usmle step 1 exam guide first aid liver, gallbladder, pancreas
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263
GASTROINTESTINAL-ANATOMY
GI blood supply
Artery Embryonic gut Structures supplied
region
Celiac Foregut Stomach to proximal duodenum; liver, gallbladder, pancreas
SMA Midgut Distal duodenum to proximal 2/3 of transverse colon
IMA Hindgut Distal 1/3 of transverse colon to upper portion of rectum
Celiac trunk Stomach receives main blood supply from branches of the celiac trunk.
HIGH-YI E LD SYSTEMS GASTROINTESTINAL
Hindgut
Inferior mesenteric
artery
Superior mesenteric
artery to midgut
Primordium
of liver
Celiac artery
Gastric and
duodenal regions
Heart Esophageal regions
Left gastric
artery
Hepatic artery
proper
Common
hepatic
artery
Right hepatic
artery
Left hepatic artery
Cystic artery Celiac trunk
Gastroduodenal
artery
Right gastric artery
Right gastroepiploic artery
Left
gastroepiploic
artery
Splenic artery
264
GASTROINTESTINAL-ANATOMY (continued)
Portal-systemic 1. Left gastric . azygous
anastomoses (esophageal varices)
2. Superior . inferior rectal
(external hemorrhoids)
3. Paraumbilical . inferior
epigastric (caput
medusae at navel)
4. Retroperitoneal . renal
5. Retroperitoneal .
paravertebral
Varices of gut, butt, and caput
are commonly seen with
portal hypertension.
Digestive tract anatomy
Layers of gut wall (inside to
outside):
1. Mucosa–epithelium
(absorption), lamina
propria (support),
muscularis mucosa
(mucosal motility)
2. Submucosa–including
Submucosal nerve plexus
(Meissner’s): controls
Secretions, blood flow, and
absorption
3. Muscularis externa–outer
longitudinal layer, inner
circular layer, Myenteric
nerve plexus (Auerbach’s):
controls Motility
4. Serosa/adventitia
GASTROINTESTINAL HIGH-YI E LD SYSTEMS
Superior
mesenteric v.
Gastroesophageal v.
Superiormiddle/
inferior rectal v.
Gastrorenalsplenorenal
v.
Paraumbilical v.
Systemic venous
Portal venous
Portal v.
L. gastric v.
Retroperitoneal
paravertebral
Splenic v.
IVC
1
2
3
4
5
v.
Lamina propria
Submucosa
Muscularis mucosa
Villus
Submucosal plexus
Myenteric plexus
Gland in submucosal layer
Muscularis externa
inner circular
layer
Mesentery (binding
of digestive tract to
abdominal wall)
Serosa
Muscularis externa
outer longitudinal
layer
(Adapted, with permission, from McPhee S et al. Pathophysiology of Disease: An Introduction to
Clinical Medicine, 3rd ed. New York: McGraw-Hill, 2000:296.)
265
Abdominal layers
Enteric nerve plexi
Myenteric Coordinates Motility along entire gut wall. Also known as Auerbach’s plexus. Contains
cell bodies of some parasympathetic terminal effector neurons. Located between inner
and outer layers (longitudinal and circular) of smooth muscle in GI tract wall.
Submucosal Regulates local Secretions, blood flow, and absorption. Also known as Meissner’s plexus.
Contains cell bodies of some parasympathetic terminal effector neurons. Located
between mucosa and inner layer of smooth muscle in GI tract wall.
Brunner’s glands Secrete alkaline mucus to neutralize acid contents entering the duodenum from the
stomach. Located in duodenal submucosa (the only GI submucosal glands).
Hypertrophy of Brunner’s glands seen in peptic ulcer disease.
Peyer’s patch Unencapsulated lymphoid tissue found in lamina Think of IgA, the
propria and submucosa of small intestine. Intra-gut Antibody. And
Covered by single layer of cuboidal enterocytes always say “secretory IgA.”
(no goblet cells) with specialized M cells
interspersed. M cells take up antigen. Stimulated
B cells leave Peyer’s patch and travel through
lymph and blood to lamina propria of intestine,
where they differentiate to IgA-secreting plasma
cells. IgA receives protective secretory component
and is then transported across epithelium to gut to
deal with intraluminal antigen.
HIGH-YI E LD SYSTEMS GASTROINTESTINAL
(Reproduced, with permission, from White JS. USMLE Road Map: Gross Anatomy, 1st ed. New York: McGraw-Hill,
2003:67.)
Erector spinae
Latissimus dorsi
Quadratus lumborum
Psoas
Transversalis fascia
Transversus abdominis
Internal oblique
External oblique
Superficial fascia
Skin
Extraperitoneal tissue
Peritoneum
Rectus abdominis
Rectus sheath
IVC
Aorta
Sympathetic trunk
266
GASTROINTESTINAL-ANATOMY (continued)
Sinusoids of liver Irregular “capillaries” with fenestrated endothelium (pores 100-200 nm in diameter). No
basement membrane. Allows macromolecules of plasma full access to basal surface of
hepatocytes through perisinusoidal space (space of Disse).
Biliary structures
Pectinate line Formed where hindgut meets ectoderm.
Above pectinate line–internal hemorrhoids (not Internal hemorrhoids receive
painful), adenocarcinoma. Visceral innervation. visceral innervation.
Arterial supply is from the superior rectal artery
(branch of IMA). Venous drainage is to superior
rectal vein .inferior mesenteric vein .portal
system.
Below pectinate line–external hemorrhoids External hemorrhoids receive
(painful), squamous cell carcinoma. Somatic somatic innervation and are
innervation. Arterial supply is from the inferior therefore painful.
rectal artery (branch of internal pudendal artery).
Venous drainage is to inferior rectal vein .
internal pudendal vein .internal iliac vein .
IVC.
Femoral triangle Femoral triangle contains femoral vein, femoral Lateral to medial: N-(AVEL) =
artery, and femoral nerve. Femoral sheath– Nerve-(Artery-Vein-Empty
fascial tube extending 3-4 cm below inguinal space-Lymphatics).
ligament; contains femoral artery, femoral vein, Femoral hernia is entrance of
and femoral canal (containing deep inguinal abdominal contents through
lymph nodes). Femoral nerve lies outside the femoral canal.
femoral sheath. Femoral hernia protrudes
below and lateral to the
pubic tubercle.
GASTROINTESTINAL HIGH-YI E LD SYSTEMS
Gallbladder
Cystic duct
Right hepatic duct Left hepatic duct
Common hepatic duct
Pancreatic duct
Common duct
Duodenum
External
hemorrhoid
Pectinate
line
Internal
hemorrhoids
Adductor
longus
muscle
Sartorius
muscle Femoral triangle
Inguinal
ligament
267
Inguinal canal
HIGH-YI E LD SYSTEMS GASTROINTESTINAL
(Adapted, with permission, from White JS. USMLE Road Map: Gross Anatomy, 1st ed. New York: McGraw-Hill, 2003:69.)
Parietal peritoneum
Transversalis fascia
Deep inguinal ring
Transversus
abdominis
Internal
oblique
Inguinal ligament
External inguinal ring
Internal inguinal ring:
site of protrusion
of indirect hernia
Inferior epigastric
vessels
Abdominal wall:
site of protrusion
of direct hernia
Medial umbilical ligaments
Rectus abdominis m.
Pyramidalis m.
Linea alba
Spermatic cord
External spermatic fascia
Cremasteric muscle and fascia
Internal spermatic fascia
External
oblique
268
GASTROINTESTINAL-PHYSIOLOGY
Salivary secretion
Source Parotid, submandibular, submaxillary, and Salivary secretion is stimulated
sublingual glands. by both sympathetic (T1-T3
Function 1. a-amylase (ptyalin) begins starch digestion; superior cervical ganglion)
inactivated by low pH on reaching stomach and parasympathetic (facial,
2. Bicarbonate neutralizes oral bacterial acids, glossopharyngeal nerve) activity.
maintains dental health Low flow rate . hypotonic.
3. Mucins (glycoproteins) lubricate food High flow rate . closer to
isotonic.
GI secretory products
GASTROINTESTINAL HIGH-YI E LD SYSTEMS
Product Source Action Regulation Notes
Intrinsic Parietal cells, Vitamin B12 binding Autoimmune destruction
factor stomach protein (required for of parietal cells .
B12 uptake in terminal chronic gastritis and
ileum) pernicious anemia
Gastric acid Parietal cells, . stomach pH . by histamine, ACh,
stomach gastrin; . by
somatostatin, GIP,
prostaglandin,
secretin
Pepsin Chief cells, Protein digestion; . by vagal stimulation, Inactive pepsinogen
stomach optimal function at local acid . pepsin by H+
pH 1.0-3.0
HCO3
- Mucosal cells, Neutralizes acid; prevents . by secretin
stomach and autodigestion
duodenum
269
GI hormones
Nutrient absorption
HIGH-YI E LD SYSTEMS GASTROINTESTINAL
Hormone Source Action Regulation Notes
Gastrin G cells, antrum . gastric H+ secretion, . by stomach .. in Zollingerof
stomach . growth of gastric distention, amino Ellison syndrome;
mucosa, . gastric acids, peptides, phenylalanine and
motility vagal stimulation; tryptophan are
. by H+ secretion potent stimulators
and stomach acid
pH < 1.5
Cholecysto- I cells, . pancreatic secretion, . by secretin and In cholelithiasis, pain
kinin duodenum, . gallbladder stomach pH < 1.5; worsens after fatty
jejunum contraction; . gastric . by fatty acids, food ingestion due
emptying, . growth of amino acids to . CCK
exocrine pancreas and
gallbladder
Secretin S cells, . pancreatic HCO3
- . by acid, fatty acids . HCO3
- neutralizes
duodenum secretion, . in lumen of gastric acid in
gastric acid secretion duodenum duodenum, allowing
pancreatic enzymes
to function
Somatostatin D cells, . gastric acid and . by acid; . by vagal Inhibitory hormone;
pancreatic pepsinogen secretion stimulation antigrowth hormone
islets; GI . pancreatic and small effects (digestion
mucosa intestine fluid secretion and absorption of
. gallbladder contraction substances needed
. insulin and glucagon for growth)
release
Gastric K cells, Exocrine: . gastric . by fatty acids, amino . GIP is why an oral
inhibitory duodenum H+ secretion acids, oral glucose glucose load is used
peptide and jejunum Endocrine: . insulin (only GI hormone more rapidly than the
(GIP) release stimulated by all 3 equivalent given by IV
nutrient classes)
STOMACH DUODENUM PROXIMAL TERMINAL ILEUM COLON
JEJUNUM JEJUNUM
EtOH Glucose, via Na Glucose, galactose, Water-soluble Proteins and H2O
co-transporter monosaccharides, vitamins amino acids K+
Vitamins A and D disaccharides Disaccharides Vitamin B12 NaCl
Fatty acids Vitamins A and D Fatty acids Bile salts Short-chain
Iron Fatty acids Proteins and *Acts as reserve; fatty acids
Calcium Proteins and amino acids can absorb
amino acids additional
nutrients
if required
270
GASTROINTESTINAL-PHYSIOLOGY (continued)
Regulation of gastric acid secretion
Pancreatic a-amylase–starch digestion, secreted in active form.
enzymes Lipase, phospholipase A, colipase–fat digestion.
Proteases (trypsin, chymotrypsin, elastase, carboxypeptidases)–protein digestion,
secreted as proenzymes.
Trypsinogen is converted to active enzyme trypsin by enterokinase, a duodenal brushborder
enzyme. Trypsin then activates the other proenzymes and can also activate
trypsinogen (positive feedback loop).
Pancreatic insufficiency is seen in cystic fibrosis and other conditions. Patients present
with malabsorption, steatorrhea (greasy, malodorous stool). Limit fat intake, monitor for
signs of fat-soluble vitamin (A, D, E, K) deficiency.
Carbohydrate Only monosaccharides (glucose, galactose, fructose) are absorbed.
digestion
Salivary amylase Starts digestion, hydrolyzes a-1,4 linkages to yield disaccharides (maltose, maltotriose,
and a-limit dextrans).
Pancreatic amylase Highest concentration in duodenal lumen, hydrolyzes starch to oligosaccharides and
disaccharides.
Oligosaccharide At brush border of intestine, the rate-limiting step in carbohydrate digestion, produce
hydrolases monosaccharides from oligo- and disaccharides.
GASTROINTESTINAL HIGH-YI E LD SYSTEMS
Parietal cell
Proton
pump
inhibitors
(e.g.,
omeprazole)
Lumen
H2 receptor
antagonists
Ranitidine
Cimetidine
Famotidine
Histamine
Anticholinergics
ACh
Gastrin
increased in Zollinger-
Ellison syndrome
No clinically
useful inhibitor
Gastrin receptor
ACh receptor
Prostaglandin receptor
Histamine receptor
H+/K+ATPase
K+Cl-
K+
K+
Cl-
M3
H2
H+
Misoprostol
PGI2 and PGE2
271
Liver anatomy Apical surface of hepatocytes faces bile canaliculi. Basolateral surface faces sinusoids.
HIGH-YI E LD SYSTEMS GASTROINTESTINAL
Space of Disse
(lymphatic drainage)
Branch of
hepatic artery
Branch of
portal vein
Sinusoids draining to central vein Liver cell plates
Bile canaliculus
Bile ductule
Kupffer cell
Blood flow
Bile flow
Central vein
272
GASTROINTESTINAL-PHYSIOLOGY (continued)
Bilirubin Product of heme metabolism; actively taken up by hepatocytes. Direct bilirubin–
conjugated with glucuronic acid; water soluble. Indirect bilirubin–unconjugated;
water insoluble. Jaundice (yellow skin, sclerae) results from elevated bilirubin levels.
Bile Composed of bile salts (bile acids conjugated to glycine or taurine to make them water
soluble), phospholipids, cholesterol, bilirubin, water, and ions. The only significant
mechanism for cholesterol excretion.
GASTROINTESTINAL HIGH-YI E LD SYSTEMS
Bone marrow
Red blood cells
(normal life span 120 days)
Incomplete or immature
erythroid cells
Bilirubin produced
from nonerythroid
enzymes in liver
Renal excretion of Conjugation
urobilirubin (4 mg/day)
Enterohepatic circulation
of urobilinogen
Direct bilirubin
Indirect
bilirubin
Uptake
Heme catabolism in
reticuloendothelial system
80%
20%
Excretion of conjugated
bilirubin into bile
Bacterial conversion
to urobilinogen
primarily in colon
Some excretion as
stercobilin in feces
(gives stool its dark color)
Biliverdin
Free bilirubin-albumin
complex
273
GASTROINTESTINAL-PATHOLOGY
Abdominal hernias Hernias are protrusions of peritoneum through an opening, usually sites of weakness.
Diaphragmatic hernia Abdominal structures enter the thorax; may occur MDs don’t LIe:
in infants as a result of defective development of Medial to inferior epigastric
pleuroperitoneal membrane. Most commonly artery = Direct hernia.
a hiatal hernia, in which stomach herniates Lateral to inferior epigastric
upward through the esophageal hiatus of the artery = Indirect hernia.
diaphragm.
Indirect inguinal INdirect hernia goes through the INternal (deep)
hernia inguinal ring and external (superficial) inguinal
ring and INto the scrotum. Indirect hernia
enters internal inguinal ring lateral to inferior
epigastric artery. INdirect hernias occur in
INfants owing to failure of processus vaginalis to
close. Much more common in males.
Direct inguinal Protrudes through the inguinal (Hesselbach’s) Hesselbach’s triangle:
hernia triangle. Direct hernia bulges directly through Inferior epigastric artery
abdominal wall medial to inferior epigastric Lateral border of rectus
artery. Goes through the external (superficial) abdominis
inguinal ring only. Usually in older men. Inguinal ligament
Achalasia Failure of relaxation of lower esophageal sphincter A-chalasia = absence of
due to loss of myenteric (Auerbach’s) plexus. relaxation.
Causes progressive dysphagia. Barium swallow 2° achalasia may arise from
shows dilated esophagus with an area of distal Chagas’ disease.
stenosis. Associated with an . risk of esophageal “Bird beak” on barium swallow.
carcinoma.
HIGH-YI E LD SYSTEMS GASTROINTESTINAL
Inferior
epigastric vessels
Rectus
abdominis
muscle
Direct inguinal hernia
(through Hesselbach´s
triangle)
Indirect
inguinal hernia
Inguinal
(Poupart´s)
ligament
2.
3.
1.
x
x
Esophagus
Lower
esophageal
sphincter Stomach
274
GASTROINTESTINAL-PATHOLOGY (continued)
Meckel’s Persistence of the vitelline duct or yolk stalk. May The five 2′s:
diverticulum contain ectopic acid-secreting gastric mucosa 2 inches long.
and/or pancreatic tissue. Most common congenital 2 feet from the ileocecal valve.
anomaly of the GI tract. Can cause bleeding, 2% of population.
intussusception, volvulus, or obstruction near the Commonly presents in first 2
terminal ileum. Contrast with omphalomesenteric years of life.
cyst = cystic dilatation of vitelline duct. May have 2 types of
epithelia.
Enzyme markers Serum enzyme Major diagnostic use
of GI pathology Aminotransferases (AST and ALT) Viral hepatitis (ALT > AST)
Alcoholic hepatitis (AST >
ALT)
Myocardial infarction (AST
only)
GGT (.-glutamyl transpeptidase) Various liver diseases
Alkaline phosphatase Obstructive liver disease
(hepatocellular carcinoma),
bone disease
Amylase Acute pancreatitis, mumps
Lipase Acute pancreatitis
Ceruloplasmin (.) Wilson’s disease (see Color
Image 51)
Barrett’s esophagus Glandular (columnar epithelial) metaplasia– BARRett’s = Becomes
replacement of nonkeratinized squamous epithelium Adenocarcinoma, Results
with gastric (columnar) epithelium in the distal from Reflux.
esophagus. Due to chronic acid reflux.
GASTROINTESTINAL HIGH-YI E LD SYSTEMS
Umbilicus
Meckel´s
diverticulum
Esophagus
Lower
esophageal
sphincter
Stomach
Squamocolumnar
(epithelial) junction
(SCJ)
275
Esophageal cancer Risk factors for esophageal cancer are:
Alcohol ABCDEF.
Barrett’s esophagus Usually squamous cell
Cigarettes carcinoma (Barrett’s leads to
Diverticuli (e.g., Zenker’s diverticulum) adenocarcinoma).
Esophageal web (e.g., Plummer-Vinson)/
Esophagitis (due to reflux, irritants,
infection)
Familial
Congenital pyloric Hypertrophy of the pylorus causes obstruction. Palpable “olive” mass in epigastric region
stenosis and nonbilious projectile vomiting at ˜ 2 weeks of age. Treatment is surgical incision.
Occurs in 1/600 live births, often in 1st-born males.
Malabsorption Can cause diarrhea, steatorrhea, weight loss, weakness.
syndromes
Celiac sprue Autoantibodies to gluten (gliadin) in wheat and other grains. Proximal small bowel only.
Tropical sprue Probably infectious; responds to antibiotics. Can affect entire small bowel.
Whipple’s disease Infection with Tropheryma whippelii; PAS-positive macrophages in intestinal lamina
propria, mesenteric nodes.
Disaccharidase Most common is lactase deficiency . milk intolerance.
deficiency
Pancreatic Due to CF, chronic pancreatitis. Causes malabsorption of protein, fat, vitamins A, D,
insufficiency E, K.
Gastritis
Acute gastritis Disruption of mucosal barrier . inflammation. Can
(erosive) be caused by stress, NSAIDs, alcohol, uricemia,
burns (Curling’s ulcer), and brain injury (Cushing’s
ulcer).
Chronic gastritis
(nonerosive)
Type A (fundal) Autoimmune disorder characterized by Type A = 4 A’s.
Autoantibodies to parietal cells, pernicious
Anemia, and Achlorhydria.
Type B (antral) Caused by H. pylori infection. Type B = a Bug, H. pylori.
Both carry . risk of gastric
carcinoma.
HIGH-YI E LD SYSTEMS GASTROINTESTINAL
276
GASTROINTESTINAL-PATHOLOGY (continued)
Peptic ulcer disease
Gastric ulcer Pain Greater with meals–weight loss.
H. pylori infection in 70%; chronic NSAID use also implicated.
Due to . mucosal protection against gastric acid.
Duodenal ulcer Pain Decreases with meals–weight gain.
Almost 100% have H. pylori infection.
Due to . gastric acid secretion or . mucosal protection.
Hypertrophy of Brunner’s glands.
Tend to have clean, “punched-out” margins unlike the raised/irregular margins of
carcinoma. Potential complications include bleeding, penetration, perforation, and
obstruction (not intrinsically precancerous). H. pylori infection can be treated with
“triple therapy” (metronidazole, bismuth salicylate, and either amoxicillin or
tetracycline) with or without a proton pump inhibitor. Incidence of peptic ulcer
disease is twice as great in smokers (see Image 111).
Stomach cancer Almost always adenocarcinoma. Early aggressive Virchow’s node–involvement
local spread and node/liver mets. Associated with of supraclavicular node by
dietary nitrosamines, achlorhydria, chronic mets from stomach.
gastritis. Termed linitis plastica when diffusely Krukenberg’s tumor–bilateral
infiltrative (thickened, rigid appearance). mets to ovaries. Abundant
mucus, “signet-ring” cells.
Inflammatory bowel disease
Crohn’s disease Ulcerative colitis
Possible etiology Infectious. Autoimmune.
Location May involve any portion of the GI tract, usually Colitis = colon inflammation.
the terminal ileum and colon. Skip lesions, Continuous lesions, always
rectal sparing. with rectal involvement.
Gross morphology Transmural inflammation. Cobblestone mucosa, Mucosal and submucosal
creeping fat, bowel wall thickening (“string sign” inflammation only. Friable
on barium swallow x-ray), linear ulcers, fissures, mucosal pseudopolyps with
fistulas. freely hanging mesentery.
Microscopic Noncaseating granulomas and lymphoid Crypt abscesses and ulcers,
morphology aggregates. bleeding, no granulomas.
Complications Strictures, fistulas, perianal disease, malabsorption, Severe stenosis, toxic
nutritional depletion. megacolon, colorectal
carcinoma.
Extraintestinal Migratory polyarthritis, erythema nodosum, Pyoderma gangrenosum, 1°
manifestations ankylosing spondylitis, uveitis, immunologic sclerosing cholangitis.
disorders.
For Crohn’s, think of a fat granny and an old crone skipping down a cobblestone road
away from the wreck (rectal sparing) (see Images 114, 115).
Appendicitis All age groups; most common indication for emergent abdominal surgery in children.
Initial diffuse periumbilical pain .localized pain at McBurney’s point. Nausea, fever;
may perforate .peritonitis.
Differential: diverticulitis (elderly), ectopic pregnancy (use ß-hCG to rule out).
GASTROINTESTINAL HIGH-YI E LD SYSTEMS
277
Diverticular disease
Diverticulum Blind pouch leading off the alimentary tract, lined by “True” diverticulum–all 3 gut
mucosa, muscularis, and serosa, that communicates wall layers outpouch.
with the lumen of the gut. Most diverticula “False” diverticulum or
(esophagus, stomach, duodenum, colon) are pseudodiverticulum–only
acquired and are termed “false” in that they lack or mucosa and submucosa
have an attenuated muscularis externa. Most often outpouch. Occur especially
in sigmoid colon. where vasa recta perforate
Diverticulosis The prevalence of diverticulosis (many diverticula) in muscularis externa.
patients > 60 years of age approaches 50%. Caused
by . intraluminal pressure and focal weakness in the
colonic wall. Most frequently involves the sigmoid
colon. Associated with low-fiber diets. Most often
asymptomatic or associated with vague discomfort
and/or rectal bleeding.
Diverticulitis Inflammation of diverticula classically causing LLQ
pain. May .perforation, peritonitis, abscess
formation, or bowel stenosis (see Color Image 31).
Intussusception Intussusception–”telescoping” of 1 bowel segment into distal segment; can compromise
and volvulus blood supply (see Color Image 34). Often due to intraluminal mass.
Volvulus–twisting of portion of bowel around its mesentery; can lead to obstruction and
infection. May occur at sigmoid colon, where there is redundant mesentery.
Hirschsprung’s Congenital megacolon characterized by lack of Think of a giant spring that
disease enteric nervous plexus in segment (Auerbach’s and has sprung in the colon.
Meissner’s plexuses) on intestinal biopsy. Due to Risk . with Down syndrome.
failure of neural crest cell migration. Presents as
chronic constipation early in life. Dilated portion
of the colon proximal to the aganglionic segment,
resulting in a “transition zone.”
Colorectal cancer 3rd most common cancer. Risk factors–colorectal villous adenomas, chronic
inflammatory bowel disease (especially ulcerative colitis), high-fat and low-fiber diets,
. age, familial adenomatous polyposis (FAP), hereditary nonpolyposis colorectal
cancer (HNPCC), DCC gene deletion, personal and family history of colon cancer.
Peutz-Jeghers, a benign polyposis syndrome, is not a risk factor. Screen patients > 50
years old with stool occult blood test, colonoscopy. Visualized on barium swallow
x-ray as “apple core” lesion. CEA–nonspecific tumor marker.
HIGH-YI E LD SYSTEMS GASTROINTESTINAL
Diverticulum
Colon
Dilated
megacolon
Transition
zone
Constricted
aganglionic
segment
GASTROINTESTINAL-PATHOLOGY (continued)
Cirrhosis and
portal hypertension Cirrho (Greek) = tawny yellow.
Diffuse fibrosis of liver, destroys
normal architecture.
Nodular regeneration.
Micronodular–nodules < 3 mm,
uniform size. Due to
metabolic insult (e.g., alcohol,
hemochromatosis, Wilson’s
disease).
Macronodular–nodules >
3 mm, varied size. Usually
due to significant liver injury
leading to hepatic necrosis
(e.g., postinfectious or druginduced
hepatitis). . risk of
hepatocellular carcinoma.
Portacaval shunt between
splenic vein and left renal
vein may relieve portal
hypertension (see Color
Image 29).
Alcoholic hepatitis Swollen and necrotic hepatocytes, neutrophil A Scotch and Tonic:
infiltration, Mallory bodies (intracytoplasmic AST elevated (> ALT)
eosinophilic inclusions), fatty change, and with alcoholic hepatitis.
sclerosis around central vein. SGOT (AST) to ALT > AST in viral hepatitis.
SGPT (ALT) ratio is usually > 1.5.
Budd-Chiari Occlusion of IVC or hepatic veins with centrilobular congestion and necrosis, leading to
syndrome congestive liver disease (hepatomegaly, ascites, abdominal pain, and eventual liver
failure). Associated with polycythemia vera, pregnancy, hepatocellular carcinoma.
Wilson’s disease Inadequate hepatic copper excretion and failure of Treat with penicillamine.
copper to enter circulation as ceruloplasmin. Autosomal-recessive
Leads to copper accumulation, especially in inheritance.
liver, brain, cornea, kidneys, joints. Also
known as hepatolenticular degeneration.
Wilson’s disease is characterized by: ABCD.
Asterixis
Basal ganglia degeneration (parkinsonian
symptoms)
Ceruloplasmin ., Cirrhosis, Corneal deposits
(Kayser-Fleischer rings), Copper accumulation,
Carcinoma (hepatocellular), Choreiform
movements
Dementia
GASTROINTESTINAL HIGH-YI E LD SYSTEMS
(Adapted, with permission, from Chandrasoma P, Taylor CE.
Concise Pathology, 3rd ed. Stamford, CT: Appleton & Lange,
1998:654.)
Effects of
liver cell failure
- Coma
- Scleral icterus
- Fetor hepaticus (breath
smells like a freshly
opened corpse)
- Spider nevi
- Gynecomastia
- Jaundice
- Loss of sexual hair
- Liver “flap” = asterixis
(coarse hand tremor)
- Bleeding tendency
(decreased prothrombin
and clotting factors)
- Anemia
- Ankle edema
Effects of
portal hypertension
- Esophageal varices
Hematemesis
Peptic
ulcer
- Melena
- Splenomegaly
- Caput medusae
- Ascites
- Hemorrhoids
278
279
Hemochromatosis Hemosiderosis is the deposition of hemosiderin Total body iron may reach 50 g,
(iron); hemochromatosis is the disease caused by enough to set off metal
this iron deposition. Classic triad of micronodular detectors at airports.
cirrhosis, pancreatic fibrosis, and skin Treat with repeated
pigmentation . “bronze”diabetes. Results in phlebotomy, deferoxamine.
CHF and . risk of hepatocellular carcinoma.
Disease may be 1° (autosomal recessive) or 2° to
chronic transfusion therapy. . ferritin, . iron,
. TIBC ..transferrin saturation (see Color
Image 26).
Jaundice Normally, liver cells convert unconjugated (indirect) bilirubin into conjugated (direct)
bilirubin. Direct bilirubin is water soluble and can be excreted into urine and by the
liver into bile to be converted by gut bacteria to urobilinogen (some of which is
reabsorbed). Some urobilinogen is also formed directly from heme metabolism.
Jaundice type Hyperbilirubinemia Urine bilirubin Urine urobilinogen
Hepatocellular Conjugated/unconjugated . Normal/.
Obstructive Conjugated . .
Hemolytic Unconjugated Absent (acholuria) .
Hereditary hyperbilirubinemias
Gilbert’s syndrome Mildly . UDP-glucuronyl transferase. Asymptomatic, Gilbert’s has no clinical
but unconjugated bilirubin is elevated without consequences.
overt hemolysis. Associated with stress.
Crigler-Najjar Absent UDP-glucuronyl transferase. Presents early Crigler-Najjar type I is a severe
syndrome, type I in life; patients die within a few years. disease. Type II is less
Findings: jaundice, kernicterus (bilirubin deposition severe and responds to
in brain), . unconjugated bilirubin. phenobarbital.
Treatment: plasmapheresis and phototherapy.
Dubin-Johnson Conjugated hyperbilirubinemia due to defective Rotor’s syndrome is similar but
syndrome liver excretion. Grossly black liver. Benign. even milder and does not
cause black liver.
HIGH-YI E LD SYSTEMS GASTROINTESTINAL
(Adapted, with permission, from Junqueira LC, Carneiro J, Kelley RO. Basic Histology, 9th ed. Stamford, CT: Appleton
& Lange, 1999.)
Glucuronyl transferase
3
2
1
Bilirubin
glucuronide
Dubin-Johnson and
Rotor’s syndromes
Crigler-Najjar
syndrome
and neonatal
hyperbilirubinemia
Gilbert’s syndrome
Bilirubin formed in other parts of the
mononuclear phagocyte system
Hemoglobin
Kupffer cell
Water-insoluble bilirubin
Water-soluble
bilirubin
glucuronide
280
GASTROINTESTINAL-PATHOLOGY (continued)
Primary sclerosing Both intra- and extrahepatic. Inflammation and fibrosis Charcot’s triad of cholangitis:
cholangitis of bile ducts .alternating strictures and dilation 1. Jaundice
with “beading” on ERCP. Associated with 2. Fever
ulcerative colitis. Can lead to 2° biliary cirrhosis. 3. RUQ pain
Biliary cirrhosis
Primary Intrahepatic, autoimmune disorder; severe obstructive jaundice, steatorrhea, pruritus,
hypercholesterolemia (xanthoma). . alkaline phosphatase, . serum mitochondrial
antibodies.
Secondary Due to extrahepatic biliary obstruction. . in pressure in intrahepatic ducts . injury/
fibrosis. Often complicated by ascending cholangitis (bacterial infection), bile stasis,
and “bile lakes.” . alkaline phosphatase, . conjugated bilirubin.
Hepatocellular Also called hepatoma. Most common 1° malignant Hepatocellular carcinoma, like
carcinoma tumor of the liver in adults. . incidence of renal cell carcinoma, is
hepatocellular carcinoma is associated with commonly spread by
hepatitis B and C, Wilson’s disease, hematogenous
hemochromatosis, a1-antitrypsin deficiency, dissemination.
alcoholic cirrhosis, and carcinogens (e.g., Elevated a-fetoprotein. May
aflatoxin B1). Can present with tender lead to Budd-Chiari
hepatomegaly, ascites, polycythemia, and syndrome.
hypoglycemia.
Reye’s syndrome Rare, often fatal childhood hepatoencephalopathy. Findings: fatty liver (microvesicular
fatty change), hypoglycemia, coma. Associated with viral infection (especially VZV
and influenza B) and salicylates; thus, aspirin is no longer recommended for children
(use acetaminophen, with caution).
Gallstones Form when solubilizing bile acids and lecithin are Risk factors (4 F’s):
overwhelmed by . cholesterol and/or bilirubin. 1. Female
Three types of stones: 2. Fat
1. Cholesterol stones (radiolucent with 10-20% 3. Fertile
opaque due to calcifications)–associated with 4. Forty
obesity, Crohn’s disease, cystic fibrosis,
advanced age, clofibrate, estrogens,
multiparity, rapid weight loss, and Native
American origin.
2. Mixed stones (radiolucent)–have both
cholesterol and pigment components. Most
common type.
3. Pigment stones (radiopaque)–seen in patients
with chronic RBC hemolysis, alcoholic cirrhosis,
advanced age, and biliary infection.
Diagnose with ultrasound. Treat with cholecystectomy.
GASTROINTESTINAL HIGH-YI E LD SYSTEMS
Stone
in the
common
bile duct
Pancreatic
duct
Fibrosed
gallbladder
with gallstones
Hepatic
duct
Cystic
duct
281
Acute pancreatitis Caused by activation of pancreatic enzymes . GET SMASHeD.
autodigestion. ddI can cause a fatal
Causes: Gallstones, Ethanol, Trauma, Steroids, pancreatitis!
Mumps, Autoimmune disease, Scorpion sting,
Hypercalcemia/Hyperlipidemia, Drugs (e.g.,
sulfa drugs).
Clinical presentation: epigastric abdominal pain
radiating to back; anorexia, nausea.
Labs: elevated amylase, lipase (higher specificity).
Can lead to DIC, ARDS, diffuse fat necrosis,
hypocalcemia, pseudocyst formation, hemorrhage,
and infection.
Chronic calcifying pancreatitis is strongly associated
with alcoholism (see Image 135). Chronic
obstructive pancreatitis is strongly associated
with gallstones.
Pancreatic Prognosis averages 6 months or less; very aggressive; usually already metastasized at
adenocarcinoma presentation; tumors more common in pancreatic head (obstructive jaundice).
Often presents with:
1. Abdominal pain radiating to back
2. Weight loss (due to malabsorption and anorexia)
3. Migratory thrombophlebitis (Trousseau’s syndrome)
4. Obstructive jaundice with palpable gallbladder (Courvoisier’s sign) (see Image
134)
HIGH-YI E LD SYSTEMS GASTROINTESTINAL
282
GASTROINTESTINAL-PHARMACOLOGY
GI therapy
H2 blockers Cimetidine, ranitidine, famotidine, nizatidine.
Mechanism Reversible block of histamine H2 receptors ..H+ secretion by parietal cells.
Clinical use Peptic ulcer, gastritis, mild esophageal reflux.
Toxicity Cimetidine is a potent inhibitor of P-450; it also has an antiandrogenic effect and
. renal excretion of creatinine. Other H2 blockers are relatively free of these effects.
Proton pump
inhibitors Omeprazole, lansoprazole.
Mechanism Irreversibly inhibit H+/K+ ATPase in stomach parietal cells.
Clinical use Peptic ulcer, gastritis, esophageal reflux, Zollinger-Ellison syndrome.
Bismuth, sucralfate
Mechanism Bind to ulcer base, providing physical protection, Triple therapy of H. pylori
and allow HCO3 -
secretion to reestablish pH ulcers–metronidazole,
gradient in the mucus layer. bismuth, amoxicillin (or
Clinical use . ulcer healing, traveler’s diarrhea. tetracycline).
Misoprostol
Mechanism A PGE1 analog. . production and secretion of gastric mucous barrier, . acid
production.
Clinical use Prevention of NSAID-induced peptic ulcers; maintenance of a patent ductus arteriosus.
Also used to induce labor.
Toxicity Diarrhea. Contraindicated in women of childbearing potential (abortifacient).
GASTROINTESTINAL HIGH-YI E LD SYSTEMS
(Adapted, with permission, from Katzung BG, Trevor AJ. USMLE Road Map: Pharmacology, 1st ed. New York: McGraw-Hill, 2003:159.)
Gastrincontaining
cell
Antrum
Gastrin
Food
+
M1 ST2 G (CCK-B)
M3
Somatostatin
Enteric
nervous
system
+
+
+
K+
H+
ATPase
Ulcer bed
Stomach lumen
H+
H+
H+
H+
- – -
Antacids
-
cAMP
Parietal
cell
ECL
cell
Fundus
- -
+
+
H H
H
G
(CCK-B)
-
-
Muscarinic
antagonists H2 blockers
Proton
pump
inhibitors
Antacids
H2
Sucralfate,
bismuth
Vagus
Misoprostol
283
Muscarinic antagonists Pirenzepine, propantheline.
Mechanism Block M1 receptors on ECL cells (. histamine secretion) and M3 receptors on
parietal cells (. H+ secretion).
Clinical use Peptic ulcer.
Toxicity Bradycardia, dry mouth, difficulty focusing eyes.
Infliximab
Mechanism A monoclonal antibody to TNF-a, proinflammatory cytokine.
Clinical use Crohn’s disease, rheumatoid arthritis.
Toxicity Respiratory infection, fever, hypotension.
Sulfasalazine
Mechanism A combination of sulfapyridine (antibacterial) and mesalamine (anti-inflammatory).
Activated by colonic bacteria.
Clinical use Ulcerative colitis, Crohn’s disease.
Toxicity Malaise, nausea, sulfonamide toxicity, reversible oligospermia.
Ondansetron
Mechanism 5-HT3 antagonist. Powerful central-acting antiemetic. You will not vomit with
Clinical use Control vomiting postoperatively and in patients ONDANSetron, so you can
undergoing cancer chemotherapy. go ON DANCing.
Toxicity Headache, constipation.
Antacid overuse Can affect absorption, bioavailability, or urinary
excretion of other drugs by altering gastric and
urinary pH or by delaying gastric emptying.
Overuse can also cause the following problems:
1. Aluminum hydroxide–constipation and Aluminimum amount of
hypophosphatemia feces.
2. Magnesium hydroxide–diarrhea Mg = Must go to the bathroom.
3. Calcium carbonate–hypercalcemia,
rebound acid .
All can cause hypokalemia.
HIGH-YI E LD SYSTEMS GASTROINTESTINAL
284 GASTROINTESTINAL HIGH-YI E LD SYSTEMS
NOTES
High-Yield Clinical
Vignettes
Anatomy
Physiology
Pathology
Pharmacology
H I G H -Y I E L D S Y S T E M S
Hematology
and Oncology
285
“The best blood will at some time get into a fool or mosquito.”
–Austin O’Malley
“A day without blood is like a day without sunshine.”
–Joker in Full Metal Jacket
286
HEMATOLOGY AND ONCOLOGY-HIGH-YIELD CLINICAL VIGNETTES
Child has been anemic since Splenectomy would Spherocytosis.
birth. result in . hematocrit
in what disease?
Patient presents with fatigue, and What is the danger of Masks signs of neural damage
blood tests show a macrocytic, giving folate alone? with vitamin B12 deficiency.
megaloblastic anemia.
Patient presents with anemia, What is the diagnosis, Multiple myeloma (plasma cell
hypercalcemia, and bone pain and what may be found neoplasm); Bence Jones protein
on palpation; bone marrow on urinalysis? (Ig light chains).
biopsy shows a slide packed
with cells that have a large,
round, off-center nucleus.
AIDS patient has just been What neoplasms are B-cell lymphoma, Kaposi’s
diagnosed with cancer. associated with AIDS? sarcoma.
Patient with a new cancer What chemotherapeutic Doxorubicin (cardiotoxic).
diagnosis and known history agent should be avoided
of CHF is being evaluated in this patient?
for chemotherapy.
Chromosome analysis reveals What is the latest targeted Imatinib (Gleevec) is used to
the presence of the Philadelphia therapy for this disease, treat CML; monoclonal antibody
chromosome, t(9;22). and how does it work? against the bcr-abl tyrosine kinase.
HEMATOLOGY AND ONCOLOGY HIGH-YI E LD SYSTEMS
287
HEMATOLOGY AND ONCOLOGY-ANATOMY
Blood cell differentiation
Erythrocyte Anucleate, biconcave .large surface area: volume Eryth = red; cyte = cell.
ratio .easy gas exchange (O2 and CO2). Source Erythrocytosis = polycythemia =
of energy–glucose (90% anaerobically degraded to . number of red cells.
lactate, 10% by HMP shunt). Survival time–120 Anisocytosis = varying sizes.
days. Membrane contains the chloride-bicarbonate Poikilocytosis = varying shapes.
antiport important in the “physiologic chloride shift,” Reticulocyte = immature
which allows the RBC to transport CO2 from the erythrocyte.
periphery to the lungs for elimination.
Leukocyte Types: granulocytes (basophils, eosinophils, Leuk = white; cyte = cell.
neutrophils) and mononuclear cells (lymphocytes,
monocytes). Responsible for defense against
infections. Normally 4000-10,000 per microliter.
Basophil Mediates allergic reaction. < 1% of all leukocytes. Basophilic–staining readily
Bilobate nucleus. Densely basophilic granules with basic stains.
containing heparin (anticoagulant), histamine
(vasodilator) and other vasoactive amines, and
leukotrienes (LTD-4). Found in the blood.
Mast cell Mediates allergic reaction. Degranulation– Involved in type I
histamine, heparin, and eosinophil chemotactic hypersensitivity reactions.
release of factors. Can bind IgE to membrane. Cromolyn sodium prevents
Mast cells resemble basophils structurally and mast cell degranulation
functionally but are not the same cell type. (used to treat asthma).
Found in tissue.
HIGH-YI E LD SYSTEMS HEMATOLOGY AND ONCOLOGY
Pluripotent hematopoietic stem cell
Proerythroblast Lymphoblast Myeloblast Monoblast Megakaryoblast
Neutrophil Eosinophil Basophil
Reticulocyte B cell T cell Megakaryocyte
Erythrocyte
Plasma
cell
Active
T cell
Myelocyte Monocyte Platelets
Metamyelocyte
Stab cell
Neutrophil Eosinophil Basophil
Promyelocyte
288
HEMATOLOGY AND ONCOLOGY-ANATOMY (continued)
Eosinophil 1-6% of all leukocytes. Bilobate nucleus. Packed Eosin = a dye; philic = loving.
with large eosinophilic granules of uniform Causes of eosinophilia =
size. Defends against helminthic and protozoan NAACP:
infections (major basic protein). Highly Neoplastic
phagocytic for antigen-antibody complexes. Asthma
Produces histaminase and arylsulfatase. Allergic processes
Collagen vascular
diseases
Parasites
Neutrophil Acute inflammatory response cell. 40-75% WBCs. Hypersegmented polys are
Phagocytic. Multilobed nucleus. Large, spherical, seen in vitamin B12/
azurophilic 1° granules (called lysosomes) contain f olate deficiency.
hydrolytic enzymes, lysozyme, myeloperoxidase,
and lactoferrin.
Monocyte 2-10% of leukocytes. Large. Kidney-shaped nucleus. Mono = one, single; cyte = cell.
Extensive “frosted glass” cytoplasm. Differentiates
into macrophages in tissues.
Lymphocyte Small. Round, densely staining nucleus. Small amount of pale cytoplasm. B lymphocytes
produce antibodies. T lymphocytes manifest the cellular immune response as well as
regulate B lymphocytes and macrophages.
B lymphocyte Part of humoral immune response. Arises from stem B = Bone marrow.
cells in bone marrow. Matures in marrow.
Migrates to peripheral lymphoid tissue (follicles
of lymph nodes, white pulp of spleen,
unencapsulated lymphoid tissue). When antigen
is encountered, B cells differentiate into plasma
cells and produce antibodies. Has memory.
Can function as antigen-presenting cell (APC)
via MHC II.
Plasma cell Off-center nucleus, clock-face chromatin Multiple myeloma is a plasma
distribution, abundant RER and well-developed cell neoplasm.
Golgi apparatus. B cells differentiate into plasma
cells, which can produce large amounts of
antibody specific to a particular antigen.
HEMATOLOGY AND ONCOLOGY HIGH-YI E LD SYSTEMS
CD19
CD20
B
289
T lymphocyte Mediates cellular immune response. Originates from T is for Thymus. CD is for
stem cells in the bone marrow, but matures in the Cluster of Differentiation.
thymus. T cells differentiate into cytotoxic T cells MHC × CD = 8 (e.g., MHC 2 ×
(MHC I, CD8), helper T cells (MHC II, CD4), CD4 = 8, and MHC 1 ×
and suppressor T cells. CD8 = 8).
Macrophage Phagocytizes bacteria, cell debris, and senescent red Macro = large; phage = eater.
cells and scavenges damaged cells and tissues.
Long life in tissues. Macrophages differentiate
from circulating blood monocytes. Activated by
.-interferon. Can function as APC via MHC II.
Dendritic cells Professional APCs. Express MHC II and Fc receptor (FcR) on surface. Main inducers of
1° antibody response. Called Langerhans cells on skin.
HIGH-YI E LD SYSTEMS HEMATOLOGY AND ONCOLOGY
CD3
CD4
CD3
Th Tc CD8
HEMATOLOGY AND ONCOLOGY-PHYSIOLOGY
Blood composition Normal adult blood composition. Note that serum = plasma – clotting factors (e.g., fibrinogen).
Coagulation cascade
Coagulation factor Protein C and protein S–inactivate Va and VIIIa; vitamin K-dependent.
inhibitors and Antithrombin III–inactivates thrombin, IXa, Xa, and XIa; activated by heparin.
fibrinolysis tPA–generates plasmin, which cleaves fibrin.
290 HEMATOLOGY AND ONCOLOGY HIGH-YI E LD SYSTEMS
XI XIa
IX IXa
XII
Intrinsic pathway (PTT)
XIIa
XIIIa
Fibrinogen (I) Fibrin (Ia)
Prothrombin (II) Thrombin (IIa)
Va
X Xa
Cross-linked
fibrin clot
Tissue factor
VII
Extrinsic pathway (PT)
VIIa + tissue factor
VIIIa
- Step requires Ca2+ and platelet phospholipid
Total
body
weight
92% body fluids
and tissues
8% blood
55% albumin
38% globulins
7% fibrinogen
PMNs 40-70%
Lymphocytes 20-40%
Monocytes 2-10%
Eosinophils 1-6%
Basophils < 1%
91.5% H2O
7% proteins
Salts, lipids,
enzymes, vitamins
Erythrocytes
Leukocytes
Platelets
55% plasma
45% formed
elements
(hematocrit)
291
Convergence of coagulation, complement, and kinin pathways
HIGH-YI E LD SYSTEMS HEMATOLOGY AND ONCOLOGY
Plasminogen
Plasmin
Prekallikrein
Kallikrein
Bradykinin
Fibrinolytic
system
Clotting
cascade
Collagen, basement
membrane,
activated platelets
Complement
cascade
Kinin cascade
Factor XIIa
HMWK
C3
C3a
Fibrinogen Fibrin
Prothrombin Thrombin
Factor XI Factor XIa
Fibrin split products
vasodilation
permeability
pain
Factor XII
292
HEMATOLOGY AND ONCOLOGY-PATHOLOGY
Neoplastic progression
-plasia definitions Hyperplasia– . in number of cells (reversible).
Metaplasia–1 adult cell type is replaced by another (reversible). Often 2° to
irritation and/or environmental exposure (e.g., squamous metaplasia in trachea and
bronchi of smokers).
Dysplasia–abnormal growth with loss of cellular orientation, shape, and size in
comparison to normal tissue maturation; commonly preneoplastic (reversible).
Anaplasia–abnormal cells lacking differentiation; like primitive cells of same tissue, often
equated with undifferentiated malignant neoplasms. Tumor giant cells may be formed.
Neoplasia–a clonal proliferation of cells that is uncontrolled and excessive.
HEMATOLOGY AND ONCOLOGY HIGH-YI E LD SYSTEMS
(Adapted, with permission, from McPhee S et al. Pathophysiology of Disease: An Introduction to Clinical Medicine, 3rd ed. New York:
McGraw-Hill, 2000:84.)
Epithelial
cell layer
Basement
Normal membrane
Hyperplasia
Carcinoma in situ/
preinvasive
Invasive carcinoma
Blood or
lymphatic
vessel
Metastatic
focus
- Normal cells with basal . apical differentiation
- Cells have increased in number–hyperplasia
- Abnormal proliferation of cells with loss of size, shape, and
orientation–dysplasia
- In situ carcinoma
- Neoplastic cells have not invaded basement membrane
- High nuclear/cytoplasmic ratio and clumped chromatin
- Neoplastic cells encompass entire thickness
- Cells have invaded basement membrane using collagenases and
hydrolases
- Can metastasize if they reach a blood or lymphatic vessel
Metastasis–spread to distant organ
- Must survive immune attack
- “Seed and soil” theory of metastasis
- Seed = tumor embolus
- Soil = target organ–liver, lungs, bone, brain…
293
Tumor grade vs. stage
Grade Degree of cellular differentiation based on Stage usually has more prognostic
histologic appearance of tumor. Usually graded value than grade.
I-IV based on degree of differentiation and Stage = Spread.
number of mitoses per high-power field; character TNM staging system:
of tumor itself. T = size of Tumor
Stage Degree of localization/spread based on site and N = Node involvement
size of 1° lesion, spread to regional lymph M = Metastases
nodes, presence of metastases; spread of
tumor in a specific patient.
Tumor nomenclature
Cell type Benign Malignanta
Epithelium Adenoma, papilloma Adenocarcinoma, papillary carcinoma
Mesenchyme
Blood cells Leukemia, lymphoma
Blood vessels Hemangioma Angiosarcoma
Smooth muscle Leiomyoma Leiomyosarcoma
Skeletal muscle Rhabdomyoma Rhabdomyosarcoma
Bone Osteoma Osteosarcoma
Fat Lipoma Liposarcoma
> 1 cell type Mature teratoma Immature teratoma
aThe term carcinoma implies epithelial origin, whereas sarcoma denotes mesenchymal origin. Both terms imply malignancy.
HIGH-YI E LD SYSTEMS HEMATOLOGY AND ONCOLOGY
294
HEMATOLOGY AND ONCOLOGY-PATHOLOGY (continued)
Diseases Condition Neoplasm
associated with 1. Down syndrome 1. ALL (we ALL fall Down),
neoplasms AML
2. Xeroderma pigmentosum, albinism 2. Melanoma and basal,
squamous cell carcinomas
of skin
3. Chronic atrophic gastritis, pernicious anemia, 3. Gastric adenocarcinoma
postsurgical gastric remnants
4. Tuberous sclerosis (facial angiofibroma, seizures, 4. Astrocytoma and cardiac
mental retardation) rhabdomyoma
5. Actinic keratosis 5. Squamous cell carcinoma
of skin
6. Barrett’s esophagus (chronic GI reflux) 6. Esophageal
adenocarcinoma
7. Plummer-Vinson syndrome (atrophic glossitis, 7. Squamous cell carcinoma
esophageal webs, anemia; all due to iron of esophagus
deficiency)
8. Cirrhosis (alcoholic, hepatitis B or C) 8. Hepatocellular carcinoma
9. Ulcerative colitis 9. Colonic adenocarcinoma
10. Paget’s disease of bone 10. 2° osteosarcoma and
fibrosarcoma
11. Immunodeficiency states 11. Malignant lymphomas
12. AIDS 12. Aggressive malignant
lymphomas (non-Hodgkin’s)
and Kaposi’s sarcoma
13. Autoimmune diseases (e.g., Hashimoto’s 13. Benign and malignant
thyroiditis, myasthenia gravis) thymomas
14. Acanthosis nigricans (hyperpigmentation and 14. Visceral malignancy
epidermal thickening) (stomach, lung, breast,
uterus)
15. Dysplastic nevus 15. Malignant melanoma
Oncogenes Gain of function . cancer.
Gene Associated tumor
abl CML
c-myc Burkitt’s lymphoma
bcl-2 Follicular and undifferentiated lymphomas (inhibits apoptosis)
erb-B2 Breast, ovarian, and gastric carcinomas
ras Colon carcinoma
L-myc Lung tumor
N-myc Neuroblastoma
ret Multiple endocrine neoplasia (MEN) types II and III
HEMATOLOGY AND ONCOLOGY HIGH-YI E LD SYSTEMS
295
Tumor suppressor Loss of function . cancer; both alleles must be lost for expression of disease.
genes
Gene Chromosome Associated tumor
Rb 13q Retinoblastoma, osteosarcoma
BRCA1 and 2 17q, 13q Breast and ovarian cancer
p53 17p Most human cancers, Li-Fraumeni syndrome
p16 9p Melanoma
APC 5q Colorectal cancer
WT1 11q Wilms’ tumor
NF1 17q Neurofibromatosis type 1
NF2 22q Neurofibromatosis type 2
DPC 18q Pancreatic cancer
DCC 18q Colon cancer
Tumor markers
PSA (prostatic Prostate-specific antigen. Prostatic carcinoma. Tumor markers should not be
acid phosphatase) Used for screening. used as the 1° tool for
CEA Carcinoembryonic antigen. Very nonspecific but cancer diagnosis. They may
produced by 70% of colorectal and pancreatic be used to confirm diagnosis,
cancers; also produced by gastric and breast to monitor for tumor
carcinomas. recurrence, and to monitor
a-fetoprotein Normally made by fetus. Hepatocellular carcinomas. response to therapy.
Nonseminomatous germ cell tumors of the testis
(e.g., yolk sac tumor).
ß-hCG Hydatidiform moles, Choriocarcinomas, and
Gestational trophoblastic tumors.
CA-125 Ovarian, malignant epithelial tumors.
S-100 Melanoma, neural tumors, astrocytomas.
Alkaline phosphatase Metastases to bone, obstructive biliary disease, Paget’s
disease of bone.
Bombesin Neuroblastoma, lung and gastric cancer.
TRAP Tartrate-resistant acid phosphatase. Hairy cell
leukemia–a B-cell neoplasm.
Psammoma bodies Laminated, concentric, calcific spherules seen in: PSaMMoma:
1. Papillary adenocarcinoma of thyroid Papillary (thyroid)
2. Serous papillary cystadenocarcinoma of ovary Serous (ovary)
3. Meningioma Meningioma
4. Malignant mesothelioma Mesothelioma
Oncogenic viruses Virus Associated cancer
HTLV-1 Adult T-cell leukemia
HBV, HCV Hepatocellular carcinoma
EBV Burkitt’s lymphoma, nasopharyngeal carcinoma
HPV Cervical carcinoma (16, 18), penile/anal
carcinoma
HHV-8 (Kaposi’s Kaposi’s sarcoma, body cavity fluid B-cell
sarcoma-associated lymphoma
herpesvirus)
HIGH-YI E LD SYSTEMS HEMATOLOGY AND ONCOLOGY
296
HEMATOLOGY AND ONCOLOGY-PATHOLOGY (continued)
Chemical Toxin Affected organ
carcinogens Aflatoxins Liver (hepatocellular carcinoma)
Vinyl chloride Liver (angiosarcoma)
CCl4 Liver (centrilobular necrosis, fatty change)
Nitrosamines Esophagus, stomach
Cigarette smoke Larynx, lung
Asbestos Lung (mesothelioma and bronchogenic carcinoma)
Arsenic Skin (squamous cell carcinoma)
Naphthalene (aniline) dyes Bladder (transitional cell carcinoma)
Alkylating agents Blood (leukemia)
Paraneoplastic effects of tumors
Neoplasm Causes Effect
Small cell lung carcinoma ACTH or ACTH-like peptide Cushing’s syndrome
Small cell lung carcinoma and ADH SIADH
intracranial neoplasms
Squamous cell lung carcinoma, PTH-related peptide, TGF-ß, TNF-a, IL-1 Hypercalcemia
renal cell carcinoma, breast
carcinoma, multiple
myeloma, and bone
metastasis (lysed bone)
Renal cell carcinoma, Erythropoietin Polycythemia
hemangioblastoma
Thymoma, small cell lung Antibodies against presynaptic Ca2+ Lambert-Eaton syndrome
carcinoma channels at neuromuscular junction (muscle weakness)
Leukemias and lymphomas Hyperuricemia due to excess nucleic acid Gout, urate nephropathy
turnover (i.e., cytotoxic therapy)
Metastasis to brain 1° tumors that metastasize to brain–Lung, Lots of Bad Stuff Kills Glia.
Breast, Skin (melanoma), Kidney (renal cell Typically multiple wellcarcinoma),
GI. Overall, approximately 50% circumscribed tumors at
of brain tumors are from metastases. gray-white border.
Metastasis to liver The liver and lung are the most common sites of Metastases >> 1° liver tumors.
metastasis after the regional lymph nodes. 1° Cancer Sometimes Penetrates
tumors that metastasize to the liver–Colon > Benign Liver.
Stomach > Pancreas > Breast > Lung.
Metastasis to bone These 1° tumors metastasize to bone–Prostate, P. T. Barnum Loves Kids.
Thyroid, Testes, Breast, Lung, Kidney. Lung = Lytic.
Metastases from breast and prostate are most Prostate = blastic.
common. Breast = Both lytic and blastic.
Metastatic bone tumors are far more common than
1° bone tumors.
HEMATOLOGY AND ONCOLOGY HIGH-YI E LD SYSTEMS
297
Cancer epidemiology
Male Female Deaths from lung cancer have
Incidence Prostate (32%) Breast (32%) plateaued in males but
Lung (16%) Lung (13%) continue to . in females.
Colon and rectum (12%) Colon and rectum (13%) Cancer is the 2nd leading
Mortality Lung (33%) Lung (23%) cause of death in the United
Prostate (13%) Breast (18%) States (heart disease is 1st).
RBC forms
Biconcave Normal.
Spherocytes Hereditary spherocytosis, autoimmune hemolysis.
Elliptocyte Hereditary elliptocytosis.
Macro-ovalocyte Megaloblastic anemia (also hypersegmented PMNs),
marrow failure.
Helmet cell, DIC, traumatic hemolysis.
schistocyte
Sickle cell Sickle cell anemia.
Teardrop cell Myeloid metaplasia with myelofibrosis.
Acanthocyte Spiny appearance in abetalipoproteinemia.
Target cell HbC disease, Asplenia, Liver disease, Thalassemia. HALT.
Poikilocytes Nonuniform shapes in TTP/HUS, microvascular
damage, DIC.
Burr cell TTP/HUS.
HIGH-YI E LD SYSTEMS HEMATOLOGY AND ONCOLOGY
298
HEMATOLOGY AND ONCOLOGY-PATHOLOGY (continued)
Anemia
Type Etiology Comments
Microcytic, Iron deficiency– . serum iron, . TIBC, . ferritin Vitamin B12 and folate
hypochromic (see Color Image 20) deficiencies are
(MCV < 80) Thalassemias–target cells (see Color Image 18) associated with
Lead poisoning, sideroblastic anemias hypersegmented PMNs.
Macrocytic Megaloblastic–vitamin B12/folate deficiency Unlike folate deficiency,
(MCV > 100) Drugs that block DNA synthesis (e.g., sulfa drugs, vitamin B12 deficiency
AZT) (e.g., pernicious anemia) is
Marked reticulocytosis (bigger than mature RBCs) associated with neurologic
Normocytic, Acute hemorrhage problems.
normochromic Enzyme defects (e.g., G6PD deficiency, PK deficiency) . serum haptoglobin and
RBC membrane defects (e.g., hereditary spherocytosis) . serum LDH indicate
Bone marrow disorders (e.g., aplastic anemia, leukemia) RBC hemolysis. Direct
Hemoglobinopathies (e.g., sickle cell disease) Coombs’ test is used to
Autoimmune hemolytic anemia distinguish between
Anemia of chronic disease (ACD)– . TIBC, . ferritin, immune- vs. non-immune-
. storage iron in marrow macrophages mediated RBC hemolysis.
HEMATOLOGY AND ONCOLOGY HIGH-YI E LD SYSTEMS
0
100
200
300
400
500
20-50% sat.
< 20% sat.
> 60% sat.
20-50% sat.
Iron
(µg/dL)
Normal Iron
deficiency
ACD Iron overload
Serum
Fe
TIBC
=
=
2+
0
100
200
300
Ferritin
(ng/mL)
Normal Iron
deficiency
ACD Iron overload
299
Aplastic anemia Pancytopenia characterized by severe anemia, neutropenia, and thrombocytopenia caused
by failure or destruction of multipotent myeloid stem cells, with inadequate production
or release of differentiated cell lines.
Causes Radiation, benzene, chloramphenicol, alkylating agents, antimetabolites, viral agents
(parvovirus B19, EBV, HIV), Fanconi’s anemia, idiopathic (immune-mediated,
1° stem-cell defect). May follow acute hepatitis.
Symptoms Fatigue, malaise, pallor, purpura, mucosal bleeding, petechiae, infection.
Pathologic features Pancytopenia with normal cell morphology; hypocellular bone marrow with fatty
infiltration. Diagnose with bone marrow biopsy.
Treatment Withdrawal of offending agent, allogenic bone marrow transplantation, RBC and platelet
transfusion, G-CSF or GM-CSF.
Blood dyscrasias
Sickle cell anemia HbS mutation is a single amino acid replacement in 8% of African-Americans
ß chain (substitution of normal glutamic acid with carry the HbS trait; 0.2%
valine). Low O2 or dehydration precipitates have the disease.
sickling. Heterozygotes (sickle cell trait) are relatively Sickled cells are crescentmalaria
resistant (balanced polymorphism). shaped RBCs.
Complications in homozygotes (sickle cell disease) “Crew cut” on skull x-ray due to
include aplastic crisis (due to parvovirus B19 marrow expansion from
infection), autosplenectomy, . risk of encapsulated . erythropoiesis (also in
organism infection, Salmonella osteomyelitis, thalassemias).
painful crisis (vaso-occlusive), and splenic
sequestration crisis (see Color Image 21). New
therapies for sickle cell anemia include hydroxyurea
(. HbF) and bone marrow transplantation.
HbC defect is a different ß-chain mutation; patients
with HbC or HbSC (1 of each mutant gene) have
milder disease than do HbSS patients.
a-thalassemia There are 4 a-globin genes. In a-thalassemia, the a-thalassemia is prevalent in
a-globin chain is underproduced (as a function of Asia and Africa. ß-thalassemia
number of bad genes, 1-4). There is no is prevalent in Mediterranean
compensatory . of any other chains. HbH (ß4- populations.
tetramers, lacks 3 a-globin genes). Hb Barts
(.4-tetramers, lacks all 4 a-globin genes) results
in hydrops fetalis and intrauterine fetal death.
ß-thalassemia In ß-thalassemia minor (heterozygote), the ß chain is ß-thalassemia major results in
underproduced; in ß-thalassemia major severe anemia requiring
(homozygote), the ß chain is absent. In both cases, blood transfusions. Cardiac
fetal hemoglobin production is compensatorily failure due to 2°
. but is inadequate. HbS/ß-thalassemia hemochromatosis. Marrow
heterozygote has mild to moderate disease (see expansion . skeletal
Color Image 19). deformities.
HIGH-YI E LD SYSTEMS HEMATOLOGY AND ONCOLOGY
300
HEMATOLOGY AND ONCOLOGY-PATHOLOGY (continued)
Hemolytic anemias . serum bilirubin (jaundice, pigment gallstones), . reticulocytes (marrow compensating
for anemia).
Autoimmune anemia Mostly extravascular hemolysis (accelerated RBC Autoimmune hemolytic anemias
destruction in liver Kupffer cells and spleen). are Coombs positive.
Warm agglutinin (IgG)–chronic anemia seen in Direct Coombs’ test: anti-Ig Ab
SLE, in CLL, or with certain drugs (e.g., added to patient’s RBCs
a-methyldopa). agglutinate if RBCs are
Cold agglutinin (IgM)–acute anemia triggered by coated with Ig.
cold; seen during recovery from Mycoplasma Indirect Coombs’ test: normal
pneumoniae or infectious mononucleosis. RBCs added to patient’s
Erythroblastosis fetalis–seen in newborn due to Rh serum agglutinate if serum
or other blood antigen incompatibility . mother’s has anti-RBC surface Ig.
antibodies attack fetal RBCs. Warm weather is GGGreat.
Cold ice cream . . . MMM.
Hereditary Intrinsic, extravascular hemolysis due to spectrin or Coombs negative. Osmotic
spherocytosis ankyrin defect. RBCs are small and round with no fragility test used to confirm.
central pallor . less membrane .. MCHC,
. RDW.
Paroxysmal nocturnal Intravascular hemolysis due to membrane defect . .urine hemosiderin.
hemoglobinuria . sensitivity of RBCs to the lytic activity of
complement.
Microangiopathic Intravascular hemolysis seen in DIC, TTP/HUS, Schistocytes (helmet cells) seen
anemia SLE, or malignant hypertension. on blood smear.
DIC Activation of coagulation cascade leading to microthrombi and global consumption of
platelets, fibrin, and coagulation factors.
Causes Obstetric complications (most common cause), gram-negative sepsis, transfusion, trauma,
malignancy, acute pancreatitis, nephrotic syndrome.
Lab findings . PT, . PTT, . fibrin split products (D-dimers), . platelet count. Helmet-shaped cells
and schistocytes on blood smear.
Bleeding disorders
Platelet Causes include: Microhemorrhage: mucous
abnormalities 1. ITP (antiplatelet antibodies, . megakaryocytes) membrane bleeding,
2. TTP (schistocytes, . LDH, neurologic epistaxis, petechiae, purpura,
symptoms) . bleeding time.
3. DIC (schistocytes, . fibrin split products)
4. Aplastic anemia
5. Drugs (e.g., immunosuppressive agents)
Coagulation factor Coagulopathies include: Macrohemorrhage:
defects 1. Hemophilia A (factor VIII deficiency) hemarthroses (bleeding into
2. Hemophilia B (factor IX deficiency) joints), easy bruising, . PT
3. von Willebrand’s disease (mild; most common and/or PTT.
bleeding disorder; deficiency of von Willebrand
factor . defect of platelet adhesion and .
factor VIII survival)
HEMATOLOGY AND ONCOLOGY HIGH-YI E LD SYSTEMS
301
Hemorrhagic disorders
Platelet Bleeding
Disorder countb time PTc PTTd
Qualitative platelet defectsa — . — –
Thrombocytopenia . . — –
Hemophilia A or B — – — .
von Willebrand’s disease — . — .
DIC . . . .
aBernard-Soulier disease = defect of platelet adhesion (. GP Ib); Glanzmann’s
thrombasthenia = defect of platelet aGgregation (. GP IIb-IIIa).
bNote: platelet count must reach a very low value (15,000-20,000/mm3) before
generalized bleeding occurs; thrombocytopenia = < 100,000/mm3.
cPT (extrinsic)–factors II, V, VII, and X.
dPTT (intrinsic)–all factors except VII.
Lymphomas
Hodgkin’s Non-Hodgkin’s
Presence of Reed-Sternberg cells (RS cells are CD30+ Associated with HIV and immunosuppression
and CD15+ B-cell origin) (see Color Image 25) Multiple, peripheral nodes; extranodal involvement
Localized, single group of nodes; extranodal rare; common; noncontiguous spread
contiguous spread Majority involve B cells (except those of
Constitutional (“B”) signs/symptoms-low-grade fever, lymphoblastic T-cell origin)
night sweats, weight loss No hypergammaglobulinemia
Mediastinal lymphadenopathy Fewer constitutional signs/symptoms
50% of cases associated with EBV; bimodal distribution Peak incidence 20-40 years old
-young and old; more common in men except for
nodular sclerosing type
Good prognosis = . lymphocytes, . RS
Hodgkin’s lymphoma
Type RS Lymphos Prognosis Comments
Nodular sclerosing (65-75%) + +++ Excellent Most common; collagen banding;
lacunar cells; women > men;
primarily young adults.
Mixed cellularity (25%) ++++ +++ Intermediate Numerous RS cells.
Lymphocyte predominant (6%) + ++++ Excellent < 35-year-old males.
Lymphocyte depleted (rare) * + Poor Older males with disseminated
disease.
*RS high relative to lymphocytes
HIGH-YI E LD SYSTEMS HEMATOLOGY AND ONCOLOGY
HEMATOLOGY AND ONCOLOGY-PATHOLOGY (continued)
Reed-Sternberg Distinctive tumor giant cell seen in Hodgkin’s disease; binucleate or bilobed with
cells the 2 halves as mirror images (“owl’s eyes”). Necessary but not sufficient for a
diagnosis of Hodgkin’s disease. Variants include lacunar cells in nodular sclerosis
variant.
Non-Hodgkin’s lymphoma
Type Occurs in Cell type Genetics Comments
Small lymphocytic Adults B cells Like CLL with focal mass;
lymphoma low grade.
Follicular lymphoma Adults B cells t(14;18) Most common (adult).
(small cleaved cell) bcl-2 Difficult to cure; indolent
expression course; bcl-2 is involved
in apoptosis.
Diffuse large cell Usually older adults, but 80% B cells Aggressive, but up to 50%
20% occur in children 20% T cells are curable.
(mature)
Lymphoblastic Most often children T cells Most common in
lymphoma (immature) children; commonly
presents with ALL and
mediastinal mass; very
aggressive T-cell
lymphoma.
Burkitt’s Most often children B cells t(8;14) c-myc “Starry-sky” appearance
lymphoma gene moves (sheets of lymphocytes
next to with interspersed
heavy-chain macrophages);
Ig gene (14) associated with EBV;
jaw lesion in endemic
form in Africa; pelvis or
abdomen in sporadic form
(see Color Image 24).
HEMATOLOGY AND ONCOLOGY HIGH-YI E LD SYSTEMS 302
303
Leukemias General considerations– . number of circulating leukocytes in blood; bone marrow
infiltrates of leukemic cells; marrow failure can cause anemia (. RBCs), infections
(. WBCs), and hemorrhage (. platelets); leukemic cell infiltrates in liver, spleen,
and lymph nodes are common (see Color Image 22).
ALL Children; lymphoblasts; most responsive to therapy. May spread to CNS and testes.
AML Auer rods; myeloblasts; adults.
CLL Older adults; lymphadenopathy; hepatosplenomegaly; few symptoms; indolent course;
. smudge cells in peripheral blood smear; warm antibody autoimmune hemolytic
anemia; very similar to SLL (small lymphocytic lymphoma).
CML Most commonly associated with Philadelphia chromosome (t[9;22], bcr-abl); myeloid
stem cell proliferation; presents with . neutrophils and metamyelocytes;
splenomegaly; may accelerate to AML (“blast crisis”). Very low leukocyte alkaline
phosphatase (vs. leukemoid reaction).
Auer bodies (rods) Auer rods are peroxidase-positive cytoplasmic inclusions in granulocytes and myeloblasts.
Primarily seen in acute promyelocytic leukemia (M3). Treatment of AML M3 can
release Auer rods . DIC.
HIGH-YI E LD SYSTEMS HEMATOLOGY AND ONCOLOGY
LEUKEMIA
Increased leukocytes
Full bone marrow
ACUTE LEUKEMIAS
Blasts predominate
Children or elderly
Short and drastic course
ALL
Lymphoblasts
(pre-B or pre-T)
AML
Myeloblasts
CLL
Lymphocytes
Non-antibodyproducing
B cells
CML
Myeloid stem cells
“Blast crisis”
CHRONIC LEUKEMIAS
More mature cells
Midlife age range
Longer, less devastating course
304
HEMATOLOGY AND ONCOLOGY-PATHOLOGY (continued)
Leukemia classification
Chromosomal translocations
Translocation Associated disorder
t(9;22) (Philadelphia CML (bcr-abl hybrid)
chromosome)
t(8;14) Burkitt’s lymphoma (c-myc activation)
t(14;18) Follicular lymphomas (bcl-2 activation)
t(15;17) M3 type of AML (responsive to all-trans retinoic acid)
t(11;22) Ewing’s sarcoma
t(11;14) Mantle cell lymphoma
Multiple myeloma Monoclonal plasma cell (“fried-egg” appearance) cancer that arises in the marrow and
produces large amounts of IgG (55%) or IgA (25%). Most common 1° tumor arising within
bone in adults. Destructive bone lesions and consequent hypercalcemia. Renal
insufficiency, . susceptibility to infection, and anemia. Associated with 1° amyloidosis
and punched-out lytic bone lesions on x-ray. Characterized by monoclonal
immunoglobulin spike (M protein) on serum protein electrophoresis and Ig light chains
in urine (Bence Jones protein). Blood smear shows RBCs stacked like poker chips
(rouleau formation). Compare with Waldenström’s macroglobulinemia .M spike = IgM
(.hyperviscosity symptoms); no lytic bone lesions (see Color Image 23).
HEMATOLOGY AND ONCOLOGY HIGH-YI E LD SYSTEMS
(Adapted, with permission, from Chandrasoma P, Taylor CE. Concise Pathology, 3rd ed. Stamford, CT: Appleton & Lange, 1998:410.)
Proliferating
“undifferentiated” cells
Mature
cell types
Acute
leukemias
Chronic
leukemias
FAB
classification
T lymphoblast T lymphocytes
B lymphoblast
Nonmarking
lymphoblast
B lymphocytes
Monocytes
Eosinophils
Erythrocytes
(Eosinophilic)
Neutrophils and
basophils
Megakaryocytes
and platelets
Acute
megakaryocytic
leukemia
Idiopathic
thrombocythemia
AML
Promyelocytic
AML
Acute
monocytic
Acute
myelomonocytic
Acute
erythroleukemia
(Chronic
erythroid)
(Chronic
myelomonocytic)
Polycythemia
rubra vera
CML
Myelofibrosis
(Chronic
monocytic)
ALL-T
ALL-B
ALL-null
ALL-common
L2
L1
L3
M5
M4
M2
M1
M6
M7
M3
Sézary
syndrome
CLL-T
CLL-B
CML
Monoblast
Myeloblast
CFU-GM
CFU-S (myeloid stem cell)
CFU-Eos myeloblast
CFU-E normoblast
CFUmegakaryoblast
Hematopoietic
stem cell
Myeloid
stem cell
Lymphoid
stem cell
CFU: Colony- forming unit
GM: Granulocyte -monocyte
E: Erythrocyte
Eos: Eosinophil
AML: Acute myeloblastic leukemia
CML: Chronic myelocytic leukemia
ALL: Acute lymphoblastic leukemia
CLL: Chronic lymphocytic leukemia
Leukemias in parentheses ( ) are rare
Lymphocytic
leukemias
Myeloid
leukemias
(Adapted, with permission,
from Stobo J et al. The Principles
and Practice of Medicine,
23rd ed. Stamford, CT: Appleton
& Lange, 1996:806.)
Albumin a1 a2 ß .
M spike
305
HEMATOLOGY AND ONCOLOGY-PHARMACOLOGY
Heparin
Mechanism Catalyzes the activation of antithrombin III, . thrombin and Xa. Short half-life.
Clinical use Immediate anticoagulation for pulmonary embolism, stroke, angina, MI, DVT. Used
during pregnancy (does not cross placenta). Follow PTT.
Toxicity Bleeding, thrombocytopenia, drug-drug interactions. For rapid reversal of
heparinization, use protamine sulfate (positively charged molecule that acts by
binding negatively charged heparin).
Note Newer low-molecular-weight heparins (enoxaparin) act more on Xa, have better
bioavailability and 2-4 times longer half-life. Can be administered subcutaneously
and without laboratory monitoring. Not easily reversible.
Warfarin (Coumadin)
Mechanism Interferes with normal synthesis and .-carboxylation The EX-PaTriot went to
of vitamin K-dependent clotting factors II, VII, IX, WAR(farin).
and X and protein C and S. Affects EXtrinsic
pathway and . PT.
Long half-life.
Clinical use Chronic anticoagulation. Not used in pregnant
women (because warfarin, unlike heparin, can
cross the placenta). Follow PT values.
Toxicity Bleeding, teratogenic, drug-drug interactions.
Heparin vs. warfarin
Heparin Warfarin
Structure Large anionic polymer, acidic Small lipid-soluble molecule
Route of Parenteral (IV, SC) Oral
administration
Site of action Blood Liver
Onset of action Rapid (seconds) Slow, limited by half-lives of
normal clotting factors
Mechanism of action Activates antithrombin III, which . the action of Impairs the synthesis of vitamin
IIa (thrombin) and Xa K-dependent clotting
factors II, VII, IX, and X
(vitamin K antagonist)
Duration of action Acute (hours) Chronic (weeks or months)
Inhibits coagulation Yes No
in vitro
Treatment of acute Protamine sulfate IV vitamin K and fresh frozen
overdose plasma
Monitoring PTT (intrinsic pathway) PT (extrinsic pathway)
Crosses placenta No Yes (teratogenic)
HIGH-YI E LD SYSTEMS HEMATOLOGY AND ONCOLOGY
306
HEMATOLOGY AND ONCOLOGY-PHARMACOLOGY (continued)
Thrombolytics Streptokinase, urokinase, tPA (alteplase), APSAC (anistreplase).
Mechanism Directly or indirectly aid conversion of plasminogen to plasmin, the major fibrinolytic
enzyme, which cleaves thrombin and fibrin clots.
Clinical use Early MI, early ischemic stroke.
Toxicity Bleeding. Contraindicated in patients with active bleeding, history of intracranial
bleeding, recent surgery, known bleeding diathesis, or severe hypertension. Treat
toxicity with aminocaproic acid, an inhibitor of fibrinolysis.
Mechanism of antiplatelet interaction
HEMATOLOGY AND ONCOLOGY HIGH-YI E LD SYSTEMS
Plasminogen
Various stimuli
Blood
proactivator
Blood
activator
tPA, urokinase
Streptokinase
Activator
Proactivator
Anistreplase
Degradation
products Fibrinogen
Thrombin
Fibrin
Fibrin split
products
Plasmin
Aminocaproic
acid
Antiactivators
ACTIVATION INHIBITION
-
-
+
+
+
+ +
+
(Adapted, with permission, from Katzung BG. Basic and Clinical Pharmacology, 7th ed. Stamford, CT: Appleton
& Lange, 1997:550.)
Collagen
Binds to
exposed
collagen
Glycoproteins
TxA2
ADP
5-HT
Aspirin
Clopidogrel
–both inhibit
glycoprotein
expression
in activated
platelets
Fibrinogen
Vascular endothelium
vWF
GP Ia GP Ib
Abciximab
Platelet
GP IIb / IIIa
GP IIb / IIIa
Activated platelets
Break in endothelium
(-)
(-)
(-)
(+)
307
Aspirin (ASA)
Mechanism Acetylates and irreversibly inhibits cyclooxygenase (both COX-1 and COX-2) to prevent
conversion of arachidonic acid to prostaglandins. . bleeding time. No effect on PT,
PTT.
Clinical use Antipyretic, analgesic, anti-inflammatory, antiplatelet drug.
Toxicity Gastric ulceration, bleeding, hyperventilation, Reye’s syndrome, tinnitus (CN VIII).
Clopidogrel, ticlopidine
Mechanism Inhibit platelet aggregation by irreversibly blocking ADP receptors. Inhibit fibrinogen
binding by preventing glycoprotein IIb/IIIa expression.
Clinical use Acute coronary syndrome; coronary stenting. . incidence or recurrence of
thrombotic stroke.
Toxicity Neutropenia (ticlopidine).
Abciximab
Mechanism Monoclonal antibody that binds to the glycoprotein receptor IIb/IIIa on activated
platelets, preventing aggregation.
Clinical use Acute coronary syndromes, percutaneous transluminal coronary angioplasty.
Toxicity Bleeding, thrombocytopenia.
Cancer drugs–site of action
Cell cycle specific–
antimetabolites (MTX,
5-FU, 6-MP), etoposide,
bleomycin, vinca alkaloids,
paclitaxel.
Cell cycle nonspecific–
alkylating agents,
antibiotics (dactinomycin,
doxorubicin, bleomycin).
HIGH-YI E LD SYSTEMS HEMATOLOGY AND ONCOLOGY
Nucleotide synthesis
DNA
mRNA
Protein
1. Methotrexate + 5-FU– . thymidine synthesis
2. 6-MP– . purine synthesis
3. Cytarabine
4. Alkylating agents + cisplatin–DNA cross-linkage
5. Dactinomycin + doxorubicin–DNA intercalation
6. Bleomycin-strand breakage + DNA intercalation
7. Etoposide–strand breakage
9. Tamoxifen
10. Vinca alkaloids–inhibit microtubule formation
11. Paclitaxel–inhibits microtubule disassembly
8. Steroids
308
HEMATOLOGY AND ONCOLOGY-PHARMACOLOGY (continued)
Cancer drugs–cell cycle
Methotrexate (MTX)
Mechanism S-phase-specific antimetabolite. Folic acid analog that inhibits dihydrofolate
reductase, resulting in . dTMP and therefore . DNA and protein synthesis.
Clinical use Leukemias, lymphomas, choriocarcinoma, sarcomas. Abortion, ectopic pregnancy,
rheumatoid arthritis, psoriasis.
Toxicity Myelosuppression, which is reversible with leucovorin (folinic acid) “rescue.”
Macrovesicular fatty change in liver.
5-fluorouracil (5-FU)
Mechanism S-phase-specific antimetabolite. Pyrimidine analog bioactivated to 5F-dUMP, which
covalently complexes folic acid. This complex inhibits thymidylate synthase, resulting
in . dTMP and same effects as MTX.
Clinical use Colon cancer and other solid tumors, basal cell carcinoma (topical). Synergy with
MTX.
Toxicity Myelosuppression, which is NOT reversible with leucovorin; photosensitivity.
HEMATOLOGY AND ONCOLOGY HIGH-YI E LD SYSTEMS
Differentiation
Synthesis Resting
of components
needed for
DNA synthesis
Synthesis of
components
needed for
mitosis
DNA
synthesis
M
G2
G1 G0
S
-
-
-
-
-
Vinca alkaloids
and taxols
Bleomycin
Etoposide
Antimetabolites
5-FU
-
Thymidylate
synthase
dUMP dTMP
CH2-THF DHF
THF
DHF
reductase
-
-
MTX
(Adapted, with permission, from Katzung BG, Trevor AJ. USMLE Road Map: Pharmacology, 1st ed. New York: McGraw-Hill, 2003:133.)
309
6-mercaptopurine (6-MP)
Mechanism Blocks de novo purine synthesis. Activated by HGPRTase.
Clinical use Leukemias, lymphomas (not CLL or Hodgkin’s).
Toxicity Bone marrow, GI, liver. Metabolized by xanthine oxidase; thus . toxicity with allopurinol.
Cytarabine (ara-C)
Mechanism Inhibits DNA polymerase.
Clinical use AML.
Toxicity Leukopenia, thrombocytopenia, megaloblastic anemia.
Cyclophosphamide, ifosfamide
Mechanism Alkylating agents; covalently x-link (interstrand) DNA at guanine N-7. Require
bioactivation by liver.
Clinical use Non-Hodgkin’s lymphoma, breast and ovarian carcinomas. Also immunosuppressants.
Toxicity Myelosuppression; hemorrhagic cystitis, which can be partially prevented with mesna.
Nitrosoureas Carmustine, lomustine, semustine, streptozocin.
Mechanism Alkylate DNA. Require bioactivation. Cross blood-brain barrier . CNS.
Clinical use Brain tumors (including glioblastoma multiforme).
Toxicity CNS toxicity (dizziness, ataxia).
Cisplatin, carboplatin
Mechanism Act like alkylating agents.
Clinical use Testicular, bladder, ovary, and lung carcinomas.
Toxicity Nephrotoxicity and acoustic nerve damage.
Busulfan
Mechanism Alkylates DNA.
Clinical use CML.
Toxicity Pulmonary fibrosis, hyperpigmentation.
Doxorubicin (Adriamycin), daunorubicin
Mechanism Generate free radicals and noncovalently intercalate in DNA (creating breaks in DNA
strand to . replication).
Clinical use Part of the ABVD combination regimen for Hodgkin’s and for myelomas, sarcomas, and
solid tumors (breast, ovary, lung).
Toxicity Cardiotoxicity; also myelosuppression and marked alopecia. Toxic extravasation.
Dactinomycin (actinomycin D)
Mechanism Intercalates in DNA. ACTinomycin D is used for
Clinical use Wilms’ tumor, Ewing’s sarcoma, childhood tumors (children
rhabdomyosarcoma. ACT out).
Toxicity Myelosuppression.
Bleomycin
Mechanism Induces formation of free radicals, which cause breaks in DNA strands.
Clinical use Testicular cancer, lymphomas (part of the ABVD regimen for Hodgkin’s).
Toxicity Pulmonary fibrosis, skin changes, but minimal myelosuppression.
HIGH-YI E LD SYSTEMS HEMATOLOGY AND ONCOLOGY
310
Etoposide (VP-16)
Mechanism G2-phase-specific agent that inhibits topoisomerase II and . DNA degradation.
Clinical use Small cell carcinoma of the lung and prostate, testicular carcinoma.
Toxicity Myelosuppression, GI irritation, alopecia.
Prednisone
Mechanism May trigger apoptosis. May even work on nondividing cells.
Clinical use Most commonly used glucocorticoid in cancer chemotherapy. Used in CLL, Hodgkin’s
lymphomas (part of the MOPP regimen). Also an immunosuppressant used in
autoimmune diseases.
Toxicity Cushing-like symptoms; immunosuppression, cataracts, acne, osteoporosis, hypertension,
peptic ulcers, hyperglycemia, psychosis.
Tamoxifen, raloxifene
Mechanism Estrogen receptor mixed agonist/antagonists (“SERMs”) that block the binding of estrogen
to estrogen receptor-positive cells.
Clinical use Breast cancer. Also useful to prevent osteoporosis.
Toxicity Tamoxifen may . the risk of endometrial carcinoma via partial agonist effects; “hot
flashes.”
Trastuzumab (Herceptin)
Mechanism Monoclonal antibody against HER-2 (erb-B2). Helps kill breast cancer cells that
overexpress HER-2, possibly through antibody-dependent cytotoxicity.
Clinical use Metastatic breast cancer.
Toxicity Cardiotoxicity.
Imatinib (Gleevec)
Mechanism Myoclonal antibody against the Philadelphia chromosome brc-abl tyrosine kinase.
Clinical use CML, GI stromal tumors.
Toxicity Fluid retention.
Vincristine, vinblastine
Mechanism M-phase-specific alkaloids that bind to tubulin and block polymerization of microtubules
so that mitotic spindle cannot form.
Clinical use Part of the MOPP (Oncovin [vincristine]) regimen for lymphoma, Wilms’ tumor,
choriocarcinoma.
Toxicity Vincristine–neurotoxicity (areflexia, peripheral neuritis), paralytic ileus.
VinBLASTine BLASTs Bone marrow (suppression).
Paclitaxel, other taxols
Mechanism M-phase-specific agents that bind to tubulin and hyperstabilize polymerized
microtubules so that mitotic spindle cannot break down (anaphase cannot occur).
Clinical use Ovarian and breast carcinomas.
Toxicity Myelosuppression and hypersensitivity.
HEMATOLOGY AND ONCOLOGY HIGH-YI E LD SYSTEMS
High-Yield Clinical
Vignettes
Anatomy
Physiology
Pathology
Pharmacology
H I G H -Y I E L D S Y S T E M S
Musculoskeletal
and Connective Tissue
311
“I just use my muscles like a conversation piece, like someone walking a
cheetah down 42nd Street.”
–Arnold Schwarzenegger
“There’s 215 bones in the human body. That’s one.”
–Sarah Connor in Terminator 2: Judgment Day
312
MUSCULOSKELETAL AND CONNECTIVE TISSUE-HIGH-YIELD C LINICAL VIGNETTES
Soccer player who was kicked in What else is likely to Anterior cruciate ligament
the leg suffered a damaged have been damaged? (remember the “unhappy triad”).
medial meniscus.
Gymnast dislocates her shoulder What nerve is most Axillary nerve (C5, C6).
anteriorly. likely to have been
damaged?
X-ray shows bilateral hilar What is the diagnosis? Sarcoidosis.
lymphadenopathy.
Child exhibits weakness and What is the disease, Duchenne’s muscular dystrophy;
enlarged calves. and how it is inherited? X-linked recessive.
25-year-old woman presents with You are concerned SLE.
a low-grade fever, a rash across about what disease?
her nose that gets worse when
she is out in the sun, and
widespread edema.
85-year-old man presents with What is the diagnosis, Pseudogout; rhomboid calcium
acute knee pain and swelling. and what would you pyrophosphate crystals.
X-ray shows joint space without find on aspiration?
erosion.
MUSCULOSKELETAL HIGH-YI E LD SYSTEMS
313
MUSCULOSKELETAL AND CONNECTIVE TISSUE-ANATOMY
Epidermis layers From surface to base: stratum Corneum, Californians Like Girls in
stratum Lucidum, stratum Granulosum, String Bikinis.
stratum Spinosum, stratum Basalis.
Epithelial cell junctions
Bone formation
Intramembranous Spontaneous bone formation without preexisting cartilage.
Endochondral Ossification of cartilaginous molds. Long bones form by this type of ossification at 1°
and 2° centers.
Unhappy triad/ This common football injury (caused by clipping Positive anterior drawer sign
knee injury from the lateral side) consists of damage to medial indicates tearing of the
collateral ligament (MCL), medial meniscus, and ACL.
anterior cruciate ligament (ACL). Abnormal passive abduction
PCL = posterior cruciate ligament. LCL = lateral indicates a torn MCL.
collateral ligament.
“Anterior” and “posterior” in ACL and PCL refer to
sites of tibial attachment.
HIGH-YI E LD SYSTEMS MUSCULOSKELETAL
Stratum corneum
Epidermis
Dermis
Stratum lucidum
Stratum granulosum
Stratum spinosum
Stratum basalis
Actin
filaments
Desmoplakin
Connection
with central
channel
Keratin
Integrin–maintains
integrity of basement
membrane Hemidesmosome–connects cells to underlying extracellular matrix
E-cadherin
Zona occludens (tight junction)–
prevents diffusion across intracellular space
Zona adherens (intermediate junction)–
surrounds perimeter just below
zona occludens
Macula adherens (desmosome)–
small, discrete sites of attachment
Gap junction–allows adjacent cells to
communicate for electric and metabolic functions
LCL
PCL
MCL
Medial
condyle
Lateral
condyle
Medial
meniscus
ACL
Lateral
meniscus
314
MUSCULOSKELETAL AND CONNECTIVE TISSUE-ANATOMY (continued)
Rotator cuff Shoulder muscles that form the rotator cuff: S I t S (small t is for teres
muscles Supraspinatus–helps deltoid abduct arm. minor).
Infraspinatus–laterally rotates arm.
Teres minor–adducts and laterally rotates arm.
Subscapularis–medially rotates and adducts arm.
MUSCULOSKELETAL HIGH-YI E LD SYSTEMS
Posterior Anterior
Coracoid
Biceps
tendon
Acromion Supraspinatus
Subscapularis
Infraspinatus
Teres
minor
315
MUSCULOSKELETAL AND CONNECTIVE TISSUE-PHYSIOLOGY
Skeletal muscle contraction
ATP binds to myosin head
and releases actin filament,
allowing cross-bridge
cycling and shortening to
occur.
Ca2+ binds to troponin C,
causing conformational
change. This causes
tropomyosin to move out
of the way to allow actin/
myosin cycling.
HIGH-YI E LD SYSTEMS MUSCULOSKELETAL Actin
Myosin head Myosin
ATP
ADP Pi
1.
2.
3.
4.
(-) (+)
ADP
(-) (+)
(-) (+)
(-) (+)
Tropomyosin
316
MUSCULOSKELETAL AND CONNECTIVE TISSUE-PHYSIOLOGY (continued)
Conduction to contraction
Action potential reaches axon terminal . depolarization opens voltage-gated Ca2+ channels and causes
neurotransmitter vesicle fusion and exocytosis. Postsynaptic ligand binding leads to depolarization of the
postsynaptic (muscle) cell (A). Depolarization travels down T tubule. A dihydropyridine receptor (voltagesensing
Ca2+ channel protein) lies in the T-tubule membrane next to a ryanodine receptor, which lies in the
sarcoplasmic reticulum (B). Released calcium binds to troponin C, which causes a conformational change
and moves tropomyosin out of myosin-binding groove on actin filament. Myosin hydrolyzes its bound ATP
and is displaced on the actin filament (power stroke). Contraction results in HIZ shrinkage–H, I, and Z
bands contract (B). A band length stays constant throughout the cycle.
MUSCULOSKELETAL HIGH-YI E LD SYSTEMS
A.
T tubule
M line Z line Plasma membrane
Myosin
Sarcoplasmic reticulum
Actin
Mitochondria
Sarcomere
A band
H band
Myofibril
I band
Ryanodine receptor
Cytosol
T-tubule membrane
Ca2+
Dihydropyridine receptor
Sarcoplasmic
reticulum
Exterior
B.
317
Smooth muscle contraction
HIGH-YI E LD SYSTEMS MUSCULOSKELETAL
Action potential
Smooth muscle
membrane
depolarization
Voltage-gated
Ca2+ channels
open
. Ca2+
in cytoplasm
Ca2+ binds
to calmodulin
Activates
myosin
light-chain
kinase
Myosin
+ actin
Myosin P
+ actin
Relaxation
Myosin
light-chain
phosphatase
Cross-bridge
formation
and contraction
318
MUSCULOSKELETAL AND CONNECTIVE TISSUE-PATHOLOGY
Achondroplasia Autosomal-dominant trait. Failure of longitudinal bone growth . short limbs.
Membranous ossification is not affected (skull, facial bones, and axial skeleton are
normal). Head and trunk are normal in size, but limbs are much shorter than normal.
Osteoarthritis Mechanical–wear and tear of joints leads to destruction of articular cartilage, subchondral
bone formation, sclerosis, osteophytes, eburnation, Heberden’s nodes (DIP), and
Bouchard’s nodes (PIP).
Common in older patients.
Classic presentation: pain in weight-bearing joints after use (e.g., at the end of the day),
improving with rest. No systemic symptoms.
Rheumatoid Autoimmune–inflammatory disorder affecting synovial joints, with pannus formation in
arthritis joints (MCP, PIP), subcutaneous rheumatoid nodules, ulnar deviation, subluxation
(see Color Image 56).
Females > males. 80% of RA patients have positive rheumatoid factor (anti-IgG antibody).
Classic presentation: morning stiffness improving with use, symmetric joint
involvement, and systemic symptoms (fever, fatigue, pleuritis, pericarditis).
MUSCULOSKELETAL HIGH-YI E LD SYSTEMS
Normal Osteoarthritis
Capsule
Synovium
Cartilage
Bone
Thickened capsule
Slight synovial
hypertrophy
Osteophyte
Ulcerated,
narrowed
cartilage
Sclerotic bone
(Adapted, with permission, from Stobo J et al. The Principles and Practice of Medicine, 23rd ed. Stamford,
CT: Appleton & Lange, 1996:241.)
Rheumatoid
arthritis
Normal
Joint
capsule
Synovial
membrane
Cartilage
Increased
synovial
fluid
Bone
and
cartilage
erosion
Pannus
formation
Boutonnière
deformity
Swan-neck deformity
Z-thumb deformity
319
Osteoporosis Reduction of bone mass in spite of normal bone Affects whites > blacks
mineralization. > Asians.
Type I Postmenopausal; . bone resorption due to . Vertebral crush fractures–
estrogen levels. Estrogen replacement is acute back pain, loss of
controversial as prophylaxis (side effects). height, kyphosis.
Type II Senile osteoporosis–affects men and women > 70 Distal radius (Colles’) fractures,
years. vertebral wedge fractures.
Bisphosphonates or pulsatile
PTH for severe cases.
Osteopetrosis Failure of normal bone resorption . thickened, dense bones. Bone defect is due to
(marble bone disease) abnormal function of osteoclasts. Serum calcium, phosphate, and alkaline
phosphatase are normal.
Osteomalacia/rickets Defective mineralization of osteoid . soft bones. Vitamin D deficiency in adults .
. calcium levels .. secretion of PTH, . in serum phosphate. Reversible when
vitamin D is replaced. Vitamin D deficiency in childhood causes rickets.
Osteitis fibrosa Caused by hyperparathyroidism. Characterized by “brown tumors” (cystic spaces lined
cystica by osteoclasts, filled with fibrous stroma and sometimes blood). High serum calcium,
low serum phosphorus, and high alkaline phosphatase.
Paget’s disease Abnormal bone architecture caused by . in both osteoblastic and osteoclastic activity.
(osteitis deformans) Serum calcium, phosphorus, and PTH levels are normal. Serum alkaline
phosphatase is elevated.
Polyostotic fibrous Bone is replaced by fibroblasts, collagen, and irregular bony trabeculae. Affects many
dysplasia bones. Albright’s syndrome is a form of polyostotic fibrous dysplasia in which there
are multiple unilateral bone lesions associated with endocrine abnormalities
(precocious puberty) and unilateral pigmented skin lesions.
Polymyalgia Pain and stiffness in shoulders and hips, often with fever, malaise, and weight loss. Does
rheumatica not cause muscular weakness. . ESR. Occurs in patients > 50 years of age; associated
with temporal (giant cell) arteritis. Treated with prednisone.
Polymyositis/ Polymyositis-progressive proximal muscle weakness caused by CD8+ T-cell-induced
dermatomyositis injury to myofibers. Muscle biopsy with evidence of inflammation is diagnostic.
Dermatomyositis-similar to polymyositis but also involves skin rash and . risk of
malignancy.
Labs for polymyositis/dermatomyositis show . CK, . aldolase, and positive ANA,
anti-Jo-1.
Mixed connective Raynaud’s phenomenon, arthralgias, myalgias, fatigue, and esophageal hypomotility.
tissue disease Antibodies to U1RNP.
HIGH-YI E LD SYSTEMS MUSCULOSKELETAL
Mild compression fracture Normal vertebra
320
MUSCULOSKELETAL AND CONNECTIVE TISSUE-PATHOLOGY (continued)
Sjögren’s syndrome Classic triad–xerophthalmia (dry eyes, Associated with rheumatoid
conjunctivitis), xerostomia (dry mouth, dysphagia), arthritis.
arthritis. Parotid enlargement, . risk of B-cell Sicca syndrome–dry eyes, dry
lymphoma. Autoantibodies to ribonucleoprotein mouth, nasal and vaginal
antigens, SS-A (Ro), SS-B (La). dryness, chronic bronchitis,
Predominantly affects females between 40 and reflux esophagitis.
60 years of age.
Systemic lupus 90% are female and between ages 14 and 45. Most I’M DAMN SHARP:
erythematosus common and severe in black females. Symptoms Immunoglobulins
include fever, fatigue, weight loss, nonbacterial (anti-dsDNA, anti-Sm,
verrucous endocarditis, hilar adenopathy, and antiphospholipid)
Raynaud’s phenomenon. Wire loop lesions in Malar rash
kidney with immune complex deposition (with Discoid rash
nephrotic syndrome); death from renal failure and Antinuclear antibody
infections. False positives on syphilis tests Mucositis (oropharyngeal
(RPR/VDRL) due to antiphospholipid antibodies. ulcers)
Lab tests detect presence of: Neurologic disorders
1. Antinuclear antibodies (ANA)–sensitive, Serositis (pleuritis,
but not specific for SLE pericarditis)
2. Antibodies to double-stranded DNA Hematologic disorders
(anti-dsDNA)–very specific, poor prognosis Arthritis
3. Anti-Smith antibodies (anti-Sm)– Renal disorders
very specific, but not prognostic Photosensitivity
4. Antihistone antibodies–drug-induced lupus
(see Color Image 52)
Celiac sprue Autoimmune-mediated intolerance of gliadin (wheat) leading to steatorrhea. Associated
with people of northern European descent. Findings include blunting of villi,
lymphocytes in the lamina propria, and abnormal D-xylose test. Tends to affect
jejunum. Associated with dermatitis herpetiformis. 10-15% lead to malignancy (most
often T-cell lymphoma).
Gout Precipitation of monosodium urate crystals into joints due to hyperuricemia, which can be
caused by Lesch-Nyhan syndrome, PRPP excess, . excretion of uric acid, or glucose-6-
phosphatase deficiency. Also associated with the use of thiazide diuretics, which
competitively inhibit the secretion of uric acid. Asymmetric joint distribution. Classic
manifestation is painful MTP joint in the big toe (podagra). Tophus formation (often
on external ear or Achilles tendon). Crystals are needle shaped and negatively
birefringent. More common in men. Acute attack tends to occur after alcohol
consumption or a large meal (see Color Image 54). Treatment includes allopurinol,
probenecid, colchicine, and NSAIDs.
MUSCULOSKELETAL HIGH-YI E LD SYSTEMS
Malar
rash
Uric acid crystals
321
Pseudogout Caused by deposition of calcium pyrophosphate crystals within the joint space. Forms
basophilic, rhomboid crystals that are weakly positively birefringent (as opposed to the
negatively birefringent, needle-shaped crystals in gout). Usually affects large joints
(classically the knee). > 50 years old; both sexes affected equally. No treatment.
Goodpasture’s Findings: pulmonary hemorrhages . hemoptysis; There are 2 Good Pastures
syndrome renal lesions . hematuria, anemia, crescentic for this disease: Glomerulus
glomerulonephritis. and Pulmonary. A type II
Anti-glomerular basement membrane antibodies hypersensitivity disease.
produce linear staining on immunofluorescence. Most common in men 20-40
years.
Sarcoidosis Characterized by immune-mediated, widespread GRAIN:
noncaseating granulomas and elevated serum Gammaglobulinemia
ACE levels. Common in black females. Rheumatoid arthritis
Associated with restrictive lung disease, bilateral ACE increase
hilar lymphadenopathy, erythema nodosum, Interstitial fibrosis
Bell’s palsy, epithelial granulomas containing Noncaseating granulomas
microscopic Schaumann and asteroid bodies,
uveoparotitis, and hypercalcemia (due to
elevated conversion of vitamin D to its active
form in epithelioid macrophages) (see
Image 104).
Seronegative Arthritis without rheumatoid factor (no anti-IgG antibody). Strong association with HLAspondylo-
B27 (gene that codes for HLA MHC I). Occurs more often in males.
arthropathies
Ankylosing Chronic inflammatory disease of spine and sacroiliac
spondylitis joints . ankylosis (stiff spine), uveitis, and aortic
regurgitation.
Reiter’s syndrome Classic triad: “Can’t see (anterior uveitis/
1. Urethritis conjunctivitis), can’t pee
2. Conjunctivitis and anterior uveitis (urethritis), can’t climb a
3. Arthritis tree (arthritis).”
Post-GI or chlamydia
infections.
Scleroderma Excessive fibrosis and collagen deposition throughout the body. 75% female. Commonly
(progressive sclerosis of skin but also of cardiovascular and GI systems and kidney. 2 major
systemic categories:
sclerosis–PSS) 1. Diffuse scleroderma–widespread skin involvement, rapid progression, early visceral
involvement. Associated with anti-Scl-70 antibody.
2. CREST syndrome–Calcinosis, Raynaud’s phenomenon, Esophageal dysmotility,
Sclerodactyly, and Telangiectasia. Limited skin involvement, often confined to
fingers and face. More benign clinical course. Associated with anticentromere
antibody (see Color Image 53).
HIGH-YI E LD SYSTEMS MUSCULOSKELETAL
Calcium pyrophosphate
crystals
322
MUSCULOSKELETAL AND CONNECTIVE TISSUE-PATHOLOGY (continued)
Skin disorders
Dermatitis A group of inflammatory pruritic skin disorders. Etiology: allergy (usually type IV
hypersensitivity), chemical injury, or infection.
Atopic dermatitis Pruritic eruption, commonly on flexor surfaces. Often associated with other atopic
(eczema) diseases (asthma, allergic rhinitis).
Allergic contact Type IV hypersensitivity reaction that follows exposure to allergen (poison ivy, poison oak,
dermatitis nickel, rubber, chemicals). Lesions occur at site of contact.
Psoriasis Epidermal hyperplasia (acanthosis) with parakeratotic scaling (nuclei still in stratum
corneum) especially on knees and elbows. . stratum spinosum, . stratum granulosum
(see Color Image 65). Auspitz sign.
Dermatitis Pruritic papules and vesicles. Associated with celiac disease.
herpetiformis
Lichen planus Pruritic, purple, polygonal papules; infiltrate of lymphocytes at dermoepidermal junction.
Erythema multiforme Associated with infections, drugs, cancers, and autoimmune disease. Presents with
multiple types of lesions, including macules, papules, vesicles, and target lesions (red
papules with a pale central area).
Stevens-Johnson syndrome is the major form of erythema multiforme. Characterized by
high fever, bulla formation and necrosis, ulceration of skin, and a high mortality rate.
Seborrheic keratosis Flat, pigmented squamous epithelial proliferation with keratin-filled cysts (horn cysts).
Benign.
Actinic keratosis Caused by sun exposure. Small, rough erythematous or brownish papules. Premalignant
lesion. Risk of carcinoma is proportional to epithelial dysplasia.
Keloid Tumor of connective tissue elements of dermis that causes raised, thickened scars.
Follows trauma to skin, especially in African-Americans.
Bullous pemphigoid Autoimmune disorder with IgG antibody against epidermal basement membrane (linear
immunofluorescence). Similar to but less severe than pemphigus vulgaris–affects skin
but spares oral mucosa (see Color Image 64).
Pemphigus vulgaris Potentially fatal autoimmune skin disorder. Intradermal bullae involving the oral mucosa
and skin. Findings: acantholysis (breakdown of epithelial cell-to-cell junctions), IgG
antibody against epidermal cell surface (immunofluorescence throughout epidermis)
(see Color Image 63).
Skin cancer
Squamous cell Very common. Associated with excessive exposure to Actinic keratosis is a precursor
carcinoma sunlight and arsenic exposure. Commonly appear to squamous cell carcinoma.
on hands and face. Locally invasive, but rarely
metastasizes. Histopathology: keratin “pearls”
(see Color Image 60).
Basal cell carcinoma Most common in sun-exposed areas of body. Locally Basal cell tumors have
invasive, but almost never metastasizes. Gross “palisading” nuclei.
pathology: pearly papules (see Color Image 62).
Melanoma Common tumor with significant risk of metastasis. Dysplastic nevus is a precursor
Associated with sunlight exposure; fair-skinned to melanoma.
persons are at . risk. Incidence .. Depth of
tumor correlates with risk of metastasis (see
Color Image 61).
MUSCULOSKELETAL HIGH-YI E LD SYSTEMS
323
Primary bone tumors
Benign
Giant cell tumor Occurs most commonly at epiphyseal end of long bones. Peak incidence 20-40 years
old. Locally aggressive benign tumor often around the distal femur, proximal tibial
region. Characteristic “double bubble” or “soap bubble” appearance on x-ray.
Spindle-shaped cells with multinucleated giant cells.
Osteochondroma Most common benign bone tumor. Usually in men < 25 years of age. Commonly
(exostosis) originates from long metaphysis. Malignant transformation to chondrosarcoma is rare.
Enchondroma Benign cartilaginous neoplasm found in intramedullary bone. Usually distal extremities
(vs. chondrosarcoma).
Malignant
Osteosarcoma Most common 1° malignant tumor of bone. Peak incidence in men 10-20 years old.
(osteogenic Commonly found in the metaphysis of long bones. Predisposing factors include
carcinoma) Paget’s disease of bone, bone infarcts, radiation, and familial retinoblastoma.
Codman’s triangle (from elevation of periosteum) on x-ray.
Ewing’s sarcoma Anaplastic small blue cell malignant tumor. Most common in boys < 15. Extremely
aggressive with early mets, but responsive to chemotherapy. Characteristic
“onion-skin” appearance in bone (“going out for Ewings and onion rings.”)
Commonly appears in diaphysis of long bones, pelvis, scapula, and ribs. 11;22
translocation.
Chondrosarcoma Malignant cartilaginous tumor. Most common in men aged 30-60. Usually located in
pelvis, spine, scapula, humerus, tibia, or femur. May be of 1° origin or from
osteochondroma.
Buerger’s disease Also known as thromboangiitis obliterans; idiopathic, segmental, thrombosing vasculitis
of intermediate and small peripheral arteries and veins. Seen in heavy smokers.
Findings Intermittent claudication, superficial nodular phlebitis, cold sensitivity
(Raynaud’s phenomenon), severe pain in affected part; may lead to gangrene.
Treatment Quit smoking.
Takayasu’s arteritis Known as “pulseless disease”–granulomatous Affects medium and large
thickening of aortic arch and/or proximal great arteries.
vessels. Associated with an elevated ESR.
Primarily affects Asian females < 40 years old. FAN MY SKIN On
Fever, Arthritis, Night sweats, MYalgia, SKIN Wednesday.
nodules, Ocular disturbances, Weak pulses in
upper extremities.
HIGH-YI E LD SYSTEMS MUSCULOSKELETAL
Epiphysis Metaphysis Diaphysis
Enchondroma (hands/feet)
Ewing’ sarcoma
Osteochondroma
(exostosis)
Osteosarcoma
(Codman’s
triangle)
Giant cell
tumor
(soap bubble)
Chodrosarcoma
Marrow
324
MUSCULOSKELETAL AND CONNECTIVE TISSUE-PATHOLOGY (continued)
Temporal arteritis Most common vasculitis that affects medium and TEMporal = signs near
(giant cell small arteries, usually branches of carotid artery. TEMples. ESR is markedly
arteritis) Focal, granulomatous. Findings include unilateral elevated. Affects elderly
headache, jaw claudication, impaired vision females.
(occlusion of ophthalmic artery, which can lead
to blindness). Half of patients have systemic
involvement and polymyalgia rheumatica
(proximal muscle pain, periarticular pain).
Associated with elevated ESR. Responds well to
steroids.
Polyarteritis Characterized by necrotizing immune complex Lesions are of different ages.
nodosa inflammation of medium-sized muscular arteries,
typically involving renal and visceral vessels.
Symptoms Fever, weight loss, malaise, abdominal pain, melena,
headache, myalgia, hypertension, neurologic
dysfunction, cutaneous eruptions.
Findings Hepatitis B seropositivity in 30% of patients. Multiple
aneurysms and constrictions on arteriogram. Not
associated with ANCA.
Treatment Corticosteroids, cyclophosphamide.
Wegener’s Characterized by triad of focal necrotizing vasculitis, necrotizing granulomas in the
granulomatosis lung and upper airway, and necrotizing glomerulonephritis.
Symptoms Perforation of nasal septum, chronic sinusitis, otitis media, mastoiditis, cough, dyspnea,
hemoptysis, hematuria.
Findings C-ANCA is a strong marker of disease; chest x-ray may reveal large nodular densities;
hematuria and red cell casts.
Treatment Cyclophosphamide and corticosteroids.
Other ANCA-positive vasculitides
Microscopic Like Wegener’s but lacks granulomas. P- or C-ANCA.
polyangiitis
1° pauci-immune Vasculitis limited to kidney.
crescentic
glomerulonephritis
Churg-Strauss Granulomatous vasculitis with eosinophilia. Involves lung, heart, skin, kidneys, nerves.
syndrome Often seen in atopic patients.
Kawasaki disease Acute, self-limiting disease of infants/kids. Acute necrotizing vasculitis of small/
medium-sized vessels. Fever, congested conjunctiva, changes in lips/oral mucosa,
lymphadenitis. May develop coronary aneurysms.
Henoch-Schönlein Most common form of childhood systemic vasculitis. Skin rash, arthralgia, intestinal
purpura hemorrhage, abdominal pain, and melena.
MUSCULOSKELETAL HIGH-YI E LD SYSTEMS
325
MUSCULOSKELETAL AND CONNECTIVE TISSUE-PHARMACOLOGY
Opioid analgesics Morphine, fentanyl, codeine, heroin, methadone, meperidine, dextromethorphan.
Mechanism Act as agonists at opioid receptors (mu = morphine, delta = enkephalin, kappa = dynorphin)
to modulate synaptic transmission.
Clinical use Pain, cough suppression (dextromethorphan), diarrhea (loperamide and diphenoxylate),
acute pulmonary edema, maintenance programs for addicts (methadone).
Toxicity Addiction, respiratory depression, constipation, miosis (pinpoint pupils), additive CNS
depression with other drugs. Tolerance does not develop to miosis and constipation.
Toxicity treated with naloxone or naltrexone (opioid receptor antagonist). O2 is
contraindicated if morphine overdose–might contribute to respiratory failure.
NSAIDs Ibuprofen, naproxen, indomethacin, ketorolac.
Mechanism Reversibly inhibit cyclooxygenase (both COX-1 and COX-2). Block prostaglandin
synthesis.
Clinical use Antipyretic, analgesic, anti-inflammatory. Indomethacin is used to close a PDA.
Toxicity Renal damage, aplastic anemia, GI distress, ulcers.
COX-2 inhibitors (celecoxib, valdecoxib)
Mechanism Selectively inhibit cyclooxygenase (COX) isoform 2, which is found in inflammatory
cells and mediates inflammation and pain; spares COX-1, which helps maintain
the gastric mucosa. Thus, should not have the corrosive effects of other NSAIDs
on the GI lining.
Clinical use Rheumatoid and osteoarthritis.
Toxicity Similar to other NSAIDs; may have less toxicity to GI mucosa (i.e., lower incidence of
ulcers, bleeding).
Acetaminophen
Mechanism Reversibly inhibits cyclooxygenase, mostly in CNS. Inactivated peripherally.
Clinical use Antipyretic, analgesic, but lacking anti-inflammatory properties.
Toxicity Overdose produces hepatic necrosis; acetaminophen metabolite depletes glutathione
and forms toxic tissue adducts in liver. N-acetylcysteine is antidote–regenerates
glutathione.
Gout drugs
Colchicine Acute gout. Depolymerizes microtubules,
impairing leukocyte chemotaxis and
degranulation. GI side effects, especially if
given orally. (Note: indomethacin is less
toxic, more commonly used.)
Probenecid Chronic gout. Inhibits reabsorption of uric
acid (also inhibits secretion of penicillin).
Allopurinol Chronic gout. Inhibits xanthine oxidase,
. conversion of xanthine to uric acid. Also
used in lymphoma and leukemia to prevent
tumor lysis-associated urate nephropathy.
HIGH-YI E LD SYSTEMS MUSCULOSKELETAL
Diet Purines Nucleic acids
Hypoxanthine
Allopurinol
Xanthine
oxidase
Xanthine
oxidase
Urate crystals
deposited
in joints
Xanthine
Plasma Gout
uric acid
Urine
Probenecid and
high-dose salicylates
Tubular
reabsorption
Diuretics and
low-dose salicylates
Tubular
secretion
-
-
326
MUSCULOSKELETAL AND CONNECTIVE TISSUE-PHARMACOLOGY (continued)
Etanercept
Mechanism Recombinant form of human TNF receptor that binds TNF-a.
Clinical use Rheumatoid arthritis, psoriasis, ankylosing spondylitis.
Infliximab
Mechanism TNF-a antibody.
Clinical use Crohn’s disease, rheumatoid arthritis, ankylosing spondylitis.
Immunosuppressive
agents: sites of action
Agent Site
Prednisone 2, 5
Cyclosporine 2, 3
Azathioprine 2
Methotrexate 2
Dactinomycin 2, 3
Cyclophosphamide 2
Antilymphocytic 1, 2, 3
globulin and
monoclonal anti-
T-cell antibodies
Rh3(D) immune 1
globulin
Tacrolimus 4
Cyclosporine
Mechanism Binds to cyclophilins. Complex blocks the differentiation and activation of T cells
by inhibiting calcineurin, thus preventing the production of IL-2 and its receptor.
Clinical use Suppresses organ rejection after transplantation; selected autoimmune disorders.
Toxicity Predisposes patients to viral infections and lymphoma; nephrotoxic (preventable with
mannitol diuresis).
Tacrolimus (FK506)
Mechanism Similar to cyclosporine; binds to FK-binding protein, inhibiting secretion of IL-2 and
other cytokines.
Clinical use Potent immunosuppressive used in organ transplant recipients.
Toxicity Significant–nephrotoxicity, peripheral neuropathy, hypertension, pleural effusion,
hyperglycemia.
Azathioprine
Mechanism Antimetabolite derivative of 6-mercaptopurine that interferes with the metabolism and
synthesis of nucleic acids. Toxic to proliferating lymphocytes.
Clinical use Kidney transplantation, autoimmune disorders (including glomerulonephritis and
hemolytic anemia).
Toxicity Bone marrow suppression. Active metabolite mercaptopurine is metabolized by
xanthine oxidase; thus, toxic effects may be . by allopurinol.
MUSCULOSKELETAL HIGH-YI E LD SYSTEMS
2
1
3
5
Proliferation
Antigen
recognition
(B and T cells)
Differentiation
synthesis
T cells
or
antibody
Interaction
Complement
Antigen
Tissue injury
4
Cytokine
secretion
(Adapted, with permission, from Katzung BG. Basic and Clinical Pharmacology,
7th ed. Stamford, CT: Appleton & Lange, 1997:924.)
327
Recombinant cytokines and clinical uses
Agent Clinical uses
Aldesleukin (interleukin-2) Renal cell carcinoma, metastatic melanoma
Erythropoietin (epoetin) Anemias (especially in renal failure)
Filgrastim (granulocyte Recovery of bone marrow
colony-stimulating factor)
Sargramostim (granulocyte- Recovery of bone marrow
macrophage colonystimulating
factor)
a-interferon Hepatitis B and C, Kaposi’s sarcoma, leukemias, malignant melanoma
ß-interferon Multiple sclerosis
.-interferon Chronic granulomatous disease
Oprelvekin (interleukin-11) Thrombocytopenia
Thrombopoietin Thrombocytopenia
HIGH-YI E LD SYSTEMS MUSCULOSKELETAL
328 MUSCULOSKELETAL HIGH-YI E LD SYSTEMS
NOTES
High-Yield Clinical
Vignettes
Anatomy and
Physiology
Pathology
Pharmacology
H I G H -Y I E L D S Y S T E M S
Neurology and
Psychiatry
329
“What a terrible thing to have lost one’s mind. Or not to have a mind at all.
How true that is.”
–Dan Quayle
“He has two neurons held together by a spirochete.”
–Anonymous
330
NEUROLOGY AND PSYCHIATRY-HIGH-YIELD CLINICAL VIGNETTES
Patient presents with . pain What is the lesion? Syringomyelia.
and temperature sensation over
the lateral aspects of both arms.
Penlight in patient’s right eye What is the defect? Atrophy of the left optic nerve.
produces bilateral pupillary
constriction. When moved to
the left eye, there is paradoxical
dilatation.
Patient describes . prick A deficit in what Dorsiflexion and eversion of foot
sensation on the lateral aspect muscular action can (common peroneal nerve).
of her leg and foot. also be expected?
Elderly woman presents with What is the diagnosis? Carpal tunnel syndrome,
arthritis and tingling over the median nerve compression.
lateral digits of her right hand.
20-year-old dancer reports . What spinal nerve Tibial (L4-S3).
plantar flexion and . sensation is involved?
over the back of her thigh, calf,
and lateral half of her foot.
Woman involved in a motor What structure is Right CN XI (runs through
vehicle accident cannot turn damaged? jugular foramen with CN IX
her head to the left and has and X), innervating
right shoulder droop. sternocleidomastoid and
trapezius muscles.
Man presents with one wild, Where is the lesion? Contralateral subthalamic nucleus
flailing arm. (hemiballismus).
Patient with cortical lesion does Where is the lesion? Right parietal lobe.
not know that he has a disease.
Patient cannot protrude tongue Where is the lesion? Left medulla, CN XII.
toward left side and has a
right-sided spastic paralysis.
Teen falls while rollerblading Which nerve and what Ulnar nerve due to broken medial
and hurts his elbow. He can’t injury? condyle.
feel the medial part of his palm.
Field hockey player presents to Which nerve and which Radial nerve and deep brachial
the ER after falling on her arm artery are most likely artery, which run together.
during practice. X-ray shows damaged?
midshaft break of the humerus.
Patient cannot blink his right What is the diagnosis, Bell’s palsy; CN VII.
eye or seal his lips and has mild and which nerve is
ptosis on the right side. affected?
Patient complains of pain, What is the diagnosis, Carpal tunnel syndrome; median
numbness, and a tingling and what nerve is often nerve.
sensation. On exam, she has affected?
wasting of the thenar eminence.
NEUROLOGY AND PSYCHIATRY HIGH-YI E LD SYSTEMS
NEUROLOGY AND PSYCHIATRY-HIGH-YIELD CLINICAL VIGNETTES (continued)
During a particular stage of sleep, What stage of sleep is REM sleep.
man has variable blood pressure, he in?
penile tumescence, and variable
EEG.
Person demands only the best What is the personality Narcissistic personality disorder.
and most famous doctor in town. disorder?
Nurse has episodes of What is the diagnosis? Factitious disorder; self-scripted
hypoglycemia; blood analysis insulin.
reveals no elevation in C
protein.
55-year-old businessman What might be the Fear of sudden death during
complains of lack of successful cause of his problem? intercourse.
sexual contacts with women and
lack of ability to reach a full
erection. Two years ago he had
a heart attack.
15-year-old girl of normal height What is the diagnosis? Bulimia.
and weight for her age has
enlarged parotid glands but no
other complaints. The mother
confides that she found laxatives
in the daughter’s closet.
Woman presents with headache, What is the diagnosis? Prolactinoma.
visual disturbance, galactorrhea,
and amenorrhea.
43-year-old man experiences What is the diagnosis? Schwannoma.
dizziness and tinnitus. CT
shows enlarged internal
acoustic meatus.
25-year-old female presents What is the diagnosis? Multiple sclerosis.
with sudden uniocular vision
loss and slightly slurred speech.
She has a history of weakness
and paresthesias that have resolved.
10-year-old child “spaces out” in What is the diagnosis? Absence seizures.
class (e.g., stops talking
midsentence and then continues
as if nothing had happened).
During spells, there is slight
quivering of lips.
Man on several medications, What is the cause of TCA.
including antidepressants and his symptoms?
antihypertensives, has mydriasis
and becomes constipated.
Woman on MAO inhibitor What did she ingest? Tyramine (wine or cheese).
has hypertensive crisis after
a meal.
HIGH-YI E LD SYSTEMS NEUROLOGY AND PSYCHIATRY
331
332
NEUROLOGY AND PSYCHIATRY-ANATOMY AND PHYSIOLOGY
CNS/PNS Astrocytes–physical support, repair, K+ metabolism;
supportive cells help maintain blood-brain barrier. Astrocyte
marker: GFAP.
Ependymal cells–inner lining of ventricles.
Microglia–phagocytosis.
Oligodendroglia–central myelin production.
Schwann cells–peripheral myelin production.
Microglia, like macrophages, originate from
mesoderm. All other CNS/PNS supportive
cells originate from ectoderm.
Microglia CNS phagocytes. Mesodermal origin. Not readily HIV-infected microglia fuse to
discernible in Nissl stains. Have small irregular form multinucleated giant
nuclei and relatively little cytoplasm. In response cells in the CNS.
to tissue damage, transform into large ameboid
phagocytic cells.
Oligodendroglia Each oligodendrocyte myelinates multiple CNS These cells are destroyed in
axons, up to 30 each. In Nissl stains, they appear multiple sclerosis.
as small nuclei with dark chromatin and little
cytoplasm. Predominant type of glial cell in white
matter.
Schwann cells Each Schwann cell myelinates only 1 PNS axon. Acoustic neuroma is an
Also promote axonal regeneration. example of a schwannoma.
Location commonly associated
with internal acoustic
meatus (CN VII, VIII).
Peripheral nerve Endoneurium invests single nerve fiber. Perineurium–Permeability
layers Perineurium (permeability barrier) surrounds a barrier; must be rejoined in
fascicle of nerve fibers. microsurgery for limb
Epineurium (dense connective tissue) surrounds reattachment.
entire nerve (fascicles and blood vessels). Endo = inner.
Peri = around.
Epi = outer.
NEUROLOGY AND PSYCHIATRY HIGH-YI E LD SYSTEMS
Oligodendrocyte
Astrocyte
Axon
Node of Ranvier
Oligodendrogliocyte
Nerve fibers
Epineurium
Perineurium
Endoneurium
Nerve trunk
333
Sensory corpuscles
Meissner’s Small, encapsulated nerve endings found in
dermis of palms, soles, and digits of skin. Involved
in light discriminatory touch of glabrous (hairless)
skin.
Pacinian Large, encapsulated nerve endings found in deeper
layers of skin at ligaments, joint capsules, serous
membranes, mesenteries. Involved in pressure,
coarse touch, vibration, and tension.
Merkel’s Cup-shaped nerve endings (tactile disks) in dermis
of fingertips, hair follicles, hard palate. Involved
in light, crude touch.
Inner ear Consists of a series of tubes in the temporal bone Peri–think outside of cell (Na+).
(bony labyrinth) filled with perilymph (Na+ rich, Endo–think inside of cell (K+).
similar to ECF) that includes cochlea, vestibule, Endolymph is made by the stria
and semicircular canals. Within the bony vascularis.
labyrinth is a 2nd series of tubes (membranous Utricle and saccule contain
labyrinth) filled with endolymph (K+ rich, maculae–detect linear
similar to ICF) that includes cochlear duct acceleration.
(within the cochlea), utricle and saccule (within Semicircular canals contain
the vestibule), and semicircular canals. Hair cells Ampullae–detect Angular
are the sensory elements in both vestibular acceleration.
apparatus (spatial orientation) and cochlea Hearing loss in the elderly–
(hearing). high frequency . low
Base of the cochlea (narrow and stiff) picks up high- frequency.
frequency sound. Apex of the cochlea (wide and
flexible) picks up low-frequency sound.
Blood-brain Formed by 3 structures: Other barriers include:
barrier 1. Tight junctions between nonfenestrated 1. Blood-testis barrier
capillary endothelial cells 2. Maternal-fetal blood
3. Basement membrane barrier of placenta
2. Astrocyte processes
Glucose and amino acids cross by carrier-mediated
transport mechanism.
Nonpolar/lipid-soluble substances cross more
readily than do polar/water-soluble ones.
A few specialized brain regions with fenestrated
capillaries and no blood-brain barrier allow
molecules in the blood to affect brain function
(e.g., area postrema–vomiting after chemo) or
neurosecretory products to enter circulation
(e.g., neurohypophysis–ADH release).
HIGH-YI E LD SYSTEMS NEUROLOGY AND PSYCHIATRY
Cochlear
duct
Membranous labyrinth
Semicircular canals
Utricle
Saccule
Ampullae
Basement
membrane
Astrocyte foot
processes
Tight
junction
Capillary
lumen
334
NEUROLOGY AND PSYCHIATRY-ANATOMY AND PHYSIOLOGY (continued)
Hypothalamus Thirst and water balance (supraoptic nucleus). The hypothalamus wears TAN
functions Adenohypophysis control via releasing factors. HATS.
Neurohypophysis releases hormones synthesized in
hypothalamic nuclei.
Hunger (lateral nucleus–destruction . anorexia If you zap your ventromedial
and starvation) and satiety (ventromedial nucleus, you grow ventrally
nucleus–destruction . hyperphagia and obesity). and medially.
Autonomic regulation (anterior hypothalamus
regulates parasympathetic; posterior hypothalamus
regulates sympathetic), circadian rhythms
(suprachiasmatic nucleus).
Temperature regulation (posterior hypothalamus If you zap your Posterior
regulates heat conservation and production hypothalamus, you become a
when cold; Anterior hypothalamus Poikilotherm (cold-blooded
coordinates Cooling when hot). snake).
Sexual urges and emotions (Septal nucleus– A/C = anterior cooling.
destruction . rage).
Posterior pituitary Receives hypothalamic axonal projections from Oxytocin: oxys = quick; tocos =
(neurohypophysis) supraoptic (ADH) and paraventricular (oxytocin) birth.
nuclei.
Thalamus Major relay for ascending sensory information
that ultimately reaches the cortex.
Lateral geniculate nucleus (LGN)–visual. Lateral for Light.
Medial geniculate nucleus (MGN)–auditory. Medial for Music.
Ventral posterior nucleus, lateral part (VPL)
–body sensation (proprioception, pressure,
pain, touch, vibration via dorsal columns,
spinothalamic tract).
Ventral posterior nucleus, medial part (VPM)
–facial sensation (via CN V).
Ventral anterior/lateral (VA/VL) nuclei
–motor.
NEUROLOGY AND PSYCHIATRY HIGH-YI E LD SYSTEMS
LGN MGN
VPM Pulvinar
VL
VPL
Mediodorsal
nucleus
Anterior nuclear group
VA
335
Limbic system Responsible for Feeding, Fighting, Feeling, Flight, The famous 5 F’s.
and sex.
Basal ganglia Important in voluntary movements and making postural adjustments.
Parkinson’s disease symptoms due to . input from the substantia nigra (leading
to . stimulation of the direct pathway and . inhibition of the indirect pathway).
[1] stimulatory
[1] inhibitory
SNc Substantia nigra pars compacta
GPe Globus pallidus externus
GPi Globus pallidus internus
STN Subthalamic nucleus
D1 Dopamine D1 receptor
D2 Dopamine D2 receptor
HIGH-YI E LD SYSTEMS NEUROLOGY AND PSYCHIATRY
(Adapted, with permission, from Kandel ER, Schwartz JH, Jessell TM. Principles of Neural Science, 4th ed. Stamford, CT: Appleton & Lange,
2000.)
D1 D2
Dopamine
Spinal
cord
Pedunculopontine
nucleus
STN
From
SNc
GPi
Putamen
Indirect
Direct
GPe
Indirect
pathway
inhibits
movement
Direct
pathway
facilitates
movement
Thalamus
Input from SNc
Motor cortex
336
NEUROLOGY AND PSYCHIATRY-ANATOMY AND PHYSIOLOGY (continued)
Cerebral cortex functions
Frontal lobe “Executive functions”–planning, inhibition, concentration, orientation, language,
functions abstraction, judgment, motor regulation, mood. Lack of social judgment is most
notable in frontal lobe lesion.
Homunculus Topographical representation of sensory
and motor areas in the cerebral cortex.
Use to localize lesion (e.g., in blood
supply) leading to specific defects.
For example, lower extremity deficit in
sensation or movement indicates
involvement of the anterior cerebral
artery (see following entry).
NEUROLOGY AND PSYCHIATRY HIGH-YI E LD SYSTEMS
Premotor area (6)
(part of extrapyramidal circuit)
Principal motor area (4)
Principal sensory areas (3, 1, 2)
Principal
visual
cortex
(17)
Frontal eye
fields (8)
Motor speech
(Broca’s) area
(44, 45)
TEMPORAL LOBE
Frontal association areas
Arcuate
fasciculus
Association areas
OCCIPITAL
LOBE
PARIETAL
LOBE
FRONTAL
LOBE
Associative auditory cortex (Wernicke´s area) (22)
Primary auditory cortex
(41, 42)
Lateral fissure
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