratio 2:1
•
Tracer taken up by gastric cells cells in diverticulum
•
Within 2 feet from the ileocecal ileocecal valve
•
Also capsule endoscopy
•
Usually 2 inches inches in size
•
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Treatment:Surgery
Other Vitelline Duct Anomalies •
Cyst •
•
Often discovered incidentally at surgery
Sinus •
•
Atresia and Stenosis
Intestinal discharge discharge from umbilicus
•
Duodenum most common
•
Colon most rare
•
Polyhydramnios
•
Biliousvomiting
•
Vascular disruption ischemicnecrosis of intestine
In early development, development, duodenum occludes
•
Necrotic tissue resorbed
•
Due to endodermal endodermal proliferation of epithelium epithelium
•
Leaves blind ends ends of bowel
•
Patency restored by recanalization
•
Reproduced in animals with arterial ligation
•
Double bubble sign •
Distention of duodenum duodenum stump and stomach
•
Tight pylorus in middle
•
•
•
•
“Projectile,” non-bilious vomiting (clear/yellow)
Palpable mass •
“ Apple peel atresia ”
Pyloric Stenosis
Pylorus: Connection stomach duodenum Hypertrophy of pylorus = pyloric stenosis Intestinal obstruction •
Bowel distal to blind end may be curled •
Pyloric Stenosis
•
Can occur anywhere in GI tract
•
Associated with Down syndrome
•
•
Jejunal-Ileal-Colonic Atresia
Probably due to failure of “recanalization ”
•
•
•
Cavity behind umbilicus
Duodenal Atresia
•
Atresia = closed/absent opening Stenosis= narrowing/obstruction narrowing/obstruction
Persistent duct •
•
•
Feels like “olive”
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Often occurs as newborn (few weeks old) 30% are first born children More common inmales in males
Spleen Embryology •
Arises from dorsal mesodermal tissue of stomach •
Not from endoderm!
•
Blood supply: celiac trunk (like stomach)
•
Stomach rotation spleen on left side
•
Retained connection to stomach •
Gastrosplenic (gastrolienal) ligament
•
Carries short gastric arteries, left gastroepiploic vessels
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Intra versus versus Retroperitoneal Retroperitoneal •
Gastrointestinal Anatomy
Intraperitoneal Structures •
Covered by mesentery (visceral peritoneum)
•
Stomach, appendix, liver, spleen
•
Small intestine: 1 st part duodenum, jejunum, ileum
•
Colon: Transverse, sigmoid, part of rectum
•
Pancreas: Tail
Jason Ryan, MD, MPH
Intra versus versus Retroperitoneal Retroperitoneal •
Retroperitoneal Bleeding
Retroperitoneal Structures •
•
Aorta, IVC
•
Kidneys
•
Small intestine: 2 nd/3rd portions duodenum
•
Colon: ascending/descending, ascending/descending, part of rectum
•
Pancreas: Head, Head, body
•
•
•
•
•
Often a complication of surgical procedures
Pectinate Line
Greater and Lesser Sac •
Blood visible on CT scan Many causes
Dentate or anocutaneous line
Peritoneal cavity divided into greater/lesser sac Greater sac
•
•
Part of anal canal canal Above line
•
Entire width of abdomen
•
Derived from hindgut
•
Diaphragm to pelvic pelvic floor
•
Columnar epithelium
•
Similar to digestive tract
Lesser sac •
Closed space
•
Behind liver, liver, stomach, lesser omentum
•
•
Epiploic foramen (Omental, Winslow’s) •
Below line
Opening between greater/lesser sacs
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Derived from proctodeum proctodeum (ectoderm)
•
Stratified squamous epithelium
•
Similar to skin
Above Pectinate Line •
Superior rectal artery •
•
•
•
Below Pectinate Line
Superior rectal vein
•
May swell in portal hypertension
Adenocarcinoma Adenocarcinoma (rare form of anal cancer)
•
•
•
•
Imperforate Anus
•
Venous drainage to IVC
•
Lymphdrainage: Internal iliac nodes Visceral innervation (no pain)
•
•
•
inferior mesenteric portal system
•
Internalhemorrhoids
•
Inferior rectal artery artery •
Venous drainage:
•
•
•
Branch of IMA (like distal distal colon)
Hindgut and ectoderm meet to form anus Absence of anal opening = imperforate anus Commonly associated with GU malformations •
Renal agenesis
•
Bladder exstrophy
Presentations: •
Failure to pass meconium
•
Meconium from urethra urethra or vagina (fistula)
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Branch of internal pudendal artery (off (off iliac) Inferior rectal internal pudendal
internal iliac IVC
Lymph drainage: Superficial inguinal nodes Somaticinnervation(painful) Externalhemorrhoids Squamous cell carcinomas (more common anal CA)
Celiac Trunk Key Points
Gastrointestinal Blood Supply
•
Supplies foregut structures structures
•
Esophagus, stomach, liver, gallbladder, spleen
•
•
Part of duodenum, pancreas Mainbranches: •
Common hepatic
•
Splenic
•
Left gastric
Jason Ryan, MD, MPH
Perforated Ulcers •
Gastric ulcers common lesser curvature •
•
Short Gastric Arteries •
Rupture bleeding from left gastric artery
•
Posterior duodenal ulcers •
•
Rupture bleeding from gastroduodenal artery
•
Five to seven small vessels Branches of splenic artery (celiac trunk) Supply fundus and upper cardiac portions stomach stomach Vulnerable to ischemia if splenicartery occluded •
•
•
•
•
•
Key Points
Connects liver to duodenum Found on “free border of lesser omentum” Contains: •
Proper hepatic artery (branch of common common hepatic)
•
Portal vein
•
Cystic duct
•
•
•
•
Pringle’s maneuver •
Clamping of hepatoduodenal ligament
•
Used to controls controls liver bleeding
•
If bleeding continues: continues: IVC or hepatic veins
Supplied by dual sources
SMA
Hepatoduodenal Ligament •
No dual blood supply
Contrast with gastric and gastroepiploic
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Supplies midgut structures Distal duodenum, jejunum, ileum, cecum, appendix Ascending colon, first 2/3 of transverse colon Descends across pancreas head and duodenum
Arcades and Vasa Recta
SMA Syndrome
•
Arcades: Anastamoses of ileal/jejunal arteries
•
Rare cause of bowel obstruction
•
Vasa recta: Arteries extending from arcades
•
SMA courses over distal 1/3 of duodenum
•
•
•
Distal duodenum between aorta and and SMA
•
Mesenteric fat keeps keeps SMA away from duodenum
If pressed downwards obstruction Classic patient: Recent, massive weight loss •
Fat pad shrinks
IMA
Dual Blood Supply Areas
Key Points
Abdominal Collaterals
•
•
Supplies hindgut structures Last 1/3 transverse, descending, sigmoid colon
•
Celiac trunk – SMA •
Superior and inferior pancreaticoduodenal pancreaticoduodenal arteries
•
Gastric ischemia from vessel occlusion rare
Dual Blood Supply Areas
Dual Blood Supply Areas
Abdominal Collaterals
Abdominal Collaterals
•
SMA –IMA
•
IMA – Iliac
•
Marginal artery of Drummond
•
•
Branches from middle (SMA) and left (IMA) colic arteries
•
Superior rectal (IMA) merges with middle rectal rectal (iliac)
•
Rectal ischemia from from occlusion rare
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Occurs in rectum
Mesenteric Ischemia
Intestinal Ischemia •
•
Causes
Mesenteric ischemia
•
Embolism (most common)
•
Ischemia of the intestines
•
Often cardiac origin
•
Ischemia of small small intestine is most severe
•
LV thrombus
•
Often life threatening
•
LA appendage appendage (atrial fibrillation)
•
Often affects jejunum (via SMA)
Ischemic Colitis •
Ischemia of the colon
•
May spontaneously resolve
•
Arterial thrombosis thrombosis •
Usually occurs at at site of atherosclerosis
Mesenteric Ischemia
Mesenteric Ischemia
Causes
Symptoms
•
•
Venous thrombosis
•
Venous clot
•
Hypercoagulable states, malignancy
•
resistance to flow out of mesentery
•
Non-occlusive Non-occlusive ischemia •
Under perfusion (shock)
•
Usually affects watershed areas areas of colon
•
Often results in ischemic colitis
Mesenteric Ischemia
Watershed Areas
Causes •
Physical exam: •
•
Usually sudden onset Abdominal pain, cramping
•
“Pain out of proportion proportion to exam”
•
Usually mild tenderness
•
No rebound tenderness or peritoneal signs
•
Occult blood in stool
•
•
•
Labs: •
↑WBC
•
↑ lactate and acidosis
•
Colon areas located between major vessels At risk for ischemia in shock/hypoperfusion Often ischemic in ICU patient: hypotension, pressors #1 Splenic flexure •
Supplied by small branches
•
Marginal artery of Drummond v ery small
•
Splenic flexure vulnerable to under perfusion
#2: Rectosigmoid junction •
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Supplied by narrow branches branches of IMA
Chronic mesenteric ischemia Intestinal Angina •
Usually older patient with other vascular disease •
•
•
•
PAD risk factors common (smoking, DM)
Recurrent abdominal pain after eating Fear of eating weight loss Sudden worsening on top of history of recurrent pain may suggestacute thrombosis
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Digestive Tract Layers
Gastrointestinal Tract
•
Mucosa
•
Submucosa
•
•
Muscularlayer Serosa
Jason Ryan, MD, MPH
Mucosa •
•
•
Submucosa
Epithelium: absorption of nutrients Lamina propria •
Support
•
Gastric glands in stomach
•
•
•
•
Clinicalcorrelation: Hirschsprung's disease
Muscularis mucosa: motility
Muscular Layer •
Connectivetissue Contains Meissner’s plexus (submucosal (submucosal plexus)
Serosa
Layers of smooth muscle muscle •
Inner circular layer
•
Outer longitudinal layer
•
•
•
Auerbach’s Auerbach’s plexus •
Between layers
•
Abnormal in achalasia achalasia
Surrounds GI tract Layer of surface epithelial cells: mesothelium
•
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Secretes lubricating fluid
Retroperitonealstructures:adventicia •
Loose connective tissue
•
Not lubricated
Esophagus •
•
Stomach
Stratifiedsquamous epithelium Non-keratinized
Crypts, Villi and Microvilli •
•
Mucosa extensions into lumen
•
Increase surface area for absorption
•
•
•
Gastric glands •
Found in lamina propria
•
Parietal cells
•
Chief cells
•
Mucous neck cells
•
G cells
•
Valves Valves of Kerckring or Kerckring folds
•
Valvulae conniventes
•
Folds of mucosa and submucosa Most abundant in jejunum
Microvilli •
Microscopic extensions
•
Epithelial cell membrane membrane
Brunner’s Glands
Found in small and large intestine Produce mucinogen mucous Increase in number from duodenum to ileum •
•
•
Contain goblet cells
Goblet Cells •
•
•
Crypts ( of Lieberkuhn) Lieberkuhn) •
Simple columnar epithelium epithelium Gastric pits
Plicae Circulares
Villi •
•
•
•
•
Ileum has most
•
Not normally found in stomach •
Occur in stomach stomach in setting of chronic inflammation (gastritis)
•
“Intestinal metaplasia”
•
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Only induodenum in duodenum Found insubmucosa in submucosa Produces alkaline (basic) fluid Protects from acidic stomach fluid and chyme
↑ thickness in peptic ulcer disease
Peyer’s Patches •
More lymph cells duodenum ileum •
•
Lacteal
Found in lamina propria (mucosa)
•
Lymphatic channels within villi
•
Important for absorption of fats
In ileum, ileum, lymph cells aggregate Peyer’s patches •
Found in muscularis mucosa/submucosa mucosa/submucosa
Duodenum = Brunner’s Glands Ileum = Peyer’s patches Jejunum = Neither
Colon •
•
•
•
Haustra
Produces lots of mucous mucous Absorbs fluid and e lectrolytes
•
•
•
Pouches of the colon
•
Can be seen on imaging to identify large bowel
Crypts without villi Lots of goblet cells
Ulcers and Erosions •
•
Enteric Nervous System
Breakdown of GI tract lining Dyspepsia,bleeding Erosions: mucosa only
•
Submucosal plexus (Meissner's plexus)
•
Myenteric nerve plexus(Auerbach’s plexus)
•
•
Ulcers: submucosa and muscularis mucosa
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Controls secretion and blood flow
Major role is control control of GI motility
Slow Waves •
Oscillating membrane membrane potential of GI smooth muscle
•
Original in interstitial cells of Cajal
•
•
Slow Waves
Membranepotential “slowly” rises near threshold When near threshold, action potentials may occur
Voltage
Tension
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•
Sets maximum number of contractions per time
•
Characteristic Characteristic for each part of GI tract •
Stomach: 3/min
•
Duodenum: 12/min
•
Ileum: 8/min
Ampulla of Vater
Liver, Gall Bladder, Pancreas
•
Ampulla = roman flask flask
•
Cystic/pancreatic Cystic/pancreaticducts merge
•
•
•
Empties into major duodenal papilla Bile, pancreatic enzymes into duodenum Halfway along second part of duodenum
•
Anatomical transition from foregut to midgut
•
Point where celiac trunk transitions to SMA
Jason Ryan, MD, MPH
Major Duodenal Papilla •
Sphincter of Oddi
Bile, pancreatic enzymes into duodenum
•
•
•
•
Sphincter of Oddi Dysfunction •
•
•
Episodes of RUQ pain
•
Possible abnormal LFTs, hyperbilirubinemia
•
Pancreaticsymptoms
•
Potential therapies
•
Smooth muscle relaxants (Ca channel channel blockers, nitrates)
•
Endoscopic sphincterotomy
•
May be caused by opioids (i.e. morphine)
•
Meperidine (Demerol) used in acute pancreatitis
•
•
Recurrent pancreatitis
•
Controls flow of bile, pancreatic enzymes Prevents reflux
Sphincter of Oddi Spasm
Narrowing of Sphincter of Oddi Can occur after pancreatitis, gallstone disease Biliarysymptoms •
Circularmuscular Circular muscular(smooth) (smooth)layer Surrounds major duodenal papilla
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Smooth muscle contraction
No clinical data that morphine leads to worse outcomes or that meperidine is better
Liver Lobules •
•
Two blood supplies: •
Portal veins (80%): (80%): deoxygenated blood from GI tract
•
Hepatic artery (20%) Hepatic veins: carry processed blood away from liver
Bile duct
Liver Zones •
Zone I (periportal) •
•
Zones III (centrilobular)
t c u D e l i B
n i e V l a t r o P
Zone I
Zone II
Periportal
Mid Zone
n i e V c i t a p e H
Centrilobular
•
Two buds from foregut: Ventral and dorsal
•
Ventralbud
•
Bud off from endodermal endodermal lining of duodenum (foregut)
•
Furthest from blood supply
•
Part of head, uncinate process
•
Most vulnerable to ischemia
•
Main pancreatic duct
•
Fat accumulation begins here in alcoholic alcoholic liver disease
•
High concentration P450 enzymes in hepatocytes hepatocytes
Secondarily retroperitoneal
Zone III
Pancreas Embryology
Affected by viral hepatitis first
Pancreas •
y r e t r A c i t a p e H
One drainage vessel: vessel: •
•
Liver Zones
•
Doral bud •
Rest of head
•
Body, tail, accessory duct
Annular Pancreas •
Congenital anomaly of ventral bud
•
Forms covered in peritoneum peritoneum (intraperitoneal)
•
Initially composed of two separate pieces of tissue
•
Later fuses with posterior wall retroperitoneal
•
Normally fuse
•
Can fuse around duodenum
•
Ring of pancreatic tissue that surrounds duodenum
•
Can cause bowel obstruction
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Pancreas Divisum •
Dorsal and ventral ducts do not fuse
•
Two separate ducts
•
•
•
Accessory (dorsal) duct drains majority majority of pancreas
•
Second ventral ventral duct persists
Often asymptomatic May cause pancreatitis pancreatitis
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Salivary Glands •
Three major glands
•
Also many tiny salivary glands throughout mouth
•
All produce saliva saliva
Salivary Glands Jason Ryan, MD, MPH
Salivary Glands •
•
Submandibular gland •
Floor of mouth
•
Wharton’ duct mouth Floor of mouth
•
Behind the angle of the the jaw
•
Below and in front front of ears
•
Largest salivary gland
Mucin, glycoproteins
•
•
•
•
Protects against against infectious agents
Loss of saliva (Sjogren’s) infections •
•
Lubricate food
•
Bind bacteria
IgA antibody Lysozymes disrupt bacterial cell walls Lactoferrin prevent bacterial growth Proteins that protect teeth
Saliva
Important for innate immunity •
•
Mostly water (>90%) (>90%)
•
•
Parotidgland
Saliva •
•
Sublingual gland •
•
Saliva
Dental carries (cavities)
20
Two important enzymes for digestion •
α amylase (digests (digests carbohydrates)
•
Lingual lipase lipase (digests li pids)
α-amylase
Lipase Enzymes
Salivary amylase
•
Optimal pH >6
•
Minor contributor to lipid metabolism in adults
•
Inactivated in stomach
•
More important in newborns (lower pancreatic enzyme levels)
Pancreatic amylase
•
Salivary (lingual) lipase
•
•
•
Pancreaticlipase
•
Functional in small intestine
•
Salivary Electrolytes •
Salivary fluid produced by acinar cells
•
Modified by ductalcells
Main lipase for lipid digestion
Salivary Electrolytes •
Initial fluid similar to plasma (isotonic (isotonic)) •
•
Same Na, Cl, K, HCO 3- concentration
Ductal cells (impermeable to water): •
Remove Na, Cl
•
Secrete K, HCO 3- (bicarb raises pH protects against acid)
Na
K
Na Cl
K
Cl
HCO3-
HCO3-
Salivary Electrolytes
Salivary Electrolytes •
Saliva becomes hypotonic from removal Na, Cl •
•
•
Lower concentrations concentrations than plasma
•
Saliva: higher concentration of K, HCO3- than plasma
Na Na
K
Cl
K
Cl HCO3-
HCO3-
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Composition varies with flow rate Higher flow: •
Less time for ductal ductal modification
•
Fluid becomes more more like plasma
•
Closer to isotonic with plasma
•
[Bicarb] goes up at high flow rates
•
More CO2 in glandular cells
more bicarbonate
Regulation of Saliva
Aldosterone Effects salivary glands similar to kidneys
•
•
↑ Na absorption ↑ K secretion
•
•
Na Na
K
Increased by sympathetic AND parasympathetic •
Not regulated by gastrointestinal hormones
•
Sympathetic: smaller effect
•
Parasympathetic: greater effect (major system)
•
Activated by food smell, sight, etc.
•
Muscarinic receptors (M1 and M3) important
Cl
K
Cl HCO3-
HCO3-
Salivary Duct Stones
Regulation of Saliva •
Muscarinic antagonists •
•
•
Sialolithiasis •
Cause dry mouth
•
Atropine, Atropine, Scopolamine
•
Muscarinicagonists •
Increase saliva production
•
Pilocarpine (used in Sjogren’s syndrome)
•
Cholinesterase poisoning salivation
•
•
•
Sialadenitis •
•
•
•
•
•
•
•
Common treatment: Nafcillin (Staph coverage)
•
Metronidazole or Clindamycin (anaerobes)
Usually aggravated by eating Most common in submandibular glands Riskfactors: •
Dehydration, diuretics
•
Anticholinergic medications
Treatment: NSAIDs, hydration; rarely surgery
Mumps
Inflammation of salivary gland Often secondary to obstructingstone Most often due to Staph Aureus Also often contains anaerobes •
Obstruction of salivary flow Pain/swelling of gland
22
Caused by RNA mumps virus Largely prevented by vaccination vaccination (MMR) Key feature:Parotitis feature: Parotitis •
Often bilateral
•
Inflammation of parotid glands (facial (facial swelling)
Pleomorphic Adenoma
Salivary Tumors •
Usually present in the parotid gland
•
Often present asfacial as facial swelling
•
Most are benign •
Mobile (not growing into into other tissues)
•
Painless (not invading invading nerves)
•
When pain present usually indicates invasive lesion
•
May involve facial nerve (paralysis)
Benign Mixed Tumor •
Most common salivary gland tumor
•
Usually benign
•
•
•
Rarely can undergo undergo malignant transformation
•
Often results in pain, pain, facial nerve dysfunction
Most common in superficial lobe of parotid gland Painless, mobile mass at angle of jaw
Pleomorphic Adenoma
Pleomorphic Adenoma
Benign Mixed Tumor
Benign Mixed Tumor
•
Epithelial and stromal tissue cells •
Epithelial: Glandular cells
•
Stromal: Cartilage, sometimes may see bone
•
•
•
Risk factors: Prior radiation Treatment: Surgery +/- radiation Can have local recurrence •
Often has irregular margins
•
Tumor cells left behind after surgery
recurrence
Warthin’s Tumor
Warthin’s Tumor
Papillary Cystadenoma Lymphomatosum
Papillary Cystadenoma Lymphomatosum
•
•
•
Second most common salivary tumor Usually occurs in parotid gland Key risk factor: Smoking (8x more common!) common!)
•
23
Key histological histological finding: •
Cysts filled with fluid
•
Cysts surrounded by dense lymphoid infiltrate
•
Lymph tissue can aggregate into germinal centers
Mucoepidermoid Carcinoma •
Most common malignant salivary tumor
•
Key risk factor: prior radiation
•
•
Mucoepidermoid Carcinoma •
Occur in parotids •
Sometimes invade facial nerve (paralysis)
•
Can also cause cause pain
Also commonly found in minor salivary glands
24
Mixture of cells: •
Squamous (epidermoid) cells
•
Mucus-secreting cells
•
Intermediate hybr id cells
Hernia •
Protrusion of organ through cavity wall
•
Can lead to organ dysfunction, necrosis/infection
•
Common in areas of discontinuity of abdominal wall •
Hernias
Inguinal canal
•
Esophagus
•
Umbilicus
Jason Ryan, MD, MPH
Femoral Vessels •
Lateral to medial •
•
Femoral Sheath •
Nerve-artery-vein-lymphatics
•
“NAVeL”
•
“Venous to the penis”
•
•
Superior: Inguinal ligament
•
Medial: Adductor Adductor longus
•
Lateral: Sartorius
Femoral Ring and Canal •
Site of femoral hernias
•
Component of femoral sheath
•
Lymph vessels and deep inguinal nodes
Does not contain contain nerve
Inguinal Canal
Opening to femoral canal is femoral ring •
Contains femoral vein, artery, and ring •
Femoraltriangle •
Tunnel of fascia Below inguinal ligament
25
•
Runs across femoral vessels
•
Testes descend through inguinal canal to scrotum
Spermatic Cord
Inguinal Canal
•
Travels in inguinal canal
•
Passage in abdominal abdominal wall
•
Ductus deferens, arteries, veins, nerves
•
Carries spermatic spermatic cord in males
•
Three fasciallayers
•
•
External spermatic fascia
•
Cremasteric fascia
•
Internal spermatic fascia
•
•
•
Inguinal Hernias •
Three types of hernias occur in inguinal region
•
•
•
•
•
“Indirectly” through abdominal wall
•
Indirect inguinal hernias
•
Travel Travel through inguinal canal
•
Direct inguinal hernias
•
Not “directly” through a hole
•
Femoral hernias
•
Origin lateralto lateral to epigastric vessels
•
Follows path of descent of testes Covered by all layers of spermatic fascia
•
Contrast with direct hernias (outer layer layer only)
Congenital defect •
Bowel protrudes through patent processus vaginalis
•
Should close after descent of testes
Demographics
Testes descend throughprocessus throughprocessus vaginalis Outpouching of peritoneum Remains open in newborn period Should close (“obliterate“) (“obliterate “) in infancy
•
Most common type of inguinal hernia •
Males = 50% hernias are indirect
•
Females = 70% are are indirect
•
More common in men
•
Typically occurs right side
•
Commonly extend into scrotum
•
Replaced by fibrous tissue Part remains as tunica vaginalis testis •
•
Indirect Inguinal Hernia
Processus Vaginalis •
Floor: Inguinal ligament ligament
Indirect Inguinal Hernia
•
•
Round ligament in females Entrance: Deep inguinalring Exit: Superficial inguinal ring
•
Serous covering of testes
26
Men 10x more likely than women Persistent processus processus vaginalis more common on right
Indirect Inguinal Hernia
Indirect Inguinal Hernia
Demographics
Key Points
•
•
Usually occurs in adulthood with risk factors •
Heavy lifting
•
Straining (constipation)
•
Through internal and external inguinal rings
•
Follows path of descent of testes (in men) •
Can occur in newborns on mechanical ventilation
•
•
•
•
•
•
•
•
Bowel bulges “directly” through abdominal wall Protrudesthrough Hesselbach’s triangle
•
•
Origin is medial to epigastric vessels Through external ring (not deep/internal)
•
•
•
•
Inguinalligament Inferior epigastrics Rectus abdominis Floor:Transversalisfascia
Covered by external spermatic fascia only Should never bulge into scrotum
Direct Inguinal Hernia •
Most common type of inguinal hernia
Hesselbach’s Triangle
Direct Inguinal Hernia •
In women follows round round ligament toward labia majora
In men, covered by spermatic fascia fascia (three (three layers) layers) Origin lateralto lateral to inferior epigastric vessels
Femoral Hernias
Caused by transversalis transversalis fascia breakdown Weakness in floor of inguinal canal Usually occurs in older men •
•
Hernia through femoral ring
•
Bowel protrudesbelow protrudes below inguinal ligament
•
More common in women than men
•
High risk of incarceration
•
•
Years of stress on connective tissue (“acquired”)
•
•
27
Medial to femoral femoral vessels Differentiates from both types of inguinal hernias But indirect most common type for both genders Femoral ring is small small opening
Inguinal Hernias
Inguinal Hernias
Physical Exam
Complications
•
Most hernias obvious on inspection •
•
•
Bulge in the groin
Coughing often increases size of bulge •
Incarceration •
Bowel trapped in hernia sac
•
Cannot be “reduced” back into abdomen/pelvis
Increased abdominal pressure with cough cough
Inguinal Hernias
Inguinal Hernias
Complications
Diagnosis
•
Strangulation •
•
Blood flow cutoff
•
Bowel in hernia sac becomes ischemic/necrotic
•
Painful, red, swollen
•
Fever
•
Urgent surgery indicated
•
Femoral hernias in women
•
Inguinal Hernias
Ventral Hernias
Treatment •
•
•
Usuallydiagnosedclinically Ultrasound/CT sometimesused
All treated surgically surgically Primary closure Mesh placement
•
•
•
•
28
Anterior abdominal wall Many subtypes Umbilical – near umbilicus umbilicus Incisional hernias – site of abdominal incision
Hiatal Hernias •
Stomach herniation into thorax
•
Leads to GERD (heartburn) (heartburn)
•
Hiatal Hernias •
Major risk factor: obesity
•
Displacement of GE junction above above diaphragm
•
Stomach in usual usual alignment
•
Fundus remains below GE junction
•
“Hourglass” appearance
•
Herniation through hiatus
CDH
Hiatal Hernias •
Type I: Sliding hiatal hernia (95%)
Congenital diaphragmatic hernia
Types II, III, IV: Paraesophageal
•
Developmental defect of diaphragm
•
GE junction in normal location
•
Defective formation pleuroperitoneal membrane
•
Protrusion of stomach stomach fundus
•
Hole in diaphragm
•
Defect in the “phrenoesophageal “phrenoesophageal membrane”
•
Bowel sounds in lung fields is classic classic finding
29
•
Abdominal organs herniate into chest
•
In utero herniation pulmonary hypoplasia
•
Often fatal
Bile •
Produced in liver
•
Stored in gall bladder
•
•
•
Bile
Secreted into duodenum after meal Mostlywater Phospholipids, electrolytes
•
Bile salts – necessary for lipid absorption
•
Bilirubin – mode of excretion from body
Jason Ryan, MD, MPH
Absorption of Fats
Lipids Glycerol Fatty Acid
Fatty Acids Triglyceride Pancreatic Lipase
Triglyceride
Mono-glyceride H
H
Bile Salts
Bile Salts
Emulsification
Surfactant
Hydrophobic
Lipids
Hydrophilic
30
Bile Acids
Bile Acids •
•
Taurine (organic acid) and glycine(AA): glycine (AA):hydrophilic hydrophilic Conjugation Conjugation to bile acids better surfactant •
One end = hydrophobic
•
One end = hydrophilic
Cholic acid Taurine
Cholesterol
Cholic acid
Chenodeoxycholic Chenodeoxycholic acid
Hydrophobic
Bile Salts
Glycine
Bile Acids
Hydrophilic
Synthesis •
Synthesized only in liver
•
Cholesterol7Cholesterol7-α hydroxylase
•
Taurocholic acid
•
Taurine
Two pathways: classic classic (>90%) and and acidic (<10%) Rate limiting enzyme classic pathway
•
Cytochrome P450 enzymes
•
Requires NADPH and and oxygen
Glycocholic acid lycine 7-α hydroxylase
holic acid
Cholesterol
7-α hydroxycholesterol
Bile Acids
Bile Salts
Enterohepatic Circulation Circulation
Functions
•
•
•
•
Most lipid absorption (TGs) occurs jejunum Conjugated bile acids not absorbed with lipids •
Pancreatic lipase releases fatty acids absorbed
•
Bile salts remain behind
•
•
•
Pass to distal small intestine Absorbed by active transporters interminal in terminal ileum
•
About 95% absorbed and recycled
•
~5% excreted in stool
31
#1: Emulsification Emulsification of fats #2: Excretion of cholesterol #3: Antimicrobial
Cholic acid
Bile Salts
Bile Salts
Cholesterol Excretion
Antimicrobial
•
•
•
Cholesterol not soluble in water Conjugated bile water soluble excretion in stool
•
•
•
•
•
Seen in liver disease
•
Cholestyramine, colestipol, colesevelam
•
•
Retain bile acids
•
•
Prevent reabsorption
•
More excreted in stool
Disrupt bacterial cell membranes Other antibacterial effects described
Cholic acid
Alkaline Phosphatase Alk Phos
Disrupted bile flow to intestines Lab findings: •
Direct (conjugated) hyperbilirubinemia
•
Elevated alkaline phosphatase
•
•
Symptoms •
Jaundice (yellowing of skin)
•
Pruritus (itching – bile salts in skin)
•
Dark urine (conjugated bilir ubin in urine)
•
Clay colored stools (loss of stercobilin)
Produced by bile duct epithelial cells •
Obstruction of bile flow ↑ alkaline phosphatase synthesis
•
Plasma levels will rise with obstruction
Hepatocytes contain AST/ALT Damage to cells
•
•
↑ AST/ALT
Cholestasis: •
↑ alk phos >> ↑ AST/ALT
•
Primary site of dysfunction is bile ducts
•
Some secondary effects on hepatocytes
Long term: fat malabsorption, ↓ fat soluble vitamins
Hepatocellular Damage •
•
•
Cholestasis •
Small intestine has few bacteria Loss of bile salts bacterialovergrowth
Bile acid resins
Cholesterol
•
•
Patterns of Bile/Liver Damage
Primary site of dysfunction is hepatocytes Phos ↑ AST/ALT >> ↑ Alk Phos Some secondary effect on bile ducts
•
•
Seen in many forms of liver disease
When ↑ Alk Phos >> ↑ AST/ALT •
Primary abnormality relates relates to bile ducts
•
“Cholestatic pattern”
AST/ALT T >> ↑ Alk Phos Phos When ↑ AST/AL •
Primary abnormality r elates to hepatocytes
•
“Hepatocellular pattern”
Example #1 AST 100 IU/L ALT 120 IU/L Alk Phos 500 IU/L IU/L
32
Example #2 AST 500 IU/L ALT 550 IU/L Alk Phos 200 IU/L IU/L
Cholestasis •
Cholestasis
Best first test: Right upper quadrantultrasound quadrant ultrasound •
•
Differentiates extrahepatic from intrahepatic
•
Extrahepatic causes (workup: additional imaging) •
Gallstones
•
Pancreatic mass
•
Biliary strictures
Intrahepatic causes (workup: lab tests, biopsy) •
33
Primary biliary cirrhosis
•
Cholestasis of pregnancy
•
Contraceptives
•
Erythromycin
Bile •
Produced in liver
•
Stored in gall bladder
•
•
•
Bilirubin
Secreted into duodenum after meal Mostlywater Phospholipids, electrolytes
•
Bile salts – necessary for lipid absorption
•
Bilirubin – mode of excretion from body
Jason Ryan, MD, MPH
Bilirubin
Heme Metabolism •
Heme released from old RBCs •
•
•
Some from myoglobin, myoglobin, cytochromes, cytochromes, bone marrow cells
Macrophages engulf residual heme Converted to biliverdin then bilirubin NADPH
Bilirubin (brown/yellow (brown/yellow color)
Heme
Heme
Bilirubin •
•
NADPH
Heme Oxygenase
Biliverdin (green)
Bilirubin ( brown/yellow) Biliverdin Reductase
Bilirubin Conjugation Conjugation in Liver
Poor solubility in water Carried by albumin to liver Unconjugated Bilirubin UDP glucuronyltransferase
Glucuronic Acid Bilirubin
34
Conjugated Bilirubin (Bilirubin diglucuronide)
Bilirubin Metabolism Metabolism
Bilirubin Conjugation
Intestines
•
Bilirubin-UDP-glucuronyltransferase Bilirubin-UDP- glucuronyltransferase (UGT)
•
Two conversions by bacteria
•
Adds glucuronic acid molecules to bilirubin
•
#1: Converted back to unconjugated in intestines
•
Produce more water soluble compounds
•
•
Bilirubin monoglucuronide
•
Bilirubin diglucuronide
•
facilitates excretion with bile ↑ water solubility facilitates
•
Distal small intestine intestine and colon
•
Bacteria beta-glucuronidase enzymes
#2: Unconjugated bilirubin urobilinogen •
Urobilinogen
Via bacterial enzymes
Urobilinogen •
Fate #1: Excretion in feces (80-90%)
•
Fate #2: Reabsorbed by intestines ( 10-20%)
•
Bilirubin
Converted to stercobilin (makes stool dark)
•
Most taken up by liver
•
Small amount excreted excreted in urine
•
Converted to urobilin (makes urine yellow)
Stercobilin
Urobilinogen
Bilirubin
Bilirubin
Clinical Measurements
Clinical Measurements
•
•
•
Van den Bergh reaction
•
Urine
•
Coupling of bilirubin with a diazonium salt
•
Bilirubin (conjugated only): Normal absent
•
Forms a colored complex
•
Urobilinogen: Urobilinogen: Normally a small amount
Serum Conjugated Conjugated bilirubin •
Soluble in water
•
Can direct ly ly undergo the the reaction in solution
Serum Unconjugated Unconjugatedbilirubin •
Not soluble in water
•
Must be mixed with alcohol first
•
Then can add to Van Van den Berg medium
•
“Indirect ” bilirubin
35
Urobilin
Jaundice •
Dark Urine
Yellowingof Yellowing of skin, conjunctiva, mucous membranes •
Scleral icterus (eyes) often earliest earliest sign
•
Also visualized early early under the tongue
•
Normal: total bilirubin <1.0mg/dL
•
Jaundice usually total >3.0mg/dl
Seen with elevated conjugated bilirubin
•
Also seen in:
•
Bilirubin Metabolism
Only conjugated conjugated bilirubin is water soluble
•
Rhabdomyolysis (myoglobin)
•
Hematuria any cause
•
Dehydration (common in actual practice)
Hyperbilirubinemia
Clinical Assessment •
•
#1: Serum bilirubin
•
Four general causes of ↑ bilirubin
•
Total
•
•
Direct
•
Biliary obstruction (cholestasis)
•
Indirect
•
Liver disease
•
Special causes
•
#2: Urine urobilinogen urobilinogen (normally small amount)
•
#3: Urine bilirubin (conjugated - normally absent)
Hemolysis
Hyperbilirubinemia
Hyperbilirubinemia
Hemolysis
Biliary Obstruction
•
•
Hemolysis or large hematomas ↑ heme metabolism Elevated serum unconjugated bilirubin •
•
Too much bilirubin to liver (overwhelms capacity)
No urine bilirubin detected •
•
•
Unconjugated bilirubin cannot cross glomerulus
Increased urobilinogen •
More bilirubin more urobilinogen
36
Cholestasis = lack of bile flow •
Extrahepatic: Gallstone, pancreatic mass
•
Intrahepatic: Alcoholic liver disease, viral hepatitis
•
Conjugation occurs normally
•
Excretionimpaired Elevated direct bilirubin
Hyperbilirubinemia
Hyperbilirubinemia
Biliary Obstruction
Biliary Obstruction
•
Findings:
•
Urine bilirubin detected
•
Cholestatic LFT pattern : ↑ AlkP >> ↑ ALT/AST
•
Conjugated bilirubin water soluble
•
Clay colored stools (lack of stercobilin)
•
Crosses glomerulus urine
•
Results in dark urine
•
Absenturobilinogen •
No bilirubin to intestine
•
Loss of formation of urobilinogen
Hyperbilirubinemia
Hyperbilirubinemia
Primary Liver Diseases
Primary Liver Diseases
•
Bilirubin fractionation fractionation unreliable for liver disease
•
Unconjugated
hyperbilirubinemia
Often mixed increase increase of direct/indirect
•
Occurs in liver disease disease with significant hepatocyte damage
•
Usual finding: elevated total bilirubin
•
Chronic hepatitis, hepatitis, advanced cirrhosis
•
Diagnosis made by: LFTs, antibody antibody tests, imaging, biopsy
•
•
•
Conjugated hyperbilirubinemia •
Occurs i n “intrahepatic “intrahepatic cholestasis”
•
Liver disease with prominent prominent damage to bile ducts
•
Viral hepatitis, alcoholic hepatitis, hepatitis, NASH
Many liver diseases have elements of hepatocyte and intrahepatic bile duct involvement
Urobilinogen
Hyperbilirubinemia
Primary Liver Diseases
Lab Findings
•
↑↑ early in liver disease •
•
Urobilinogen from intestines reabsorbed as usual
•
Cannot be excreted in bile
•
Spills into urine
↓↓ late in liver disease •
Lack of conjugated conjugated bilirubin to intestines
•
Less formation of urobilinogen
•
Less urobilinogen in urine
Source: Sircar, S. (2008) Principles of Medical Physiology, Thieme Medical Publishers
37
Hyperbilirubinemia
Rifampin/Probenecid
Special Causes •
Rifampin/Probenecid
•
Gilbert’s Syndrome
•
•
•
•
Crigler-Najjar Crigler-Najjar Syndrome Dubin-JohnsonSyndrome Rotor’s Syndrome
•
•
•
•
Result: Mild decrease decrease in enzyme enzyme levels
•
•
•
•
•
Findings: •
Jaundice can occur with ↑ bilirubin production Fasting
•
Febrile illnesses
•
Heavy physical exertion
•
Stress
•
Menses
•
•
•
Severely reduced/absen t UGTenzyme Cannot conjugate bilirubin Type I usuallypresents usually presents in infancy ↑ unconjugated bilir ubin (often >20 mg/dl)
•
Jaundice
•
Kernicterus (cause of death)
Often fatal
No serious clinical consequences
Kernicterus •
All other LFTs normal
•
Mild ↑ total and unconjugated bilirubin (usually <3 mg/dl)
•
Compete with bilirubin for uptake by liver Blunt hepatic uptake of unconjugated bilirubin Result: mild ↑ unconjugated bilirubin (and total)
Crigler-Najjar Syndrome
UDP-glucuronyltransferasefunction ↓ UDP-glucuronyltransferase Commonly defective promotor UGT gene
•
•
NeonatalJaundice
•
Rifampin (antibiotic) (antibiotic) Probenecid(gout)
•
Gilbert’s Syndrome •
•
Crigler-Najjar Syndrome
Unconjugated bilirubin soluble in fats Easily crosses blood-brain barrier or enters placenta Acts as a neurotoxin •
•
•
•
Basal ganglia; brain stem nuclei
•
Usually need bilirubin level >25mg/dl
•
Newborns (esp. preterm) particularly vulnerable
38
Type II: Less severe (bilirubin <20mg/dl) <20mg/dl) Reduced risk of neurologic consequences consequences Sometimes treated with phenobarbitalor phenobarbital or clofibrate •
Phenobarbital: Seizure drug/sedative
•
Clofibrate: Lipid-lowering Lipid-lowering agent
•
Both induce liver glucuronidation
•
Lower bilirubin levels up to 25%
Dubin-Johnson Syndrome •
Conjugated hyperbilirubinemia
•
Defective liver excretion of conjugated bilirubin
Dubin-Johnson Syndrome •
•
Abnormal gene that that codes for multidrug resistance proteins
•
Total bilirubin usually 2 to 5 mg/dL (~50% conjugated)
•
MRPs: Necessary Necessary for bilirubin excretion excretion to bile
•
May see bilirubin in urine
•
No pruritus
•
Liver turns black (classically seen in abdominal surgery)
Rotor’s Syndrome •
•
Similar to Dubin-Johnson Milder
•
•
Neonatal Jaundice
•
Isomerization (same chemical f ormula; different structure)
•
More water soluble
•
Allows excretion w ithout conjugation
↑ bilirubin (more RBCs, shorter lifespan)
•
↓ UDP-glucuronyl transferase activity (“immature”)
•
Takes 14 weeks for enzyme to reach reach adult level of function
Result: ↑ unconjugated bilirubin Can lead tokernicterus to kernicterus Preterm infants at greatest risk
Bilirubin Algorithm
Treatment: Phototherapy Exposes skin to light of specific wavelength Converts bilirubin to lumirubin •
Several mechanisms •
No black liver (differentiates Dubin-Johnson)
•
•
Benign condition; no treatment required
Neonatal Jaundice
•
•
↑ conjugated bilirubin
•
•
•
Findings:
39
Gastric Acid •
Gastrointestinal Secretions
•
•
Jason Ryan, MD, MPH
Parietal cells •
•
•
•
Parietal cells of stomach •
Found in gastric glands
•
Secrete hydrochloric acid (HCL)
Maintains very low pH in stomach (<5; as low as 1) •
Protection against infectious agents
•
Denatures proteins for breakdown/absorption
Stomach cells protected by: •
Mucous and bicarb
•
Secreted by neck cells
Stimuli for Acid Secretion
Found in gastric glands Mucosal layer (lamina propria)
•
More in upper layers Pink colored (eosinophilic) (eosinophilic)
•
•
#1: Gastrin (direct) •
Hormone from G cells cells of antrum (distal) stomach
•
Binds CCKb receptor on parietal cells
#2: Gastrin (indirect) (indirect) •
Activates ECL cells
•
Histamine released
•
Vagotomy & Atropine •
•
Old therapy for gastric ulcers
•
Surgical disruption of vagus nerve to stomach
•
Result: decreased decreased acid production
Atropine •
Muscarinic blocker
•
Blunts parietal cell cell stimulation by ACh
•
Does not block stimulation by vagus
stimulation
ACh muscarinic (M3) receptors
•
Also activates G cells
•
Not via ACh; uses gastrin releasing releasing peptide (GRP)
Gastrin
Intrinsic Factor
Vagotomy •
#3: Vagus nerve
gastrin HCL
40
•
Necessary for vitamin B12 absorption
•
Released by parietal cells (along with H+)
Parietal Cells •
•
Parietal Cells
Separate secretion of H+ and Cl- forHCL Proton pump inhibitors block H+ secretion •
•
•
Omeprazole, pantoprazole
Vomiting •
Urinary Chloride
Loss of HCl •
↑ production HCl
•
HCO3- generated during production
•
Metabolic alkalosis
•
Urinary chloride is low (<20)
•
•
Useful in metabolic alkalosis unknown cause Low (<10-20) in v omiting •
Loss of Cl in gastric secretions
•
High (>20) in diuretic use
•
Classicscenario:
•
Parietal Cells •
H+ formed by carbonic anhydrase Alkaline tide tide after meals due to ↑ serum HCO3-
Diuretics block NaCl resorption
•
Young woman with unexplained metabolic alkalosis
•
Urinary Cl is low
•
Diagnosis: surreptitious vomiting
Parietal Cells
Secretion activated by ACh, gastrin, histamine
•
H+ secretion inhibited by: •
41
Somatostatin and prostaglandins
Second Messengers
Second Messengers •
ACh and gastrin work via Gq proteins with IP3/Ca
•
Histamine, somatostatin, PGs work via Gs/i and cAMP
Acetylcholine Gastrin
Parietal Cells •
•
Parietal Cells
Histamine (H2) blockers Cimetidine, ranitidine, famotidine, nizatidine
•
•
Chief cells •
•
•
•
Histamine Prostaglandins Somatostatin
Misoprostol (PGE1 (PGE1 analog) Blunts acid secretion
Pepsin
Found in gastric glands Mucosal layer (lamina propria) Mostly in deeper layers
•
•
Digests proteins (like chymotrypsin, trypsin) Released by chief cells of stomach •
Dark colored (basophilic) •
42
Cells release pepsinogen
•
Activated to pepsin by H+
•
Works best pH 1 to 3
Stimuli for release: vagus
Gastrin •
Hormone for acid secretion in stomach
•
Produced byG-cells by G-cells
•
Secreted into portal vein blood
•
Physiologic action on parietal cells
•
Gastrointestinal Hormones
Found in mucosa of antrum of stomach
Jason Ryan, MD, MPH
Gastrin
Gastrin
Effects
Mechanism of Effect
•
•
•
Stimulates H+ secretion by parietal cells Stimulates growth of gastric mucosa •
Important in gastrin tumors
•
Hypertrophy and hyperplasia hyperplasia
•
•
•
Increases gastric motility motility
Enterochromaffin-like Enterochromaffin-like cells mediate gastrin effects Gastrin ECL Histamine Parietal cell Parietal cell receptors: •
Histamine (most important)
•
Gastrin
•
Ach (vagus nerve)
Gastrin
Gastrinoma
Stimuli
Zollinger-Ellison Syndrome
•
•
Released in response to:
•
•
Stomach distention
•
Alkalinization
•
Amino acids (especially phenylalanine and tryptophan) tryptophan)
•
Vagal stimulation (mediated by GRP – atropine atropine does does not block)
•
•
•
•
Inhibited by low pH, somatostatin
Phenylalanine
Gastrin secreting tumors Occur in duodenum or pancreas
Tryptophan
43
G cells found in pancreas pancreas in fetus
Excessive acid secretion Hypertrophy/hyperplasia Hypertrophy/hyperpl asiaof mucosa
Gastrinoma
Gastrinoma
Zollinger-Ellison Syndrome
Diagnosis
•
Abdominal pain •
•
•
•
•
Differentiate gastrinomas from other causes ↑ gastrin
Low pH inactivates inactivates pancreatic enzymes
•
Normal G cells inhibited by secretin (leads to ↓ gastric pH)
•
Also inhibits sodium/water absorption in small intestines
•
Gastrinomas stimulated by secretin
•
Result: Poor digestion, steatorrhea, secretory secretory diarrhea
•
Gastrin level will rise after secretin secretin administration
Ulcers •
Most in distal duodenum (often past bulb) or jejunum
•
Refractory to PPI therapy
Heartburn
Pernicious Anemia
High dose proton pump inhibitors
•
Omeprazole, lansoprazole, pantoprazole
•
Octreotide (somatostatin)
•
Inhibits gastrin release for some some patients
•
Surgicalexcision
•
Cholecystokinin •
•
>10 times upper upper limit of normal in gastrinomas
Excessive gastric acid acid cannot be neutralized in intestines
•
•
Secretin test
•
•
•
•
•
Treatment
•
Fasting serum gastrin level •
Chronicdiarrhea Chronic diarrhea
Gastrinoma •
•
Improves with food (raises (raises pH)
Cannot absorb vitaminB12 High gastrin levels typical finding Also G-cell hyperplasia
Cholecystokinin
Hormone for gall bladder contraction Pancreatic enzymesecretion enzyme secretion Released by I cells •
Autoimmunegastritis Loss of parietal cells loss of intrinsic factor
•
•
Small intestine (mostly duodenum and jejunum)
44
Contraction of gall bladder Pancreaticenzymesecretion •
CCK receptors in vagus nerve
•
CCK stimulates vagus nerve
ACh stimulates pancreas
•
Relaxation of sphincter of Oddi
•
Inhibits gastric emptying
HIDA Scan
Cholecystokinin •
Hepatic iminodiacetic acid scan
Stimuli: •
•
Fatty acids and monoglycerides (not triglycerides)
•
Methodof cholecystography cholecystography
•
Test to evaluate RUQ pain
•
Procedure
Amino acids and small proteins
•
Fatty Acid
H
•
•
Mono-glyceride
Usually when ultrasound ultrasound non-diagnostic 99mTc-hepatic i minodiacetic acid administered
•
Should concentrate in gall bladder, pass to intestines
•
Radioactivity can be followed
•
Failure to fill gall bladder suggests obstruction
Sometimescholecystokinin Sometimescholecystokininadministered administered •
Gall bladder radioactivity radioactivity measured before/after
•
Gall bladder ejection ejection fraction determined
H
Secretin •
•
•
•
Secretin
Hormone to raise pH in small intestine Released by S cells of duodenum
•
Released in response to H+ in duodenum Fatty acids in duodenum
•
Secretin •
Secretin stimulation test
•
Increases gastrin production only in gastrinoma cells
•
Neutralizes gastric acids
•
Allows pancreatic enzymes to function
Inhibits gastric H+ secretion •
Many mechanisms mechanisms described
•
Suppresses gastrin release
•
Increases bile production production
•
Promotespancreaticflow •
Water secreted with bicarb
•
Flushes pancreatic pancreatic enzymes into intestines
Somatostatin
Key clinical use: gastrinomas •
Increases HCO3- secretion by pancreatic duct cells
•
•
•
•
Inhibits most GI hormones Released by D cells throughout GI tract Also found in nerves throughout entire body Originallydiscoveredin hypothalamus hypothalamus •
•
45
Shown to inhibit growth growth hormone release
Can act as: •
Hormone (via blood to affect distant targets)
•
Paracrine (affects nearby cells)
Somatostatin
Octreotide •
Analog of somatostatin
•
Used in GI bleeding and other niche roles
•
Bleeding varices: varices: Reduces splanchnic blood flow
Food in stomach ↓ Somatostatin hormone release Acid in stomach Somatostatin release hormone shutdown Regulates digestion/acid digestion/acid secretion
GIP
Octreotide •
•
Carcinoid Syndrome •
Somatostatin receptors receptors found on majority of carcinoid tumors
•
Flushing and diarrhea significantly improve
•
•
•
Acromegaly •
•
Glucose-dependent insulinotropic peptide
•
Inhibit growth hormone hormone secretion •
Inhibit release of of hormones
VIP Neurocrine •
Synthesized in neurons
•
Released in response to action action potential onto onto target cells
•
Causes relaxation of smooth muscle
•
Raises pH (similar to secretin)
•
•
•
•
Important for LES
•
Stimulates pancreatic pancreatic HCO3- secretion
•
Bicarb draws water increased fluid secretion
Only hormone release release in response response to fats, protein, and carbs
Special note: •
Oral glucose metabolized faster than IV glucose
•
IV glucose does does not stimulate GIP release
VIPoma
Vasoactive Vasoactive Intestinal Peptide •
Released by K cells of duodenum/jejunum Stimuli: Glucose, fatty acids, amino acids •
Gastrinoma/Glucagonoma •
Stimulatesinsulin Stimulates insulin release from pancreas Also blunts H+ secretion secretion
•
•
Rare VIP secreting tumors in pancreas (islet cells) Waterydiarrhea (secretorydiarrhea) VIP promotes bicarb secretion
•
Tea-colored, odorless diarrhea
•
Resembles cholera (“pancreatic (“pancreatic cholera syndrome”)
•
Absence of gastric acid
WDHA syndrome •
46
water secretion
Hypokalemia(from Hypokalemia(from high volume diarrhea) Achlorhydria Achlorhydria •
Inhibits gastric H+ secretion
•
Watery diarrhea, hypokalemia, achlorhydria
VIPoma •
VIPoma
Typicalcase
•
Initialtreatment:
•
Adult (30-50 years old)
•
Fluid/electrolyte replacement
•
Long-standing watery diarrhea (no blood, blood, pus)
•
Octreotide (somatostatin)
•
No response to diet changes (elimination of lactose)
•
Endoscopic sampling: High pH in stomach
•
Elevated VIP on serum testing
•
Often metastatic at presentation
•
Often progresses
•
•
•
Released by cells in stomach, intestines, intestines, colon Promotes motility in the fasting state •
•
Highest levels found between meals
Key clinical point: point: •
Erythromycin binds motilin receptors
•
Used to treat gastroparesis
Median survival ~ 8 year
Major Hormone Locations
Motilin •
Surgical resection sometimes possible
47
48
Pancreas •
•
Endocrinefunctions •
Insulin
•
Glucagon
Exocrinefunctions Exocrinefunctions •
Exocrine Pancreas
Secretions that aids aids in digestion
•
Fluid: Fluid: Bicarb, water and electrolytes
•
Digestive enzymes
Jason Ryan, MD, MPH
Exocrine Cells •
•
Pancreatic Fluid
Acinar cells •
Secrete enzymes
•
Secrete some fluid (mostly Na, Cl)
•
•
Also Na+, Cl-, K+
•
Neutralizes acidic fluid from stomach
Modify fluid
•
Secrete bicarb
•
Permeable to water
•
Add water to pancreatic pancreatic juice
Pancreatic Fluid •
Containsbicarb Contains bicarb
Ductal cells •
•
•
Pancreatic Fluid
Composition varies with flow rate Low flow: •
High Cl-
•
Low bicarb
High flow: •
Low Cl-
•
High bicarb
49
Pancreatic Fluid
Pancreatic Fluid
•
Bicarb secreted secreted small ducts
•
•
Reabsorbed large ducts
•
•
Reabsorption ineffective ineffective at high flow rates
•
Pancreatic Enzymes Secreted by acinar cells
•
Cholecystokinin is major stimulus for release
•
Also ACh via vagovagal reflexes •
•
•
GI tract reflex circuits Afferent and efferent fibers both in vagus vagus nerve +
H , amino acids, and and fats in duodenum
Starch= polysaccharide polysaccharide •
•
•
•
•
Repeating alpha-D-glucose alpha-D-glucose molecules linked together
•
Found in plants (humans have glycogen) Starchcontains amylose andamylopectin α-amylase hydrolyzes (breaks) α1-4 linkages
Amylose
Digestcarbohydrates,fats,proteins •
α-amylase
•
Lipase
•
Phospholipase A
•
Colipase
•
Proteases
•
Trypsinogen
α-amylase
α-amylase •
Secreted by S cells of duodenum
Pancreatic Enzymes
•
•
Secretin is main stimulus for HCO 3- secretion Released in response to H+ in duodenum
•
Amylopectin
50
Secreted in active form Salivary(lingual)amylase •
Optimal pH >6
•
Inactivated in stomach
Pancreatic amylase •
Functional in small intestine
•
Elevated in acute pancreatitis
α-amylase
α-amylase Maltose •
Maltotriose Amylopectin
•
•
•
•
Further digestion of carbs at intestinalbrush intestinal brush border •
“Oligosaccharide hydrolases ”
•
Maltase
•
Sucrase
•
Lactase, etc.
Rate limiting step of carbohydrate digestion All carbs broken down to glucose, fructose, galactose Only monosaccharides are absorbed All isomers of glucose (same formula: C6H12O6)
Amylose Limit Dextrins
Pancreatic Fat Digestion •
Pancreatic Fat Digestion
Pancreatic Lipase •
Hydrolyzes 1- and 3- bonds of triglycerides
•
Result: fatty acids acids plus monoglycerides
•
Also elevated in acute pancreatitis
•
Colipase
•
Phospholipase A2
•
Fatty Acids Triglyceride Pancreatic Lipase
Assists pancreatic pancreatic lipase
•
Hydrolyzes phospholipids
•
Secreted as inactive pro-phospholipase pro-phospholipase A2
•
Activated by trypsin
Mono-glyceride H
H
Protein Digestion •
•
Protein Digestion
Several different pancreatic enzymes •
Trypsin
•
Chymotrypsin
•
Elastase
•
Carboxypeptidases
•
•
•
All secreted as proenzymes (zymogens (zymogens))
51
Trypsin secreted as inactivetrypsinogen inactive trypsinogen Activated by brush border enzyme:enterokinase enzyme: enterokinase Trypsin activates all other protein enzymes
Acute Pancreatitis
Acute Pancreatitis
•
Acute inflammation of pancreas
•
Diagnosis: Elevated serum pancreatic enzyme levels
•
Epigastric pain, nausea, vomiting
•
↑ Amylase and lipase
•
Blocked secretion of enzymes while synthesis ongoing
•
•
Large amounts of trypsin activated
•
Trypsin activates more trypsin
•
Also activates activates phospholipase, phospholipase, chymotrypsin, and elastase
•
“ Auto-digestion” by enzymes occurs
•
Pancreatic Enzyme Replacement •
Multiplecommercialreplacements available
•
Uses:
•
Different ratios of lipase, lipase, protease, and and amylase
•
Cystic fibrosis
•
Chronic pancreatitis
•
Post pancreatectomy
52
Both elevated in conditions other than pancreatitis Lipase more specific for pancreatic damage
GERD Gastroesophageal Gastroesophageal Reflux Disease •
Gastric juice from stomach to esophagus
•
Represents a failure oflower of lower esophageal sphincter
•
Esophageal Disorders
“Reflux” back into esophagus
•
Decrease in LES tone
•
Precise mechanism mechanism not well established
Jason Ryan, MD, MPH
Reflux Esophagitis •
•
•
Reflux Esophagitis
Inflammation Inflammation of epithelial layer
•
Mucosa: erythema and edema Erosions (loss of epithelial layer)
•
•
•
Basal zone (epithelium) hyperplasia
•
Lamina propria papilla elongate
•
Eosinophils and neutrophils
GERD
Pediatric GERD •
Histology:
Risk Factors
Immature lower esophageal sphincter Vomiting
•
•
Crying
•
•
53
Alcohol Smoking Obesity Fatty foods
•
Caffeine
•
Hiatal Hernia
GERD
GERD
Symptoms
Treatment
•
•
Heartburn •
Retrosternal “burning” sensation
•
After meals, or when lying flat
•
Painful esophagitis Reflux into respiratory tract Asthma (adult-onset)
•
Cough
•
Dyspnea
•
•
•
Histamine (H2) blockers •
Famotidine, Ranitidine, Nizatidine, Cimetidine
•
Block histamine receptors in parietal cells
•
•
•
Proton Pump Inhibitors •
Omeprazole, Pantoprazole, Lansoprazole, Esomeprazole
•
Inhibit H+/K+ pump in parietal parietal cells
•
•
•
•
•
Chocolate
•
Spicy foods
•
Carbonated beverages
•
Peppermint
Refractory GERD: Nissen fundoplication fundoplication
Potential consequences of GERD Acid destroys mucosa (causes ulcers) Replaced by fibrous tissue Can lead to strictures dysphagia
Barrett’s Esophagus
Alkalisubstances Contain sodium or potassium hydroxide Usually ingested accidentally by children •
•
Caffeine
•
Ulcers, Fibrosis, Strictures
Ingestion of Lye •
Fatty foods
•
Damage to enamel of teeth
Treatment
•
Dietary modification (avoid triggers) •
GERD •
•
Respiratorysymptoms •
•
Weightloss
Dysphagia •
•
•
•
•
Result of long-standing GERD Metaplasia of esophagus •
Found in household household cleaners, cleaners, drain openers
Causesliquefactivenecrosis Rapid injury through mucosa into wall of esophagus Neutralized in stomach by acid Child usually recovers Can result in strictures strictures
54
Squamous epithelium
intestinal epithelium
Barrett’s Esophagus
Barrett’s Esophagus •
Endoscopy often performed in GERD patients
•
If Barrett’s seen regular surveillance endoscopy •
Normal Esophagus Non-keratinized Squamous epithelium
Normal (squamous): White Intestinal: Pink/Red
Barrett’s Esophagus Intestinal Mucosa Non-ciliated Columnar Epithelium Goblet Cells
Esophageal Cancer •
•
•
•
•
Esophageal Cancer
Squamous cell or adenocarcinoma Both types: ↑ risk in smokers
•
•
Starts with solids
•
Progresses to liquids as tumor grows
•
Normally no glandular glandular tissue in esophagus
•
Need GERD Barrett’s Glandular epithelium
•
Develops in lower 1/3 1/3 of esophagus esophagus (near stomach stomach acid)
•
Obesity is risk factor (also GERD)
Other symptoms •
Weight loss
•
Hematemesis
Lymph Nodes
Squamous cell most common worldwide •
•
Adenocarcinoma most common in US •
Often presents late with advanced disease/mets Presentswith “progressive” dysphagia
Esophageal Cancer •
Biopsies taken to look for carcinoma
•
Upper esophagus (neck): (neck):
•
Middle (chest):
Usually in middle or upper esophagus
•
Results from processes that damage upper esophagus
Cervical nodes
•
Food (alcohol, hot hot tea)
•
Mediastinal nodes
•
Achalasia (backup (backup of food)
•
Tracheobronchial nodes
•
Esophageal webs webs (backup of food)
•
Zenker’s
•
Lye ingestion
•
Can cause special symptoms due to upper location •
Hoarse voice voice (recurrent laryngeal nerve)
•
Cough (tracheal involvement)
55
Lower(abdomen): •
Celiac nodes
•
Gastric nodes
Esophagitis
Eosinophilic Esophagitis
Infectious causes •
•
•
Candida •
White membranes
•
Pseudohyphae on biopsy Usually causes oral herpes
•
Can involve esophagus
•
“Punched out” ulcers
•
•
•
AIDS (CD4<50) Linear ulcers
•
•
•
Causes Often idiopathic
•
Chronic Chagas Disease (Protozoa: Trypanosoma cruzi)
•
Dilation of esophagus
•
“Bird’s beak” on barium swallow
Esophageal manometry •
Poor response to GERD treatment
•
Eosinophils on biopsy
Dysphagia to solids and liquids •
Closed LES
•
Contrast with obstruction obstruction (solids only)
Bad breath Accumulation of food in esophagus
Esophageal Varices
Diagnostic Testing
•
Dysphagia
•
•
Achalasia •
•
Symptoms
Found in muscular muscular layer (below submucosa)
•
Must exclude other other causes of esophagitis (i.e. GERD)
Classicscenario:
Achalasia
Inability to relax lower esophageal sphincter Due to loss of ganglion cells in Auerbach’s Auerbach’s plexus •
Esophagealdysfunction (dysphagia) Biopsy: eosinophil-predominant eosinophil-predominantinflammation Diagnosis of exclusion •
•
Achalasia •
•
•
CMV •
Allergic reaction (unknown antigen) Immune-mediated
•
HSV-1 •
•
Helpful in dysphagia
•
Dilated submucosal submucosal veins •
Usually in lower 1/3 1/3 of esophagus
•
Usually due to portal hypertension (cirrhosis)
Can lead to upper GI bleeding (variceal rupture)
•
Measures pressure change with contraction
•
Painless bleeding
•
Shows ↑ LES tone in achalasia
•
Common cause of death in liver disease
•
Contrast with scleroderma (↓LES tone)
•
Cirrhotic patients often screening with endoscopy endoscopy
•
Treatment for variceal bleed: •
56
Emergent endoscopy for banding/ligation
Malloy-Weiss Syndrome •
Damage to esophageal mucosaat mucosa at GE junction
•
Causes painfulhematemesis painfulhematemesis •
•
BoerHaave Syndrome
Epigastric pain or pain in the back
•
•
•
•
•
•
Air exits esophagus •
Air in mediastinum on chest x-ray (pneumomediastinum)
Air under skin in neck (“ subcutaneous emphysema ”)
Bulimia
Schatzki Ring
Extension/protrusion Extension/protrusionof mucosa Extends into lumen of esophagus
•
•
Obstructs movement of food dysphagia Webs: Common in upper esophagus
•
Ring at squamocolumnar junction Common cause of dysphagia to solids Squamousmucosaproximally,columnardistally
Rings: Common in lower esophagus Risk of squamous cell carcinoma
Zenker’s Diverticulum
Rare condition; poorly understood cause Triad: •
#1: Iron deficiency deficiency anemia
•
#2: Beefy red tongue
•
•
•
•
Plummer-Vinson Syndrome •
•
Alcoholism
Esophageal Webs and Rings •
Transmural rupture of esophagus Result of severe, chronic vomiting or retching
Caused by severe, chronic vomiting •
•
•
•
Damage to tongue mucosal layer
•
Bright red from exposure of blood vessels
•
•
•
#3: Esophageal web
Common in middle-age, white women
57
Occurs at junction of esophagus and pharynx Mucosa/submucosa through muscular wall Usually result of chronic swallowing problem •
Cricopharyngeal muscle must relax to allow food to pass
•
Failure to relax difficulty swallowing
•
Chronic high pressure pressure in pharynx to force food down
•
This leads to diverticulum
Zenker’s Diverticulum •
Zenker’s Diverticulum
Classiclocation: Killian’s Triangle
•
Symptoms
•
In the hypopharynx
•
Dysphagia
•
Just proximal to upper esophageal esophageal sphincter
•
Halitosis (food trapped trapped in diverticulum)
•
Cleavage plane between thyropharyngeus muscle and cricopharyngeus muscles
58
Liver Tests •
•
Liver Disease
AspartateAminotransferase Aminotransferase (AST) •
Located in mitochondria mitochondria
•
Alcohol is mitochondrial mitochondrial toxin
•
alcoholic hepatitis ↑ AST> ↑ALT in alcoholic
Alanine Aminotransferase Aminotransferase (ALT) (ALT) •
Located in cytoplasm
•
↑ ALT > ↑AST in most types of hepatitis with cellular damage
Jason Ryan, MD, MPH
Liver Tests •
Liver Tests
Alkaline phosphatase phosphatase (Alk Phos) Phos)
•
Enzyme from liver, liver, bones, GI tract
•
Similar to alk phos but not elevated elevated in bone disease
•
Precise function not known
•
Used to determine determine origin of alk phos phos elevation
•
↑ synthesis with obstructed bile flow (cholestasis)
•
↑ Alk Phos plus ↑ GGT = hepatobiliary cause of ↑ Alk Phos
•
Serum levels rise with cholestasis
•
Also elevated after heavy alcohol consumption
•
Levels rise in many non-liver conditions •
Pregnancy (placenta)
•
Thyroid disease
•
Bone disease
•
•
Liver Tests •
•
Albumin PT/PTT(coagulationfactors) Glucose •
•
5'-Nucleotidase Bilirubin (total, direct, indirect)
Alcoholic Liver Disease
Tests of Synthetic Function •
Gamma-glutamyl transpeptidase (GGT)
•
•
Need liver for glycogen glycogen breakdown and and gluconeogenesis
Abnormalities Abnormalities = severe liver disease
59
Three ways alcohol (ethanol) can damage liver •
#1: Alcoholic fatty liver disease
•
#2: Acute hepatitis
•
#3: Cirrhosis
Alcoholic Fatty Liver Liver Disease •
Accumulation Accumulation of fatty acids (fatty infiltration of liver)
•
Usually asymptomatic among heavy drinkers
•
•
•
•
•
•
•
•
•
Fatty infiltration of liver not due to alcohol •
NAFL: Fatty liver
•
NASH: Steatohepatitis Steatohepatitis (fat and inflammation)
Often asymptomatic
•
•
•
•
•
Associated with obesity May improve with weight loss
Classic histopathology finding alcoholic liver disease Cytoplasmicinclusions Damaged intermediate filaments in hepatocytes
t c u D e l i B
n i e V l a t r o P
Zone I
Zone II
Periportal
Mid Zone
Zone III
n i e V c i t a p e H
Centrilobular
Alcoholic Hepatitis
Abnormal LFTs ( ALT>AST ALT>AST)) May progress to cirrhosis
Mallory bodies •
y r e t r A c i t a p e H
↑ risk of cirrhosis
NAFLD •
Liver Zones
May cause hepatomegaly on exam Abnormal LFTs ( AST>ALT AST>ALT)) Often reversible with cessation of alcohol
Non-alcoholic Non-alcoholic Fatty Liver Disease
Fatty infiltration in Alcoholic Liver Disease Disease begins here (also fibrosis in cirrhosis)
Classically occurs after heavy, binge drinking on top of long history of alcohol consumption Toxic effects fromacetaldehyde from acetaldehyde Symptoms •
Fever
•
Jaundice
•
RUQ pain/tenderness
Budd Chiari Syndrome •
•
•
•
Thrombosis of hepatic vein Abdominal pain, ascites, hepatomegaly Zone 3 congestion,necrosis,he morrhage Common causes: •
60
Myeloproliferative disorder (P. (P. vera, ET, CML)
•
Hepatocellular carcinoma
•
OCP/Pregnancy
•
Hypercoagulable states
Reye’s Syndrome
Right Heart Failure •
•
•
•
“Cardiaccirrhosis” “Cardiac cirrhosis” Rare cause of liver failure Chronic liver edema cirrhosis Results in nutmeg liver •
•
•
Rare cause of liver failure and encephalopathy
•
Children with viral infections who take aspirin
•
Rapid, severe liver failure
•
•
Also seen Budd Chiari
•
Mitochondrial damage seen
•
Fatty changes in liver (hepatomegaly)
•
Vomiting, coma, death
α1 Anti-trypsin Deficiency •
•
Evidence that aspirin inhibits beta oxidation oxidation
Mottled liver like a nutmeg
•
•
Classically chicken pox ( varicella zoster) zoster ) and influenza B
Avoid aspirin in children (except Kawasaki’s)
α1 Anti-trypsin Deficiency
Inherited(autosomal (autosomalco-dominant co-dominant ) Decreased or dysfunctional AAT
•
Lung •
•
AAT balances naturally occurring proteases •
Imbalance between neutrophil elastase (destroys elastin) and elastase inhibitor AAT AAT (protects (protects elastin)
Liver •
α1 Anti-trypsin Deficiency
Emphysema
Cirrhosis
•
Abnormal α1 builds up in liver (endoplasmic reticulum)
•
Pathologic polymerization of AAT
•
Occurs in endoplasmic reticulum of hepatocytes
Liver Abscess
AAT polymers stain with PAS Resist resist digestion by diastase (unlike glycogen)
•
•
•
•
61
Walled-off infection of the liver In the US usually bacteria •
Bacteremia
•
Cholangitis (GN Rods; Klebsiella often identified)
Entameba histolytica(protozoa) histolytica (protozoa) •
Cysts in contaminated contaminated water bloody diarrhea (dysentery)
•
Ascends in the biliary tree
Echinococcus(helminth) Echinococcus(helminth) •
Fecal-oral ingestion of eggs
•
Massive liver cysts
Viral Hepatitis
Autoimmune Hepatitis
•
Hepatitis A, B, C, D, or E
•
Autoimmune inflammation inflammation of the liver
•
Very high AST/ALT
•
Most common among women in 40s/50s
•
Range of symptoms
•
Anti-nuclear antibodies (ANAs)
•
•
•
Hyperbilirubinemiaand Hyperbilirubinemiaand jaundice If severe, may see abnormal synthetic function •
•
Often >1000 (>25x normal)
•
Hypoglycemia, elevated PT/PTT, PT/PTT, low albumin
Diagnosed via viral antibody tests •
acute liver disease
•
Most common antibody abnormality
•
Sensitive, not specific More specific for AHA
Tylenol Overdose
Acetaminophen, Paracetamol, APAP (N-acetyl- para-amino phenol)
Treatment
•
•
Maximum recommended recommended dose = 4 grams per 24 hours Overdose causes acute liver failure ( hepatic necrosis)
•
•
Extremely high AST/ALT (in 1000s)
•
•
Activated charcoal may prevent absorption N-acetylcysteineis N-acetylcysteineis treatment of choice Used to replenish glutathione Usually given orally to patients with overdose
N-acetylcysteine
Tylenol Overdose
Shock Liver
Treatment
Ischemic Hepatitis
•
•
Three metabolites of acetaminophen NAPQI is toxic to liver •
•
•
•
N-acetyl-p-benzoquinone imine
•
Metabolized by glutathione
•
•
62
cirrhosis
Treatment:steroidsand immunosuppressants immunosuppressants
Tylenol Overdose •
Anti-smooth Anti-smooth muscle antibodies (ASMA) •
•
Asymptomatic
Cysteine
Glutathione
Diffuse liver injury fromhypoperfusion from hypoperfusion Often seen in ICU patients with shock from any cause Markedly elevated AST/ALT (1000s) Usuallyself-limited Pathology:zone Pathology: zone 3 necrosis (near central vein)
Cirrhosis •
End stage liver disease (irreversible)
•
Result from many causes of chronic liver disease: •
Viral Hepatitis (especially (especially B and C)
•
Alcoholic liver disease disease
•
Non-alcoholic fatty liver disease
Cirrhosis Jason Ryan, MD, MPH
Cirrhosis
Cirrhosis •
•
•
Clinical Features
Shrunkenliver Liver tissue replaced by fibrosis and nodules
•
Hyperammonemia •
Asterixis, confusion, confusion, coma
Smoother liver surface replaced by nodules
Hyperammonemia
Cirrhosis
Treatment
Clinical Features
•
•
Low protein diet Lactulose
STEAK
•
Synthetic disaccharide disaccharide (laxative)
•
Colon breakdown by bacteria to fatty fatty acids
•
Lowers colonic pH; favors formation of NH 4+ over NH3
•
•
•
Jaundice
•
Hypoglycemia
•
Coagulopathy
•
•
NH4+ not absorbed trapped in colon Result: ↓plasma ↓plasma ammonia concentrations •
63
Loss of bilirubin metabolism Loss of gluconeogenesis
•
Loss of clotting factors
•
Elevated PT/PTT
Hypoalbuminemia •
May cause low oncotic pressure
•
Contributes to ascites, edema
Cirrhosis
Cirrhosis
Capillary Fluid Shifts
Clinical Features
•
Capillaryhydrostatic Capillary hydrostatic pressure (Pc) •
•
•
Drives fluid out of capillaries into tissues
Capillary oncoticpressure oncotic pressure (∏c ) •
•
Proteins (albumin) pull water into capillaries Resists movement of fluid out of capillaries
Elevatedestrogen Elevatedestrogen •
Normally removed by liver
•
Gynecomastia in men
•
Spider angiomata
•
Palmar erythema
Pc ∏c
Cirrhosis
Portal Hypertension •
•
•
↑Nitric Oxide
Hemodynamics
Blood flows portal vein liver hepatic vein Cirrhosis obstructed flow through liver
↑ Splanchnic vasodilation
↓ Albumin ↓ Oncotic Pressure
High pressure in portal vein (“hypertension”)
↓ BP
↓ SVR ↓ Effective Circulating Volume
Sympathetic Activation
↑ RAAS ↑ ADH
↑ CO
↑ Na/H2O ↑ Total Body Water
Venous Collaterals
Ascites and Edema
Venous Anastamoses •
•
↑ Total Body Water
Portal HTN
•
•
•
Edema Edema
Ascites
↓ albumin
High portal pressure opens “venouscollaterals” “venous collaterals” Connection between portal-systemic veins Normally small, collapsed vessels Engorge in portal hypertension Keycollaterals: •
Patients with cirrhosis but without portal HTN do not develop ascites ascites
64
Umbilicus – physical exam exam finding: “caput medusa”
•
Esophagus – upper gastrointestinal gastrointestinal bleeding
•
Stomach – upper gastrointestinal bleeding
•
Rectum – hemorrhoids which may also bleed
Esophageal Varices
Gastric Varices
Most esophageal venous drainage via esophageal veins to SVC
Short gastric veins drain blood from stomach fundus to left gastric vein and splenic vein (both part of portal system)
Small amount of superficial blood via left gastric vein to portal vein
Caput Medusa
Internal Hemorrhoids
Caput Medusa is a physical exam finding of engorged veins around the umbilicus
Internal hemorrhoids hemorrhoids (above dentate line) occur in portal HTN
Hypersplenism
Portal Vein Thrombosis •
Engorgement of the spleen in portal HTN leads to low platelets
•
•
•
•
65
Rare cause of portal hypertension Acute onset abdominal pain Splenomegaly (palpable (palpable spleen one exam) May result in gastric v arices withbleeding with bleeding Liver biopsy will be normal
SAAG
Ascites •
•
Serum Ascites Albumin Gradient
Accumulation Accumulation of fluid in peritoneal cavity In liver disease, from portal hypertension +/- low albumin
•
Test of ascitic fluid
•
Two reasons for new/worsening ascites ascites
•
•
SAAG
•
SAAG >1.1 g/dL •
Large difference between serum and ascites albumin
•
High pressure driving fluid (not albumin) into peritoneum
•
Seen in portal hypertension
•
•
Albumin levels similar between serum and ascites
•
Leaky vasculature leading to fluid/albumin into peritoneum
•
Seen in malignant malignant ascites (malignant (malignant cells in peritoneal peritoneal cavity)
Malignancy (leaky vasculature)
Sample of ascitic fluid via paracentesis Serum albumin – ascites albumin = SAAG
Sodiumrestriction Spironolactone(drug Spironolactone(drug of choice) •
SAAG <1.1 g/dL •
Portal hypertension
•
Ascites Treatment
Serum Ascites Albumin Gradient •
•
•
•
•
Potassium-sparing diuretic
•
Blocks aldosterone distal tubule
•
Most effective drug for ascites
Loop diuretics (2nd line) Large volumeparacentesis volume paracentesis TIPS
TIPS
SBP
Transjugular Intrahepatic Portosystemic Shunt
Spontaneous Bacterial Peritonitis
•
•
•
Treatment of portal hypertension Creation of channel in liver Connects portal vein to hepatic vein
•
•
Ascitic fluid infection Bacteria in gut gain entry into ascitic fluid •
•
•
•
•
66
Usually E. coli and Klebsiella; Klebsiella ; rarely strep/staph
Fever, abdominal pain/tenderness ↑ ascitic absolute PMNs (≥250 cells/mm3) Common treatment: 3rd generation cephalosporin cephalosporin (cefotaxime)
•
Gram positive and gram negative coverage
•
Achieves good levels in ascitic fluid
MELD Score
Child-Pugh classification
Model For End-Stage Liver Disease •
•
•
Scoring system for chronic liver disease or cirrhosis Estimates 3-month mortality from liver disease
•
•
INR
>40 = 71% mortality mortality <9 = 2% mortality mortality
Cirrhosis Gold standard isliver is liver biopsy •
Not required if diagnosis diagnosis is clear from history
•
Done only when biopsy will change management
•
•
•
Imaging (ultrasound, CT, MRI) •
May show small, nodular nodular liver
•
Not sensitive or specific for diagnosis
•
•
•
•
More helpful for for detection of hepatocellular hepatocellular carcinoma
Clinical diagnosis (common) •
Presence of ascites
•
Low platelet count
•
Spider angiomata
Points for encephalopathy, encephalopathy, ascites, bilirubin, albumin, PT
•
5 or 6: Child-Pugh Child-Pugh class A cirrhosis
•
7 to 9: Child-Pugh Child-Pugh class B cirrhosis
•
10 to 15: Child-Pugh class C cirrhosis (worst)
Stellate Cells
Diagnosis
•
Score ranges from 5 to 15
Creatinine level
•
•
•
Bilirubin level
•
•
Five variables to predict risk/survival risk/survival •
Point system using: •
•
67
Perisinusoidalcell Storage site for retinoids (vitamin A metabolites) Activated in liver disease Secrete TGF-β Proliferate and produce fibrous tissue Major contributor to cirrhosis
Hepatocellular Carcinoma •
Most common primary liver tumor
•
Usually a consequence of chronic liver disease
Liver Tumors
•
Hepatitis B, C
•
Alcoholic cirrhosis
•
Wilson’s disease
•
Hemochromatosis
•
α-1 antitrypsin
Jason Ryan, MD, MPH
Hepatocellular Carcinoma
Aspergillus •
•
•
•
•
Clinical Features
Fungus that producesaflatoxin produces aflatoxin Can contaminate corn, corn, soybeans, and peanuts
Food from non-industrialized non-industrialized countries Locally grown foods
•
Liver function tests variable •
•
Exposure from: •
Often asymptomatic asymptomatic •
High rates of dietary intake associated with HCC Industrialized countries screen for aflatoxin •
•
•
Regular screening done in high risk patients
Usually abnormal in a non-specific non-specific pattern
Hepatomegaly Can cause liver failure •
Obstructive jaundice, ascites
Hepatocellular Carcinoma
Hepatocellular Carcinoma
Clinical Features
Diagnosis
•
Hypoglycemia
•
Alpha fetal protein protein (AFP)
•
Seen with large tumors due to high metabolic rate
•
•
Rarely tumors produces produces insulin-like growth factor-II
•
Can be elevated in chronic liver disease
•
Rise in level from baseline suspicious for HCC
•
Erythrocytosis
•
Can cause the Budd Chiari syndrome
•
•
HCC can secrete EPO
•
Hypercoagulable state plus compression venous structures
•
Occlusion of hepatic hepatic veins that that drain liver
•
Classic triad: abdominal pain, ascites, hepatomegaly
•
68
Secreted by HCC
Imaging •
CT scan, MRI, ultrasound
•
Chronic liver disease disease patients often screened
Biopsy
Hepatocellular Carcinoma
Hepatocellular Carcinoma
Metastatic Disease
Treatment
•
Rare at time of diagnosis (5-15% cases)
•
Usually spreads via blood not lymph
•
Common sites: Lung, Lung, bone
•
Poorly responsive to chemotherapy or radiation
•
Surgicalexcision •
•
•
•
Chemoembolization
•
Poorprognosisoverall •
•
•
•
•
•
•
•
Median survival 6 to 20 months
Cavernous Hemangioma
Benign epithelial liver tumors Usually solitary in right lobe
•
•
Common in young women (20s to 40s) Rarely symptomatic
Most common benign liver tumor Composed of vascular spaces •
Often detected during work-up abdominal pain Associatedwith contraceptive use, use, anabolic steroids
Often filled with thrombus
•
Often discovered incidentally at surgery or imaging
•
Case reports of fatal hemorrhage with biopsy
Case reports of rupture during pregnancy
Hepatic Angiosarcoma •
Chemo plus a pro-coagulant directly directly injected into tumor
Hepatic Hemangioma Hemangioma
Hepatic Adenoma •
Radiofrequency thermal energy to the lesion
•
•
•
Often not possible due to extensive extensive liver involvement
Liver transplantation transplantation Radiofrequencyablation
Hepatic Angiosarcoma Angiosarcoma
Rare, high-grade malignant vascular tumor Abdominal pain, jaundice, ascites, weight loss
•
Associatedwith toxic exposures •
Vinyl chloride •
Used to make PVC plastic
•
Inhalation can lead to angiosarcoma
Arsenic •
69
Found in rocks, soil, water
•
Certain geographic areas areas have high levels
•
Many industrial uses
Metastasis to Liver •
•
Most common malignancies of liver •
Much more common common than HCC
•
GI (colon, stomach, pancreas), pancreas), breast, lung
Multiple nodules
70
Wilson’s Disease •
Autosomal recessive disorder ofcopper of copper metabolism
Wilson’s Disease & Hemochromatosis Jason Ryan, MD, MPH
Wilson’s Disease
Copper Metabolism •
•
•
Copper consumed in diet and absorbed Liver is key organ for metabolism
•
•
Mutation of ATP7B gene (chromosome 13) Lack of copper excretion in bile
•
Excess copper excreted mostly in bile
•
Copper accumulates accumulates in liver
•
Copper incorporated in ceruloplasmin (transport molecule)
•
↑ free radical production
•
Ceruloplasmin secreted into serum
•
Copper spills into plasma
ATP7B ATP7B:: Hepatic copper transport protein •
Incorporates copper into ceruloplasmin
•
Excretes copper copper into bile
serum •
tissue damage in liver
•
Increased free serum copper
•
Deposits in brain, cornea, cornea , kidneys, joints
Lack of ceruloplasmin secretion into plasma •
Low ceruloplasmin ceruloplasmin level (diagnostic hallmark)
•
Total serum copper reduced (despite copper copper overload)
Wilson’s Disease
Wilson’s Disease
Clinical Features
Clinical Features
•
•
•
Mean age onset 12 to 23 years Liver features •
Cirrhosis
•
High risk of hepatocellular hepatocellular carcinoma
•
CNS Features •
Basal ganglia
•
Movement symptoms symptoms (Parkinsonian)
•
Dyskinesia (abnormal movements)
•
Dysarthria (abnormal speech)
•
Tremor
•
Dementia, depression, behavioral changes
71
Hemolysis •
Related to copper in RBCs – exact exact mechanism mechanism unclear
•
Coombs-negative hemolytic anemia
Wilson’s Disease
Kayser-Fleischer Rings •
•
•
•
Diagnosis and Treatment
Corneal copperdeposits •
Descemet's membrane
•
Corneo-scleral junction (limbus)
Lowceruloplasminlevel
•
High urinary copper excretion (24 hour test)
•
Seen in 50% patients with liver disease
•
Seen in 90% patients with CNS involvement Early lesions detectable on slit lamp exam
Autosomal recessive disorder ofiron of ironmetabolism metabolism
•
•
Iron Metabolism •
•
•
Small amount in sweat, sloughing of skin/GI cells
•
Women lose iron from menst ruation
•
Binds copper
•
Promotes urinary excretion
Heme iron •
Found in meats
•
Easily absorbed
Non-heme iron •
Absorbed in Fe2+ state
•
Aided by vitamin C
Vocabulary
Iron consumed in diet Uptake to plasma regulated by enterocytes Few mechanisms to excrete excess iron •
Kayser-Fleischer Rings (slit lamp exam) Treatment: Penicillamine
Iron Absorption
Hemochromatosis •
•
•
•
Ferritin •
Iron storage protein
•
Found inside cells cells and in plasma
Hemosiderin •
Iron storage compound
•
Clumps of many many molecules molecules including ferritin
•
Found only inside cells (often (often in macrophages)
•
Hemosiderosis
•
Hemochromatosis
•
•
72
Accumulation of hemosiderin iron in cells Disease due to iron accumulation
Hereditary Hemochromatosis •
Autosomal recessive disorder (usually)
•
AbnormalHFE Abnormal HFE gene (chromosome (chromosome 6)/HFE protein
•
Most commonly due to homozygous homozygousC282Y C282Y mutation •
Hereditary Hemochromatosis
Less common C282Y/H63D mutation
•
Both mutations common among Americans
•
•
•
•
•
•
Common in hematologic disorders that require chronictransfusiontherapy Beta thalassemia major
•
Sickle cell anemia
•
Refractory aplastic anemia
•
Myelodysplastic syndromes
•
Leukemia
•
Takes years for iron accumulation
•
Women present later (menstruation)
Clinical Features
Commonly due to excessive excessive blood transfu sions Body unable to excrete excess iron
•
Heme and non-heme
With few mechanisms for excretion accumulation Usually presents in adulthood
Hemochromatosis
Secondary Hemochromatosis •
Exact function HFE protein in iron absorption unclear Leads to unregulated absorption iron •
Cysteine-to-tyrosine substitution at amino acid 282
•
•
Liver •
Hepatomegaly
•
Abnormal LFTs
•
Cirrhosis
•
Risk of hepatocellular hepatocellular carcinoma
•
Pancreas
•
Skin
•
Diabetes
•
Iron + melanin turns turns skin bronze
•
“Bronze diabetes”
Hemochromatosis
Hemochromatosis
Clinical Features
Special Features
•
•
Heart •
Iron infiltration of myocardium
•
Commonly causes causes dilated cardiomyopathy cardiomyopathy (rarely restrictive)
Testes Atrophy
•
Decreased libido
•
Impotence
73
Accelerates liver disease
Vitamin C •
Arthropathy (joint pain)
•
Alcoholconsumption Alcohol consumption •
•
Joints •
•
•
May increase iron absorption
Hemochromatosis
Hemochromatosis
Laboratory Tests
Diagnosis
•
•
•
Normal ferritin <300 ng/ml Hemochromatosis Hemochromatosis can get >1000 High % saturation is an early sign
•
Genetic testing for C282Y mutation
•
MRI
•
Biopsy
•
•
Hemochromatosis Treatment •
•
Phlebotomy •
Removes iron
•
Repeated until ferritin falls within normal normal limits
Iron chelating agents (rarely used) •
Deferoxamine
•
Deferiprone
•
Deferasirox
74
C282Y/C282Y genotype confirms diagnosis
Liver turns black from iron iron (“low signal”)
•
Prussian blue staining
•
Blue granules from iron deposition
Gallstones Cholelithiasis •
Components of bile in gallbladder •
Bilirubin, Bilirubin, Bile Salts, Salts , Cholesterol
•
Delicate balance balance between these components components keeps bile fluid
•
If balance is upset
precipitation
stones
Gallstones Jason Ryan, MD, MPH
Cholesterol
Cholesterol Gallstones •
•
•
Cholesterol Gallstones
Usuallynot Usually not visible on X-ray (radiolucent) Severalimportant associations associations
•
Classically occurs occurs in 40-year-olds
•
Rare in children, children, elderly
•
Pearl: Elderly patient with gallstone symptoms = cancer
•
Excess estrogen increased cholesterol
•
Altered lipid metabolism Excess cholesterol in bile
•
Loss of bile salts
Hispanics
•
Native Americans
Less common Eastern Europeans
•
Japanese
•
African-Americans
Cholesterol Gallstones Estrogen Risk Factors
Risk factorscategories: categories: •
Western Caucasians
•
•
Cholesterol Gallstones •
More common certain demographics demographics groups: •
Age: •
Bilirubin
•
Femalegender
•
Pregnancy, Multiparity
•
•
75
Estrogen increased cholesterol synthesis Estrogen plus progesterone which slows gallbladder emptying
Cholesterol Gallstones
Bile Salts
Excess Cholesterol Risk Factors
Enterohepatic Circulation Circulation
•
Obesity: Obesity: Increased total body cholesterol
•
•
Rapid weight loss: Increasedcholesterol mobilization mobilization
•
•
Both factors lead to more cholesterol in bile
Produced in liver secreted into bile Reabsorbed in terminal ileum •
•
About 95% absorbed and recycled
Reduced bile salts cholesterolgallstones •
Underproduction
•
Poor absorption absorption from ileum ileum
Taurocholic acid
Cholesterol Gallstones
Cholesterol Gallstones
Bile Salt Risk Factors
Bile Salt Risk Factors
•
Cirrhosis •
•
•
Cystic Fibrosis
•
Clofibrate(and Clofibrate (and other fibrates)
•
Bile acid resins
Decreased synthesis of bile salts
•
Crohn’s Disease •
Crohn’s Disease: Inflammation of ileum is common
•
Abnormal resorption of bile salts
•
Fat malabsorption loss of bile acids in stool Inhibit bile acid synthesis
•
Old, rarely used cholesterol drugs
•
Prevent intestinal intestinal reabsorption bile acids/salts
Pigment Stones
Pigment Stones
Bilirubin Stones
Bilirubin Stones
•
•
•
•
•
Composed of calcium bilirubinate Can be seen on x-ray (radiopaque) Black or brown
•
Extravascular hemolysis
•
Cirrhosis or chronic liver disease
•
Recurrentbiliary Recurrent biliary tree infections
•
•
Key principle: unconjugated bilirubin insoluble in H2O Rise in unconjugated bilirubin in bile gallstones
•
76
Excess bilirubin Impaired bilirubin conjugation Bacterial glucuronidases
•
Convert conjugated bilirubin
•
Brown (not black) stones (↑ calcium/some cholesterol)
unconjugated
Gallstone Disease •
Ursodeoxycholic Acid
Often asymptomatic •
•
Discovered incidentally on imaging of abdomen
•
Can cause a number of clinical conditions
•
Mainstay of treatment is surgery (cholecystectomy)
•
•
•
Biliary Colic •
•
•
•
•
•
•
Reduces cholesterol secretion into bile •
Less cholesterol
•
↑ ratio bile acids:cholesterol
May dissolve gallstones
Acute Cholecystitis
Episodic RUQ pain May radiate to right shoulder blade
•
•
Gallbladder contracts against stone in outlet Pain lasts ~30 minutes then subsides
•
•
Inflammation of gallbladder Stone in cystic duct obstruction Gallbladder squeezes constricts blood supply Gallbladder dilates becomes inflamed
Often after eating, especiallyfatty especially fatty meals Cholecystokinin stimulatesgallbladder contraction
Acute Cholecystitis •
Bile acid Rarely used medical therapy for cholesterol stones
Choledocolithiasis
Clinicalfeatures •
RUQ pain, fever, ↑ WBC
•
Radiates to right scapula
•
•
•
Murphy’s sign •
•
↑ Alk Phos >>↑AST/ALT >> ↑AST/ALT
•
May lead to cholangitis cholangitis
Examiner presses RUQ
•
Patient asked to inspire
•
Patient abruptly stops inspiration due to pain
•
Risk of rupture/peritonitis rupture/peritonitis
•
Usually treated with urgent surgery
77
Common bile duct stone Biliaryobstruction Jaundice
Chronic Cholecystitis
Acalculous cholecystitis
•
Long-standing, Long-standing, untreatedcholecystitis
•
Acute cholecystitis not due to gallstones
•
Chronic inflammation
•
Caused by gall bladder ischemia and stasis
•
Usually occurs in critically ill patients
•
•
•
Causes a porcelaingallbladder Risk of gall bladder carcinoma Treatment:surgery
AIDS Cholangiopathy •
Rare complication of end-stage HIV infection •
•
Ascending Cholangitis •
Usually CD4 < 100/mm 3
•
Result of chronicinfection involving biliary tree •
Cryptosporidium (most common)
•
CMV infection
•
Biliary obstruction from strictures of the biliary tract
•
RUQ pain, sometimes fever, jaundice
•
Stone blocks flow of bile GI bacteria able to “ascend” in biliary tree Cholestasis plus signs of infection
Ascending Cholangitis
Ascending Cholangitis
Clinical Features
Microbiology
•
Charcot’s triad •
•
•
•
Fever, abdominal pain, jaundice
•
Reynoldspentad
Gram negatives: negatives: E. coli, Klebsiella, Enterobacter Rare cause: Clonorchis sinensis •
Chinese liver fluke
•
Fever, abdominal pain, jaundice, confusion, hypotension
•
Helminth found in infected fish
•
Indicates sepsis and shock from infection
•
Ascends in biliary tree
•
Will see peripheral eosinophilia
Labs •
↑ WBC
•
Cholestasis: ↑Alk Phos >> ↑ AST/ALT
•
↑ conjugated conjugated bilirubin (and total)
78
Ascending Cholangitis
ERCP
Treatment
Endoscopic retrograde cholangiopancreatograph cholangiopancreatography y
•
•
Antibiotics Antibiotics •
Gram negative and anaerobic anaerobic coverage
•
Ampicillin-sulbactam
•
Ciprofloxacin-Metronidazole
•
•
•
•
Endoscopic sphincterotomy wi th stone extraction
•
Sometimes stent insertion
•
Rarely surgery (replaced (replaced by drainage techniques)
Large stone bowel obstruction at ileocecal valve Key imaging finding (X-ray or CT scan) Air in the biliary tree
•
Biliary structures normally filled with bile (no air)
•
Air from intestine fills biliary tree in gallstone ileus
Gallbladder Carcinoma •
•
•
•
Imaging and therapy of biliary disorders
Gallstone Pancreatitis
Massive gallstone erodes through gallbladder wall Creates fistula with small intestine
•
•
Combination of endoscopy and fluoroscopy
Biliary drainage
Gallstone Ileus •
•
Rare malignancy Adenocarcinoma fromchronic from chronic inflammation Gallstone disease (Porcelain gallbladder) Chronic salmonella infection (S. (S. typhi) typhi) •
S. typhi can remain in gall bladder ( carrier state) state )
•
Endemic countries 1-4% people may be carriers
•
Risk factor for carcinoma
79
•
Obstruction of common common bile duct by stone
•
Leads to acute pancreatitis
Biliary Atresia •
Idiopathic biliary obstruction in neonates
•
Key findings:
•
Ultrasound:
•
•
Biliary Disorders
•
Jason Ryan, MD, MPH •
•
•
Gallbladder absent or abnormal Absence of common bile duct
•
No other causes causes (no obstruction)
Treatment: surgery (Kasai procedure) Create conduit for bile drainage using small intestine
Primary Biliary Cirrhosis
Old term for liver damage from biliary obstruction Chronic obstruction bile liver damage •
Jaundice, dark urine, pale stools (“acholic”)
•
•
Biliary Cirrhosis
Biliary ducts do not form, or degenerate degenerate early in life
•
•
Gallstone, pancreatic pancreatic cancer, cancer, bi liary stricture
Biliary cirrhosis without extra-hepaticobstruction Autoimmunedisorder •
T-cell attack on small interlobular bile ducts
•
Granulomatous inflammation
Primary Biliary Cirrhosis
Primary Biliary Cirrhosis
Clinical Features
Diagnosis
•
•
More common among women Fatigue and pruritus most common initial symptoms •
Associated with increased bile acids in serum/skin
•
Pruritus often precedes development of jaundice
•
Itching may be severe, often worse at night
•
•
•
•
•
ITCHING Michalak A, Pruritus in liver disease – pathenogenisis and treatment. Journal of Pre-Clinical and Clinical Research, 2011, Vol 5, No 2, 47-49
80
Anti-mitochondrial Anti-mitochondrial antibodies antibodies •
Hallmark of PBC
•
Present in ~95% of patients
Anti-nuclear antibodies antibodies seen in ~70% Markedlyelevatedalkaline elevated alkaline phosphatase May see mild elevations AST/ALT
↑ bilirubin occurs late poor prognosis
Primary Biliary Cirrhosis
Primary Biliary Cirrhosis
Diagnosis
Treatment
•
•
•
•
Serum lipids may be markedly elevated
•
Ursodeoxycholic acid
•
Total cholesterol >1000 >1000 can be seen
•
Only effective therapy
•
Xanthomas may occur
•
Similar to other bile acids but less toxic to hepatocytes
Imaging shows absence of biliary obstruction Liver biopsy is gold standard but often not required Typicalcase •
Woman with itching, fatigue
•
LFTs show markedly elevated Alk Phos
•
Positive anti-mitochondrial anti-mitochondrial antibodies
•
•
With treatment, UDCA replaces endogenous bile acids
•
Improves LFTs, disease disease progression
Livertransplant
Ursodeoxycholic Ursodeoxycholic acid
Primary Biliary Cirrhosis
Primary Sclerosing Cholangitis
Associated Disorders •
•
Associated with other autoimmune disorders Most common is Sjogren’s
•
•
Autoimmunedisorder Inflammation,fibrosis, Inflammation,fibrosis, strictures in biliary tree
•
Involvesintra Involves intra and extra-hepatic bile ducts
•
Stronglyassociatedwith ulcerativecolitis
•
Contrast with PBC
•
~90% of PSC patients have IBD
•
Of those, ~90% have UC
Primary Sclerosing Cholangitis
Primary Sclerosing Cholangitis
Clinical Features
Lab Findings
•
•
•
Strictures obstruct bile flow Symptoms of biliary obstruction RUQ pain, fatigue, jaundice
•
Cholestasis •
Elevated alkaline phosphatase phosphatase
•
Elevated conjugated conjugated bilirubin
•
Usually mildly elevated AST/ALT AST/ALT
•
Elevated IgM levels
•
Positive p-ANCA
•
•
81
Up to 50% of patients
Up to 80% patients (note: also seen in UC)
Primary Sclerosing Cholangitis
Primary Sclerosing Cholangitis •
Diagnosis
Histopathology Histopathology finding:Periductal finding:Periductalfibrosis •
“Onion skin” fibrosis of bile ducts
•
Suspected from cholestasis, especially in UC
•
Cholangiogramconfirms Cholangiogramconfirmsdiagnosis
•
Primary Sclerosing Cholangitis Endoscopictherapy
•
Livertransplant
•
Annual screening for cholangiocarcinoma
•
Dilation or stenting of strictures in bile ducts
Cholangiocarcinoma •
•
•
Rare cancer of bile duct epithelial cells Symptoms usually from bile duct obstruction Key risk factors (chronic biliary inflammation) •
Primary sclerosing cholangitis (ulcerative colitis)
•
Clonorchis sinensis (Chinese liver fluke)
ERCP
•
MRCP (MRI cholangiography)
Biliary strictures and dilations (“beading ”)
PBC vs. PSC
Treatment •
•
82
Vocabulary •
Gastritis: inflammation of mucosa
•
Erosion: loss of epithelial layer
•
Gastric Disorders
•
Jason Ryan, MD, MPH •
•
•
•
Mucosal damage from acid
•
Neutrophil infiltration
•
Numerous causes
•
•
If they break through: ulcer
Ulcer: loss of mucosal layer •
Can extend into submucosa or muscular layer
•
Usually focal
•
Mostly occur in stomach stomach and duodenum
Significant overlap of causes, symptoms, treatment
Dyspepsia •
Nausea, vomiting, loss of appetite
•
Abdominal or epigastric pain
Symptoms often worsened by food •
More H+ secretion
Chronicgastritis Chronic gastritis •
Lymphocytes, plasma cells, macrophages
•
Autoimmune
•
H. Pylori
Acute Gastritis •
Extend into muscularis mucosa
•
Symptoms
Inflammation of the gastric mucosa Acutegastritis Acute gastritis •
•
Gastritis
Gastritis •
Often generalized
Parietal Cells
General points: •
Epithelium produces produces mucous and bicarb
•
Protects mucosa
•
Requires normal blood flow
Inflammation from: •
Too much acid
•
Loss of protection
83
•
Ach, Histamine: Stimulate acid production(BAD!) production (BAD!)
•
Prostaglandins: Inhibit acid pr oduction(GOOD!) oduction(GOOD!)
Curling’s Ulcer
Acute Gastritis •
NSAIDs •
Block prostaglandin production
•
Increase acid production
•
PGs also promote mucous/bicarb production
•
•
•
•
•
Common in chronic NSAID users
Hypotension to stomach mucosal damage Result: Acute gastritis and ulcers Burn
Damages mucosa
Chemotherapy •
•
Occurs in burn patients Loss of skin Loss of fluids dehydration
Alcohol •
•
•
↓Plasma Volume
Inhibits epithelial cell replication
H. Pylori (bacterialinfection)
↓Mucosal Perfusion
Cushing’s Ulcer •
Stress Ulcers
Caused by increased intracranial pressure •
•
Tumor, hemorrhage
•
•
Increased vagal stimulation ↑ Ach to stomach
•
•
Excess acid production gastritis/ulcers
•
↑ICP
Shock, sepsis, trauma ↓ mucosal perfusion Loss of protective barrier of mucous/bicarb mucous/bicarb Common among critically ill patients Prophylactictherapy: therapy:Proton Proton pump inhibitors •
Pantoprazole, Omeprazole, etc.
•
Often administered to all ICU patients
↑Vagal Tone ↑ACh
Autoimmune Gastritis
Chronic Gastritis
Pernicious Anemia
Chronic Gastritis
•
•
•
Type A Autoimmune Autoimmune
Type B Bacteria (H. Pylori)
May cause dyspepsia Often asymptomatic until complications develop
84
Autoimmune destruction of gastric parietal cells Loss of secretion of intrinsic factor IF necessary for B12 absorptionterminal absorptionterminal ileum
Autoimmune Gastritis
H. Pylori
Pernicious Anemia •
Chronic inflammation of gastric body/fundus
•
Most common cause chronicgastritis
•
More common among women
•
Gram negative rod
•
•
Associatedwith HLA-DR antigens Associatedwith gastric adenocarcinoma
•
•
•
•
Associated Malignancies Malignancies
Urease positive •
•
Hydrolyzes urea
•
•
Produces ammonium (alkaline)
•
Protects bacteria from stomach acid
•
Forms ammonium chloride
•
damaging to stomach
B-cell cancer, usually in the the stomach
•
HIGHLY HIGHLY associated with H. Pylori infection
H. Pylori
Diagnosis Biopsy Urea breath test •
•
Mucosal associated associated lymphoid tissue
•
Ammonium
H. Pylori •
Gastric Adenocarcinoma MALTlymphoma
Increased pH gastrin release ↑ acid production
Urea
•
Mostly occurs in antrum of stomach
H. Pylori
H. Pylori •
Causes acute and chronic gastritis Causes ulcers
•
Patients swallow urea with isotopes (carbon-14 (carbon-14 or carbon-13)
•
Detection of isotope-labelled isotope-labelled carbon dioxide in exhaled breath
•
Indicates urea was split (i.e. urease present)
Treatment: “Triple therapy” for 7-10 days •
Proton pump inhibitor
•
Clarithromycin
•
Amoxicillin/Metronidazole
•
Testing often repeated to confirm eradication
•
Treatmentfailures~20%
Stool antigen
•
•
Urea
85
Breath test, stool antigen, or biopsy
Alternate regimens can be tried
Metaplastic Atrophic Gastritis
Chronic Gastritis Chronic Gastritis
Type A Autoimmune Pernicious Anemia Body and fundus
•
Chronic inflammation inflammation intestinal metaplasia •
Stomach tissue changes changes to intestinal intestinal tissue
•
Key path finding: Goblet cells appear in stomach
Type B Bacteria (H. Pylori) Ulcers Antrum MALT Lymphoma
gastric Both types ↑ risk gastric adenocarcinoma
Peptic Ulcer Disease •
Peptic Ulcer Disease
Solitary Ulcer
•
Antrum of stomach stomach (~10%)
•
H. pylori infection
•
Proximal duodenum (~90%)
•
NSAIDs
•
Smoking
Duodenal Ulcer •
•
Risk factors
•
Duodenal Ulcer
Nearly always related to H. Pylori
•
Symptoms: Epigastric pain
•
H. pylori can increase gastric gastric acid production
•
Improves with meals
•
Especially if antrum antrum infection only (↑gastrin (↑gastrin release)
•
Meal stimulates bicarb secretion
Rare cause: Zollinger-Ellison Syndrome •
Gastrin-secreting tumor
•
Often multiple ulcers
•
Often ulcers in distal duodenum duodenum (beyond bulb) bulb) or jejunum
•
•
Pancreas (secretin/VIP); Brunner’s glands (duodenum)
•
Pain may be worse at night (empty stomach)
Almost never cancerous (benign) •
86
When seen on endoscopy, endoscopy, rarely biopsied
Brunner’s Gland Hypertrophy •
Only induodenum in duodenum
•
Found insubmucosa in submucosa
•
•
•
Complications
Produces alkaline (basic) fluid Protects from acidic stomach fluid and chyme
•
Most duodenal ulcers are anterior
•
Posteriorulcers more likely to have complications
•
Upper GI Bleeding
↑ thickness in peptic ulcer disease •
•
Upper GI Bleeding •
•
•
•
•
•
•
•
Bleeding above the ligament of Treitz Results in hematemesis
•
•
Can be caused by peptic ulcers Melena (dark stools)
More common when when located posteriorly
•
Source is gastroduodenal artery
Pancreatitis Perforation
•
Can occur with gastric or duodenal ulcer Causes pneumoperitoneum Air under diaphragm on CXR
Blood exposed to acid, bacteria Turns stools dark black (“tarry”) Contrast with lower GI bleeding •
Hematochezia
•
“Bright red blood per rectum”
Gastric Ulcer
Much less common than duodenal ulcers Most common location is lesser curvature •
•
Duodenal ulcers can cause bleeding
•
Ulcer Perforation
Gastric Ulcer •
•
•
•
Rupture: bleeding from left gastric artery
•
Pain worse with meals •
Food stimulates acid release
•
Can lead to weight loss
About 70% associated with H. Pylori Dangerouscauses: adenocarcinoma adenocarcinoma
87
Often biopsied
Gastric Ulcer
Ulcer Treatment
Complications •
Perforation
•
H. Pylori treatment (when bacteria identified)
•
Upper GI Bleeding
•
Proton pump inhibitors are therapy of choice
•
Classic vessel is left gastric gastric artery
Gastric Carcinoma •
•
Symptoms nonspecific: nonspecific: Weight loss, abdominal pain
•
Early satiety
•
Early, noninvasive cancer: 5-year survival 95%
•
Advanced: 15%
•
Two types: Intestinal and Diffuse
•
•
•
Grossly appears as large ulcer with irregular margins
Intestinal Type Risk Factors
Similar to colonic adenocarcinoma Results from intestinal metaplasia •
•
Treat GERD, gastritis, gastritis, ulcers
Extensive screening in Japan
Intestinal Type •
PPIs often used used empirically for dyspepsia symptoms
•
Intestinal Type
95% adenocarcinoma Usuallyasymptomaticuntil advanced •
•
•
•
H. pylori; pylori ; autoimmune gastritis
Common in lesser curvature (where ulcers form!)
88
More common among older men Other risk factors •
Smoking
•
Alcohol consumption
Intestinal Type
Diffuse Type
Risk Factors •
•
Nitrosamines •
N=O attached to Nitrogen
•
Most common is NDMA
•
Found in smoked meats
•
Bacon, sausage, ham ham
•
Linked to cancer cancer by case-control studies
Less common form
•
Not associated with metaplasia, H. pylori
•
Few established risk factors
Type A blood •
↑ risk autoimmune gastritis and carcinoma
•
Mechanism unclear
Diffuse Type •
•
Metastasis
Stomachdiffuselythickened •
Early satiety is a common symptom
•
Linitis plastica: plastica : stomach thickened like leather
•
Made up of gastric mucosa cells
•
Signet ring cells •
•
Most common site is liver
Mucin forms nucleus pushed pushed to periphery
Gastric Carcinoma
Gastric Carcinoma
Special Clinical Findings
Special Clinical Findings
•
•
Acanthosis Acanthosis Nigricans
Leser-Trelatsign
Hyperpigmented plaques on skin
•
“Explosive onset” of multiple itchy seborrheic keratoses
•
Intertriginous sites (folds)
•
Probably caused by cytokines
•
Classically neck neck and axillae
•
Associated with insulin resistance •
•
•
•
•
Often seen obesity, diabetes
Rarely associated with malignancy •
Associated with many malignancies malignancies
Gastric adenocarcinoma most common
89
Gastric adenocarcinoma most common
Gastric Carcinoma
Gastric Carcinoma
Special Clinical Findings
Special Clinical Findings
•
Virchow’s node •
•
•
Left supraclavicular node (drains stomach)
•
Sister Mary Joseph nodule
•
•
•
•
•
•
•
Most common from gastric adenocarcinoma
Metastasis to periumbilical region
•
Bilateral ovarian metastasis metastasis
•
Palpable on exam
•
Signet cells often seen on pathology
Hypertrophic Gastropathy
Only about 25% patients have organic cause May be due to gastritis, ulcers, cancer, H. Pylori
Menetrier’s Disease •
Ovarian tumor secondary secondary to mets from another another site
•
•
Dyspepsia •
Krukenberg tumor
More common in men (3:1 ratio) Hyperplasia Hyperplasia of mucous cells Excessive gastric mucous secretions Loss of acid (“achlorhydria”) Protein loss (“protein losing enteropathy”) Hypoalbuminemia edema, facial swelling Can lead to gastric adenocarcinoma
90
•
Rare disorders that cause enlarged rugal folds
•
Caused by hyperplasia (not inflammatory)
Malabsorption •
Malabsorption Malabsorption of nutrients due to intestinal process
•
Generalsymptoms •
Diarrhea
•
Weight loss
•
Vitamin and mineral deficiencies
Malabsorption Jason Ryan, MD, MPH
Malabsorption
Malabsorption
Clinical Manifestations Manifestations
Clinical Manifestations Manifestations
•
Fat malabsorption
•
Carbohydrate malabsorption
•
Steatorrhea
•
Watery diarrhea
•
Pale if bile is absent (no bilirubin)
•
Osmotic effect of sugar molecules
•
Voluminous stools
•
Stools that float
•
Greasy, foul smelling
•
Loss of fat soluble vitamins
•
•
Diarrhea
Edema (loss of of albumin)
Stool Osmotic Gap •
Diarrhea
•
•
Inflammatory
Steatorrhea Watery
Secretory
Protein malabsorption
Osmotic
91
Osmotic gap = 290 – (2[Na]+2[K])stool Osmotic gap >50 seen in osmotic diarrhea diarrhea Osmotic gap <50 seen in secretory causes
Celiac Sprue
Gluten
Celiac Disease, Gluten Sensitivity •
Autoimmune disease
•
•
Destruction of small intestinal villi
•
•
Triggered by glutenexposure gluten exposure
•
Gliadin •
•
•
Gliadin and Glutenin = Proteins inwheat in wheat Gluten = Gliadin + Glutenin Formed in baking bread (with water)
Celiac Sprue
Pathogenic component of gluten Gliadin is deamidated: tissue transglutaminase (tTG)
•
•
Deamidated gliadin is immunogenic
•
•
Deamidated gliadin consumed by APCs Presented to T cells Type IV Hypersensitivity •
T-cell mediated tissue damage
•
Antibodies are present present
•
Unknown how antibodies contribute contribute to disease
Associated with HLA-DQ2 and HLA-DQ8
Histology
Celiac Sprue
Three Key Features
Demographics
•
•
•
Blunting of Villi Crypt hyperplasia
•
Lymphocytes in lamina propria
92
Common in whites of northern European descent
Antibodies
Antibodies
•
Anti-gliadin Anti-gliadin (rarely tested – poor accuracy)
•
IgA endomysial and tTG have highest accuracy
•
Anti-tissue Anti-tissue transglutaminase
•
IgA tTG is automated – used for screening
•
Anti-endomysial Anti-endomysial
•
IgG testing can also be done
•
Endomysium: smooth muscle connective tissue
•
Some patients IgA deficient
•
Antibodies occur in celiac disease
•
Negative tTG plus low low IgA level = check IgG
Diagnosis
tTG IgA IgA
Celiac Disease
Key Tests Anti-tTG IgA Level Biopsy
Symptoms •
Most commonly affected area: duodenum
•
Flatulence, Flatulence, bloating, bloating, chronic diarrhea
•
Steatorrhea
•
+ tTG IgA
Celiac Disease
+
Duodenal Biopsy
-
- tTG IgA Low IgA
- tTG IgA + IgA
+ tTG IgG
Contrast with tropical sprue: entire small small intestine
•
Fat malabsorption
•
Foul-smelling, floating stools
•
Children: Failure to thrive
•
Iron deficiency anemia
-
No Disease or Disagreement
Celiac Disease
Celiac Disease
Treatment
Complications
•
Gluten free diet •
•
Avoid wheat
•
Very difficult!
•
Many packaged packaged foods contain gluten
•
•
Small ↑ risk small bowel malignancy (rare condition!) condition!) Adenocarcinoma T-cell lymphoma •
•
•
93
Enteropathy-associated T-cell lymphoma (EATL)
ClassicScenario: Patient adherent adherent to gluten-free diet with worsening symptoms
Dermatitis Herpetiformis
Tropical Sprue
•
Skin condition associated with celiac disease
•
Malabsorption Malabsorption due to unknown infectious agent
•
Herpes-like lesions on skin
•
Occurs in tropics (especially Caribbean)
•
Caused by:
•
•
•
IgA deposition in dermal papillae
•
Resolves with gluten free diet
•
•
•
Typicalcase: •
Traveler to tropics
•
Chronic diarrhea
•
Malabsorption occurs Antibiotics (usually tetracycline)
•
Folate supplementation
•
•
Tropical: Entire small bowel affected
•
Can be associated associated w ith Folate/B12 deficiency
Often causes steatorrhea steatorrhea Can cause watery diarrhea from sugar malabsoprtion
Infection with Tropheryma whipplei
•
Systemicinfection
•
Whipple’s Disease •
Celiac: Duodenum most common (“proximal small bowel”)
•
•
Treatment: •
•
Whipple’s Disease
Tropical Sprue •
Similar to celiac sprue with blunting of villi Key difference is intestinal location
Gram-positive rod related to actinomycetes
•
Involves small intestine
•
Also joints, brain, heart
Whipple’s Disease
Most cases among white, European males 86% men
•
Average age 49 years
94
Fourcardinalfeatures •
Diarrhea (malabsorption of fats and sugars)
•
Abdominal pain
•
Weight loss
•
Joint pains (migratory arthralgias large joints)
Whipple’s Disease •
Mesenteric lymphadenopathy •
•
•
•
Whipple’s Disease •
May cause abdominal distension
Hyperpgimentation Hyperpgimentation (darkening of skin) CNS disease: Confusion Endocarditis:Culturenegative
Whipple’s Disease •
Fatal before antibiotic era
•
Usually treatment treatment with Ceftriaxone
•
Different treatments for extra-intestinal disease
•
PAS-positive foamy macrophages
•
Seen in small intestinal intestinal lamina propria
Lactose Intolerance
Treatment: •
Diagnosis: Biopsies of small intestine
•
Lactose = disaccharide
•
Digested by brush border enzyme lactase
•
Galactose plus glucose
•
“Disaccharidase”
•
Breaks down lactose into galactose and glucose
•
Lactose remains in small bowel
•
Osmotic effect = diarrhea
•
Normal histology (villi, etc.)
•
High volume, watery watery diarrhea
Lactose Intolerance
Lactose Intolerance
Causes
Causes
•
•
Lactase non-persistence (mostcommon)
•
Galactosyl β-1,4-glucose
Secondarydeficiency
•
Enzyme levels fall fall with aging
•
•
Non-persistence varies among populations
•
Bacterial overgrowth, viral infection, Giardiasis, Celiac, IBD
•
Lowest prevalence European Americans (25%)
•
Lactase usually usually first disaccharidase disaccharidase lost
•
African Americans, Native Americans, Americans, Asians (75-90%)
•
Due to distal location location on villi
Congenital lactase deficiency (rare)
•
95
Mucosal injury
Will present as lactose intolerance following GI illness
Lactose Intolerance
Lactose Intolerance •
•
Diagnosis
Symptoms with lactose ingestion •
Milk
•
Dairy (ice cream)
•
Often clear from history
•
Lactose breath hydrogen test
Bloating, abdominal pain, diarrhea •
Pancreatic Insufficiency •
•
•
Steatorrhea Deficiencies of fat soluble vitamins
If undigested, bacteria ferment lactose Hydrogen
•
Measure exhaled hydrogen level (↑ if lactose intolerant)
Lactose tolerance test (rarely done) •
Monitor blood glucose glucose level after lactose consumption
•
Should rise if lactose
•
Lactose intolerance: intolerance: tiny rise (less than 20 mg/dL)
galactose and glucose
•
Small intestine should be nearly sterile
•
If significant bacteria present:
•
Fat malabsorption •
Patient ingests lactose
•
Bacterial Overgrowth
Cystic fibrosis, chronic pancreatitis, obstruction obstruction Loss of pancreatic lipase, colipase, etc. •
•
•
•
•
•
Small number of organisms organisms can be present Excessive fermentation, inflammation, malabsorption
Bloating,flatulence, abdominaldiscomfort Chronic diarrhea (watery or steatorrhea) steatorrhea) Vitamindeficiencies
Bacterial Overgrowth
Bacterial Overgrowth
Causes
Causes
•
•
Altered motility
•
Diagnosis:
•
Diabetes mellitus (enteric nerve damage)
•
Jejunal aspirate aspirate (gold standard)
•
Scleroderma
•
Lactulose test
Partial/intermittent obstruction •
Adhesions from prior surgery
•
Crohn's disease
•
96
Treatment:antibiotics antibiotics
Fecal Fat Test
D-xylose Test
•
Stool collected over 1-3 days
•
Tests carbohydrate carbohydrate absorption small intestine
•
Amount of fat measured
•
After fasting, patient ingests D-xylose
•
•
Normal <7grams per day Increased in fat malabsorption of any cause •
Loss of bile (liver, (liver, biliary disease)
•
Loss of pancreatic enzymes
•
Loss of small bowel (resection)
•
•
Other Tests •
Stool pH
•
Clinitest
•
•
•
•
Most sugars cause acidic acidic pH (<6.0)
•
Detects undigested sugars
•
Works best in children (less sugar sugar absorption in colon)
Abnormal findings suggest sugar malabsorption malabsorption Both tests abnormal in lactose intolerance Rarely used except in resource poor settings
97
•
Monosaccharide
•
Absorbed in intestine
•
No enzymes required – only intact mucosa
Later, D-xylose measured in serum/urine Abnormal results seen in •
Small intestinal bacterial bacterial overgrowth
•
Whipple's disease
Acute Pancreatitis •
Acute inflammation of pancreas
•
Liquefactive necrosis and hemorrhage
•
•
•
Acute Pancreatitis
•
Epigastric pain, pain, classically radiating to back Nausea, vomiting Many triggers Most common: gallstones, alcohol
Jason Ryan, MD, MPH
Acute Pancreatitis Pancreatitis
Acute Pancreatitis •
Pathophysiology
Rare findings: periumbilical or flank hemorrhage •
Spread of necrosis/blood from enzyme-induced damage
•
Also seen in ruptured ectopic pregnancy (first description)
•
•
•
•
•
•
•
Trypsin activates more trypsin Activates phospholipase, chymotrypsin, and elastase Auto-digestion” of pancreas by enzymes occurs “ Auto-digestion
Acute Pancreatitis Pancreatitis
Trypsin •
Blocked flow of enzymes while synthesis ongoing Large amounts of trypsin activated
Diagnosis
Trypsin secreted as inactivetrypsinogen inactive trypsinogen Normally activated at brush border by enterokinase
•
Trypsin activates all other protein enzymes •
•
98
Elevated serum pancreatic enzyme levels •
↑ Amylase and lipase
•
Both elevated in conditions other than pancreatitis
•
Lipase more specific for pancreatic damage
Liver function tests •
May be abnormal if gallstones are cause
•
Cholestatic picture
•
↑ Alk Phos Phos > ↑AST/ALT;
•
↑ Conjugated bilirubin
Leukocytosis (↑ WBC)
Acute Pancreatitis
Acute Pancreatitis
Diagnosis
Diagnosis
•
Ultrasound •
•
May show gallstones or bile duct dilatation
CT scan •
Pancreatic edema/necrosis
•
Bile duct stones or dilatation
•
#1:Epigastricpain
•
#2:Elevated amylase/lipase >3x normal
•
•
#3: Abnormal pancreatic imaging (CT) Need at least two out of three
Acute Pancreatitis
Acute Pancreatitis Pancreatitis
Common Causes
Common Causes
•
Gallstones •
•
Abdominal imaging (ultrasound) shows dilated bile ducts
•
Acute Pancreatitis •
•
•
•
•
•
•
•
Usually apparent apparent from history
•
Often occurs i n alcoholics
•
Triggers release of pancreatic enzymes
•
Exact mechanism unclear
Trauma
Rare Causes •
Alcohol consumption consumption
Idiopathic (no identifiable cause) Trauma Infection Drugs
•
Blunt or penetrating trauma damage to pancreas
•
Rare due retroperitoneal location
•
Toxins Autoimmunediseases Hypercalcemia Hypertriglyceridemia Post-ERCP
99
Sometimes occurs in children restrained by seatbelts
Infection
Drugs
•
Rare cause of pancreatitis
•
Many drugs can rarely cause pancreatitis
•
Viruses most common than bacteria/parasites
•
Review of medication medication lists important in work-up
•
Classic cause is mumps
•
GLP-1 agonists (diabetes) (diabetes)
Some scorpions
•
Gila monster lizard
•
Sulfa drugs
•
6-Mercaptopurine (6-MP)
•
Brown recluse spider
•
Post-marketing reports of pancreatitis
AIP
Venom of arachnids and reptiles •
Exenatide, Liraglutide
•
Autoimmune Pancreatitis
Toxins •
•
•
•
•
•
Rarecondition Chronic abdominal pain Recurrentattacks of acute pancreatitis Diffusely enlarged pancreas on imaging IgG4 positive plasma cells •
•
Hypercalcemia •
Calcium may deposit deposit in pancreatic pancreatic ducts
•
Calcium may activate trypsinogen
Identified in pancreas
•
Serum IgG4 levels are elevated
Responds to treatment withsteroids with steroids
Hypertriglyceridemia
Hypercalcemia Hypercalcemia (any cause): rarely causes pancreatitis •
Marker for the disease
•
•
•
•
100
Elevated triglycerides(>1000) triglycerides (>1000) acute pancreatitis Exact mechanism unclear unclear May involve increasedchylomicrons increased chylomicronsin in plasma •
Chylomicrons usually formed after after meals and cleared
•
Always present when when triglycerides > 1000mg/dL
•
May obstruct capillaries
•
Vessel damage can expose triglycerides to pancreatic lipases
ischemia
•
Triglycerides breakdown free fatty acids
•
Acid tissue injury pancreatitis
ERCP
Duodenal Ulcers
Endoscopic retrograde cholangiopancreatograph cholangiopancreatography y •
Combination Combination of endoscopy and fluoroscopy
•
•
Imaging and therapy of biliary disorders
•
Pancreas sits behind posterior duodenum Rupture of a posterior duodenal ulcer may lead to acutepancreatitis
Acute Pancreatitis
SIRS
Treatment
Systemic Inflammatory Response Syndrome
•
•
NPO •
Nil per os
•
No food or liquid
•
“Rests” thee pancreas (prevents stimulation)
•
•
•
•
IV fluids •
•
•
•
Fluid loss to pancreatic edema
•
Inflammation leads to diffuse vascular leak
•
IV fluids needed needed to maintain BP and renal perfusion
•
Paincontrol •
Most patients with mild disease improve in 2-3 days
•
•
•
Heart rate>90bpm rate >90bpm Respiratory rate >20 breaths/min WBC > 12,000 SIRS can occur from many causes •
Trauma, pancreatitis
•
Sepsis = SIRS + infection
SIRS in pancreatitis indicates severe disease
Acute Pancreatitis Pancreatitis
Ranson’s Criteria •
Clinical syndrome of dysregulated inflammation Temperature >38.3°C or <36°C
Complications
Classic method of assessing pancreatitis pancreatitis severity Scoring system: points for each criteria present Mortality increases with higher score
•
•
•
Other scores also used ( APACHE II)
•
101
DIC ARDS Pseudocyst Abscess
•
Fat necrosis
•
Hypocalcemia
•
Multi-organfailure
DIC
ARDS
Disseminated Intravascular Coagulation Coagulation •
Diffuse activation of clotting factors •
•
•
•
•
•
“Consumption coagulopathy”
Prolonged PT/PTT Thrombocytopenia Vascular occlusion •
Microangiopathic hemolytic anemia
•
Ischemic tissue damage
•
•
Damage to capillary endothelium and alveolar epithelium Protein escapes from vascular space Fluid pours into the interstitium
Can present as bleeding
Looks like pulmonary edema but PCWP is normal
Image courtesy of James Heilman, MD
Pseudocyst •
•
Walled-offcollectionof edema/fluid/necrosis edema/fluid/necrosis “Psuedo” because no epithelium •
•
Pseudocyst •
•
Granulation/fibrous tissue surrounds fluid
Diagnosed by CT or MRI imaging
Pseudocyst •
Amylase/lipase fail to normalize
•
Abdominal pain persists or returns
•
Critically ill patient
•
Chronic pancreatitis (10% of patients)
Pseudocyst
Most common location is lesser sac •
Often identified when pancreatitis does not resolve
•
Posterior to stomach
•
•
•
•
102
Pseudocysts often resolves without intervention Sometimesrequiresdrainage Feared outcome is rupture peritonitis Can also lead to fistulas, obstruction Can become infected
Pancreatic Abscess
Fat Necrosis
•
Infection of pancreatic pseudocyst
•
Usually occurs late (~10 days) into acute pancreatitis
•
Commonly caused by intestinal bacteria
•
•
E. coli
•
Also Pseudomonas, Klebsiella, Enterococcus
•
Inflammation can involve fat surrounding pancreas
•
Can lead to hypocalcemia/hypomagnesemia
•
Presents as fever, failure to improve clinically
•
Enzymes (lipase) may may release free fatty acids
•
Fatty acids can bind calcium (“saponification”)
Low calcium is a poor prognostic indicator •
Saponification
Suggests extensive involvement involvement of fat
Multi-Organ Failure
Triglyceride
•
Free Fatty Acids +
Severe pancreatitis may lead to: •
DIC
•
ARDS
•
Infection/septic shock
•
Life-supportive treatment often required in ICU
•
Can progress to multi-system failure failure and death
Ca++
•
Ca++
Calcium Soap
103
Mechanical ventilation, vasopressors, dialysis
•
Persistent hypotension despite vasopressors
•
Failure to wean from ventilator
•
Renal failure requiring dialysis
Chronic Pancreatitis
Chronic Pancreatitis and Pancreatic Cancer
•
Fibrosis/calcification Fibrosis/calcificationof pancreas
•
Due to recurrent bouts of acute pancreatitis
•
Alcoholin Alcohol in adults; Cystic fibrosis in children •
Most causes of pancreatitis are not recurrent (i.e. gallstones)
•
Alcohol and cystic fibrosis
recurrent acute pancreatitis
Jason Ryan, MD, MPH
Chronic Pancreatitis •
Chronic Pancreatitis
CT scan: classic finding is calcified pancreas
•
•
•
Splenic Vein Thrombosis
Chronic abdominal pain •
May wax and wane
•
May be worse after meals fear of eating and weight loss
Amylase/lipase •
May be mildly elevated elevated or normal
•
Fibrosis may lead to loss of production production of enzymes
Rarely complications: complications: •
Splenic vein thrombosis
•
Pancreatic insufficiency
Pancreatic Insufficiency Insufficiency •
Results in gastric varices via engorgement of short gastric veins
•
•
•
Key Findings: Enlarged spleen Gastric varices
104
Result of chronic pancreatitis pancreatitis Fat malabsorption and steatorrhea Fat-solublevitamin deficiencies deficiencies Diabetes (loss of insulin)
Pancreatic Cancer •
Adenocarcinoma
•
More common at head of pancreas
Pancreatic Cancer •
•
•
Often causes vague abdominal pain, weight loss Classic presentation is “painlessjaundice” “painless jaundice” •
Bile flow is obstructed
•
No pain due to absence of abrupt obstruction/inflammation
•
Slow growth of tumor gradually leads leads to jaundice
•
•
Dark urine
•
Clay colored stools
•
Steatorrhea
Most patients die from their cancer
•
5-year survival node-positive: node-positive: 10%
•
5-year survival node-negative: node-negative: 25%
•
Classic physical exam finding for pancreatic cancer
•
Enlarged,non Enlarged, non tender gallbladder plus jaundice
Pancreatic Cancer Risk Factors
Classic finding of pancreatic cancer Migratory superficial thrombophlebitis •
Migratory: comes/goes comes/goes in different locations
•
Superficial: Below skin
•
Thrombophlebitis : Thrombosis/inflammation of veins
•
•
Usually metastatic metastatic at presentation
•
May see other signs of pancreatic-biliary pancreatic-biliary obstruction
Trousseau’s Syndrome •
•
Courvoisier’s Sign
Pancreatic Cancer •
Very poor prognosis
•
•
•
•
•
Redness and and induration on skin that migrates
Due to hypercoagulable hypercoagulable state
Age >50 years old Smoking Diabetes
Strongest Risk Factors
Chronic pancreatitis pancreatitis (> 2O years) NOT strongly associated with alcohol •
Studies have shown shown mixed findings
•
Some data that heavy drinking (>3/day) increases risk
Gapstur S. et al. Association al. Association of Alcohol Intake With Pancreatic Cancer Mortality in Never Smokers Arch Intern Med. 2011;171(5):444-451.
105
Pancreatic Cancer
BRCA2 Mutations •
BRCA1/BRCA2 BRCA1/BRCA2 genes DNA repair proteins
•
Gene mutation associated associated with breast/ovarian breast/ovarian cancer
•
•
Risk Factors •
African-Americans African-Americans (50-90% ↑ risk)
BRCA2 mutations also associated with pancreatic CA Especially true among Ashkenaz among Ashkenazii Jews Jews
Pancreatic Cancer
Pancreatic Cancer
Tumor Markers
Genetics
•
•
CA-19-9
•
Cancer-associated antigen 19-9
•
•
Specificity 68-92%
•
Most frequently mutated gene in pancreatic pancreatic cancer
•
Sensitivity 70-92% (may (may be negative in smaller tumors)
•
Also part of adenoma-carcinoma adenoma-carcinoma sequence for colon cancer
•
Not useful for diagnosis
•
Can be followed after treatment
•
CEA •
Can be elevated in pancreatic pancreatic cancer
•
Poor sensitivity/specificity
•
Largely replaced by CA-19-9
Pancreatic Cancer Treatment •
•
•
K-RAS gene (chromosome 12p)
•
Chemotherapy Radiation Surgery •
Classic procedure is the Whipple procedure
•
Pancreatoduodenectomy
106
Seen in 90% of pancreatic pancreatic cancers
SMAD4 gene (chromosome 18q) •
Tumor suppressor gene
•
Inactivated in 60% of pancreatic pancreatic cancers
Appendicitis •
Acute inflammation of appendix
•
“Vermiform appendix” •
Blind-ended tube attached to cecum
•
“Vermiform” = wormlike
Intestinal Disorders Jason Ryan, MD, MPH
Appendicitis
Appendicitis
Pathogenesis
Symptoms
•
Opening to cecum becomes obstructed •
Fecaliths (hard fecal masses) – more common adults
•
Lymphoid hyperplasia – more common children
•
•
•
Appendicitis
Fever, nausea Abdominalpain •
Begins mid-epigastric (visceral peritoneum inflammation)
•
Moves to RLQ (parietal peritoneum inflammation)
Classiclocation: McBurney’s Point •
Line from iliac crest crest to umbilicus
•
1/3 distance from iliac crest
The “Acute Abdomen”
Diagnosis and treatment •
Diagnosed by history/exam or CT Scan
•
•
Treatment:Surgery
•
Acute onset abdominal pain “Reboundtenderness” “Reboundtenderness” •
•
•
107
Reflects peritoneal inflammation
Several causes requireurgent require urgent surgical intervention •
Appendicitis
•
Diverticulitis
•
Ectopic pregnancy pregnancy (β-HCG testing often done)
Perforation of abdominal viscus •
Peritonitis
•
Rigid abdomen
Diverticular Disease •
Diverticular Disease
Diverticulum
•
Blind pouch/sac extending out from GI tract
•
Many diverticuli in GI tract
•
Breakdown of muscularis muscularis mucosa
•
Usually in sigmoid colon
•
Protrusion of mucosa/submucosa mucosa/submucosa to form pouch
•
“False diverticulum” - does not contain all layers of GI tract
•
Occur where vasa recta penetrate muscularis of colon
•
Lower GI bleeding (hematochezia)
•
Diverticulitis
Caused by straining to pass stool (wall stress)
•
Low fiber diet hard stools diverticulosis
•
•
•
•
•
•
LLQ pain •
Sigmoid colon
•
“Left sided appendicitis”
“Occult blood” in stool
Complications
Diagnosis: CT scan Treatment: •
Inflammation of a diverticulum Fever, ↑ WBC
Diverticulitis
Diverticulitis •
Chronic, recurrent increased intra-abdominal intra-abdominal pressure
Diverticulitis
Often asymptomatic Complications •
•
•
Diverticular Disease •
Diverticulosis
•
•
Usually antibiotics Surgery
•
108
Abscess •
Diverticulitis that does not improve after after antibiotics
•
Often requires surgery
Bowel obstruction •
May narrow intestinal intestinal lumen
•
Nausea, vomiting, abdominal distention, constipation
Diverticulitis
Adhesions
Complications •
•
Fistula •
Most commonly to bladder (“colovesical (“colovesical fistula”)
•
Presents with pneumaturia, fecaluria, or dysuria Results in peritonitis
•
Diffuse pain; rigid abdomen
Bands of scar tissue in peritoneal cavity
•
Commonly formed after surgery
•
Perforation •
•
•
•
Most common cause of SBO Can cause: •
Bowel obstruction
•
Infertility in women (interfere with ovum ovum transport)
•
Chronic abdominal/pelvic pain
Treatment: •
Intussusception •
•
Intussusception
“Telescoping” of intestine Intestine folds into lumen
•
•
•
•
•
•
Intussusception •
•
Underlying lesions often leads to intussusception Intestine trapped and dragged by peristalsis Potential lead points •
Meckel’s diverticulum
•
Lymphoid hyperplasia (Peyer’s patches; viral gastroenteritis)
•
Strong association with enteric adenovirus infection
•
In adults: tumors
Blood supply compromised compromised GI bleeding: “Currant jelly” “Currant jelly” Medicalemergency Common in children (often <1 year old) Rare in adults Often near the ileocecal junction
Volvulus
Lead Point •
Surgery (“lysis of adhesions”)
•
•
•
•
•
109
Twistingof Twisting of bowel around mesentery Pathophysiology/cause Pathophysiology/causepoorly understood Causes obstruction/infarction Classically occurs at sigmoid colon or cecum Classic sigmoid imaging findings: •
Dilated sigmoid
•
Airless rectum
•
Occurs in elderly (mean age 70)
•
In children may be 2° Meckel’s
Bowel Obstruction •
Much more common small intestine (75%)
•
Abdominal pain, nausea, vomiting
•
•
Bowel Obstruction •
Abdominaldistention Obstipation (inability (inability to pass stool)
•
X-ray: •
Dilated bowel loops
•
Air-fluid levels
•
•
•
•
•
•
•
Bulge (hernia)
•
Cancer
LBO common causes •
Tumor
•
Adhesions
•
Volvulus
Congenitaldisease Associated withDown with Down Syndrome Motor disease of intestines intestines Abnormalperistalsis of colon Absent ganglion ganglion cells •
Derived from neural crest crest cells
•
Nerve cells of Meissner’s plexus and Auerbach’s plexus
•
Muscular layer (Auerbach’s) (Auerbach’s) and mucosa (Meissner’s)
•
Fail to migrate properly in Hirschsprung’s disease
Result: Obstruction (no peristalsis)
Diagnosis and Treatment
Dilated bowel behind obstruction Presentation
•
Barium imaging •
“Transition zone”
Failure to pass meconium
•
Cone-shaped
•
Abdominal distention
•
Proximal distended bowel (normal)
•
Bilious vomiting
•
Distal bowel small small (abnormal)
•
Examination: no stool in rectal vault
•
•
Adhesion
•
Hirschsprung’s Disease
Hirschsprung’s Disease •
•
Hirschsprung’s Disease
Bowel Obstruction •
SBO common causes (ABCs)
Less severe disease (uncommon) •
Chronic constipation
110
Hirschsprung’s Disease
Ileus
Diagnosis and Treatment •
•
Rectal “suction” biopsy •
Rectum ALWAYS ALWAYS involved (other areas variable)
•
Standard biopsy may may only show mucosa
•
Need to apply suction to biopsy submucosa
•
Absence of ganglion ganglion cells
•
•
•
•
•
Common causes:
Acute “pseudo-obstruction” of intestines Dilated colon in absence of a lesion
Functionalbowel Functionalboweldisorder
•
Recurrent abdominal pain
•
Usually in hospitalized or nursing home patients Often with severe illness or recent surgery Often associated with narcotics
Irritable Bowel Syndrome
•
•
•
Post-operative
•
•
•
Meds (especially narcotics) narcotics)
•
Irritable Bowel Syndrome
•
•
•
Removal of colon colon without ganglion cells
Ogilvie Syndrome •
Loss of bowel peristalsis Can cause nausea, vomiting, constipation, obstipation
Treatment: Colon resection •
•
•
Normal intestinal structure
•
At least 3 days per month
•
Over last 3 months
One of the following features features •
Improvement with defecation
•
Change in frequency frequency of stool
•
Onset associated with a change in appearance of stool
Can cause diarrhea, constipation, constipation, or both
Necrotizing Enterocolitis
Chronic disorder Poorly understood cause More common in women Few reliably effective treatments
•
•
•
•
Treatment often directed at symptoms
111
Neonatal disorder (usually 1st month of life) Intestinal necrosis and obstruction obstruction Usually terminal ileum or colon Can lead to perforation perforation
Necrotizing Enterocolitis •
•
Necrotizing Enterocolitis
Unclear pathogenesis
•
Combination of enteral feeding + bacteria bacteria
illness
•
•
Bacteria may overgrow overgrow immature mucosal defenses
•
Abdominal distention
•
Nausea, vomiting
Major risk factor is prematurity, prematurity , low birth weight •
•
•
•
Aberrant blood vessels in GI tract Common in cecum and right sided colon
•
•
•
Caused by high wall stress •
Premature baby in NICU
Classic X-ray finding: •
Pneumatosis intestinalis
•
Air in bowel wall
•
Lucent area parallel to bowel
Treatment •
Bowel rest, antibiotics
•
Often surgery
Hereditary Hemorrhagic Telangiectasia
Angiodysplasia •
Classic case
•
•
Intermittent obstruction of submucosal veins
Also called Osler-Weber-Rendu Osler-Weber-Rendu syndrome Autosomaldominant Autosomal dominant vasculardisease Telangiectasias TelangiectasiasthroughoutGI tract •
Lower GI bleeding (hematochezia)
•
•
•
112
Nasopharynx to rectum
Rarely leads to AVMs (pulmonary, CNS) Common clinical clinical features Nose bleeds
•
GI bleeding
•
Iron deficiency
Inflammatory Bowel Disease •
Inflammatory Bowel Disease
•
Two chronic autoimmune bowel diseases •
Crohn’s disease
•
Ulcerative colitis
Both have relapsing, remitting course •
Patients have “flares”
•
Increased medication requirements
Jason Ryan, MD, MPH
Inflammatory Bowel Disease •
Inflammatory Bowel Disease
Similar symptoms both disorders •
•
•
•
Recurrent episodes
•
Abdominal pain
•
Bloody diarrhea
•
•
•
•
Stool cultures (Salmonella, (Salmonella, Shigella, Campylobacter, Campylobacter, Yersinia)
•
Testing for E. coli O157:H7
•
Other stool studies studies (C. diff, Ova and parasites)
•
White woman in 30s
•
Jewish descent
Pathologic Features
Many causes other than IBD especially infection Typical studies sent when considering IBD •
Some studies suggest suggest second spike in 50 to 80 year olds
More common among whites More common among Jewish populations Classicpresentation
Ulcerative Colitis
Bloody Diarrhea •
Slight female predominance predominancein in most studies Age of onset usually 15 to 40 years
•
113
Ulcers form in intestinal tract •
Inflammation of mucosa and sometimes submucosa
•
Importantly NOT full thickness inflammation
Ulcerative Colitis
Ulcerative Colitis
Pathologic Features
Gross Morphology
•
•
Always Always starts in rectum rectum works upward •
Always has rectal involvement
•
Left lower quadrant quadrant pain is common
•
Pseudopolyps (healing of ulcers)
Never involves small intesti ne •
“Colitis”
Ulcerative Colitis
Ulcerative Colitis
Gross Morphology
Microscopy
•
Loss of haustra (lead pipe appearance on X-ray/CT)
•
Cryptabscesses •
Common findings and pseudolesions at computedtomography colonography. Diagnóstico por Imagem. Giuseppe D'Ippolito et al. Used with permission.
Colégio Brasileiro de Radiologia e
Ulcerative Colitis
Toxic Megacolon
Extra-intestinal Extra-intestinal Features •
Pyoderma gangrenosum •
Primary sclerosingcholangitis cholangitis
•
Ankylosing spondylitis
•
Uveitis
•
•
•
Deep, necrotic skin ulceration
•
PMN infiltration of crypts
•
Rare complication of UC (also infectious colitis) Cessation of colonic contractions •
•
Inflammation of spine
•
•
Inflammation of middle layer layer eye
114
Evidence that nitric oxide inhibits smooth muscle tone
Leads to intestinal dilation rapid distention occurs Wall thins prone to rupture Can cause perforation
Ulcerative Colitis
Toxic Megacolon •
Adenocarcinoma
Presentation •
Abdominal pain
•
Distention
•
Fever
•
Diarrhea
•
Shock
•
Significant risk in UC
•
Risk based on two key factors
•
•
years before most cancers cancers form) Duration of disease (>10 years
•
Extent of disease (more disease disease = more risk)
•
Involvement into right colon = more more disease
•
“Right sided colitis” or “pancolitis” are risk factors
Screeningcolonoscopyrecommended •
•
•
Pathologic Features
p-ANCA •
•
Antibody seen in vasculitis syndromes
•
Churg-Strauss and Microscopic Polyangiitis
•
Also seen in ulcerative colitis
•
•
Anti-saccharomyces Anti-saccharomycescerevisiae antibodies antibodies (ASCA) •
Saccharomyces cerevisiae: type of yeast
•
Elevated antibody levels seen in Crohn’s
•
Both tests suggested to distinguish forms of IBD
•
Not reliable for routine clinical use
Colectomysometimes Colectomysometimesrequired
Crohn’s Disease
Antibody Tests •
Multiple biopsies biopsies taken
Granulomatous inflammation Entire wall effected (“transmural ”) Any portion of the GI tract can be effected •
“Mouth to anus”
•
Oral ulcers can be seen
Crohn’s Disease
Crohn’s Disease
Pathologic Features
Pathologic Features
•
Terminal ileum is common location •
Malabsorption
•
Vitamin deficiencies deficiencies (B12)
•
May have have non-blo ody diarrhea due to malabsorption
•
May have right lower quadrant quadrant pain
•
•
•
Often spares spares the rectum
•
•
Often “skips” sections
•
•
115
Terminal ileum is common location Malabsorption •
Vitamin deficiencies deficiencies (B12)
•
Malabsorption of bile salts
•
May have non-bloody diarrhea due to malabsorption
May have right lower quadrant pain Often spares spares the rectum
Often “skips” sections
Crohn’s Disease
Crohn’s Disease
Gross Morphology
Gross Morphology
•
Fistulas
•
Creeping fat
•
Peri-anal
•
Transmural inflammation heals heals
•
Abdominal
•
Condensed fibrous tissue tissue pulls fat around bowel wall
•
Bladder (“enterovesical fistula”)
•
Can wrap around bowel
•
Risk only when col on involved
•
When colon involved, surveillance colonoscopy
•
Healing leads to fibrous tissue
•
Dense fibrous tissue tissue narrows lumen
•
“String sign”
Crohn’s Disease
Adenocarcinoma •
Strictures
Extra-intestinal Features •
Migratory polyarthritis •
•
•
Erythemanodosum •
Crohn’s Disease Kidney stones •
•
Calcium oxalate stones
•
High oxalate levels seen in Crohn’s
•
Fat malabsorption Fat binds to calcium
•
Oxalate free to be absorbed in the gut
•
Ankylosing spondylitis
•
Uveitis
Inflammation of fat tissue tissue under skin
Immunology
Extra-intestinal Extra-intestinal Features •
Most common extra-intestinal manifestation Arthritis of large joints (knees, hips)
•
•
116
T-cells: T-cells: major contributor both disorders Ulcerativecolitis •
Th2 mediated disorder
•
No granulomas
Crohn’s disease •
Th1 mediated disorder
•
Granulomatous disease
Smoking •
•
IBD Treatments
Improves outcomes in UC Worsensoutcomes Worsens outcomes in Crohn’s
•
•
•
•
•
•
•
Sulfasalazine
•
Acetylsalicylic acid (aspirin) Sulfasalazine Colonic Bacteria
5-aminosalicylic acid (5-ASA)
5-ASA Mesalamine
•
•
•
•
Many side effects of sulfasalazine due to sulfa sulfasalazine - sulfa moiety = 5-ASA Less side effects BUT absorbed in jejunum Less delivery to colon colon Modified 5-ASA compounds resist absorption •
Coating or delayed delayed release capsules
•
Asacol, Pentasa
Infliximab/adalimumab Sulfasalazine 5-ASA
Side Effects
•
•
Methotrexate 6-MP
Sulfasalazine
Not active until reaches colon Perfect for UC!
•
Sulfapyridine
Corticosteroids Azathioprine
5-aminosalicylic acid (5-ASA)
117
GI upset (nausea, vomiting) vomiting) Sulfonamide hypersensitivity Oligospermia in men •
Mechanism unclear
•
Reversible with drug cessation
•
Problem for men trying to conceive on therapy
Colon Polyps •
•
•
Raised outgrowth of tissue into lumen May be pre-cancerous pre-cancerous Removal can prevent colon cancer
Colon Cancer Jason Ryan, MD, MPH
Adenomatous Polyp
Hyperplastic Polyp •
Benign
•
•
Most common type of polyp
•
•
•
•
•
Dysplastic with malignant potential Several sub-classifications
Common in rectosigmoid colon Normal cellular structure, no dysplasia Classically have a “saw tooth” or serrated pattern Usually no special screening required after biopsy
Sessile vs. Pedunculated •
Sessile: broad base attached to colon
•
Pedunculated: attached via stalk
Tubular vs. Villous •
•
118
Tubular •
Most common subtype subtype (80%+)
•
Adenomatous epithelium forming tubules
Villous •
Less common type
•
Often sessile
•
Long projections extending from surface
•
High risk of development development into colon colon cancer
Polyp Symptoms •
•
•
Villous Adenomas
Almost always asymptomatic Screening colonoscopy done for detection
•
•
Large polyps may cause bleeding •
Usually not visible in stool (“occult”)
•
Basis for screening with fecal occult blood testing
•
•
•
•
Often sessile Can have a broad base (3-4cm) Can lead to excessive mucous secretion Rarely cause a secretory diarrhea Usually when located in rectosigmoid Watery diarrhea Hypokalemia
Bruno et al. The Mckittrick-Wheelock Syndrome: A Rare Cause of Severe Hydroelectrolyte Disorders and Acute Renal Failure. Case Reports in Nephrology Volume 2011 (2011), Article ID 765689, 3 pages
High Risk Polyps •
•
Juvenile Polyps
Likely to develop into cancer
•
Villous histology (villous = villain)
•
Usually in rectum
•
Dysplasia grade
•
Usually pedunculated
•
Determined by pathologist
•
“High grade dysplasia” = ↑ risk
•
•
Metachronous adenoma: new lesion ~ six months after prior
•
>1 cm in diameter = ↑ risk
•
Number of polyps = ↑ risk
•
•
Pigmented spots on lips and buccal mucosa
•
Risk of gastric, small intestinal, and colon CA
•
Juvenile polyposis syndrome •
Multiple (usually >10) >10) polyps
•
Increased risk of cancer cancer
•
Surveillance colonoscopy
1. Two well-defined genetic pathways to colon cancer
“Peutz-Jeghers polyps”
•
Often “auto-amputate”
Genetics of Colon Cancer
Autosomal dominant disorder Multiple hamartomas throughout GI tract •
Cause painless rectal bleeding •
Patient likely to develop more polyps
Peutz-Jeghers Syndrome •
Benign tumors (hamartomas) that occur in children
•
•
Chromosomal Instability Pathway
•
Microsatellite Instability
2. Cyclooxygenase-2 Cyclooxygenase-2 expression ↑ in colon cancer 3. DCC gene mutated in advanced colorectal cancers
Often presents in childhood w ith spots around around lips
119
Chromosomal Instability Pathway
Chromosomal Instability Pathway •
•
•
“Adenoma-Carcinoma “Adenoma -Carcinoma sequence” Sequence of genetic events seen in colon cancer Leads to colon cancer over many years •
•
•
•
Progression probably takes 10-40 years
“Somatic” mutations occurs with aging
More common in left sided tumors •
Descending colon, sigmoid, rectum
Step 1: APC 1: APC mutation mutation •
Adenomatous polyposis coli protein/gene
•
Tumor suppressor gene
•
Prevents accumulation of β -catenin (activates oncogenes)
•
Loss of APC ↑ β-catenin oncogene activation
•
Leads to ↑ risk for polyps
Normal Colon
At Risk Colon
APC Mutation
Chromosomal Instability Pathway •
Chromosomal Instability Pathway
Step 2: K-RAS mutation
•
Proto-oncogene
•
Loss of p53 tumor suppressor gene
•
Aberrant cell signaling signaling
•
Tumor cell growth
•
Leads to adenoma adenoma polyp formation
Normal Colon
At Risk Colon
APC Mutation
Polyp
Normal Colon
•
•
Colon Cancer
Polyp
KRAS Mutation
P53
FAP Variants
Familial Adenomatous Polyposis
•
At Risk Colon
APC Mutation
KRAS Mutation
FAP •
Step 3: p53
•
Autosomal dominant disorder Germline mutation of APC gene (chromosome (chromosome 5q) Always (100%) progresses to colon cancer
•
•
•
Treatment:Colonremoval (colectomy)
•
120
All have APC gene mutation Polyposisplus extra-intestinal extra-intestinalsigns/symptoms Gardner’s Syndrome TurcotSyndrome
CHRPE
Gardner’s Syndrome •
•
•
•
Polyposis plus multiple extra-colonic manifestations Benign bone growths (osteomas) especially mandible Skin cysts: Epidermal cysts, fibromas, lipomas, Connective tissue growths: •
•
Congenital Hypertrophy of the Retinal Pigment Epithelium •
Flat dark spot in retina retina
•
Seen on slit lamp exam
•
Usually a benign findings with no symptoms
•
When seen with polyposis = Gardner’s syndrome
“desmoid tumors”, “fibromatosis”
Hypertrophy of retinal pigment
Turcot Syndrome
Microsatellite Instability
•
Polyposis plus brain tumors
•
•
Mostly medulloblastomas and gliomas
•
•
Microsatellite Instability •
•
Less common mechanism of colon CA development More common in right sided ( proximal) tumors These can arise “de novo” without polyp
Microsatellite Instability
What is a microsatellite? microsatellite?
•
What is a mismatch?
•
Short segments of of DNA (usually non-coding)
•
Bases should be paired (A-C; G-T)
•
Repeated sequence sequence (i.e. CACACACA)
•
If wrong base/nucleotide inserted into DNA = mismatch
•
Different density from other DNA
•
Separate from other genetic material in testing
•
(“satellites”)
•
What is a stable microsatellite? •
Successive cellular divisions: same length microsatellites microsatellites
•
Each person has unique, “stable” length of microsatellites
•
Different person-to-person; same for each i ndividual
•
•
Mismatch repair enzymes resolve base errors Gene mutations can lead to accumulation of errors This can occur in microsatellites microsatellites in cancer cells Result is microsatellite microsatellite instability •
121
PCR testing
•
Different length of microsatellites microsatellites in tumor cells vs other other cells
•
Indicates mismatch mismatch repair enzyme enzyme dysfunction
HNPCC
Cyclooxygenase-2
Hereditary Non-Polyposis Colorectal Cancer/Lynch Syndrome •
Inherited mutation of DNA mismatch repair enzymes
•
Leads to colon cancer via microsatellite instability instability
•
•
•
•
About 80% lifetime risk
•
Arise with out pre-existing pre-existing adenoma
Usually right-sided tumors tumors Also increased risk of: •
Endometrial cancer (most (most common non-colon malignancy)
•
Other cancers (ovary, stomach, others)
Classic case •
Patient with right sided colon CA
•
Multiple 1 st family members also also with cancer
Cyclooxygenase-2 •
•
•
DCC Gene
Increased expression in colon cancer cells More common in left sided cancers
•
•
Rationale for aspirin therapy •
Reduces risk of colorectal cancer cancer 20-40%
•
BUT increases risk of bleeding/ulcers
•
•
•
•
Frequently mutated in advanced colorectal cancers
No clinical trial evidence supporting routine aspirin use for prevention
Colon Cancer •
Deleted in Colorectal Cancer Cancer (DCC) gene Tumor suppressor gene (chromosome 18q)
Colon Cancer
3rd most common cancer 3rd most deadly cancer
•
•
More common after 50 years of age
•
122
May occur anywhere in colon Different sites may have different symptoms Treated with surgery +/- chemotherapy chemotherapy
Colon Cancer Screening
Colon Cancer
•
•
•
•
•
•
•
•
•
Lancefield group D Rarecausebacteremia/endocarditis cause bacteremia/endocarditis
•
•
Strongly associated with colon cancer Classicquestion: S. Bovis endocarditis endocarditis identified
•
What test next?
•
Answer: Colonoscopy
Usually recommended at age 50 then every ten years
•
Polyps removed and examined by pathologist
•
↑ screening high risk groups or after polyps found
Fecal occult blood testing •
Regular digital rectal rectal exam
•
Colonoscopy if blood detected
Carcinoembryonic Carcinoembryonic Antigen
Normal colonic bacteria Gram positive cocci (gamma hemolytic)
•
•
CEA
Strep Bovis •
Colonoscopy
123
Tumor marker Elevated in colon CA and other tumors (pancreas) Poor sensitivity/specificity sensitivity/specificity for screening Patients with established disease •
CEA level correlates correlates with disease burden
•
Elevated levels should should return to baseline after surgery
•
Can be monitored to detect relapse
Carcinoid Tumors •
Carcinoid Tumors
•
Neuroendocrinetumors •
Neuroendocrine cells = nerve and endocrine endocrine features
•
Found in many organs: GI tract, lungs, pancreas
•
Small intestine (GI) most common
Carcinoid = “cancerlike” “cancer like” •
Named for slow growth
Jason Ryan, MD, MPH
Carcinoid Tumors •
•
Carcinoid Syndrome
Secrete serotonin Responsible for majority of clinical effects •
Diarrhea (serotonin stimulates GI motility)
•
↑ fibroblast growth and fibr ogenesis valvular lesions
•
Flushing (other mediators also)
•
Symptoms secondary high serotonin levels
•
metabolize (inactivate)serotonin Liver and lung metabolize
•
•
No carcinoid syndrome unless metastatic to liver No left sided heart symptoms: inactivated in lungs
Serotonin 5-hydroxytryptamine (5-HT)
5-HIAA
Carcinoid Syndrome •
5-Hydroxyindoleacetic 5-Hydroxyindoleacetic acid
Alteredtryptophan Altered tryptophan metabolism
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Normally ~1% tryptophan
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Up to 70% in patients with carcinoid syndrome
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Tryptophan deficiency reported
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Tryptophan Niacin (B3)
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Symptoms = Pellagra
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serotonin
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Metaboliteofserotonin Appears in urine urine in carcinoid syndrome 24-hour urine sample for diagnosis Monoamine Oxidase (MAO)
Serotonin 5-hydroxytytamine (5-HT)
Tryptophan
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5-hydroxyindole acetaldehyde
5-Hydroxyindoleacetic acid (5-HIAA)
Carcinoid Heart Disease •
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Carcinoid Syndrome
Fibrous deposits tricuspid/pulmonic valves Stenosis/regurgitation
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Serotonin inactivated by lungs Left sided lesions rare rare •
Octreotide •
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Analog ofsomatostatin of somatostatin Used in GI bleeding and other niche roles Somatostatin receptors on many carcinoid tumors •
Inhibit release of of bioactive amines
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Serotonin, catecholamines, histamine
Octreotide therapy used •
Flushing and diarrhea significantly improve
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Clinicalscenario: •
Abdominal pain
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Flushing
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Diarrhea
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Pulmonic/tricuspid valve disease
Treatments •
Surgical excision
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Hepatic resection
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Octreotide
Antacids •
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Gastrointestinal Pharmacology
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Over the counter therapy Often used for GERD symptoms
SodiumB icarbonate icarbonate Calcium carbonate Aluminum hydroxide Magnesium hydroxide
Jason Ryan, MD, MPH
Sodium Bicarbonate
Calcium Carbonate
Alka Seltzer
Tums
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Bloating, belching (CO2)
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Alkalosis (bicarbabsorption) absorption) Fluidretention (NaCl resorption)
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Bloating, belching (CO2) Alkalosis (bicarbabsorption) absorption) Can cause constipation constipation (calcium: ↓ GI motor activity) Hypercalcemia (calciumchloride) •
NaHCO3 + HCl NaCl + H 2O + CO2
CaCO3 + 2HCl CaCl2 + H2O + CO2
Calcium Carbonate
Aluminum Hydroxide
Tums •
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Milk alkali syndrome •
High intake calcium calcium carbonate (ulcers)
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Triad: Hypercalcemia, Hypercalcemia, metabolic alkalosis, renal failure
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Acid rebound •
Mild acid surge once antacid leaves stomach
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Probable mechanism: mechanism: stimulation of acid acid secretion by calcium
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Can happen with other antacids
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Detected by stomach stomach pH monitoring monitoring studies
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Clinic effects questionable
Special use: Treatment of hypocalcemia
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No bloating or alkalosis Constipation (aluminum: ↓ GI motor activity) Binds phosphate in gut (aluminum-phosphate) •
Can be used in renal failure failure to lower phosphate levels
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“Phosphate binder”
Can causehypophosphatemia •
Muscle weakness
Al(OH)3 + 3HCl AlCl3 + 3H2O
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Aluminum Toxicity •
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Magnesium Hydroxide
Usually only occurs in renal failure patients Bones/muscles
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No bloating or alkalosis Diarrhea
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Bone pain
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Poorly absorbed colon osmotic diarrhea
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Muscle weakness
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Also used as an osmotic laxative (milk of magnesia)
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Osteomalacia
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Draws fluid into colon
Microcytic Anemia
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Accumulates in bone marrow
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“Resistant to iron” (normal iron studies; no benefit to iron)
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Bradycardia
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Cardiac arrest
Dementia
promotes peristalsis
Hypermagnesemia symptoms Hypotension
Mg(OH)2 + 2HCl MgCl2 + 2H2O
Maalox •
Magnesium and aluminum hydroxide
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Diarrhea-constipation Diarrhea-constipationeffects offset
Drug Absorption •
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Altered by all antacids •
Drug may bind antacid
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Increased gastric pH may affect absorption
Key drugs •
Tetracycline
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Fluoroquinolones
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Isoniazid
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Iron supplements
Histamine (H2) blockers
Tetracycline
Famotidine, Ranitidine, Nizatidine, Cimetidine •
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Block histamine receptors in parietal cells Most have few side effects Can cause confusion, confusion, especially among the elderly Rarely elevated AST/ALT or cardiac arrhythmias
Histamine (H2) blockers
Proton Pump Inhibitors
Famotidine, Ranitidine, Nizatidine, Cimetidine
Omeprazole, Pantoprazole, Lansoprazole, Esomeprazole
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Cimetidine •
1st H2 blocker; rarely used in modern modern era
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Potent P450 inhibitor
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Anti-androgen: Gynecomastia, impotence, prolactin release
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Crosses BBB: Dizziness, confusion, headaches headaches
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Reduces creatinine excretion (↑SCR )
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Inhibit H+/K+ pump in parietalcells
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Few side effects (usually well tolerated)
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Potential adverse effects with long term use
Proton Pump Inhibitors
Proton Pump Inhibitors
Omeprazole, Pantoprazole, Lansoprazole, Esomeprazole
Omeprazole, Pantoprazole, Lansoprazole, Esomeprazole
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C. Difficile infection (loss of protection from H+) Pneumonia (more pathogens in upper GI tract)
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Malabsorption •
Hypomagnesemia (↓ absorption)
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Hip fractures ( ↓ Ca absorption)
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B12 deficiency
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H+ required to cleave B12 from dietary proteins
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Iron
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Vitamin C
Bismuth Salicylate
Bismuth Salicylate
Pepto-Bismol/Kaopectate
Pepto-Bismol/Kaopectate
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Coats ulcers/erosion •
Protects from acid
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Most effective in H. Pylori ulcers
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Salicylate
Antimicrobial against H. Pylori Part of “quadruple” therapy: •
Proton pump inhibitor
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Clarithromycin
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Inhibits prostaglandins
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Amoxicillin/Metronidazole
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Reduced stool stool frequency in diarrheal illnesses
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Bismuth Salicylate
In colon, bismuth reacts with hydrogen sulfide •
Forms bismuth sulfide
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Blackens the stools
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Sucralfate •
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Osmotic Laxatives
Sulfated polysaccharide polysaccharide + aluminum hydroxide Binds toulcers to ulcers •
Negatively charged drug molecule to positively charge proteins
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Protects from acid
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Result: Ulcer healing
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Not absorbed so very rare
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Potential aluminum toxicity
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Dehydration
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Electrolyte abnormalities
Osmotic Laxatives
Magnesium hydroxide (milk of magnesia) Magnesium citrate: Magnesium plus citric acid
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Polyethy lene glycol (Miralax, GoLYTELY) GoLYTELY) •
Synthetic polymer
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Powder (mix with water)
Lactulose •
Potential side effects of most:
Adverseeffects
Osmotic Laxatives •
All draw water into intestines bowel movement Used in constipation, bowel prep for colonoscopy
Sodiumpolystyrenesulfonate(Kayexalate (Kayexalate)) •
“Cation Exchange Resin” (i.e. polymer)
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Bind potassium – used in hyperkalemia
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Sorbitol: Sugar alcohol alcohol
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Sodiumphosphate
Other Laxatives
Syntheticdisaccharide(laxative) Also used in hyperammonemia Colon breakdown by bacteria to fatty acids
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Bisacodyl (Dulcolax), Senna (Senokot) •
Lowers colonic pH; favors formation of NH4+ over NH3 NH4+ not absorbed trapped in colon Result: ↓plasma ammonia concentrations
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“Stimulant laxatives”
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Poorly understood mechanism
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Increase GI motility
Docusate •
Stool softener
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Makes stool soft, slippery
5-HT3 Receptor Antagonists
Laxative Abuse •
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Ondansetron
Factiousdiarrhea Bulimia Clues:
5-HT3 receptors •
Found in vomiting center in medulla
Dehydration (signs of hypovolemia, hypotension)
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Also in vagal/spinal nerves to GI tract
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Hypokalemia
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Metabolic acidosis from loss of bicarb
Metoclopramide Reglan
Commonly used in patients receiving chemotherapy Few side effects
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Dopamine (D2) receptor antagonists In gastrointestinal gastrointestinal tract Dopamine (via D2) blocks ACH effects
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Headache
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Constipation
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Blockade Increased esophagus and gastric motility
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No effect on small intestine or colon
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Used in gastroparesis
Metoclopramide Common Adverse Effects
In central nervous system •
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Metoclopramide •
Blockserotonin (5-hydroxytryptamine) (5-hydroxytryptamine)receptors
Diarrhea
5-HT3 Receptor Antagonists •
Used to treat vomiting (anti-emetic)
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Ondansetron •
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Dopamine (via D2) activates chemoreceptor trigger zone
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Area postrema in medulla
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Blockade
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Used as anti-emetic
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Drowsiness Movement symptoms •
Decreased nausea/vomiting
Also effective in migraines
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“Extrapyramidal symptoms”
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Parkinsonian movements
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Restlessness
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Akathisia (constant (constant motion)
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Dystonia (spasms)
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Tardive Tardive dyskinesia (long term use)
Metoclopramide
Metoclopramide
Rare Adverse Effects
Contraindications
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Nausea, diarrhea (GI effects)
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Lowersseizure Lowers seizure threshold
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Elevatedprolactin Elevated prolactinlevels levels
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Should not be used in patients patients with epilepsy
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Known seizure disorders Parkinson’s disease Bowel obstruction
Galactorrhea, gynecomastia, impotence, menstrual disorders
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