Boards and Beyond: Gastroenterology A Companion Book to the Boards and Beyond Website Jason Ryan, MD, MPH Version Date: 11-29-2017
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Table of Contents Gastrointestinal Embryology 1
Cirrhosis
63
Gastrointestinal Anatomy GI Blood Supply Gastrointestinal Tract Liver, Gallbladder, Pancreas Salivary Glands Hernias Bile Bilirubin Gastrointestinal Secretions Gastrointestinal Hormones Exocrine Pancreas
7 9 13 17 20 25 30 34 40 43 49
Liver Tumors Wilson’s & Hemochromatosis Gallstones Biliary Disorders Gastric Disorders Malabsorption Acute Pancreatitis Chronic Pancreatitis & Cancer Intestinal Disorders Inflammatory Bowel Disease Colon Cancer
68 71 75 80 83 91 98 104 107 113 118
Esophageal Disorders Liver Disease
53 59
Carcinoid Tumors Gastrointestinal Pharmacology
124 126
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GI Embryology •
Gastrointestinal
•
Embryology
Endoderm GI tract •
GI tract epithelium, glands
•
Many organs bud off: liver, pancreas, trachea
Mesoderm Surroundingstructures •
Stroma (GI tract connective tissue)
•
Muscles
•
Peritoneum
•
Spleen
Jason Ryan, MD, MPH
Portions of GI Tract •
•
•
Mesentery
Foregut •
Celiac trunk
•
Mouth to Ampulla of Vater
•
•
SMA
•
Suspends abdominal organs from cavity walls Intraperitonealorgans
•
Retroperitoneal organs
•
Ampulla of Vater to transverse colon
•
Hindgut •
IMA
•
Transverse colon to rectum
Mesentery •
•
Midgut •
Gut moves away posterior wall in development
•
Dorsal mesentery grows between gut and posterior wall
•
Covers most abdominal structures
Ventral mesentery •
Only exists bottom esophagus,stomach, upper duodenum
•
Derived from septum transversum (mesenchyme tissue)
•
Liver grows into this mesentery
•
In adult: lesser omentumand falciform ligament
Enclosed by mesentery
•
Covered by peritoneum only on anterior wall
•
Lie against posterior abdominal wall
Mesentery
Dorsalmesentery •
Double layer of pe ritoneum
1
•
Mesogastrium
•
Mesoduodenum
•
Mesocolon
Omentum
Foregut Development
Latin: “apron” •
•
Greateromentum
•
•
Hangs from greater curvature of stomach
•
Covers intestines
•
Formed from mesogastrium
Lesser omentum Between stomach and •
•
Lung “buds” off from foregut •
•
•
•
liver
Formed from ventral mesentery
“Respiratory diverticulum”; “lung bud”
Tracheoesophageal 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 to stomach
•
(baby cannot swallow fluid) Polyhydramnios
•
Drooling, choking, vomiting (accumulation secretions)
•
Cannot pass NG tubeinto stomach
•
•
Gastric distension (air in stomachon CXR)
•
Reflux aspiration pneumonia respiratory distress
•
•
Sometimes residual dysmotility
•
GERD
Omphalocele
Herniation
•
•
Fistula esophagus trachea
Midgut 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 •
Intestinescovered by membraneoutside body
•
“Simple omphalocele”
•
Liver does not herniate
•
If lateral embryonic folds fail liver in omphalocele
•
Key features:
Reduction of hernia occurs by 12th week
•
2
Liver-containing omphalocele
•
Covered by peritoneum
•
Through umbilical cord
Omphalocele •
•
Normal GI function Many genetic defects •
Trisomy 21 (Down syndrome )
•
Trisomy 18 (Edwards syndrome)
•
•
Gastroschisis •
•
•
•
Congenital heart defects (up to 50% babies)
•
Orofacial clefts
•
Neural tube defects
•
Poor GI function •
•
Usually on right side of umbilical cord
Not covered by peritoneum
Abdominal Wall Defects
Gastroschisis •
Probably involves incomplete closure of abdominal wall
Paraumbilicalabdominal wall defect •
Trisomy 13
Many associatedconditions •
Extrusion of bowel through abdominal wall Exact mechanism unclear
Often associated with atresia, stenosis
Few associated defects •
If GI function restored, good prognosis
•
Rarely associated with Down, other congenital disease
Treatment for both: Surgical reduction/closure
Midgut 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 around SMA
•
Vascular compromise
•
Vomiting, sepsis (bowel necrosis)
•
Abdominal distention, blood in stool
•
Treatment: surgery
Left sided colon •
3
Anatomic variant
ischemia obstruction
Meckel’s Diverticulum
Vitelline Duct Pathology •
In early development, midgut open to yolk sac •
•
By week 5, connection with yolk sac narrows •
•
•
•
Most common congenital GI abnormality Persistent remnant of vitelline duct
•
Diverticulum of small bowel (ileum)
“Yolk stalk,” “vitelline duct,” “omphalomesentericduct”
•
•
Meckel’s diverticulum (most common)
•
Cysts, polyps
Meckel’s Diverticulum •
“True diverticulum” •
Contains all layers of bowel : mucosa, submucosa, muscular
•
Most diverticulum only mucosa/submucosa
•
Usually defect (hole) in muscular layer
•
Usually no symptoms Can present any age but 50% <10 years
•
Often incidental discovery
Often contains stomach tissue •
“Ectopic gastric tissue ”
•
Origin unclear
•
Sometimes pancreatic tissue also
•
•
Meckel’s Diverticulum •
“Outpouching,” “Bulging”
Normally, vitelline duct disappears by week 9 Persistence congenitalanomalies
Meckel’s Diverticulum •
•
•
Does not become enclosed like other portions of gut
•
Other imaging
•
Abdominal surgery for other reason
Ectopic gastric tissue may secrete acid •
Ulceration
•
Pain
•
Bleeding
Potential cause of obstruction, diverticulitis
Meckel’s Diverticulum
Rule of2’s:
•
Diagnosis
•
2 percent of population
•
Technetium scan
•
Male-to-female ratio 2:1
•
Tracer taken up by gastric cells in diverticulum
•
Within 2 feet from the ileocecal valve
•
Also capsule endoscopy
•
Usually 2 inches in size
•
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Treatment:Surgery
Other Vitelline Duct Anomalies •
Cyst •
•
•
•
Can occur anywhere in GI tract
Cavity behind umbilicus
•
•
Intestinal discharge from umbilicus
Duodenal Atresia
•
Atresia = closed/absent opening Stenosis= narrowing/obstruction
Persistent duct •
•
•
•
Often discovered incidentally at surgery
Sinus •
•
Atresia and Stenosis
Duodenum most common Colon most rare
•
Polyhydramnios
•
Biliousvomiting
Jejunal-Ileal-Colonic Atresia •
Probably due to failure of “recanalization ”
Vascular disruption ischemic necrosisof intestine
•
In early development, duodenum occludes
•
Necrotic tissue resorbed
•
Due to endodermal proliferation of epithelium
•
Leaves blind ends of bowel
•
Patency restored by recanalization
•
Reproduced in animals with arterial ligation
Associated with Down syndrome Double bubble sign •
Distention of duodenum stump and stomach
•
Tight pylorus in middle
•
Bowel distal to blind end may be curled •
Pyloric Stenosis
“ Apple peel atresia ”
Pyloric Stenosis
•
Pylorus: Connection stomach duodenum
•
Often occurs as newborn (few weeks old)
•
Hypertrophy of pylorus = pyloric stenosis
•
30% are first bornchildren
•
Intestinal obstruction
•
More common inmales
•
•
“Projectile ,” non-bilious vomiting (clear/yellow)
Palpable mass •
Feels like “olive”
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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 Retroperitoneal •
Gastrointestinal Anatomy
Intraperitoneal Structures •
Covered by mesentery (visceral peritoneum)
•
Stomach, appendix, liver, spleen
•
Small intestine: 1st part duodenum, jejunum, ileum
•
Colon: Transverse, sigmoid, part of rectum
•
Pancreas: Tail
Jason Ryan, MD, MPH
Intra versus Retroperitoneal •
Retroperitoneal Bleeding •
Retroperitoneal Structures •
Aorta, IVC
•
Kidneys
•
Small intestine: 2nd/3rd portions duodenum
•
Colon: ascending/descending, part of rectum
•
Pancreas: Head, body
•
Blood visible on CT scan Many causes
•
Often a complication of surgical procedures
Pectinate Line
Greater and Lesser Sac
Dentate or anocutaneous line
•
Peritoneal cavity divided into greater/lesser sac
•
Part of anal canal
•
Greater sac
•
Above line
•
•
•
Entire width of abdomen
•
Derived from hindgut
•
Diaphragm to pelvic floor
•
Columnar epithelium
•
Similar to digestive tract
Lesser sac •
Closed space
•
Behind liver, stomach, lesser omentum
•
Epiploic foramen (Omental, Winslow’s) •
Opening between greater/lesser sacs
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Below line •
Derived from proctodeum (ectoderm)
•
Stratified squamous epithelium
•
Similar to skin
Above Pectinate Line •
Superior rectal artery •
•
•
•
Venous drainage to IVC
•
•
•
May swell in portal hypertension
Lymph drainage:Internal iliacnodes Visceral innervation (no pain)
•
Internalhemorrhoids
•
Adenocarcinoma (rare form of anal cancer)
•
•
•
Imperforate Anus •
Hindgut and ectoderm meet to form anus Absence of anal opening = imperforate anus
•
Commonly associated withGU malformations
•
Inferior rectal artery
Superior rectal vein inferior mesenteric portal system
•
•
•
Branch of IMA (like distal colon)
Venous drainage: •
•
Below Pectinate Line
•
Renal agenesis
•
Bladder exstrophy
Presentations: •
Failure to pass meconium
•
Meconium from urethra or vagina (fistula)
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Branch of internal pudendal artery (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 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
•
Vulnerable to ischemia if splenic artery occluded
•
Contrast with gastric and gastroepiploic
•
•
No dual blood supply
Supplied by dual sources
SMA
Hepatoduodenal Ligament
Key Points
•
Connects liver to duodenum
•
Supplies midgut structures
•
Found on “free border of lesser omentum”
•
Distal duodenum, jejunum, ileum, cecum, appendix
•
Contains:
•
•
•
Proper hepatic artery (branch of common hepatic)
•
Portal vein
•
Cystic duct
•
Pringle’s maneuver •
Clamping of hepatoduodenal ligament
•
Used to controls liver bleeding
•
If bleeding continues: IVC or hepatic veins
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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 Vasa recta: Arteries extending from arcades
•
•
•
•
Rare cause of bowel obstruction SMA courses over distal 1/3 of duodenum •
Distal duodenum between aorta and SMA
•
Mesenteric fat 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 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
•
Occurs in rectum
•
Branches from middle (SMA) and left (IMA) colic arteries
•
Superior rectal (IMA) merges with middle rectal (iliac)
•
Rectal ischemia from occlusion rare
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Mesenteric Ischemia
Intestinal Ischemia •
•
Causes
Mesenteric ischemia
•
Embolism (most common)
•
Ischemia of the intestines
•
Often cardiac srcin
•
Ischemia of small intestine is most severe
•
LV thrombus
•
Often life threatening
•
LA appendage (atrial fibrillation)
•
Often affects jejunum (via SMA)
Ischemic Colitis Ischemia of the colon
•
•
•
May spontaneously resolve
Arterial thrombosis •
Usually occurs at site of atherosclerosis
Mesenteric Ischemia
Mesenteric Ischemia
Causes
Symptoms
•
•
•
Venous thrombosis •
Venous clot resistance to flow out of mesentery
•
Hypercoagulable states, malignancy
•
Non-occlusive ischemia •
Under perfusion (shock)
•
Usually affects watershed areas of colon
•
Often results in ischemic colitis
Mesenteric Ischemia
Watershed Areas
Causes •
•
Usually sudden onset Abdominal pain, cramping
Physical exam: •
“Pain out of proportion to exam”
•
Usually mild tenderness
•
No rebound tenderness or peritoneal signs
•
Occult bloodin stool
•
Colon areas located between major vessels
•
At risk for ischemia in shock/hypoperfusion
•
•
Labs: •
↑WBC
•
↑ lactate and acidosis •
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 of IMA
Chronic mesenteric ischemia Intestinal Angina •
Usually older patient with other vascular disease
•
Recurrent abdominal pain after e ating
•
weight loss Fear of eating
•
•
PAD risk factors common (smoking, DM)
Sudden worsening on top of history of recurrent pain may suggest acute 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 glandsin stomach
•
Connectivetissue Contains Meissner’splexus(submucosal plexus)
•
Clinicalcorrelation: Hirschsprung's disease
Muscularis mucosa: motility
Muscular Layer •
•
Serosa
Layers of smooth muscle •
Inner circular layer
•
Outer longitudinal layer
Between layers
•
Abnormal in achalasia
Surrounds GI tract
•
Layer of surface epithelial cells: mesothelium
•
Retroperitonealstructures:adventicia
•
Auerbach’s plexus •
•
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Secretes lubricating fluid
•
Loose connective tissue
•
Not lubricated
Esophagus •
•
Stomach
Stratifiedsquamousepithelium Non-keratinized
•
Simple columnar epithelium Gastric pits
•
Gastric glands
•
•
•
Crypts, Villi and Microvilli •
•
Mucosaextensions into lumen
•
Increase surface area for absorption
•
•
Parietal cells Chief cells
•
Mucous neck cells
•
G cells
•
Valves of Kerckring or Kerckring folds Valvulae conniventes Folds of mucosa and submucosa
•
Most abundant in jejunum
•
Crypts ( of Lieberkuhn) •
•
Plicae Circulares
Villi •
Found in lamina propria
Contain goblet cells
Microvilli •
Microscopic extensions
•
Epithelial cell membrane
Brunner’s Glands
Goblet Cells •
Found in small and large intestine
•
Only induodenum
•
Produce mucinogen mucous
•
Found insubmucosa
•
Increase in number from duodenum to ileum
•
•
•
Ileum has most
Not normally found in stomach •
Occur in stomach in setting of chronic inflammation (gastritis)
•
“Intestinal metaplasia”
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•
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, lymph cells aggregate Peyer’s patches •
Found in muscularis mucosa/submucosa
Duodenum = Brunner’s Glands Ileum = Peyer’s patches Jejunum = Neither
Colon •
•
Produces lots of mucous Absorbs fluid and e lectrolytes
•
Crypts without villi
•
Lots of goblet cells
Haustra •
•
Ulcers and Erosions •
Breakdown of GI tract lining
•
Dyspepsia,bleeding
•
•
Pouches of the colon Can be seen on imaging to identify large bowel
Enteric Nervous System •
Submucosal plexus (Meissner's plexus)
•
Myenteric nerve plexus (Auerbach’splexus)
•
Erosions: mucosa only Ulcers: submucosa and muscularis mucosa
•
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Controls secretion and blood flow
Major role is control of GI motility
Slow Waves •
•
•
•
Slow Waves
Oscillating membrane potential of GI smooth muscle Original in interstitial cells of Cajal
•
•
Membranepotential “slowly”rises near threshold When near threshold, action potentials may occur
Sets maximum number of contractions per time Characteristic for each part of GI tract •
Stomach: 3/min
•
Duodenum: 12/min
•
Voltage
Tension
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Ileum: 8/min
Ampulla of Vater •
•
Liver, Gall Bladder, Pancreas
•
•
Ampulla = roman flask Biliary/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 •
Narrowing of Sphincter of Oddi
•
Can occur after pancreatitis, gallstone disease
•
Biliarysymptoms •
Episodes of RUQ pain
•
Possible abnormal LFTs, hyperbilirubinemia
•
Pancreaticsymptoms
•
Potential therapies
•
Smooth muscle relaxants (Ca channel blockers, nitrates)
•
Endoscopic sphincterotomy
Circularmuscular(smooth) layer Surrounds major duodenal papilla
•
Controls flow of bile, pancreatic enzymes
•
Prevents reflux
Sphincter of Oddi Spasm •
May be caused by opioids (i.e. morphine)
•
Meperidine (Demerol) used in acute pancreatitis
•
•
Recurrent pancreatitis
•
•
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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%): deoxygenated blood from GI tract
•
Hepatic artery (20%)
•
One drainage vessel:
•
Bile duct
•
Zone I (periportal) •
•
Zones III (centrilobular)
t c u D e il B
n i e V la t r
Zone I
Zone II
Periportal
Mid Zone
o P
•
Centrilobular
Two buds from foregut: Ventral and dorsal •
•
Bud off from endodermal lining of duodenum (foregut)
Ventralbud
•
Furthest from blood supply
•
Part of head, uncinate process
•
Most vulnerable to ischemia
•
Main pancreatic duct
•
Fat accumulation begins here in alcoholic liver disease
•
High concentration P450 enzymes in hepatocytes
Secondarily retroperitoneal
Zone III
Pancreas Embryology
Affected by viral hepatitis first
Pancreas •
y r e t r A ic t a p e H
Hepatic veins: carry processed blood away from liver
Liver Zones •
Liver Zones
•
Doral bud •
Rest of head
•
Body, tail, accessory duct
Annular Pancreas •
Congenital anomaly of ventral bud
•
Forms covered in peritoneum (intraperitoneal)
•
Initially composed of two separate pieces of tissue
•
Later fuses with posterior wall retroperitoneal
•
Normally fuse
•
Can fuse around duodenum
•
•
18
Ring of pancreatic tissue that surrounds duodenum Can cause bowel obstruction
n i e V c ia t p e H
Pancreas Divisum •
•
•
•
Dorsal and ventral ducts do not fuse Two separate ducts •
Accessory (dorsal) duct drains majority of pancreas
•
Second ventral duct persists
Often asymptomatic May cause pancreatitis
19
Salivary Glands •
Three major glands Also many tiny salivary glands throughout mouth
•
All produce saliva
•
Salivary Glands Jason Ryan, MD, MPH
Salivary Glands •
•
•
Submandibular gland •
Floor of mouth
•
Wharton’ duct mouth
•
Sublingual gland •
•
Saliva
Floor of mouth
•
Behind the angle of the jaw
•
Below and in front of ears
•
Largest salivary gland
Saliva •
•
Bind bacteria
•
•
Lactoferrin prevent bacterial growth
•
Proteins that protect teeth
•
Protects against infectious agents
Two important enzymes for digestion •
Loss of saliva (Sjogren’s) infections •
Lubricate food
•
Saliva
Important forinnate immunity •
•
IgA antibody Lysozymes disrupt bacterial cell walls
•
Parotidgland
Mostly water (>90%) Mucin, glycoproteins
•
Dental carries (cavities)
20
amylase (digests carbohydrates) Lingual 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 •
•
•
Pancreaticlipase •
Functional in small intestine
Salivary Electrolytes •
Salivary (lingual) lipase
•
Main lipase for lipid digestion
Salivary Electrolytes •
Salivary fluid produced by acinar cells Modified by ductal cells
Initial fluid similar -to plasma (isotonic) •
•
Same Na, Cl, K, HCO3 concentration
Ductal cells (impermeable to water): •
Remove Na, Cl
•
Secrete K, HCO3- (bicarb raises pH protects against acid)
Na Na
K
Cl
K
Cl HCO3-
Salivary Electrolytes
Salivary Electrolytes •
Saliva becomeshypotonicfrom removal Na, Cl •
•
Lower concentrations than plasma
Saliva:higher concentration of K, HCO 3 than plasma
Na Na
K
Cl
K
Cl HCO3-
HCO3-
HCO3-
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•
Compositionvaries with flow rate
•
Higher flow: •
Less time for ductal modification
•
Fluid becomes more like plasma
•
Closer to isotonicwith 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 •
•
Sialolithiasis •
Muscarinic antagonists •
Cause dry mouth
•
Atropine, Scopolamine
Muscarinicagonists •
Increase saliva production
•
Pilocarpine(used in Sjogren’s syndrome)
•
salivation Cholinesterase poisoning
•
Obstruction of salivary flow Pain/swelling of gland
•
Usually aggravated by eating
•
Most common in submandibular glands
•
Risk factors:
•
Sialadenitis
•
Dehydration, diuretics
•
Anticholinergic medications
Treatment: NSAIDs, hydration; rarely surgery
Mumps
•
Inflammation of salivary gland
•
Caused by RNA mumps virus
•
Often secondary to obstructingstone
•
Largely prevented by vaccination (MMR)
•
Key feature:Parotitis
•
Most often due to Staph Aureus Also often containsanaerobes
•
Common treatment:
•
•
Nafcillin(Staph coverage)
•
Metronidazole or Clindamycin (anaerobes)
22
•
Often bilateral
•
Inflammation of parotid glands (facial swelling)
Pleomorphic Adenoma
Salivary Tumors •
Usually present in the parotid gland Often present as facial swelling
•
Most are benign
•
•
•
Benign Mixed Tumor •
•
Mobile (not growing into other tissues) •
Painless (not invading nerves)
•
When pain present usually indicates invasive lesion
•
May involve facial nerve (paralysis)
•
Most common salivary gland tumor Usually benign •
Rarely can undergo malignant transformation
•
Often results in 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!)
•
23
Key histological finding: •
Cysts filled with fluid
•
Cysts surrounded by dense lymphoid infiltrate
•
Lymph tissuecan aggregate into germinal centers
Mucoepidermoid Carcinoma •
Most common malignant salivary tumor Key risk factor: prior radiation
•
Occur in parotids
•
•
•
•
Mucoepidermoid Carcinoma •
Sometimes invade facial nerve (paralysis) Can also 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 •
•
Femoral Sheath •
Lateral to medial •
Nerve-artery-vein-lymphatics
•
“NAVeL”
•
“Venous to the penis”
•
Superior: Inguinal ligament
•
Medial: Adductor longus
•
Lateral: Sartorius
•
•
Contains femoral vein, artery, and ring •
Does not contain nerve
Inguinal Canal
Opening to femoral canal is femoral ring •
•
Tunnel of fascia Below inguinal ligament
Femoraltriangle
Femoral Ring and Canal •
•
Site of femoral hernias
Component of femoral sheath Lymph vessels and deep inguinal nodes
25
•
Runs across femoral vessels
•
Testes descend through inguinal canal to scrotum
Spermatic Cord •
Travels in inguinal canal Ductus deferens, arteries, veins, nerves
•
Three fascial layers
•
•
•
•
Inguinal Canal •
•
•
External spermatic fascia
•
Cremasteric fascia Internal spermatic fascia
•
•
Inguinal Hernias •
Indirect inguinal hernias
•
Direct inguinal hernias
•
Femoral hernias
•
•
Outpouching of peritoneum
•
Remains open in newborn period Should close (“obliterate“) in infancy
•
Replaced by fibrous tissue
•
•
•
Travel through inguinal canal
•
Not “directly” through a hole
Origin lateralto epigastric vessels
•
Follows path of descent of testes •
Covered by all layers of spermatic fascia
•
Contrast with direct hernias (outer layer only)
Congenital defect •
Bowel protrudes through patentprocessus vaginalis
•
Should close after descent of testes
Demographics •
Most common type of inguinal hernia •
Males = 50% hernias are indirect
•
Females = 70% are indirect
•
More common in men
•
Typically occurs right side
•
Commonly extend into scrotum
•
Part remains as tunica vaginalis testis •
“Indirectly” through abdominal wall
Indirect Inguinal Hernia
Processus Vaginalis Testes descend throughprocessus vaginalis
Exit: Superficial inguinal ring Floor: Inguinal ligament
•
•
•
Round ligament in females Entrance: Deep inguinalring
Indirect Inguinal Hernia
Three types of hernias occur in inguinal region •
Passage in abdominal wall Carries spermatic cordin males
•
Serous covering of testes
26
Men 10x more likely than women
Persistent 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)
•
In men, covered by spermatic fascia (three layers )
•
•
Can occur in newborns on mechanical ventilation
• •
•
Bowel bulges “directly” through abdominal wall Protrudesthrough Hesselbach’striangle
•
•
•
•
Origin lateralto inferior epigastric vessels Most common type of inguinal hernia
Hesselbach’s Triangle
Direct Inguinal Hernia •
In women follows round ligament toward labia majora
•
•
Inguinalligament Inferior epigastrics
Origin is medialto epigastric vessels
•
Rectus abdominis
Through external ring (not deep/internal)
•
Floor:Transversalisfascia
Covered by external spermatic fascia only Should never bulge into scrotum
Direct Inguinal Hernia •
Caused by transversalis fascia breakdown
•
Weakness in floor of inguinal canal
•
Usually occurs in older men •
Femoral Hernias •
Hernia through femoral ring
•
Bowel protrudes below inguinal ligament
•
More common in women than men
•
High risk ofincarceration
•
•
Years of stress on connective tissue (“acquired”)
•
•
27
Medial to femoral vessels
Differentiates from both types of inguinal hernias
But indirect most common type for both genders
Femoral ring is 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
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
Usually diagnosedclinically Ultrasound/CT sometimesused
Ventral Hernias
Treatment •
All treated surgically
•
Anterior abdominal wall
•
Primary closure
•
Many subtypes
•
Mesh placement
•
•
28
Umbilical – near umbilicus Incisional hernias – site of abdominal incision
Hiatal Hernias •
Stomach herniation into thorax Leads to GERD (heartburn)
•
Major risk factor: obesity
•
Hiatal Hernias •
GE junction in normal location
•
Protrusion of stomach fundus
•
Defect in the “phrenoesophageal membrane”
•
Bowel sounds in lung fields is classic finding
Displacement of GE junction above diaphragm
•
Stomach in usual alignment
•
Fundus remains below GE junction
•
“Hourglass” appearance
•
Herniation through hiatus
Congenital diaphragmatic hernia •
Types II, III, IV: Paraesophageal •
•
CDH
Hiatal Hernias •
Type I: Sliding hiatal hernia (95%)
•
•
•
29
Developmental defect of diaphragm •
Defective formation pleuroperitoneal membrane
•
Hole in diaphragm
Abdominal organs herniate into chest In utero herniation pulmonary hypoplasia Often fatal
Bile •
•
•
•
Secreted into duodenum after meal Mostly water
•
Phospholipids, electrolytes Bile salts– necessary for lipid absorption
•
Bilirubin– mode of excretion from body
•
Bile
Produced in liver Stored in gall bladder
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):hydrophilic Conjugation to bile acids better surfactant •
One end = hydrophobic
•
One end = hydrophilic
Cholic acid Taurine
Cholesterol
Cholic acid
Chenodeoxycholic aci d
Hydrophobic
Bile Salts
Glycine
Bile Acids
Hydrophilic
Synthesis •
Synthesized only in liver •
•
Taurocholic acid Taurine
Two pathways: classic (>90%) and acidic (<10%)
Cholesterol7-α hydroxylase •
Rate limiting enzyme classic pathway
•
Cytochrome P450 enzymes
•
Requires NADPH and oxygen
Glycocholic acid Glycine 7-α hydroxylase
Cholic acid
Cholesterol
7-
Bile Acids
Bile Salts
Enterohepatic Circulation
Functions
hydroxycholesterol
•
Most lipid absorption (TGs) occurs jejunum
•
#1: Emulsification of fats
•
Conjugated bile acids not absorbed with lipids
•
#2: Excretion of cholesterol
•
#3: Antimicrobial
•
•
•
•
•
Pancreatic lipase releases fatty acids absorbed
•
Bile salts remain behind
Pass to distal small intestine Absorbed by active transporters interminal ileum About 95% absorbed and recycled ~5% excreted in stool
31
Cholic acid
Bile Salts
Bile Salts
Cholesterol Excretion
Antimicrobial
•
Cholesterol not soluble in water Conjugated bile water soluble excretion in stool
•
Bile acid resins
•
•
Small intestine has few bacteria Loss of bile salts bacterialovergrowth
Cholestyramine, colestipol, colesevelam
•
Disrupt bacterial cell membranes
Retain bile acids Prevent reabsorption
•
•
Other antibacterial effects described
•
More excreted in stool
•
•
Cholesterol
•
Cholic acid
Alkaline Phosphatase
Cholestasis •
•
•
•
Alk Phos •
Disrupted bile flow to intestines Lab findings: •
Direct (conjugated) hyperbilirubinemia
•
Elevated alkaline phosphatase
•
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
•
Cholestasis:
Symptoms
Damage to cells ↑ AST/ALT
•
•
↑ 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 •
Seen in liver disease
•
Patterns of Bile/Liver Damage
Primary site of dysfunction is hepatocytes
•
↑ 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 to bile ducts
•
“Cholestatic pattern”
When ↑AST/ALT>> ↑ AlkPhos •
Primary abnormality r elates to hepatocytes
•
“Hepatocellular pattern”
Example #1 AST 100 IU/L ALT 120 IU/L Alk Phos 500 IU/L
32
Example #2 AST 500 IU/L ALT 550 IU/L Alk Phos 200 IU/L
Cholestasis •
Cholestasis
Best first test: Right upper quadrantultrasound •
•
Differentiates extrahepatic from intrahepatic
•
Extrahepaticcauses (workup: additional imaging) •
Gallstones
•
Pancreatic mass
•
Biliary strictures
Intrahepatic causes (workup: lab tests, biopsy) Primary biliary cirrhosis •
33
•
Cholestasis of pregnancy
•
Contraceptives
•
Erythromycin
Bile •
•
•
•
Secreted into duodenum after meal Mostly water
•
Phospholipids, electrolytes Bile salts– necessary for lipid absorption
•
Bilirubin– mode of excretion from body
•
Bilirubin
Produced in liver Stored in gall bladder
Jason Ryan, MD, MPH
Bilirubin
Heme Metabolism •
Heme released from old RBCs •
•
•
Some from myoglobin, cytochromes, bone marrow cells
Macrophages engulf residual heme Converted to biliverdin then bilirubin NADPH
NADPH
Bilirubin (brown/yellow color)
Heme
Heme
Heme Oxygenase
Biliverdin (green)
Bilirubin ( brown/yellow) Biliverdin Reductase
Bilirubin Conjugation in Liver
Bilirubin •
Poor solubility in water
•
Carried by albuminto liver Unconjugated Bilirubin UDP glucuronyltransferase
Glucuronic Acid Bilirubin
34
Conjugated Bilirubin (Bilirubin diglucuronide)
Bilirubin Metabolism
Bilirubin Conjugation •
Bilirubin-UDP-glucuronyltransferase (UGT) Adds glucuronic acid molecules to bilirubin
•
Produce more water soluble compounds
•
•
•
•
Intestines •
•
Bilirubin monoglucuronide •
Bilirubin diglucuronide
↑ water solubility facilitates excretion with bile
Two conversions by bacteria #1: Converted back to unconjugated in intestines •
Distal small intestine and colon
•
Bacteria beta-glucuronidaseenzymes
#2: Unconjugated bilirubin urobilinogen •
Urobilinogen
Via bacterial enzymes
Urobilinogen •
Fate #1: Excretion in feces (80-90%) •
•
Bilirubin
Converted to stercobilin(makes stool dark)
Fate #2: Reabsorbed by intestines ( 10-20%) •
Most taken up by liver
•
Small amount excreted in urine
•
Converted to urobilin(makes urine yellow)
Stercobilin
Urobilinogen
Bilirubin
Bilirubin
Clinical Measurements
Clinical Measurements
•
•
•
Van den Bergh reaction
•
Urine
•
Coupling ofbilirubin with adiazonium salt
•
Bilirubin (conjugated only ): Normal absent
•
Forms a colored complex
•
Urobilinogen: Normally a small amount
Serum Conjugated bilirubin •
Soluble in water
•
Can directly undergo the reaction in solution
Serum Unconjugatedbilirubin •
Not soluble in water
•
Must be mixed with alcohol first
•
Then can add to Van den Berg medium
•
“Indirect” bilirubin
35
Urobilin
Jaundice •
•
•
Dark Urine
Yellowingof skin, conjunctiva, mucous membranes •
Scleral icterus(eyes) often earliest sign
•
Also visualized early under the tongue
•
•
Also seen in:
Normal: total bilirubin <1.0mg/dL
•
•
Jaundice usually total >3.0mg/dl
•
Only conjugated bilirubin is water soluble Rhabdomyolysis (myoglobin) Hematuria any cause Dehydration (common in actual practice)
Hyperbilirubinemia
Clinical Assessment
•
Seen withelevated conjugated bilirubin •
Bilirubin Metabolism •
•
•
#1: Serum bilirubin
Four general causes of ↑ bilirubin
•
Total
•
Hemolysis
•
Direct
•
Biliary obstruction (cholestasis)
•
Indirect
•
Liver disease
•
Special causes
#2: Urine urobilinogen (normally small amount) #3: Urine bilirubin (conjugated - normally absent)
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
•
Increased urobilinogen
•
•
•
•
Unconjugated bilirubin cannot cross glomerulus
•
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
•
Absent urobilinogen No bilirubin to intestine •
•
Loss of formation of urobilinogen
Hyperbilirubinemia
Hyperbilirubinemia
Primary Liver Diseases
Primary Liver Diseases
•
•
Bilirubin fractionation unreliable for liver disease •
Often mixed increase of direct/indirect
•
Usual finding: elevated total bilirubin
•
Diagnosis made by: LFTs, antibody tests, imaging, biopsy
•
•
Unconjugated
hyperbilirubinemia
•
Occurs in liver disease with significant hepatocyte damage
•
Chronic hepatitis, advanced cirrhosis
Conjugated hyperbilirubinemia •
Occurs i n “intrahepatic cholestasis”
•
Liver disease with prominent damage to bile ducts
•
Viral hepatitis, alcoholic hepatitis, NASH
Many liver diseases have elements of hepatocyte and intrahepatic bile duct involvement
Urobilinogen
Hyperbilirubinemia
Primary Liver Diseases
Lab Findings
•
•
↑↑ earlyin liver disease •
Urobilinogen from intestines reabsorbed as usual
•
Cannot be excreted in bile
•
Spills into urine
↓↓ latein liver disease •
Lack of 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’sSyndrome
•
•
Crigler-NajjarSyndrome Dubin-JohnsonSyndrome
•
•
Rotor’sSyndrome NeonatalJaundice
•
•
Gilbert’s Syndrome •
•
Commonly defective promotor UGT gene
•
Result: Mild decrease in enzyme levels
•
•
•
Findings: •
Severely reduced/absent UGT enzyme Cannot conjugate bilirubin
•
Type I usually presents in infancy
Jaundice can occur with↑ bilirubin production Fasting
•
Febrile illnesses
•
Heavy physical exertion
•
Stress
•
Menses
Result: mild ↑ unconjugated bilirubin (and total) 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
Crigler-Najjar Syndrome
↓ UDP-glucuronyltransferasefunction •
Rifampin (antibiotic) Probenecid(gout)
•
•
↑ unconjugated bilir ubin (often >20 mg/dl)
•
Jaundice
•
Kernicterus (cause of death)
Often fatal
No serious clinical consequences
Kernicterus
Crigler-Najjar Syndrome
•
Unconjugated bilirubin soluble in fats
•
Type II: Less severe (bilirubin <20mg/dl)
•
Easily crosses blood-brain barrier or enters placenta
•
Reduced risk of neurologic consequences
•
Acts as aneurotoxin
•
Sometimes treated withphenobarbitalor clofibrate
•
Basal ganglia; brain stem nuclei
•
Usually need bilirubin level >25mg/dl
•
Newborns (esp. preterm) particularly vulnerable
38
•
Phenobarbital: Seizure drug/sedative
•
Clofibrate: Lipid-lowering agent
•
Both induce liver glucuronidation
•
Lower bilirubin levels up to 25%
Dubin-Johnson Syndrome •
•
Dubin-Johnson Syndrome
Conjugated hyperbilirubinemia Defective liver excretion of conjugated bilirubin •
•
•
•
↑ conjugated bilirubin
Abnormal gene that codes for multidrug resistance proteins
•
Total bilirubin usually 2 to 5 mg/dL (~50% conjugated)
MRPs: Necessary for bilirubin excretion to bile
•
May see bilirubin in urine
•
No pruritus
•
Liver turns black(classically seen in abdominal surgery)
•
Rotor’s Syndrome •
Findings:
•
Similar to Dubin-Johnson Milder
•
No black liver (differentiates Dubin-Johnson)
Neonatal Jaundice •
Neonatal Jaundice Treatment: Phototherapy
•
Exposes skin to light of specific wavelength
•
Converts bilirubin to lumirubin •
Isomerization (same chemical f ormula; different structure)
•
More water soluble
•
Allows excretion w ithout conjugation
Several mechanisms •
↑ bilirubin (more RBCs, shorter lifespan)
•
↓ UDP-glucuronyl transferase activity (“immature”)
•
Takes 14 weeks for enzyme to reach adult level of function
•
Result: ↑ unconjugated bilirubin Can lead tokernicterus
•
Preterm infants at greatest risk
•
•
Benign condition; no treatment required
Bilirubin Algorithm
39
Gastric Acid •
Gastrointestinal Secretions
•
Found in gastric glands Mucosal layer (lamina propria)
•
More in upper layers
•
Pink colored (eosinophilic)
•
•
Vagotomy & Atropine
•
Old therapy for gastric ulcers
•
Surgical disruption of vagus nerve to stomach
•
Result: decreased acid production
Atropine •
Muscarinic blocker
•
Blunts parietal cell stimulation by ACh
•
Does not block stimulation by vagus gastrin HCL
Protection against infectious agents Denatures proteinsfor breakdown/absorption
Stomach cells protected by: •
Mucous and bicarb
•
Secreted by neck cells
#1: Gastrin(direct) •
Hormone from G cells of antrum (distal) stomach
•
Binds CCKb receptoron parietal cells
#2: Gastrin (indirect) •
Activates ECL cells
•
Histaminereleased
stimulation
#3: Vagus nerve •
ACh muscarinic (M3) receptors
•
Also activates G cells Gastrin
•
Not via ACh; uses gastrin releasing peptide (GRP)
Intrinsic Factor
Vagotomy •
Secrete hydrochloric acid (HCL)
Maintains very low pH in stomach (<5; as low as 1)
Stimuli for Acid Secretion
•
•
Found in gastric glands
•
•
•
Parietal cells •
•
•
Jason Ryan, MD, MPH
•
Parietal cellsof stomach
40
•
Necessary for vitamin B12 absorption
•
Released by parietal cells(along with H+)
Parietal Cells •
•
Parietal Cells
Separate secretion of H+ and Cl- for HCL 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
•
High (>20) in diuretic use
•
Classicscenario:
•
•
Parietal Cells •
H+ formed by carbonic anhydrase Alkaline tideafter meals due to ↑ serum HCO3-
Loss of Cl in gastric secretions
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 •
•
Histamine Prostaglandins Somatostatin
Parietal Cells •
Histamine (H2) blockers Cimetidine,ranitidine,famotidine, nizatidine
•
Chief cells
Misoprostol (PGE1 analog) Blunts acid secretion
Pepsin
•
Found in gastric glands
•
Digests proteins (like chymotrypsin, trypsin)
•
Mucosal layer (lamina propria)
•
Released by chief cellsof stomach
•
•
Mostly in deeper layers 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
•
Secreted into portal vein blood
•
Physiologic action onparietal cells
•
•
Gastrointestinal Hormones
Found in mucosa of antrumof 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
•
Enterochromaffin-like cells mediate gastrin effects Gastrin ECL Histamine Parietal cell
•
Parietal cell receptors:
•
Increases gastric motility
•
Histamine (most important)
•
Gastrin
•
Ach (vagus nerve)
Gastrin
Gastrinoma
Stimuli
Zollinger-Ellison Syndrome
•
•
Released in response to: •
Stomach distention
•
Alkalinization
•
Amino acids (especially phenylalanineand tryptophan )
•
Vagal stimulation (mediated byGRP – atropine does not block)
Gastrin secreting tumors
•
Occur in duodenumor pancreas •
•
•
Inhibited by low pH, somatostatin
Phenylalanine
•
Tryptophan
43
G cells found in pancreas in fetus
Excessive acid secretion Hypertrophy/hyperplasiaof mucosa
Gastrinoma
Gastrinoma
Zollinger-Ellison Syndrome
Diagnosis
•
Abdominalpain •
•
•
•
•
•
Low pH inactivates pancreatic enzymes Also inhibits sodium/water absorption in small intestines
•
Result: Poor digestion, steatorrhea, secretory diarrhea
•
•
Most in distal duodenum(often past bulb) or jejunum
•
Refractory to PPI therapy
•
•
Normal G cells inhibited by secretin (leads to ↓ gastric pH) Gastrinomas stimulated by secretin
•
Gastrin level will rise after secretin administration
Pernicious Anemia •
High dose proton pump inhibitors
Omeprazole, lansoprazole, pantoprazole
Octreotide(somatostatin) Inhibits gastrin release for some patients
Surgicalexcision
Cholecystokinin •
Differentiate gastrinomas from other causes ↑ gastrin
Heartburn
•
•
>10 times upper limit of normal in gastrinomas
Ulcers
•
•
Secretin test •
Treatment
•
•
Excessive gastric acid cannot be neutralized in intestines
Gastrinoma •
Fasting serum gastrin level •
Chronicdiarrhea •
•
Improves with food (raises pH)
Autoimmunegastritis Loss of parietal cells loss of intrinsic factor
•
Cannot absorb vitaminB12
•
High gastrin levels typical finding
•
Also G-cell hyperplasia
Cholecystokinin
Hormone for gall bladder contraction secretion Pancreatic enzyme Released by I cells •
•
•
Contraction of gall bladder
•
Pancreaticenzymesecretion
Small intestine (mostly duodenum and jejunum) •
•
44
•
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:
•
Methodof cholecystography Test to evaluate RUQ pain
•
Procedure
•
•
Fatty acids and monoglycerides (not triglycerides)
•
Amino acidsand small proteins
•
•
Fatty Acid
H
•
Mono-glyceride
Usually when 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 administered •
Gall bladder radioactivity measured before/after
•
Gall bladder ejection fraction determined
H
Secretin •
•
Hormone toraise pHin small intestine Released by S cells of duodenum
•
Released in response to H+ in duodenum
•
Fatty acids in duodenum
Secretin •
•
•
•
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 described
•
Suppresses gastrin release
Increases bile production Promotespancreaticflow •
Water secreted with bicarb
•
Flushes pancreatic enzymes into intestines
Somatostatin
Key clinical use: gastrinomas •
-
Increases HCO3 secretion by pancreatic duct cells
•
Inhibitsmost GI hormones
•
Released by D cells throughout GI tract
•
Also found in nervesthroughout entire body Originally discoveredin hypothalamus
•
Can act as:
•
•
45
Shown to inhibit growth hormone release
•
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 : Reduces splanchnic blood flow
•
Food in stomach ↓ Somatostatin hormone release Acid in stomach Somatostatin release hormone shutdown Regulates digestion/acid secretion
GIP
Octreotide •
•
•
Carcinoid Syndrome •
Somatostatin receptors found on majority of carcinoid tumors
•
Flushing and diarrhea significantly improve
Acromegaly •
•
Glucose-dependent insulinotropic peptide
Inhibit growth hormone secretion
Inhibit release of hormones
VIP
•
Neurocrine •
Synthesized in neurons
•
Released in response to action potential onto target cells
•
Released by K cells of duodenum/jejunum
•
Stimuli: Glucose, fatty acids, amino acids
•
Special note:
Raises pH (similar to secretin) Stimulates pancreatic HCO3- secretion
•
Bicarb draws water increased fluid secretion
•
Oral glucose metabolized faster than IV glucose
•
IV glucose does not stimulate GIP release
Rare VIP secreting tumors in pancreas (islet cells)
•
Watery diarrhea(secretorydiarrhea)
Important for LES
•
Only hormone release in response to fats, protein, and carbs
•
Causes relaxation of smooth muscle •
•
•
VIPoma
Vasoactive Intestinal Peptide •
Stimulatesinsulin releasefrom pancreas Also blunts H+ secretion
•
Gastrinoma/Glucagonoma •
•
•
VIP promotes bicarb secretion water secretion
•
Tea-colored, odorless diarrhea
•
Resembles cholera (“pancreatic cholera syndrome”)
•
Hypokalemia(from high volume diarrhea) Achlorhydria
•
WDHA syndrome
•
•
Inhibits gastric H+ secretion
•
46
Absence of gastric acid
Watery diarrhea, hypokalemia, achlorhydria
VIPoma •
VIPoma
Typicalcase
•
Initialtreatment:
•
Adult (30-50 years old)
•
Fluid/electrolyte replacement
•
Long-standing watery diarrhea (no 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, colon Promotes motility in the fasting state
•
Key clinical point:
•
Highest levels found between meals
•
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 •
Exocrine Pancreas
•
Secretions that aids in digestion 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)
•
•
Neutralizes acidic fluid from stomach
Also Na+, Cl-, K+
Ductal cells •
Modify fluid
•
Secrete bicarb
•
Permeable to water
•
Add water to pancreatic juice
Pancreatic Fluid •
Compositionvaries with flow rate
•
Low flow:
•
Containsbicarb
•
High Cl-
•
Low bicarb
Pancreatic Fluid
High flow: •
Low Cl-
•
High bicarb
49
Pancreatic Fluid •
•
•
Pancreatic Fluid
Bicarbsecreted small ducts
•
Reabsorbed large ducts Reabsorption ineffective at high flow rates
•
•
Pancreatic Enzymes •
•
Secreted by acinar cells Cholecystokininis major stimulus for release
•
Also ACh viavagovagal reflexes •
GI tract reflex circuits
•
Afferent and efferent fibers both in vagus nerve
•
H+, amino acids, and fats in duodenum
Pancreatic Enzymes •
Starch= polysaccharide •
•
•
•
Repeating alpha-D-glucose molecules linked together
•
α-amylase
•
Lipase
•
Phospholipase A
•
Colipase
•
Proteases
•
Trypsinogen
•
Secreted in active form
•
Salivary (lingual) amylase
Found in plants (humans have glycogen) Starchcontainsamyloseandamylopectin α-amylase hydrolyzes (breaks) α1-4 linkages
Amylose
Digest carbohydrates,fats,proteins
α-amylase
α-amylase •
Secretinis main stimulus for HCO3- secretion Released in response to H+ in duodenum Secreted by S cellsof duodenum
•
Amylopectin
50
•
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 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 plus monoglycerides
•
Also elevated in acute pancreatitis
•
•
Fatty Acids Triglyceride Pancreatic Lipase
Colipase
Assists pancreatic lipase
Phospholipase A2 •
Hydrolyzes phospholipids
•
Secreted as inactive 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)
51
•
Trypsin secreted as inactivetrypsinogen
•
Activated by brush border enzyme:enterokinase
•
Trypsin activates all other protein enzymes
Acute Pancreatitis •
Acute inflammation of pancreas Epigastric pain, nausea, vomiting
•
Blocked secretion of enzymes while synthesis ongoing
•
•
•
Acute Pancreatitis •
•
•
Large amounts of trypsin activated
•
Trypsin activates more trypsin Also activates phospholipase, chymotrypsin, and elastase
•
“ Auto-digestion ” by enzymes occurs
•
Pancreatic Enzyme Replacement •
Multiplecommercialreplacements available •
•
Different ratios of lipase, protease, and amylase
Uses: •
Cystic fibrosis
•
Chronic pancreatitis
•
Post pancreatectomy
52
Diagnosis: Elevated serum pancreatic enzyme levels ↑ Amylase and lipase Both elevated in conditions other than pancreatitis Lipase more specific for pancreatic damage
GERD Gastroesophageal Reflux Disease •
Gastric juice from stomach to esophagus
•
Represents a failure of lower esophageal sphincter
•
Esophageal Disorders
•
•
“Reflux” back into esophagus Decrease in LES tone Precise mechanism not well established
Jason Ryan, MD, MPH
Reflux Esophagitis •
•
Inflammation of epithelial layer Mucosa: erythema and edema
•
Erosions (loss of epithelial layer)
Reflux Esophagitis •
Histology: •
Basal zone (epithelium) hyperplasia
•
Lamina propria papilla elongate
•
Eosinophilsand neutrophils
GERD
Pediatric GERD
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
•
•
Dysphagia •
•
•
Fatty foods
•
Caffeine
•
Chocolate Spicy foods
•
Reflux into respiratory tract
•
Carbonated beverages
•
Asthma (adult-onset)
•
Peppermint
•
Cough
•
Dyspnea
Respiratorysymptoms
•
Refractory GERD: Nissen fundoplication
Damage to enamel of teeth
Ulcers, Fibrosis, Strictures
Treatment
•
•
•
Painful esophagitis
GERD •
Weight loss Dietary modification (avoid triggers)
•
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 cells
•
Potential consequences of GERD Aciddestroys mucosa (causes ulcers)
•
Replaced by fibrous tissue
•
Can lead to strictures dysphagia
Barrett’s Esophagus
Ingestion of Lye •
Alkalisubstances
•
Result of long-standing GERD
•
Contain sodium or potassium hydroxide
•
Metaplasiaof esophagus
•
Usually ingested accidentally by children •
•
Causesliquefactivenecrosis
•
Rapid injury through mucosa into wall of esophagus
•
Neutralized in stomach by acid
•
•
•
Found in household cleaners, drain openers
Child usually recovers Can result in 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 •
•
Squamous cell or adenocarcinoma Both types: ↑ risk in smokers
•
Often presents late with advanced disease/mets
•
Presentswith “progressive”dysphagia
•
•
Starts with solids
•
Progresses to liquids as tumor grows
Esophageal Cancer •
•
Weight loss
•
Hematemesis
•
•
Normally no glandular tissue in esophagus
•
Need GERD Barrett’s Glandular epithelium
•
Develops in lower 1/3 of esophagus (near stomach acid)
•
Obesity is risk factor (also GERD)
Lymph Nodes
Squamous cell most common worldwide •
•
Adenocarcinoma most common in US
Other symptoms
Esophageal Cancer •
Biopsies taken to look for carcinoma
•
Upper esophagus (neck):
•
Middle (chest):
Usually in middle or upper esophagus
•
Results from processes that damage upper esophagus
Cervical nodes
•
Food (alcohol, hot tea)
•
Mediastinal nodes
•
Achalasia (backup of food)
•
Tracheobronchial nodes
•
Esophageal webs (backup of food)
•
Zenker’s
•
Lye ingestion
•
Can cause special symptoms due to upper location •
Hoarse 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
•
•
HSV-1 •
•
•
•
Usually causes oral herpes Can involve esophagus
•
“Punched out” ulcers
•
AIDS (CD4<50)
•
Linear ulcers
•
•
•
•
Often idiopathic
•
Chronic Chagas Disease (Protozoa: Trypanosoma cruzi)
Must exclude other causes of esophagitis (i.e. GERD)
•
Dysphagia
•
Poor response to GERD treatment
•
Eosinophils on biopsy
Dysphagia to solids and liquids •
Closed LES
•
Contrast with obstruction (solids only)
Bad breath •
Accumulation of food in esophagus
Esophageal Varices
Diagnostic Testing
•
Classicscenario:
Found in muscular layer (below submucosa)
Causes
Dilation of esophagus •
•
•
Achalasia •
Diagnosis of exclusion
Symptoms
Inability to relax lower esophageal sphincter Due to loss of ganglion cells in Auerbach’splexus •
•
Achalasia
Achalasia •
Esophagealdysfunction(dysphagia) Biopsy: eosinophil-predominantinflammation •
CMV •
Allergic reaction (unknown antigen) Immune-mediated
•
“Bird’s beak” on barium swallow
Esophageal manometry
Dilated submucosal veins •
Usually in lower 1/3 of esophagus
•
Usually due to portal hypertension (cirrhosis)
Can lead to upper GI bleeding (variceal rupture)
•
Helpful in dysphagia
•
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
•
•
Treatment for variceal bleed: •
56
Emergent endoscopy for banding/ligation
Malloy-Weiss Syndrome •
Damage to esophageal mucosaat GE junction Causes painfulhematemesis
•
Caused by severe, chronic vomiting
•
•
•
•
BoerHaave Syndrome
Epigastric pain or pain in the back
•
Extension/protrusionof mucosa Extends into lumen of esophagus
•
Obstructs movement of food dysphagia
•
Webs: Common in upper esophagus
•
•
Transmural rupture of esophagus Result of severe, chronic vomiting or retching
•
Air exits esophagus •
•
Alcoholism Bulimia
Esophageal Webs and Rings •
•
•
Air in mediastinum on chest x-ray (pneumomediastinum)
Air under skin in neck (“subcutaneous emphysema ”)
Schatzki Ring •
•
Ring at squamocolumnar junction Common cause of dysphagia to solids
•
Squamousmucosa proximally,columnardistally
Rings: Common in lower esophagus Risk of squamous cell carcinoma
Zenker’s Diverticulum
Plummer-Vinson Syndrome •
Rare condition; poorly understood cause
•
Occurs at junction of esophagus and pharynx
•
Triad:
•
Mucosa/submucosa through muscular wall
•
Usually result of chronic swallowing problem
•
#1: Iron deficiency anemia
•
#2: Beefy red tongue
•
•
•
Damage to tongue mucosal layer
•
Bright red from exposure of blood vessels
#3: Esophageal web
Common in middle-age, white women
57
•
Cricopharyngeal muscle must relax to allow food to pass
•
Failure to relax difficulty swallowing
•
Chronic high pressure in pharynx to force food down
•
This leads to diverticulum
Zenker’s Diverticulum •
Zenker’s Diverticulum
Classiclocation: Killian’sTriangle
•
Symptoms
•
In the hypopharynx
•
Dysphagia
•
Just proximal to upper esophageal sphincter
•
Halitosis (food trapped in diverticulum)
•
Cleavage plane between thyropharyngeus muscle and cricopharyngeus muscles
58
Liver Tests •
•
Liver Disease
AspartateAminotransferase (AST) •
Located in mitochondria
•
Alcohol is mitochondrial toxin
•
↑ AST> ↑ALTin alcoholic hepatitis
Alanine Aminotransferase (ALT) Located in cytoplasm •
•
↑ ALT > ↑AST in most types of hepatitis with cellular damage
Jason Ryan, MD, MPH
Liver Tests •
Liver Tests •
Alkaline phosphatase (Alk Phos) Enzyme from liver, bones, GI tract
•
Similar to alk phos but not elevated in bone disease
•
Precise function not known
•
Used to determine srcin of alk 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 breakdown and gluconeogenesis
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 Disease •
•
•
•
•
•
Accumulation offatty acids(fatty infiltration of liver) Usually asymptomatic among heavy drinkers
Often reversible with cessation of alcohol ↑ risk of cirrhosis
Non-alcoholic Fatty Liver Disease
•
Fatty infiltration of liver not due to alcohol •
NAFL: Fatty liver
•
NASH: Steatohepatitis (fat and inflammation)
Often asymptomatic
•
Abnormal LFTs (ALT>AST) May progress to cirrhosis
•
Associated withobesity
•
May improve with weight loss
•
y r e t r A ic t a p e H
May cause hepatomegaly on exam Abnormal LFTs(AST>ALT)
NAFLD •
Fatty infiltration in Alcoholic Liver Disease begins here (also fibrosis in cirrhosis)
Liver Zones
Mallory bodies
t c u D e il B
n i e V la t r
Zone I
Zone II
Periportal
Mid Zone
Zone III
o P
n i e V c ia t p e H
Centrilobular
Alcoholic Hepatitis •
•
•
Classically occurs after heavy, binge drinking on top of long history of alcohol consumption Toxic effects fromacetaldehyde Symptoms •
Fever
•
Jaundice
•
RUQ pain/tenderness
Budd Chiari Syndrome
•
Classic histopathology finding alcoholic liver disease
•
Thrombosis of hepatic vein
•
Cytoplasmicinclusions
•
Abdominal pain, ascites, hepatomegaly
•
Damagedintermediate filaments in hepatocytes
•
•
60
Zone 3 congestion,necrosis,he morrhage Common causes: •
Myeloproliferative disorder (P. vera, ET, CML)
•
Hepatocellular carcinoma
•
OCP/Pregnancy
•
Hypercoagulable states
Reye’s Syndrome
Right Heart Failure •
•
•
•
“Cardiaccirrhosis” 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
•
•
Mottled liver like a nutmeg Also seen Budd Chiari
•
•
Evidence that aspirin inhibits beta oxidation Mitochondrial damage seen
•
Fatty changes in liver (hepatomegaly)
•
Vomiting, coma, death
Avoid aspirin in children (except Kawasaki’s)
1 Anti-trypsin Deficiency •
•
•
Classically chicken pox (varicella zoster ) and influenza B
•
1 Anti-trypsin Deficiency •
Inherited(autosomalco-dominant) Decreased or dysfunctional AAT AAT balances naturally occurring proteases
Lung •
•
•
1 Anti-trypsin Deficiency
Emphysema Imbalance between neutrophil elastase (destroys elastin) and elastase inhibitor AAT (protects elastin)
Liver •
Cirrhosis
•
Abnormal
•
Pathologic polymerizationof AAT
•
Occurs in endoplasmic reticulum of hepatocytes
1 builds up in liver (endoplasmicreticulum)
Liver Abscess
AAT polymers stain with PAS Resist resist digestion by diastase (unlike glycogen)
•
Walled-off infection of the liver
•
In the US usually bacteria
•
•
61
•
Bacteremia
•
Cholangitis (GN Rods; Klebsiella often identified)
Entameba histolytica (protozoa) •
Cysts in contaminated water bloody diarrhea (dysentery)
•
Ascends in the biliary tree
Echinococcus(helminth) •
Fecal-oral ingestion of eggs
•
Massive liver cysts
Viral Hepatitis •
Hepatitis A, B, C, D, or E Very high AST/ALT
•
Hyperbilirubinemiaand jaundice
•
If severe, may see abnormal synthetic function
•
Diagnosed via viral antibody tests
•
•
•
Autoimmune Hepatitis •
Autoimmune inflammation of the liver Most common among women in 40s/50s
•
Range of symptoms
•
Anti-nuclear antibodies (ANAs)
•
Often >1000 (>25x normal)
•
Hypoglycemia, elevated PT/PTT, low albumin
Asymptomatic
acute liver disease cirrhosis
•
Most common antibody abnormality
•
Sensitive, not specific
•
Anti-smooth muscle antibodies (ASMA)
•
Treatment:steroidsand immunosuppressants
•
More specific for AHA
Tylenol Overdose
Tylenol Overdose
Acetaminophen, Paracetamol, APAP(N-acetyl-para-aminophenol)
Treatment
•
•
Maximum 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-acetylcysteine is treatment of choice Used to replenish glutathione Usually given orally to patients with overdose
N-acetylcysteine
Tylenol Overdose
Shock Liver
Treatment
Ischemic Hepatitis
Cysteine
Glutathione
•
Three metabolites of acetaminophen
•
Diffuse liver injury from hypoperfusion
•
NAPQIis toxic to liver
•
Often seen in ICU patients with shock from any cause
•
•
N-acetyl-p-benzoquinone imine
•
Markedly elevated AST/ALT (1000s) Usuallyself-limited
•
Pathology:zone 3 necrosis (near central vein)
•
Metabolized by glutathione
62
Cirrhosis •
•
End stage liver disease (irreversible) Result from many causes of chronic liver disease: •
Viral Hepatitis (especially B and C)
•
Alcoholic liver disease
•
Cirrhosis
Non-alcoholic fatty liver disease
Jason Ryan, MD, MPH
Cirrhosis
Cirrhosis •
Clinical Features
•
Shrunkenliver Liver tissue replaced by fibrosisand nodules
•
Smoother liver surface replaced by nodules
•
•
Hyperammonemia Low protein diet
•
Lactulose
Clinical Features
STEAK
•
Synthetic disaccharide (laxative)
•
Colon breakdown by bacteria to fatty acids
•
•
•
Asterixis, confusion, coma
Cirrhosis
Treatment •
Hyperammonemia
•
Jaundice
•
Hypoglycemia
•
Coagulopathy
•
•
Lowers colonic pH; favors formation of NH4+ over NH3 NH4+ not absorbed trapped in colon Result: ↓plasma ammoniaconcentrations
•
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
•
Capillaryhydrostaticpressure (Pc)
•
Capillaryoncoticpressure (∏c )
•
• •
•
Drives fluid out of capillaries into tissues
Proteins(albumin) pullwaterinto capillaries Resists movement of fluid out of capillaries
Pc
•
Normally removed by liver
•
Gynecomastia in men
•
Spider angiomata
•
Palmar erythema
∏c
Cirrhosis
Portal Hypertension •
Elevatedestrogen
↑Nitric Oxide
Hemodynamics
↑ Splanchnic vasodilation
•
Blood flows portal vein liver hepatic vein Cirrhosis obstructed flow through liver
•
High pressure in portal vein (“hypertension”)
↓ Albumin ↓ Oncotic Pressure
↓ BP
↓ SVR
↓ Effective Circulating Sympathetic Volume Activation ↑ RAAS ↑ ADH
↑ CO
↑ Na/H2O ↑ Total Body Water
Venous Collaterals
Ascites and Edema ↑ Total Body Water Edema
Venous Anastamoses
Portal HTN
High portal pressure opens “venous collaterals”
•
Connection between portal-systemic veins
•
Normally small, collapsed vessels Engorge in portal hypertension
•
Key collaterals:
•
Ascites
↓ albumin
•
Patients with cirrhosis but without portal HTN do not develop ascites
64
•
Umbilicus– physical exam finding: “caput medusa”
•
Esophagus – upper 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
Small amount of superficial blood via left gastric vein to portal vein
part of portal system)
Caput Medusa
Internal Hemorrhoids
Caput Medusa is a physical exam finding of engorged veins around the umbilicus
Internal hemorrhoids (above dentate line) occur in portal HTN
Hypersplenism
Portal Vein Thrombosis •
Engorgement of the spleen in portal HTN leads to low platelets
•
•
Liver biopsy will be normal
•
65
Rare cause of portal hypertension Acute onsetabdominal pain Splenomegaly (palpable spleen one exam) May result in gastric v arices withbleeding
•
SAAG
Ascites •
•
Serum Ascites Albumin Gradient
Accumulation of fluid in peritoneal cavity In liver disease, from portal hypertension +/- low albumin
•
•
•
•
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
•
SAAG <1.1 g/dL •
Albumin levels similar between serum and ascites
•
Leaky vasculature leading to fluid/albumin into peritoneum
•
Seen in malignant ascites (malignant cells in peritoneal cavity)
•
Portal hypertension
•
Malignancy (leaky vasculature)
Sample of ascitic fluid via paracentesis Serum albumin – ascites albumin = SAAG
Ascites Treatment
Serum Ascites Albumin Gradient •
Test of ascitic fluid Two reasons for new/worsening ascites
•
•
•
Sodiumrestriction Spironolactone(drug of choice) •
Potassium-sparing diuretic
•
Blocks aldosterone distal tubule
•
Most effective drug for ascites
Loop diuretics (2nd line) Large volumeparacentesis TIPS
TIPS
SBP
Transjugular Intrahepatic Portosystemic Shunt
Spontaneous Bacterial Peritonitis
•
Treatment of portal hypertension
•
Ascitic fluid infection
•
Creation of channel in liver
•
Bacteria in gut gain entry into ascitic fluid
•
Connects portal vein to hepatic vein
•
66
Usually E. coli and Klebsiella ; rarely strep/staph
•
Fever, abdominal pain/tenderness ↑ ascitic absolute PMNs (≥250 cells/mm3)
•
Common treatment:
•
•
3rd generation 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 systemfor chronic liver disease or cirrhosis
•
•
•
•
•
•
•
Score ranges from 5 to 15 •
•
Creatinine level INR
•
Points for encephalopathy, ascites, bilirubin, albumin, PT 5 or 6: Child-Pugh class A cirrhosis 7 to 9: Child-Pugh class B cirrhosis 10 to 15: Child-Pugh class C cirrhosis (worst)
>40 = 71% mortality <9 = 2% mortality
Stellate Cells
Diagnosis
•
Five variables to predict risk/survival
Bilirubin level
Cirrhosis •
•
•
Estimates 3-month mortality from liver disease Point system using:
•
Gold standard isliver biopsy •
Not required if diagnosis is clear from history
•
Done only when biopsy will change management
Imaging (ultrasound, CT, MRI) •
May show small, nodular liver
•
Not sensitive or specific for diagnosis
•
More helpful for detection of hepatocellular carcinoma
Presence of ascites
•
Low platelet count
•
Spider angiomata
Perisinusoidalcell Storage site for retinoids (vitamin A metabolites)
•
Activated in liver disease
•
Secrete TGF-β
•
•
Clinical diagnosis (common) •
•
67
Proliferate and produce fibrous tissue Major contributor to cirrhosis
Hepatocellular Carcinoma •
•
Most common primary liver tumor Usually a consequence of chronic liver disease •
Hepatitis B, C
•
Alcoholic cirrhosis
•
Liver Tumors
•
Wilson’s disease Hemochromatosis
•
α-1 antitrypsin
Jason Ryan, MD, MPH
Hepatocellular Carcinoma
Aspergillus •
•
Fungus that producesaflatoxin Can contaminatecorn, soybeans, and peanuts
•
High rates of dietary intake associated with HCC
•
Industrialized countries screen for aflatoxin
•
Exposure from: •
Food from non-industrialized countries
•
Locally grown foods
Clinical Features •
Often asymptomatic •
•
•
•
•
Regular screeningdone in high risk patients
Liver function tests variable Usually abnormal in a non-specific pattern
Hepatomegaly Can cause liver failure •
Obstructive jaundice, ascites
Hepatocellular Carcinoma
Hepatocellular Carcinoma
Clinical Features
Diagnosis
•
•
Hypoglycemia
Alpha fetal protein (AFP)
Seen with large tumors due to high metabolic rate
•
Secreted by HCC
•
Rarely tumors produces insulin-like growth factor-II
•
Can be elevated in chronic liver disease
•
Rise in level from baseline suspicious for HCC
Erythrocytosis •
•
•
•
HCC can secrete EPO
•
Can cause theBudd Chiari syndrome •
Hypercoagulable state plus compression venous structures
•
Occlusion of hepatic veins that drain liver
•
Classic triad: abdominal pain, ascites, hepatomegaly
•
68
Imaging •
CT scan, MRI, ultrasound
•
Chronic liver 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, bone
•
•
Poorly responsive to chemotherapy or radiation Surgicalexcision
•
Liver transplantation
•
Radiofrequencyablation
•
Chemoembolization
•
Poor prognosis overall
•
•
•
•
•
•
Benignepithelial liver tumors Usually solitary in right lobe
•
Common in young women (20s to 40s)
•
Rarely symptomatic
•
Often detected during work-up abdominal pain Associatedwithcontraceptive use , anabolic steroids
•
•
•
Case reports of rupture during pregnancy
•
Rare, high-grade malignant vascular tumor
•
Abdominal pain, jaundice, ascites, weight loss
•
Associatedwithtoxic exposures
Median survival 6 to 20 months
Most commonbenign liver tumor Composed of vascular spaces •
Hepatic Angiosarcoma •
Chemo plus a pro-coagulant directly injected into tumor
Cavernous Hemangioma
•
•
Radiofrequency thermal energy to the lesion
Hepatic Hemangioma
Hepatic Adenoma •
Often not possible due to extensive liver involvement
Often filled with thrombus
Often discovered incidentally at surgery or imaging Case reports of fatal hemorrhage with biopsy
Hepatic Angiosarcoma •
•
69
Vinyl chloride •
Used to make PVC plastic
•
Inhalation can lead to angiosarcoma
Arsenic •
Found in rocks, soil, water
•
Certain geographic areas have high levels
•
Many industrial uses
Metastasis to Liver •
•
Most common malignancies of liver •
Much more common than HCC
•
GI (colon, stomach, pancreas), breast, lung
Multiple nodules
70
Wilson’s Disease •
Autosomal recessive disorder ofcoppermetabolism
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 in liver
•
Copper incorporated in ceruloplasmin(transport molecule)
•
↑ free radicalproduction
•
Ceruloplasmin secreted into serum
•
Copper spills into plasma
•
Increased free serum copper
•
Deposits in brain, cornea , kidneys, joints
ATP7B: Hepatic copper transport protein •
Incorporates copper into ceruloplasmin serum
•
Excretes copper into bile
•
tissue damage in liver
Lack of ceruloplasmin secretion into plasma •
Low ceruloplasmin level (diagnostic hallmark)
•
Total serum copper reduced (despite 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 carcinoma
•
CNS Features •
Basal ganglia
•
Movement symptoms (Parkinsonian)
•
Dyskinesia (abnormal movements)
•
Dysarthria (abnormal speech)
•
Tremor
•
Dementia, depression, behavioral changes
71
Hemolysis •
Related to copper in RBCs – exact mechanism unclear
•
Coombs-negative hemolytic anemia
Wilson’s Disease
Kayser-Fleischer Rings •
•
•
•
Diagnosis and Treatment
Cornealcopperdeposits •
Descemet's membrane
•
Corneo-scleral junction (limbus)
•
•
•
Seen in 50% patients with liver disease
•
Seen in 90% patients with CNS involvement Early lesions detectable on slit lamp exam
•
•
Autosomal recessive disorder ofironmetabolism
Iron Metabolism •
•
•
Uptake to plasmaregulated by enterocytes Few mechanisms to excrete excess iron Small amount in sweat, sloughing of skin/GI cells
•
Women lose iron from menstruation
Heme iron •
Found in meats
•
Easily absorbed
Non-heme iron •
Absorbed in Fe2+ state
•
Aided by vitamin C
Vocabulary
Iron consumed in diet
•
Binds copper Promotes urinary excretion
Iron Absorption
•
•
Kayser-Fleischer Rings (slit lamp exam) Treatment: Penicillamine •
Hemochromatosis •
Low ceruloplasmin level High urinary copper excretion (24 hour test)
•
Ferritin •
Iron storage protein
•
Found inside cells and in plasma
Hemosiderin •
Iron storage compound
•
Clumps of many molecules including ferritin
•
Found only inside cells (often in macrophages)
•
Hemosiderosis
•
Hemochromatosis
•
•
72
Accumulation of hemosiderin iron in cells
Disease due to iron accumulation
Hereditary Hemochromatosis •
Autosomal recessive disorder (usually) AbnormalHFE gene(chromosome 6)/HFE protein
•
Most commonly due to homozygousC282Y mutation
•
•
• •
Hereditary Hemochromatosis
•
•
Exact function HFE protein in iron absorption unclear Leads to unregulated absorption iron
•
With few mechanisms for excretion accumulation
•
Usually presents in adulthood
•
Cysteine-to-tyrosine substitution at amino acid 282
Less common C282Y/H63D mutation Both mutations common among Americans
•
Common inhematologic 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 blood transfusions Body unable to excrete excess iron
•
Heme and non-heme
Hemochromatosis
Secondary Hemochromatosis •
•
•
Liver •
Hepatomegaly
•
Abnormal LFTs
•
Cirrhosis
•
Risk of hepatocellular carcinoma
•
Pancreas
•
Skin
•
Diabetes
•
Iron + melanin turns skin bronze
•
“Bronze diabetes”
Hemochromatosis
Hemochromatosis
Clinical Features
Special Features
•
•
Heart •
Iron infiltration of myocardium
•
Commonly causes dilated cardiomyopathy (rarely restrictive)
•
Testes Atrophy
•
Decreased libido
•
Impotence
•
Vitamin C •
Arthropathy (joint pain)
•
Alcoholconsumption •
Joints •
•
73
Accelerates liver disease
May increase iron absorption
Hemochromatosis
Hemochromatosis
Laboratory Tests
Diagnosis
•
Normal ferritin <300 ng/ml Hemochromatosis can get >1000
•
High % saturation is an early sign
•
•
Genetic testing for C282Y mutation
•
MRI
•
•
•
Hemochromatosis Treatment •
•
Phlebotomy •
Removes iron
•
Repeated until ferritin falls within normal limits
Iron chelating agents (rarely used) •
Deferoxamine
•
Deferiprone
•
Deferasirox
74
C282Y/C282Y genotype confirms diagnosis
Liver turns black from iron (“low signal”)
Biopsy •
Prussian bluestaining
•
Blue granules from iron deposition
Gallstones Cholelithiasis •
Components of bile in gallbladder •
Bilirubin , Bile Salts , Cholesterol
•
Delicate balance between these components keeps bile fluid
•
If balance is upset precipitation
stones
Gallstones Jason Ryan, MD, MPH
Cholesterol
Cholesterol Gallstones •
•
Usually not visible on X-ray (radiolucent) Severalimportant associations
•
Age: •
Classically occurs in 40-year-olds
•
Rare in children, elderly
•
Pearl: Elderly patient with gallstone symptoms = cancer
Cholesterol Gallstones •
•
Excess estrogen increased cholesterol
•
Altered lipid metabolism Excess cholesterol in bile
•
Loss of bile salts
•
Western Caucasians
•
Hispanics
•
Native Americans
Less common •
Eastern Europeans
•
Japanese
•
African-Americans
Estrogen Risk Factors
Risk factorscategories: •
More common certain demographics groups:
Cholesterol Gallstones
Cholesterol Gallstones •
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
•
Obesity: Increased total body cholesterol Rapid weight loss: Increasedcholesterol mobilization
•
Both factors lead to more cholesterol in bile
•
•
Produced in liver secreted into bile Reabsorbed in terminal ileum
•
Reduced bile salts cholesterolgallstones
•
•
•
•
About 95% absorbed and recycled
Underproduction Poor absorption absorption from ileum
Taurocholic acid
Cholesterol Gallstones
Cholesterol Gallstones
Bile Salt Risk Factors
Bile Salt Risk Factors
•
•
•
•
Cirrhosis
Decreased synthesis of bile salts
•
Crohn’sDisease •
Crohn’s Disease: Inflammation of ileum is common
•
Abnormal resorption of bile salts
Cystic Fibrosis
Fat malabsorption loss of bile acids in stool
•
Clofibrate(and other fibrates)
•
Bile acid resins
•
Inhibit bile acid synthesis
•
Old, rarely used cholesterol drugs
•
Prevent intestinal reabsorption bile acids/salts
Pigment Stones
Pigment Stones
Bilirubin Stones
Bilirubin Stones
•
•
•
•
•
Composed of calcium bilirubinate (radiopaque) Can be seen on x-ray Black or brown Key principle: unconjugated bilirubin insoluble in H 2O Rise in unconjugated bilirubin in bile gallstones
•
Extravascular hemolysis
•
Cirrhosis or chronic liver disease
•
Recurrent biliary tree infections
•
•
76
Excess bilirubin
Impaired bilirubin conjugation
•
Bacterial glucuronidases
•
Convert conjugated bilirubin unconjugated
•
Brown(not black) stones (↑ calcium/some cholesterol)
Gallstone Disease •
Often asymptomatic •
•
•
Ursodeoxycholic Acid •
Bile acid Rarely used medical therapy for cholesterol stones
•
Reduces cholesterol secretion into bile
•
Discovered incidentally on imaging of abdomen
Can cause a number of clinical conditions Mainstay of treatment is surgery (cholecystectomy)
•
•
•
Biliary Colic •
•
Episodic RUQ pain May radiate toright shoulder blade Gallbladder contracts against stone in outlet
•
Pain lasts ~30 minutes then subsides
•
•
•
•
•
•
↑ ratio bile acids:cholesterol
May dissolve gallstones
Acute Cholecystitis •
•
Inflammation of gallbladder Stone in cystic duct obstruction
•
Gallbladder squeezes constricts blood supply
•
Gallbladder dilates becomes inflamed
Often after eating, especiallyfatty meals stimulatesgallbladder contraction Cholecystokinin
Acute Cholecystitis •
Less cholesterol
Choledocolithiasis
Clinicalfeatures •
RUQ pain, fever,↑ WBC
•
Radiates to right scapula
Examiner presses RUQ
•
Patient asked to inspire
•
Patient abruptly stops inspiration due to pain
Common bile duct stone
•
Biliary obstruction
•
Jaundice ↑ Alk Phos >> ↑AST/ALT
•
May lead to cholangitis
•
Murphy’ssign •
•
Risk of rupture/peritonitis Usually treated with urgent surgery
77
Chronic Cholecystitis •
•
•
•
•
Acalculous cholecystitis
Long-standing,untreated cholecystitis Chronic inflammation Causes a porcelain gallbladder Risk ofgall bladder carcinoma
•
Usually occurs in critically ill patients
Ascending Cholangitis •
Rare complication of end-stage HIV infection 3 •
•
Acute cholecystitisnot due to gallstones Caused by gall bladder ischemia and stasis
Treatment:surgery
AIDS Cholangiopathy •
•
•
Usually CD4 < 100/mm
Result of chronic infectioninvolving biliary tree •
Cryptosporidium (most common)
•
CMV infection
•
Biliary obstruction from stricturesof 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 : 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 bilirubin (and total)
78
Ascending Cholangitis
ERCP
Treatment
Endoscopic retrograde cholangiopancreatography
•
•
Antibiotics •
Gram negative and anaerobic coverage
•
Ampicillin-sulbactam
•
Ciprofloxacin-Metronidazole
•
•
Combination of endoscopy and fluoroscopy Imaging and therapy of biliary disorders
Biliary drainage Endoscopic sphincterotomy w ith stone extraction •
•
Sometimes stent insertion
•
Rarely surgery (replaced by drainage techniques)
Gallstone Ileus •
•
Massive gallstone erodes through gallbladder wall Createsfistulawith small intestine
•
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
Gallstone Pancreatitis •
•
Gallbladder Carcinoma •
•
•
•
Rare malignancy Adenocarcinoma fromchronic inflammation Gallstone disease (Porcelain gallbladder) Chronic salmonella infection (S. typhi) •
S. typhi can remain in gall bladder (carrier state )
•
Endemic countries 1-4% people may be carriers
•
Risk factor for carcinoma
79
Obstruction of common bile duct by stone Leads to acute pancreatitis
Biliary Atresia •
Idiopathic biliary obstruction inneonates
•
Key findings:
•
•
•
Biliary Disorders Jason Ryan, MD, MPH •
•
•
•
Gallbladder absentor abnormal
•
Absence of common bile duct
•
No other 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”)
Ultrasound:
•
Biliary Cirrhosis
Biliary ducts do not form, or degenerate early in life
•
Gallstone, pancreatic cancer, bi liary stricture
Biliary cirrhosis withoutextra-hepaticobstruction Autoimmunedisorder •
T-cellattack on small interlobular bile ducts
•
Granulomatous inflammation
Primary Biliary Cirrhosis
Primary Biliary Cirrhosis
Clinical Features
Diagnosis
•
More common amongwomen
•
most common initial symptoms Fatigue and pruritus •
Associated with increased bile acids in serum/skin
•
Pruritus often precedesdevelopment of jaundice
•
Itching may be severe, often worse at night
•
•
MichalakA, Pruritus in liver disease – pathenogenisis and treatment. Journal of Pre-Clin ical and Clinical Research, 2011, Vol 5, No 2, 47-49
80
•
Hallmark of PBC
•
Present in ~95% of patients
Anti-nuclear antibodies seen in ~70%
•
Markedly elevatedalkaline phosphatase May see mild elevations AST/ALT
•
↑ bilirubin occurs late poor prognosis
•
ITCHING
Anti-mitochondrial antibodies
Primary Biliary Cirrhosis
Primary Biliary Cirrhosis
Diagnosis
Treatment
•
•
•
•
Serum lipidsmay be markedly elevated
•
Ursodeoxycholic acid
•
Total cholesterol >1000 can be seen
•
Only effective therapy
•
Xanthomasmay occur
•
Similar to other bile acids but less toxic to hepatocytes
•
With treatment, UDCAreplaces endogenous bile acids
•
Improves LFTs, disease progression
Imaging showsabsence 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 antibodies
•
Livertransplant
Ursodeoxycholic acid
Primary Biliary Cirrhosis
Primary Sclerosing Cholangitis
Associated Disorders •
•
•
Associated with other autoimmune disorders Most common isSjogren’s
•
Autoimmunedisorder Inflammation,fibrosis, strictures in biliary tree Involvesintra and extra-hepatic bile ducts
•
Strongly associatedwithulcerativecolitis
•
•
Contrast with PBC
•
~90% of PSC patients have IBD
•
Of those, ~90% have UC
PrimarySclerosing Cholangitis
Primary Sclerosing Cholangitis
Clinical Features
Lab Findings
•
Strictures obstruct bile flow
•
Symptoms of biliary obstruction
•
RUQ pain, fatigue, jaundice
•
Cholestasis •
Elevated alkaline phosphatase
•
Elevated conjugated bilirubin
•
Usually mildly elevated AST/ALT
•
Elevated IgM levels
•
Positive p-ANCA
•
•
81
Up to 50% of patients
Up to 80% patients (note: also seen in UC)
PrimarySclerosing Cholangitis
PrimarySclerosing Cholangitis •
Diagnosis
Histopathology finding:Periductal fibrosis •
•
“Onion skin” fibrosis of bile ducts
•
•
PrimarySclerosing Cholangitis Endoscopictherapy •
Dilation or stenting of strictures in bile ducts
•
Livertransplant
•
Annual screening for cholangiocarcinoma
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 •
Suspected from cholestasis, especially in UC Cholangiogramconfirmsdiagnosis
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
•
•
•
•
Can extend into submucosa or muscular layer
•
Usually focal
•
Mostly occur in 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 •
Lymphocytes, plasma cells, macrophages
•
Autoimmune
•
H. Pylori
Acute Gastritis •
If they break through: ulcer
Ulcer: loss of mucosal layer
Symptoms
Inflammation of the gastric mucosa Acutegastritis •
Extend into muscularis mucosa
Gastritis
Gastritis •
Often generalized
Parietal Cells
General points: •
Epithelium 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!)
•
Prostaglandins: Inhibit acid pr 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
•
•
•
Occurs in burn patients Loss of skin Loss of fluids dehydration Hypotension to stomach mucosal damage Result: Acute gastritis and ulcers
Alcohol •
Burn
Damages mucosa
•
Chemotherapy
•
H. Pylori(bacterialinfection)
•
↓Plasma Volume
Inhibits epithelial cell replication
↓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
•
Shock, sepsis, trauma ↓ mucosal perfusion Loss of protective barrier of mucous/bicarb
•
Common among critically ill patients
•
Prophylactictherapy:Proton pump inhibitors
↑ICP
•
Pantoprazole, Omeprazole, etc.
•
Often administered to all ICU patients
↑Vagal Tone ↑ACh
Autoimmune Gastritis
Chronic Gastritis
Pernicious Anemia
Chronic Gastritis
•
•
•
Type A Autoimmune
Type B Bacteria (H. Pylori)
May cause dyspepsia Often asymptomatic until complications develop
84
Autoimmune destruction ofgastric parietal cells Loss of secretion of intrinsic factor IF necessary for B12 absorptionterminal ileum
Autoimmune Gastritis
H. Pylori
Pernicious Anemia •
•
•
•
Chronic inflammation ofg astric body/fundus More common amongwomen
•
•
Associated withHLA-DR antigens Associatedwithgastric adenocarcinoma
•
•
•
•
Mostly occurs in antrumof stomach
Associated Malignancies •
Urease positive •
Hydrolyzes urea
•
Produces ammonium (alkaline)
•
Protects bacteria from stomach acid
•
Forms ammonium chloride damaging to stomach
•
Gastric Adenocarcinoma MALT lymphoma •
Mucosal associated lymphoid tissue
•
B-cell cancer, usually in the stomach
•
HIGHLY associated with H. Pylori infection
Increased pH gastrinrelease ↑ acid production
Urea
Ammonium
H. Pylori
H. Pylori
Diagnosis •
Biopsy
•
Urea breath test
•
Causes acute and chronic gastritis Causes ulcers
H. Pylori
H. Pylori •
Most common causechronic gastritis Gram negative rod
•
Treatment: “Tripletherapy”for 7-10 days •
Proton pump inhibitor
•
Patients swallow urea with isotopes (carbon-14 or carbon-13)
•
Clarithromycin
•
Detection of isotope-labelled carbon dioxide in exhaled breath
•
Amoxicillin/Metronidazole
•
Indicates urea was split (i.e. urease present)
•
Testing often repeated to confirm eradication
•
Treatment failures~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
•
Type B Bacteria (H. Pylori) Ulcers Antrum MALT Lymphoma
Chronic inflammation intestinal metaplasia •
Stomach tissue changes to intestinal tissue
•
Key path finding: Goblet cellsappear in stomach
Both types ↑ risk gastric adenocarcinoma
Peptic Ulcer Disease •
Peptic Ulcer Disease •
Solitary Ulcer •
Antrum of stomach (~10%)
•
Proximal duodenum (~90%)
Duodenal Ulcer •
•
Risk factors •
H. pylori infection
•
NSAIDs
•
Smoking
Duodenal Ulcer
Nearly always related toH. Pylori
•
Symptoms: Epigastric pain
•
H. pylori can increase gastric acid production
•
Improves with meals
•
Especially if antrum infection only (↑gastrin release)
•
Meal stimulates bicarb secretion
•
Pancreas (secretin/VIP); Brunner’s glands (duodenum)
•
Pain may be worse at night(empty stomach)
Rare cause: Zollinger-Ellison Syndrome •
Gastrin-secreting tumor
•
Often multiple ulcers
•
Often ulcers in distal duodenum (beyond bulb) or jejunum
•
Almost never cancerous (benign) •
86
When seen on endoscopy, rarely biopsied
Brunner’s Gland Hypertrophy •
•
•
•
•
Complications
Only induodenum Found insubmucosa Produces alkaline (basic) fluid Protects from acidic stomach fluid and chyme
•
Bleeding above the ligament of Treitz Results in hematemesis
•
Can be caused by peptic ulcers
•
Melena (dark stools)
•
Blood exposed to acid, bacteria Turns stools dark black (“tarry”)
•
Contrast with lower GI bleeding
•
Most duodenal ulcers are anterior Posterior ulcersmore likely to have complications
•
Upper GI Bleeding •
•
↑ thickness in peptic ulcer disease
•
Upper GI Bleeding •
•
•
•
Hematochezia
•
“Bright red blood per rectum”
Duodenal ulcers can cause bleeding More common when located posteriorly Source is gastroduodenal artery
•
Pancreatitis
•
Perforation
Ulcer Perforation •
Gastric Ulcer
•
Can occur with gastric or duodenal ulcer Causes pneumoperitoneum
•
Air under diaphragm on CXR
Gastric Ulcer
•
Much less common than duodenal ulcers
•
About 70% associated with H. Pylori
•
Most common location is lesser curvature
•
Dangerouscauses: adenocarcinoma
•
•
Rupture: bleeding from left gastric artery
•
Pain worse with meals •
Food stimulates acid release
•
Can lead to weight loss
87
Often biopsied
Gastric Ulcer
Ulcer Treatment
Complications •
•
Perforation Upper GI Bleeding •
•
•
Classic vessel is left gastric artery
Gastric Carcinoma •
•
Symptoms nonspecific: Weight loss, abdominal pain
•
Early satiety
•
Early, noninvasive cancer: 5-year survival 95%
•
Advanced: 15%
•
Two types: Intestinal and Diffuse
•
•
PPIs often used empirically for dyspepsia symptoms
•
Treat GERD, gastritis, ulcers
Intestinal Type •
95% adenocarcinoma Usually asymptomaticuntil advanced •
H. Pylori treatment (when bacteria identified) Proton pump inhibitors are therapy of choice
Grossly appears as large ulcer with irregular margins
Extensive screening in Japan
Intestinal Type
Intestinal Type
Risk Factors
•
Similar to colonic adenocarcinoma
•
More common amongolder men
•
Results from intestinal metaplasia
•
Other risk factors
•
•
H. pylori; autoimmune gastritis
Common inlesser curvature (where ulcers form!)
88
•
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
•
Linked to cancer by case-control studies
Less common form Not associated with metaplasia, H. pylori
•
Few established risk factors
Type A blood •
↑ risk autoimmune gastritis andcarcinoma
•
Mechanism unclear
Diffuse Type •
•
•
Metastasis •
Stomachdiffusely thickened •
Early satiety is a common symptom
•
: stomach thickened like leather Linitis plastica
•
Made up of gastric mucosa cells
•
Signet ring cells •
Most common site is liver
Mucin forms nucleus pushed to periphery
Gastric Carcinoma
Gastric Carcinoma
Special Clinical Findings
Special Clinical Findings
•
•
Acanthosis Nigricans
Leser-Trelatsign
Hyperpigmented plaques on skin
•
“Explosive onset” of multiple itchy seborrheic keratoses
•
Intertriginous sites (folds)
•
Probably caused by cytokines
•
Classically neck and axillae
•
Associated with insulin resistance •
•
•
•
•
Often seen obesity, diabetes
Rarely associated with malignancy •
Associated with many malignancies
Gastric adenocarcinoma most common
89
Gastric adenocarcinoma most common
Gastric Carcinoma
Gastric Carcinoma
Special Clinical Findings
Special Clinical Findings
•
Virchow’snode •
•
•
Left supraclavicular node (drains stomach)
Sister Mary Joseph nodule •
•
Metastasis to periumbilical region
•
•
Only about 25% patients have organic cause May be due to gastritis, ulcers, cancer, H. Pylori
•
More common in men (3:1 ratio)
•
Hyperplasia of mucous cells Excessive gastric mucous secretions Loss of acid (“achlorhydria”)
•
Protein loss (“protein losingenteropathy”)
•
•
•
•
Ovarian tumor secondary to mets from another site
•
Most common from gastric adenocarcinoma
•
Bilateral ovarian metastasis
•
Signet cells often seen on pathology
Hypertrophic Gastropathy
Menetrier’s Disease •
•
Palpable on exam
Dyspepsia •
Krukenberg tumor
Hypoalbuminemia edema, facial swelling Can lead to gastric adenocarcinoma
90
Rare disorders that cause enlarged rugal folds Caused by hyperplasia (not inflammatory)
Malabsorption •
•
Malabsorption of nutrients due to intestinal process Generalsymptoms •
Diarrhea
•
Weight loss
•
Malabsorption
Vitamin and mineral deficiencies
Jason Ryan, MD, MPH
Malabsorption
Malabsorption
Clinical Manifestations
Clinical Manifestations
•
•
Fatmalabsorption •
Steatorrhea
•
Pale if bile is absent (no bilirubin)
•
Voluminous stools
•
Stools that float
•
Greasy, foul smelling
•
Loss of fat soluble vitamins
•
•
Watery diarrhea
•
Osmotic effect of sugar molecules
Proteinmalabsorption •
Diarrhea
Edema (loss of albumin)
Stool Osmotic Gap •
Diarrhea
•
•
Inflammatory
Steatorrhea Watery
Secretory
Carbohydrate malabsorption
Osmotic
91
Osmotic gap = 290 – (2[Na]+2[K])stool Osmotic gap >50 seen in osmotic diarrhea Osmotic gap <50 seen in secretory causes
Celiac Sprue
Gluten
Celiac Disease, Gluten Sensitivity
•
Autoimmunedisease Destruction of small intestinal villi
•
Triggered by glutenexposure
•
•
•
•
Gliadin •
•
Pathogenic component of gluten Gliadin is deamidated: tissue transglutaminase (tTG)
•
Deamidated gliadin is immunogenic
Gliadin and Glutenin = Proteins in wheat Gluten = Gliadin + Glutenin Formed in baking bread (with water)
Celiac Sprue •
•
Deamidated gliadin consumed by APCs Presented to T cells
•
Type IV Hypersensitivity
•
•
T-cell mediated tissue damage
•
Antibodies are present
•
Unknown how antibodies contribute to disease
Associated withHLA-DQ2and HLA-DQ8
Histology
Celiac Sprue
Three Key Features
Demographics
•
•
•
Blunting of Villi
•
Crypt hyperplasia Lymphocytes in lamina propria
92
Common in whites ofnorthern European descent
Antibodies
Antibodies
•
Anti-gliadin(rarely tested – poor accuracy) Anti-tissue transglutaminase
•
Anti-endomysial
•
•
•
•
IgA endomysial and tTG have highest accuracy IgA tTG is automated – used for screening
•
IgG testing can also be done
•
Endomysium: smooth muscle connective tissue
•
•
Antibodies occur in celiac disease
Diagnosis
tTG IgA IgA
Symptoms Most commonly affected area: duodenum •
+ tTG IgA
Celiac Disease
+
Duodenal Biopsy
-
Negative tTG plus low IgA level = check IgG
Celiac Disease
Key Tests Anti-tTG IgA Level Biopsy
•
- tTG IgA Low IgA
Some patients IgA deficient
- tTG IgA + IgA
+ tTG IgG
-
Contrast with tropical sprue: entire small intestine
•
Flatulence, bloating, chronic diarrhea
•
Steatorrhea •
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 foods contain gluten
•
Small ↑ risk small bowel malignancy (rare condition!)
•
Adenocarcinoma
•
T-cell lymphoma
•
ClassicScenario:
•
•
93
Enteropathy-associated T-cell lymphoma (EATL)
Patient adherent to gluten-free diet with worsening symptoms
Dermatitis Herpetiformis •
Skin condition associated with celiac disease Herpes-like lesions on skin
•
Caused by:
•
•
•
Tropical Sprue •
•
•
IgA depositionin dermal papillae
•
Resolves with gluten free diet
•
Traveler to tropics
•
Chronic diarrhea
•
Malabsorption occurs
Antibiotics (usually tetracycline)
•
Folate supplementation
Most cases among white, European males
•
86% men
•
Average age 49 years
Can be associated w ith Folate/B12 deficiency
Often causes steatorrhea
•
Can cause watery diarrhea from sugar malabsoprtion
•
Infection with Tropheryma whipplei •
•
Whipple’s Disease •
Celiac: Duodenum most common (“proximal smallbowel”) Tropical: Entire small bowel affected
•
•
Treatment: •
•
Whipple’s Disease
Typicalcase: •
Similar to celiac sprue with blunting of villi Key difference is intestinal location •
Tropical Sprue •
Malabsorption due to unknown infectious agent Occurs in tropics (especially Caribbean)
Gram-positive rod related to actinomycetes
Systemicinfection •
Involves small intestine
•
Also joints, brain, heart
Whipple’s Disease •
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 (darkening of skin) CNS disease: Confusion
•
PAS-positive foamy macrophages
•
Seen in small intestinal lamina propria
Endocarditis:Culturenegative
Whipple’s Disease •
Diagnosis: Biopsies of small intestine
Lactose Intolerance •
Treatment: •
Fatal before antibiotic era
•
Usually treatment with Ceftriaxone
•
Different treatments for extra-intestinal disease
Lactose = disaccharide •
•
Galactose plus glucose
Digested by brush border enzyme lactase •
“Disaccharidase”
•
Breaks down lactose into galactose and glucose
•
Lactose remains in small bowel
•
Osmotic effect = diarrhea •
•
Normal histology (villi, etc.)
Lactose Intolerance
Lactose Intolerance
Causes
Causes
•
•
Lactase non-persistence (most common)
•
Galactosyl -1,4-glucose
High volume, watery diarrhea
Secondarydeficiency
•
Enzyme levels fall with aging
•
Mucosal injury
•
Non-persistence varies among populations
•
Bacterial overgrowth, viral infection, Giardiasis, Celiac, IBD
•
Lowest prevalence European Americans (25%)
•
Lactase usually first disaccharidase lost
•
African Americans, Native Americans, Asians (75-90%)
•
Due to distal location on villi
Congenital lactase deficiency (rare)
•
95
Will present as lactose intolerance following GI illness
Lactose Intolerance
Lactose Intolerance •
•
Diagnosis
Symptoms with lactose ingestion •
Milk
•
Dairy(ice cream)
•
•
Bloating, abdominal pain, diarrhea
Often clear from history Lactosebreath hydrogen test •
Patient ingests lactose
•
If undigested, bacteria ferment lactose Hydrogen
•
•
Pancreatic Insufficiency •
•
Cystic fibrosis, chronic pancreatitis, obstruction Loss of pancreatic lipase, colipase, etc.
•
Fat malabsorption •
Steatorrhea
•
Deficiencies of fat soluble vitamins
Measure exhaled hydrogen level (↑ if lactose intolerant)
Lactose tolerance test (rarely done) •
Monitor blood glucose level after lactose consumption
•
Should rise if lactose galactose and glucose
•
Lactose intolerance: tiny rise (less than 20 mg/dL)
Bacterial Overgrowth •
Small intestine should be nearly sterile •
•
Small number of organisms can be present
If significant bacteria present: •
Excessive fermentation, inflammation, malabsorption
•
Bloating,flatulence, abdominaldiscomfort Chronic diarrhea (watery or steatorrhea)
•
Vitamindeficiencies
•
Bacterial Overgrowth
Bacterial Overgrowth
Causes
Causes
•
•
Altered motility
•
Diagnosis:
•
Diabetes mellitus (enteric nerve damage)
•
Jejunal aspirate (gold standard)
•
Scleroderma
•
Lactulose test
Partial/intermittent obstruction •
Adhesions from prior surgery
•
Crohn's disease
•
96
Treatment:antibiotics
Fecal Fat Test •
•
•
•
D-xylose Test
Stool collected over 1-3 days Amount of fat measured
•
•
Normal <7grams per day Increased in fat malabsorption of any cause •
Loss of bile (liver, biliary disease) Loss of pancreatic enzymes
•
Loss of small bowel (resection)
•
•
•
Stool pH •
•
•
•
•
Most sugars cause acidic pH (<6.0)
Clinitest •
Detects undigested sugars
•
Works best in children (less sugar absorption in colon)
•
Monosaccharide
•
Absorbed in intestine
•
Other Tests •
Tests carbohydrate absorption small intestine After fasting, patient ingests D-xylose
Abnormal findings suggest sugar malabsorption Both tests abnormal in lactose intolerance Rarely used except in resource poor settings
97
No enzymes required – only intact mucosa
Later, D-xylose measured in serum/urine Abnormal results seen in •
Small intestinal bacterial overgrowth
•
Whipple's disease
Acute Pancreatitis •
•
•
•
•
Acute Pancreatitis
•
Acute inflammation of pancreas Liquefactive necrosis and hemorrhage Epigastric pain , classically radiating to back Nausea, vomiting Many triggers Most common: gallstones, alcohol
Jason Ryan, MD, MPH
Acute 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 secreted as inactivetrypsinogen
•
Normally activated at brush border byenterokinase
•
Trypsin activates all other protein enzymes
Blocked flow of enzymes while synthesis ongoing Large amounts of trypsinactivated
•
Trypsin activates more trypsin
•
Activates phospholipase, chymotrypsin, and elastase
•
“ Auto-digestion ” of pancreas by enzymes occurs
Acute Pancreatitis
Trypsin •
•
Diagnosis •
•
•
98
Elevated serum pancreatic enzyme levels •
↑ Amylase andlipase
•
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 > ↑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
•
#1:Epigastricpain #2:Elevated amylase/lipase >3x normal #3: Abnormal pancreatic imaging (CT) Need at least two out of three
Bile duct stones or dilatation
Acute Pancreatitis
Acute Pancreatitis
Common Causes
Common Causes
•
Gallstones Abdominal imaging (ultrasound) •
•
shows dilated bile ducts
Acute Pancreatitis Idiopathic (no identifiable cause)
•
Trauma
•
•
•
•
•
•
•
•
Usually apparent from history
•
Often occurs i n alcoholics
•
Triggers release of pancreatic enzymes
•
Exact mechanism unclear
Trauma
Rare Causes •
Alcohol consumption
•
Blunt or penetrating trauma damage to pancreas
•
Rare due retroperitoneal location
•
Infection Drugs Toxins Autoimmunediseases Hypercalcemia Hypertriglyceridemia Post-ERCP
99
Sometimes occurs in children restrained by seatbelts
Infection •
Rare cause of pancreatitis Viruses most common than bacteria/parasites
•
Classic cause ismumps
•
Drugs •
Many drugs can rarely cause pancreatitis Review of medication lists important in work-up
•
GLP-1 agonists (diabetes)
•
•
•
Brown recluse spider
•
Some scorpions
•
Gila monster lizard
Sulfa drugs
•
6-Mercaptopurine (6-MP)
AIP •
Venom of arachnids and reptiles •
•
Rarecondition Chronic abdominal pain
•
Recurrent attacksof acute pancreatitis
•
Diffusely enlarged pancreas on imaging
•
IgG4 positive plasma cells
•
Hypercalcemia •
Calcium may deposit in pancreatic ducts
•
Calcium may activate trypsinogen
•
Marker for the disease
•
Identified in pancreas
•
Serum IgG4 levels are elevated
Responds to treatment withsteroids
Hypertriglyceridemia
Hypercalcemia (any cause): rarely causes pancreatitis •
Post-marketing reports of pancreatitis
•
Autoimmune Pancreatitis
Toxins •
Exenatide, Liraglutide
100
•
Elevated triglycerides(>1000) acute pancreatitis
•
Exact mechanism unclear
•
May involve increasedchylomicronsin plasma •
Chylomicrons usually formed after meals and cleared
•
Always present when triglycerides > 1000mg/dL
•
May obstruct capillaries ischemia
•
Vessel damage can expose triglycerides to pancreatic lipases
•
Triglycerides breakdown free fatty acids
•
Acid tissue injury pancreatitis
ERCP
Duodenal Ulcers
Endoscopic retrograde cholangiopancreatography •
•
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 acute pancreatitis
Acute Pancreatitis
SIRS
Treatment
Systemic Inflammatory Response Syndrome
•
•
•
•
•
NPO •
Nil per os
•
No food or liquid
•
“Rests” thee pancreas (prevents stimulation) Fluid loss to pancreatic edema
•
Inflammation leads to diffuse vascular leak
•
IV fluids needed to maintain BP and renal perfusion
Clinical syndrome of dysregulated inflammation Temperature>38.3°C or <36°C
•
Heart rate>90bpm
•
IV fluids •
•
•
•
Pain control Most patients with mild disease improve in 2-3 days
•
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
Ranson’s Criteria
Complications
•
Classic method of assessing pancreatitis severity
•
DIC
•
Scoring system: points for each criteria present
•
ARDS
•
•
Mortality increases with higher score Other scores also used ( APACHE II)
•
•
•
•
•
101
Pseudocyst Abscess Fat necrosis Hypocalcemia Multi-organfailure
DIC
ARDS
Disseminated Intravascular Coagulation •
Diffuse activation of clotting factors •
•
Prolonged PT/PTT
•
Thrombocytopenia
•
Vascular occlusion
•
•
“Consumption coagulopathy”
•
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
Imagecourtesy of James Heilman, MD
Pseudocyst •
•
•
Walled-offcollectionof 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
•
Pseudocysts often resolves without intervention
•
Sometimesrequiresdrainage
•
Feared outcome is rupture peritonitis Can also lead to fistulas, obstruction
•
Can become infected
•
102
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
Presents as fever, failure to improve clinically
Inflammation can involvefat surrounding pancreas Can lead to hypocalcemia/hypomagnesemia •
Enzymes (lipase) may release free fatty acids
•
Fatty acids can bind calcium (“saponification”)
Low calcium is a poor prognostic indicator •
Saponification
Suggests extensive 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 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/calcificationof pancreas Due to recurrent bouts of acute pancreatitis
•
Alcoholin 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 or normal
•
Fibrosis may lead to loss of production of enzymes
Rarely complications: •
Splenic vein thrombosis
•
Pancreatic insufficiency
Pancreatic Insufficiency •
Results in gastric varicesvia engorgement of short gastric veins
•
•
•
Key Findings: Enlarged spleen Gastric varices
104
Result of chronic pancreatitis and steatorrhea Fat malabsorption Fat-solublevitamin deficiencies Diabetes(loss of insulin)
Pancreatic Cancer •
•
Pancreatic Cancer
Adenocarcinoma More common at head of pancreas
•
•
•
•
Often causes vague abdominal pain, weight loss Classic presentation is “painlessjaundice” •
Bile flow is obstructed
•
No pain due to absence of abrupt obstruction/inflammation
•
Slow growth of tumor gradually leads to jaundice
•
Usually metastatic at presentation
•
Most patients die from their cancer
•
5-year survival node-positive: 10%
•
5-year survival node-negative: 25%
Classic physical exam finding for pancreatic cancer Enlarged, non tendergallbladder plus jaundice
May see other signs of pancreatic-biliary obstruction •
Dark urine
•
Clay colored stools
•
Steatorrhea
Pancreatic Cancer
Trousseau’s Syndrome
Risk Factors
•
Classic finding of pancreatic cancer
•
•
Migratory superficial thrombophlebitis
•
•
•
Courvoisier’s Sign
Pancreatic Cancer •
Very poor prognosis
•
Migratory: comes/goes in different locations
•
Superficial: Below skin
•
Thrombophlebitis : Thrombosis/inflammation of veins
•
Redness and induration on skin that migrates
•
•
•
Due to hypercoagulable state
Age >50 years old Smoking Diabetes
Strongest Risk Factors
Chronic pancreatitis (> 2O years) NOT strongly associated with alcohol •
Studies have shown mixed findings
•
Some data that heavy drinking (>3/day) increases risk
Gapstur S. et 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 •
•
•
•
Risk Factors
BRCA1/BRCA2genes DNA repair proteins Gene mutation associated with breast/ovarian cancer
•
African-Americans (50-90%↑ risk)
BRCA2 mutations also associated with pancreatic CA Especially true among Ashkenazi Jews
Pancreatic Cancer
Pancreatic Cancer
Tumor Markers
Genetics
•
•
•
CA-19-9
K-RASgene (chromosome 12p)
•
Cancer-associated antigen 19-9
•
Seen in 90% of pancreatic cancers
•
Specificity 68-92%
•
Most frequently mutated gene in pancreatic cancer
•
Sensitivity 70-92% (may be negative in smaller tumors)
•
Also part of adenoma-carcinoma sequence for colon cancer
•
Not useful for diagnosis
•
Can be followed after treatment
•
CEA •
Can be elevated in pancreatic cancer
•
Poor sensitivity/specificity
•
Largely replaced by CA-19-9
Pancreatic Cancer Treatment •
Chemotherapy
•
Radiation
•
Surgery •
Classic procedure is the Whipple procedure
•
Pancreatoduodenectomy
106
SMAD4gene (chromosome 18q) •
Tumor suppressor gene
•
Inactivated in 60% of 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) – morecommon adults
•
Lymphoid hyperplasia – more common children
•
•
Appendicitis
Fever, nausea Abdominalpain •
Begins mid-epigastric (visceral peritoneum inflammation)
•
Moves to RLQ(parietal peritoneum inflammation)
Classiclocation: McBurney’sPoint •
Line from iliac crest to umbilicus
•
1/3 distance from iliac crest
The “Acute Abdomen”
Diagnosis and treatment •
Diagnosed by history/exam or CT Scan
•
Acute onset abdominal pain
•
Treatment:Surgery
•
“Reboundtenderness”
•
Several causes requireurgent surgical intervention
•
•
107
Reflects peritoneal inflammation
•
Appendicitis
•
Diverticulitis
•
Ectopic pregnancy ( -HCG testing often done)
Perforationof 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 mucosa
•
Usually in sigmoid colon
•
Protrusion of mucosa/submucosa to form pouch
•
“False diverticulum” - does not contain all layers of GI tract
•
Occur where vasa rectapenetrate muscularis of colon
•
Lower GI bleeding(hematochezia)
•
Diverticulitis
Caused by straining to pass stool (wall stress)
•
Low fiber diet hard stools diverticulosis
•
•
Inflammation of a diverticulum Fever,↑ WBC
•
LLQ pain
•
Diagnosis: CT scan
•
Treatment: •
Usually antibiotics
•
Surgery
•
Sigmoid colon
•
“Left sided appendicitis”
“Occult blood” in stool
Diverticulitis
Diverticulitis •
Chronic, recurrent increased intra-abdominal pressure
Diverticulitis
Often asymptomatic Complications •
•
•
Diverticular Disease •
Diverticulosis
•
Complications •
•
108
Abscess •
Diverticulitis that does not improve after antibiotics
•
Often requires surgery
Bowel obstruction •
May narrow intestinal lumen
•
Nausea, vomiting, abdominal distention, constipation
Diverticulitis
Adhesions
Complications •
•
Fistula •
Most commonly to bladder (“colovesical fistula”)
•
Presents with pneumaturia, fecaluria, or dysuria
•
•
•
Perforation •
•
•
Results in peritonitis Diffuse pain; rigid abdomen
Bands of scar tissue in peritoneal cavity Commonly formed after surgery Most common cause of SBO Can cause: •
Bowel obstruction Infertility in women (interfere with ovum transport)
•
Chronic abdominal/pelvic pain
•
•
Treatment: •
Intussusception •
•
Surgery (“lysis of adhesions”)
Intussusception •
“Telescoping”of intestine Intestine folds into lumen
•
Blood supply compromised GI bleeding: “Currant jelly”
•
Medicalemergency
•
Common in children (often <1 year old)
•
•
Intussusception
Rare in adults Often near the ileocecal junction
Volvulus
Lead Point •
Underlying lesions often leads to intussusception
•
Twistingof bowel around mesentery
•
Intestine trapped and dragged by peristalsis
•
Pathophysiology/causepoorly understood
•
Potential lead points
•
•
Meckel’sdiverticulum
•
Lymphoid hyperplasia (Peyer’s patches; viral gastroenteritis)
•
Strong association with entericadenovirus infection
•
In adults: tumors
109
•
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 •
•
•
•
Bowel Obstruction
Much more commonsmall intestine(75%) Abdominal pain, nausea, vomiting
•
Abdominaldistention Obstipation (inability to pass stool)
•
SBO common causes (ABCs) •
Adhesion
•
Bulge (hernia)
•
Cancer
LBO common causes Tumor •
•
X-ray: •
Dilated bowel loops
•
Air-fluid levels
•
•
Abnormalperistalsis of colon
•
Absent ganglion cells
•
Presentation
•
•
Derived from neural crest cells
•
Nerve cells of Meissner’s plexus and Auerbach’s plexus
•
Muscular layer (Auerbach’s) and submucosa (Meissner’s)
•
Fail to migrateproperly in Hirschsprung’s disease
Result: Obstruction (no peristalsis)
Hirschsprung’s Disease
Hirschsprung’s Disease Dilated bowel behind obstruction
Volvulus
Congenitaldisease Associated withDown Syndrome Motor disease of intestines
•
•
•
Adhesions
•
Hirschsprung’s Disease
Bowel Obstruction •
•
Diagnosis and Treatment •
Barium imaging •
“Transitionzone”
•
Failure to pass meconium
•
Cone-shaped
•
Abdominal distention
•
Proximal distended bowel (normal)
•
Bilious vomiting
•
Distal bowel small (abnormal)
•
Examination: no stool in rectal vault
Less severe disease (uncommon) •
Chronic constipation
110
Hirschsprung’s Disease
Ileus
Diagnosis and Treatment •
•
Rectal“suction”biopsy •
Rectum ALWAYS involved (other areas variable)
•
Standard biopsy may only show mucosa
•
Need to apply suction to biopsy submucosa
•
Absence of ganglion cells
Loss of bowel peristalsis Can cause nausea, vomiting, constipation, obstipation
•
Common causes: •
•
Treatment: Colon resection •
Meds (especially narcotics) Post-operative
Removal of colon without ganglion cells
Ogilvie Syndrome •
•
•
•
Acute “pseudo-obstruction”of intestines Dilated colon in absence of a lesion
•
Usually in hospitalized or nursing home patients
•
Often with severe illness or recent surgery
•
Often associated with narcotics
Irritable Bowel Syndrome •
Functionalboweldisorder •
•
•
•
Irritable Bowel Syndrome
Normal intestinal structure
Recurrent abdominal pain •
At least 3 days per month
•
Over last 3 months
One of the following features •
Improvement with defecation
•
Change in frequency of stool
•
Onset associated with a change in appearance of stool
Can cause diarrhea, constipation, or both
Necrotizing Enterocolitis
•
Chronic disorder
•
Neonatal disorder (usually 1st month of life)
•
Poorly understood cause
•
Intestinal necrosis and obstruction
•
More common in women Few reliably effective treatments
•
Treatment often directed at symptoms
•
•
•
111
Usually terminal ileum or colon Can lead to perforation
Necrotizing Enterocolitis •
•
Necrotizing Enterocolitis
Unclearpathogenesis
•
Classic case
•
Combination of enteral feeding + bacteria illness
•
Premature baby in NICU
•
Bacteria may overgrow immature mucosal defenses
•
Abdominal distention
•
Nausea, vomiting
Major risk factor is prematurity , low birth weight •
Classic X-ray finding: Pneumatosis intestinalis •
•
•
•
•
•
Aberrant blood vessels in GI tract Common incecum and right sided colon Caused by high wall stress •
Air in bowel wall
•
Lucent area parallel to bowel
Treatment •
Bowel rest, antibiotics
•
Often surgery
Hereditary Hemorrhagic Telangiectasia
Angiodysplasia •
•
•
Also called Osler-Weber-Rendu syndrome Autosomaldominantvasculardisease
•
Telangiectasiasthroughout GI tract
•
Rarely leads to AVMs (pulmonary, CNS)
•
Common clinical features
Intermittent obstruction of submucosal veins
•
(hematochezia) Lower GI bleeding
112
Nasopharynx to rectum
•
Nose bleeds
•
GI bleeding
•
Iron deficiency
Inflammatory Bowel Disease •
Inflammatory Bowel Disease
•
Two chronic autoimmune bowel diseases •
Crohn’s disease
•
Ulcerative colitis
Both haverelapsing, 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
•
•
Many causes other than IBD especially infection
•
Typical studies sent when considering IBD •
Stool cultures (Salmonella, Shigella, Campylobacter, Yersinia)
•
Testing for E. coli O157:H7
•
Other stool studies (C. diff, Ova and parasites)
Some studies suggest second spike in 50 to 80 year olds
•
More common amongwhites More common amongJewish populations
•
Classicpresentation
•
•
White woman in 30s
•
Jewish descent
Ulcerative Colitis
Bloody Diarrhea •
Slight female predominance in most studies Age of onset usually 15 to 40 years
Pathologic Features •
113
Ulcersform in intestinal tract •
Inflammation of mucosa and sometimes submucosa
•
Importantly NOT full thickness inflammation
Ulcerative Colitis
Ulcerative Colitis
Pathologic Features
Gross Morphology
•
•
Always starts in rectum works upward •
Always has rectal involvement
•
Left lower quadrant pain is common
•
Pseudopolyps(healing of ulcers)
Never involves small intestine •
“Colitis”
Ulcerative Colitis
Ulcerative Colitis
Gross Morphology
Microscopy
•
•
Loss of haustra (lead pipeappearance on X-ray/CT)
Crypt abscesses •
PMN infiltration of crypts
Common finding s and pseudolesions at computedtomog raphy colonog raphy. Colégio Brasileiro de Radiologia e Diagnósticopor Imagem.GiuseppeD'Ippolitoet al.Used withpermission.
Ulcerative Colitis
Toxic Megacolon
Extra-intestinal Features •
Pyoderma gangrenosum •
Deep, necrotic skin ulceration
•
Primary sclerosingcholangitis
•
Ankylosing spondylitis
•
Uveitis
•
•
•
Rare complication of UC (also infectious colitis)
•
Cessation of colonic contractions •
Inflammation of spine
Inflammation of middle layer eye
114
Evidence that nitric oxideinhibits smooth muscle tone
•
Leads to intestinal dilation rapiddistentionoccurs Wall thins prone to rupture
•
Can causeperforation
•
Ulcerative Colitis
Toxic Megacolon •
Adenocarcinoma
Presentation •
Abdominal pain
•
Distention
•
Fever
•
Diarrhea
•
Shock
•
•
Significant risk in UC Risk based on two key factors •
Duration of disease (>10 years before most cancers form)
•
Extent of disease (more disease = more risk)
•
•
Screeningcolonoscopyrecommended
•
Colectomysometimesrequired
•
•
•
•
Pathologic Features •
p-ANCA •
Antibody seen in vasculitis syndromes
•
Churg-Strauss and Microscopic Polyangiitis
•
Also seen in ulcerative colitis
•
Granulomatous inflammation Entire wall affected (“transmural ”)
•
Any portion of the GI tract can be affected
Anti-saccharomycescerevisiae antibodies (ASCA) •
Saccharomyces cerevisiae: type of yeast
•
Elevated antibody levels seen in Crohn’s
Multiple biopsies taken
Crohn’s Disease
Antibody Tests •
Involvement into right colon = more disease “Right sided colitis” or “pancolitis” are risk factors
•
•
“Mouth to anus”
•
Oral ulcers can be seen
Both tests suggested to distinguish forms of IBD Not reliable for routine clinical use
Crohn’s Disease
Crohn’s Disease
Pathologic Features
Pathologic Features
•
•
•
Terminal ileum is common location •
Malabsorption
•
Vitamin deficiencies (B12)
•
May have non-bloody diarrhea due to malabsorption
•
May have right lower quadrant pain
Often spares the rectum Often “skips”sections
•
Terminal ileum is common location
•
Malabsorption
•
•
•
115
•
Vitamin deficiencies (B12)
•
Malabsorption of bile salts
•
May have non-bloody diarrhea due to malabsorption
May haveright lower quadrant pain Often spares the rectum Often “skips”sections
Crohn’s Disease
Crohn’s Disease
Gross Morphology
Gross Morphology
•
Fistulas
•
Creeping fat
•
Peri-anal
•
Transmural inflammation heals
•
Abdominal
•
Condensed fibrous tissue pulls fat around bowel wall
•
Bladder (“enterovesical fistula”)
•
Can wrap around bowel
•
Strictures Healing leads to fibrous •
•
Dense fibrous tissue narrows lumen
•
“String sign”
Crohn’s Disease
Adenocarcinoma •
Extra-intestinal Features •
Risk only when col on involved When colon involved, surveillance colonoscopy
•
Migratory polyarthritis •
Most common extra-intestinal manifestation
•
(knees, hips) Arthritis of large joints
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
Inflammation of fat tissue under skin
Immunology
Extra-intestinal Features •
tissue
•
•
T-cells: major contributor both disorders
•
Ulcerativecolitis
•
Ankylosing spondylitis Uveitis
116
•
Th2 mediated disorder
•
No granulomas
Crohn’sdisease •
Th1 mediated disorder
•
Granulomatous disease
Smoking •
•
IBD Treatments
Improvesoutcomes in UC Worsensoutcomes in Crohn’s
•
•
•
•
Infliximab/adalimumab Sulfasalazine
•
5-ASA
Sulfasalazine
Not active until reaches colon Perfect for UC!
Side Effects •
•
•
Acetylsalicylic acid (aspirin) Sulfasalazine Colonic Bacteria
Sulfapyridine
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
•
Modified 5-ASA compounds resist absorption
•
•
Coating or delayed release capsules
•
Asacol, Pentasa
Methotrexate 6-MP
•
•
Sulfasalazine
Corticosteroids Azathioprine
5-aminosalicylic acid (5-ASA)
117
GI upset (nausea, vomiting) Sulfonamide hypersensitivity Oligospermiain men •
Mechanism unclear
•
Reversiblewith drug cessation
•
Problem for men trying to conceive on therapy
Colon Polyps •
Raised outgrowth of tissue into lumen May be pre-cancerous
•
Removal can prevent colon cancer
•
Colon Cancer Jason Ryan, MD, MPH
Adenomatous Polyp
Hyperplastic Polyp •
•
Benign Most commontype of polyp
•
Common in rectosigmoid colon
•
Normal cellular structure, no dysplasia
•
•
•
•
Dysplastic with malignant potential Several sub-classifications
Classically have a “sawtooth”or serratedpattern 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 (80%+)
•
Adenomatous epithelium forming tubules
Villous •
Less common type
•
Often sessile
•
Long projections extending from surface
•
High risk of development into colon cancer
Polyp Symptoms •
Almost always asymptomatic Screening colonoscopy done for detection
•
Large polyps may cause bleeding
•
•
•
Villous Adenomas •
•
•
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 excessivemucous 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)
•
Dysplasia grade
•
Determined by pathologist
•
“High grade dysplasia” = ↑ risk Metachronous adenoma: new lesion ~ six months after prior
•
>1 cm in diameter = ↑ risk
•
Number of polyps = ↑ risk
Peutz-Jeghers Syndrome •
Autosomal dominant disorder
•
Multiple hamartomas throughout GI tract •
Pigmented spots on lips and buccal mucosa
•
Risk of gastric, small intestinal, and colon CA
•
Usually in rectum
•
Usually pedunculated
•
Cause painless rectal bleeding
•
Juvenile polyposis syndrome
Often “auto-amputate”
•
Multiple (usually >10) polyps
•
Increased risk of cancer
•
Surveillance colonoscopy
Genetics of Colon Cancer 1. Two well-defined genetic pathways to colon cancer
“Peutz-Jeghers polyps”
•
•
•
Patient likely to develop more polyps •
Benign tumors (hamartomas) that occur in children
•
Chromosomal Instability Pathway
•
Microsatellite Instability
2. Cyclooxygenase-2 expression ↑ in colon cancer 3. DCC gene mutated in advanced colorectal cancers
Often presents in childhood w ith spots around lips
119
Chromosomal Instability Pathway
Chromosomal Instability Pathway •
•
•
“Adenoma-Carcinoma sequence” seen in colon cancer Sequence of genetic events Leads to colon cancer over many years •
•
•
•
Progression probably takes 10-40 years
“Somatic” mutations occurs withaging
More common in left sided tumors •
Descending colon, sigmoid, rectum
Step 1: APC mutation •
Adenomatous polyposis coli protein/gene
•
Tumor suppressor gene
•
Prevents accumulation of -catenin (activates oncogenes)
•
Loss of APC ↑ β-catenin oncogene activation
•
Leads to ↑ risk forpolyps
Normal Colon
At Risk Colon
APC Mutation
Chromosomal Instability Pathway •
Chromosomal Instability Pathway •
Step 2: K-RAS mutation •
Proto-oncogene
•
Aberrant cell signaling
•
Leads to adenoma polyp formation
Normal Colon
At Risk Colon
APC Mutation
Polyp
Step 3: p53 •
Loss of p53 tumor suppressor gene
•
Tumor cell growth
Normal Colon
At Risk Colon
APC Mutation
KRAS Mutation
FAP
Colon Cancer
Polyp
KRAS Mutation
P53
FAP Variants
Familial Adenomatous Polyposis •
Autosomal dominant disorder
•
All have APC gene mutation
•
Germline mutation of APC gene (chromosome 5q)
•
Polyposisplus extra-intestinalsigns/symptoms
•
•
Always (100%) progresses to colon cancer Treatment:Colonremoval (colectomy)
•
•
120
Gardner’sSyndrome 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:
•
Hypertrophy of retinal pigment
•
Congenital Hypertrophy of the Retinal Pigment Epithelium
•
•
•
•
•
•
Microsatellite Instability •
Polyposis plus brain tumors Mostly medulloblastomas and gliomas
Microsatellite Instability •
•
Usually a benign findings with no symptoms When seen with polyposis = Gardner’s syndrome
“desmoid tumors”, “fibromatosis”
Turcot Syndrome •
Flat dark spot in retina Seen on slit lamp exam
•
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?
•
What is a mismatch?
•
Short segments of DNA (usually non-coding)
•
Bases should be paired (A-T; G-C)
•
Repeated 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”)
•
•
Successive cellular divisions: same length microsatellites
•
Each person has unique, “stable” length of microsatellites
•
Different person-to-person; same for each i ndividual
•
Gene mutations can lead to accumulation of errors This can occur in microsatellites in cancer cells
•
Result is microsatellite instability
•
What is astablemicrosatellite?
121
Mismatch repair enzymes resolve base errors
•
PCR testing
•
Different length of microsatellites in tumor cells vs other cells
•
Indicates mismatch repair 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 •
About 80% lifetime risk
•
Arise with out pre-existing adenoma
Usually right-sided tumors Also increased risk of: •
Endometrial cancer (most common non-colon malignancy)
•
Other cancers (ovary, stomach, others)
Classic case •
Patient with right sided colon CA
•
Multiple 1st family members also with cancer
Cyclooxygenase-2 •
•
Increased expression in colon cancer cells More common in left sided cancers
•
Rationale for aspirintherapy •
Reduces risk of colorectal cancer 20-40%
•
BUT increases risk of bleeding/ulcers
•
DCC Gene •
•
Deleted in Colorectal Cancer (DCC) gene Tumor suppressor gene (chromosome 18q)
•
Frequently mutated in advanced colorectal cancers
No clinical trial evidence supporting routine aspirin use for prevention
Colon Cancer
Colon Cancer
•
3rd most common cancer
•
May occur anywhere in colon
•
3rd most deadly cancer
•
Different sites may have different symptoms
•
More common after 50 years of age
•
Treated with surgery +/- chemotherapy
122
Colon Cancer
Colon Cancer Screening •
•
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 exam •
•
CEA
Strep Bovis •
•
Normal colonic bacteria Gram positive cocci (gamma hemolytic)
•
•
•
•
Colonoscopy if blood detected
Carcinoembryonic Antigen •
•
Tumor marker Elevated in colon CA and other tumors (pancreas)
Lancefield group D
•
Poor sensitivity/specificity for screening
Rarecause bacteremia/endocarditis
•
Patients with established disease
Strongly associated with colon cancer Classicquestion: •
S. Bovis endocarditis identified
•
What test next?
•
Answer: Colonoscopy
123
•
CEA level correlates with disease burden
•
Elevated levels should return to baseline after surgery
•
Can be monitored to detect relapse
Carcinoid Tumors •
Carcinoid Tumors
•
Neuroendocrinetumors •
Neuroendocrine cells = nerve and endocrine features
•
Found in many organs: GI tract, lungs, pancreas
•
Small intestine (GI) most common
Carcinoid “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 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 acid
Alteredtryptophan metabolism
•
Normally ~1% tryptophan
•
Up to 70% in patients with carcinoid syndrome
•
Tryptophan deficiency reported
•
Tryptophan Niacin (B3)
•
Symptoms = Pellagra
•
serotonin
•
•
Metabolite of serotonin Appears in urinein carcinoid syndrome 24-hour urine sample for diagnosis Monoamine Oxidase (MAO)
Serotonin 5-hydroxytytamine (5-HT)
Tryptophan
124
5-hydroxyindole acetaldehyde
5-Hydroxyindoleacetic acid (5-HIAA)
Carcinoid Heart Disease •
•
•
•
Carcinoid Syndrome
Fibrous deposits tricuspid/pulmonic valves Stenosis/regurgitation
•
Serotonin inactivated by lungs Left sided lesions rare •
Octreotide •
•
Analog ofsomatostatin Used in GI bleeding and other niche roles
•
Somatostatin receptors on many carcinoid tumors
•
•
Inhibit release of bioactive amines
•
Serotonin, catecholamines, histamine
Octreotide therapy used •
Flushing and diarrhea significantly improve
125
Clinicalscenario: •
Abdominal pain
•
Flushing
•
Diarrhea
•
Pulmonic/tricuspid valve disease
Treatments •
Surgical excision
•
Hepatic resection
•
Octreotide
Antacids •
•
Gastrointestinal Pharmacology
•
•
Over the counter therapy Often used for GERD symptoms
SodiumBicarbonate Calcium carbonate Aluminum hydroxide Magnesium hydroxide
Jason Ryan, MD, MPH
Sodium Bicarbonate
Calcium Carbonate
Alka Seltzer
Tums
•
•
•
•
Bloating, belching (CO2) Alkalosis (bicarbabsorption) Fluid retention(NaCl resorption)
•
•
•
Bloating, belching (CO2) Alkalosis (bicarbabsorption) Can cause constipation (calcium: ↓ GI motor activity) Hypercalcemia(calciumchloride) •
NaHCO3 + HCl NaCl + H2O + CO2
CaCO3 + 2HCl CaCl2 + H2O + CO2
Calcium Carbonate
Aluminum Hydroxide
Tums •
•
Milk alkali syndrome •
High intake calcium carbonate (ulcers)
•
Triad: Hypercalcemia, metabolic alkalosis, renal failure
•
•
•
Acid rebound •
Mild acid surge once antacid leaves stomach
•
Probable mechanism: stimulation of acid secretion by calcium
•
Can happen with other antacids
•
Detected by stomach pH monitoring studies
•
Clinic effects questionable
Special use: Treatment of hypocalcemia
•
No bloating or alkalosis Constipation(aluminum:↓ GI motor activity) Binds phosphate in gut (aluminum-phosphate) •
Can be used in renal failure to lower phosphate levels
•
“Phosphate binder”
Can causehypophosphatemia •
Muscle weakness
Al(OH)3 + 3HCl AlCl3 + 3H2O
126
Aluminum Toxicity •
•
Usually only occurs in renal failure patients Bones/muscles
•
•
•
No bloating or alkalosis Diarrhea
•
Bone pain
•
Poorly absorbed colon osmotic diarrhea
•
Muscle weakness
•
Also used as an osmotic laxative (milk of magnesia)
•
•
Magnesium Hydroxide
•
Osteomalacia
Microcytic Anemia
•
Draws fluid into colon
•
Accumulates in bone marrow
•
Hypotension
•
“Resistant to iron” (normal iron studies; no benefit to iron)
•
Bradycardia
•
Cardiac arrest
Dementia
promotes peristalsis
symptoms Hypermagnesemia
Mg(OH)2 + 2HCl MgCl2 + 2H2O
Maalox •
•
Drug Absorption •
Magnesium and aluminum hydroxide Diarrhea-constipationeffects offset
•
Altered by all antacids •
Drug may bind antacid
•
Increased gastric pH may affect absorption
Key drugs •
Tetracycline
•
Fluoroquinolones
•
Isoniazid
•
Iron supplements
Histamine (H2) blockers
Tetracycline
Famotidine, Ranitidine, Nizatidine, Cimetidine •
Block histamine receptors in parietal cells
•
Most have few side effects
•
•
127
Can cause 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
•
Cimetidine 1st H2 blocker; rarely used in modern era
•
Potent P450 inhibitor
•
Anti-androgen: Gynecomastia, impotence, prolactin release
•
Crosses BBB: Dizziness, confusion, headaches
•
Reduces creatinine excretion (↑SCR)
Proton Pump Inhibitors •
Inhibit H+/K+ pump in parietalcells Few side effects (usually well tolerated)
•
Potential adverse effects with long term use
Proton Pump Inhibitors
Omeprazole, Pantoprazole, Lansoprazole, Esomeprazole •
•
•
•
Omeprazole, Pantoprazole, Lansoprazole, Esomeprazole
+
•
C. Difficileinfection (loss of protection from H ) Pneumonia(more pathogens in upper GI tract)
Malabsorption •
Hypomagnesemia(↓ absorption)
•
Hip fractures (↓ Ca absorption)
•
B12 deficiency
•
H+ required to cleave B12 from dietary proteins
•
Iron
•
Vitamin C
Bismuth Salicylate
Bismuth Salicylate
Pepto-Bismol/Kaopectate
Pepto-Bismol/Kaopectate
•
•
•
Coatsulcers/erosion •
Protects from acid
•
Most effective in H. Pylori ulcers
Salicylate
•
Antimicrobial against H. Pylori
•
Part of “quadruple”therapy: •
Proton pump inhibitor
•
Clarithromycin
•
Inhibits prostaglandins
•
Amoxicillin/Metronidazole
•
Reduced stool frequency in diarrheal illnesses
•
Bismuth Salicylate
In colon, bismuth reacts with hydrogen sulfide •
Forms bismuth sulfide
•
Blackens the stools
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Sucralfate •
•
Sulfated polysaccharid+aluminum e hydroxide Binds to ulcers •
Negatively charged drug molecule to positively charge proteins
•
Protects from acid
•
•
Osmotic Laxatives
•
Not absorbed so very rare
•
Potential aluminum toxicity
Magnesium hydroxide (milk of magnesia) Magnesium citrate: Magnesium plus citric acid
•
Polyethylene glycol (Miralax, GoLYTELY ) •
Synthetic polymer
•
Powder (mix with water)
•
Syntheticdisaccharide(laxative)
•
Also used in hyperammonemia
•
•
Potential side effects of most: •
•
Dehydration Electrolyte abnormalities
Osmotic Laxatives •
Lactulose
•
•
Adverseeffects
•
•
All draw water into intestines bowel movement Used in constipation, bowel prep for colonoscopy
Result: Ulcer healing
Osmotic Laxatives •
•
•
Sodiumpolystyrenesulfonate(Kayexalate ) •
“Cation Exchange Resin” (i.e. polymer)
•
Bind potassium– used in hyperkalemia
•
Sorbitol: Sugar alcohol
•
Sodiumphosphate
Other Laxatives •
Colon breakdown by bacteria to fatty acids Lowers colonic pH; favors formation of NH4+ over NH3 NH4+ not absorbed trapped in colon Result: ↓plasma ammonia concentrations
•
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Bisacodyl (Dulcolax), Senna (Senokot) •
“Stimulant laxatives”
•
Poorly understood mechanism
•
Increase GI motility
Docusate •
Stool softener
•
Makes stool soft, slippery
5-HT3 Receptor Antagonists
Laxative Abuse •
Factiousdiarrhea Bulimia
•
Clues:
•
•
•
Ondansetron
•
5-HT3 receptors
•
•
Metabolic acidosis from loss of bicarb
•
Found in vomiting center in medulla Also in vagal/spinal nerves to GI tract
Metoclopramide Reglan •
Commonly used in patients receiving chemotherapy Few side effects
•
Dopamine (D2) receptor antagonists In gastrointestinal tract
•
Headache
•
Dopamine (via D2) blocks ACH effects
•
Constipation
•
Blockade Increased esophagus and gastric motility
•
No effect on small intestine or colon
•
Used in gastroparesis
Metoclopramide
Metoclopramide •
•
•
Dehydration (signs of hypovolemia, hypotension) Hypokalemia
Ondansetron
•
Used to treat vomiting (anti-emetic) Blockserotonin (5-hydroxytryptamine)receptors
Diarrhea
5-HT3 Receptor Antagonists •
•
•
Common Adverse Effects
In central nervous system •
Dopamine (via D2) activateschemoreceptor trigger zone
•
Area postrema in medulla
•
Blockade
•
Used as anti-emetic
Decreased nausea/vomiting
Also effective inmigraines
130
•
Drowsiness
•
Movement symptoms •
“Extrapyramidal symptoms”
•
Parkinsonian movements
•
Restlessness
•
Akathisia (constant motion)
•
Dystonia (spasms)
•
Tardive dyskinesia (long term use)
Metoclopramide
Metoclopramide
Rare Adverse Effects
Contraindications
•
Nausea, diarrhea (GI effects) Lowersseizurethreshold
•
Elevatedprolactinlevels
•
•
•
Should not be used in patients with epilepsy
•
Known seizure disorders Parkinson’sdisease
•
Bowel obstruction
•
Galactorrhea, gynecomastia, impotence, menstrual disorders
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