09/19/2014

usmle step 1 exam guide first aid liver, gallbladder, pancreas

By Live Dr - Mon Dec 01, 1:24 am

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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