Pathology Metabolism Errors

Front 1

What are some inborn errors of metabolism?

Back 1

amyloidosis
lysosomal storage dz
gout

Front 2

what's the definition of amyloidosis?

Back 2

A PATHOLOGIC PROTEINACEOUS

SUBSTANCE DEPOSITED BETWEEN CELLS IN

VARIOUS TISSUES AND ORGANS OF THE

BODY IN A WIDE VARIETY OF CLINICAL

SETTINGS

Front 3

Where do congo red molecules intercalate during staining?

Back 3

between B pleated sheets

Front 4

what are the properties of amyloidosis

Back 4

form 10 nm NON-branching fibrils of indefinite length
insoluble
resistance to proteolysis
stain w/ congo red
apple green birefringence w/ polarized light

Front 5

what do all protein deposits of amyloid have in common?

Back 5

fibrillar ultrastructure
green birefringence w/ congo red staining
"crossed beta pleated sheet" xray defraction pattern

Front 6

what's the chemical nature of amyloid?

Back 6

90% fibril proteins
10% "P" component

Front 7

What's the P component of amlyoid?

Back 7

normal serum component
alpha-1 glycoprotein
EM: doughnut shaped pentagonal structure with a 90A external diameter

Front 8

What kind of proteins form amyloid?

Back 8

Ig light chains (AL)
Acute phase proteins (SAA; AA)
Transthyretin (prealbumin) AF
Beta-2 microglobulin
Beta-2 amyloid protein
hormones
keratin

Front 9

what are Ig light chains

Back 9

variable regiion of lambda and kappa. form AL amyloid

Front 10

what are acute phase proteins?

Back 10

produced by the liver in inflammatory conditions. cause AA

Front 11

whats transthyretin?

Back 11

pre-albumin.
serum carier protein for thyroid hormones and VitA (retinoic acid)
AF

Front 12

What's beta-2 microglobulin?

Beta-2 amyloid protein?

Back 12

component of MHC class I mols

transmembrane glycoprotein

Front 13

which hormones can form amyloid?

Back 13

procalcitonin, amylin

Front 14

What's AL

Back 14

amyloid of Ig origin
variable amino terminal region of light chains (5-25K daltons)
more often assoc w/ Lambda than kappa

Front 15

what's reactive systemic amyloidosis?

Back 15

SAA behaves as acute phase reactant
synthesized in the liver
increased w/ chronic inflam
incomplete cleavage of SAA produces insoluble AA intermediates

Front 16

what are some ways to classify amyloidosis?

Back 16

tissue distribution: local or generalized

primary, secondary, inherited

major fibril protein

Front 17

What's the difference b/w primary, secondary and hereditary amyloidosis?

Back 17

primary: assoc w/ B cell dyscrasias (MM, B lymphoma, Waldenstrom)

Secondary: assoc. w/ chronic inflam or tissue damage.

Front 18

what happens w/ primary amyloidosis?

Back 18

plasma cell dyscrasia--fibril (whole or frags of Ig light chains) produced by monoclonal B cell deposit in various tissues and cause organ dysfxn
assoc w/ MM in ~20% cases; monoclonal plasma cells are 5-10% of cellularity in marrow

Front 19

How is primary amyloidosis seen clinically?

Back 19

relatively rare
median age 65-70
slight male predom
Sx: fatigue/ wt loss
related to CHF, nephrotic synd, malabsorption, neuropathy
PE: hepatomegaly (1/3), purpura, edema (CHF), macroglossia (1/5), splenomegaly less common

Front 20

What tissues are affected by primary amyloidosis?

Back 20

heart, GI tract, tongue, skin , nerves

Front 21

What tissues are affected by 2ary amyloidosis?

Back 21

liver, spleen, kidneys, adrenal glands

Front 22

What's the major cause of death with amyloidosis?

Back 22

kidney faliure, deposits in glomeruli mostly
renal tubules, bld vessels also affected
Early lesions: thickening of mesangial matrix, uneven widening of BM
Late lesions: obliteration of capillary lumina and glomeruli

Front 23

How is the spleen affected by amyloid?

Back 23

"sago" spleen--deposits limited to white pulp; gross appearance of white grains (starch-like)

"lardaceous" spleen - extensive involvement of red pulp w/ sparing of white pulp

Front 24

How is the liver affected by amyloidosis?

Back 24

early lesion: deposits in space of disse, progressive encroachment on adjacent hepatic parenchyma

late: total replacement of liver parenchyma, vascular involvement and kuppfer cell deposition
*nl liver cell fxn despite severe involvement

Front 25

How is primary amyloidosis diagnosed?

Back 25

serum/urine electrophoresis, IEP

bone marrow biopsy

abd. fat pad aspirate

visceral organ biopsy (renal, liver)

gingival, rectal biopsy

Front 26

What's the outcome of primary amyloidosis?

Back 26

survival: 1-2 yrs, med 13 mo

Tx: melphenal, prednisone, colchicine

dose intensive melphalan w/ autologous growth factor-mobilized periph stem cell transpl.

Front 27

what are the characteristics of AD?

Back 27

progressive senile dementia

senile plaques

neurofibrillary tangles

B amyloid protein--precursor protein (B-APP)

amyloid angiopathy

Front 28

What constitutes senile dementia in AD?

Back 28

progressive
occurs in older individuals
memory loss, disorientation, lang dysfxn

Front 29

Neurofibrillary tangles

Back 29

composed of helical filaments in the CYTOPLASM of Neurons

visualized by silver stain

Front 30

for AL, AA, and AF fibrils, what's the precursor protein and the dz it causes?

Back 30

AL: kappa/lambda light chains; causes plasma cell dyscrasia

AA: SAA; causes inflammation, tumors (RCC, Hodgkins)

AF: transthyretin; causes FAP, cardiac, senility

Front 31

Is amyloidosis just one disease?

Back 31

No, its a group of Dz's with tissue protein deposits that have similar morphological, staining, and structural properties

very different AA sequences though

Front 32

what is seen on routine H/E stain with amyloid?

Back 32

intercellular amorphous pink material

Front 33

what is seen on EM for amyloid?

Back 33

non-branching fibrils w/ a width 7.5-10 nm

Front 34

what does x-ray crystallography tell us about amyloid?

Back 34

it shows "beta pleated sheet conformation"
any fibrillar protein in tissue like this called amyloid

Front 35

how does congo red dye stain amyloid?

Back 35

dye mols align in parallel linear config along the fibrils. when exposed to polarized light, the dye shows "Apple green birefringence"

Front 36

What's P component?

Back 36

alpha-1 glycoprotein

structural homology to CRP

Front 37

how is primary amyloidosis traditionally described?

Back 37

presence of amyloidosis w/o a detectable underlying cause

now known that most of these are due to small abnl clone of plasma cells in marrow

Front 38

what are the most commonly involved organs of amyloid?

Back 38

Kidneys (proteinuria, nephrotic syndrome)

Heart (CHF, ECG abnormalities)

Front 39

what is senile amyloidosis (heart)?

Back 39

amyloid isolated w/in the heart

cardiac dysfxn (rarely asymptomatic) including cardiomyopathy, conduction disturbances

cardiac problems = cause of death in 40%

Front 40

what's the amyloid fibril of AD?

Back 40

beta amyloid protein: degradation product of larger precursor protein (Beta-APP); found in core of senile plaques and in blood vsls

Front 41

what do lysosomes do?

Back 41

hydrolytic enzymes break down complex macromols derived exogenously (heterophagy)
or endogenously from turnover of intracell organelles (autophagy)

Front 42

which organs are especially enlarged/impaired in lysosomal storage diseases?

why?

Back 42

organs rich in macs (histiocytes):
spleen, LN's, liver

b/c cells of mononuclear phagocyte system heavily involved in lysosomal catabolism of macromolecules

Front 43

What are the 3 major categories of macromolecules that accumulate in LSD's?

Back 43

1. sphingolipids
2. mucopolysaccharides
3. glycogen

Front 44

sphingolipids:

1. examples

2. structure

3. location

Back 44

1. Sphingomyelin, cerebrosides and gangliosides.

2. Combos of sphingosine (long chain amino alcohol), esterified FA's and complex carbs

3. abundant in brain and nerve tissue membranes

Front 45

Mucopolysaccharides:
1. function
2. examples
3.structure

Back 45

1. compromise much of ground substance of CT
2. heparan/dermatan/keratan/chondroitin
sulfate
3. long, linear polymers of glu and gal

Front 46

glycogen:
1. structure
2. 2 pathways of degradation
3. which one, when defective leads to a lysosomal storage dz?

Back 46

1. long branched polysac of glu
2. main pathway: in cytoplasm via phophorylases, debranching enzyme,etc. Also degraded in lysosome (acid maltase)
3. latter pathway leads to LSD when defective

Front 47

What are 3 major Lysosomal Storage Diseases?

How are they inherited?

Back 47

1. Tay Sachs Dz
2. Niemann-Pick
3. Gaucher's

all Autosomal Recessive

Front 48

Tay Sachs Dz:
deficient enzyme?
accumulated substrate?
major organs affected?

Back 48

Hexosaminidase A
GM2 ganglioside
neural tissues and retina (cherry red spot - also seen in niemann-pick)

Front 49

Tay Sachs:
inheritance?
most common?

Back 49

AR
most common in Ashkenazi Jews
heterozygous carrier rate 1:30

Front 50

Histology of Tay Sachs?

Back 50

neurons w/ cytoplasmic vacuoles (distended lysosomes)

EM: look like whorled inclusions (layers of membranes)

Front 51

How does Tay Sachs present clinically?

Back 51

nl birth, sx by 6 months
motor/mental deterioration, muscle flaccidity, obtundation, blindness ("amaurotic familial idiocy")
death in 2-3 yrs

Front 52

how is tay sachs diagnosed?

Back 52

antenatally by assessing hex A in cultured fibroblasts obtained from amniotic fluid

Front 53

what's amaurotic familial idiocy?

Back 53

blindness that occurs after 6 months seen in Tay Sachs disease

Front 54

what's the deficient enzyme in Niemann-Pick?

Back 54

sphingomyelinase:
Type A (75-80%)
Type B

Front 55

whats the accumulated substrates in Niemann Pick?

Back 55

sphingomyelin and cholesterol

Front 56

which major organs are affected in Niemann-Pick?

Back 56

Reticuloendothelial system (spleen, liver, LN, marrow, GI)
Type A: brain involved
Type B: organomegaly w/o CNS involvement

*spleen can be 10X nl size!

Front 57

what does the histology of Niemann-Pick show?

Back 57

Macs w/ foamy cytoplasm (numerous small vacuoles)

EM: concentric "myelin" figures (Zebra bodies)

in type A: brain neurons are vacuolated and degenerated

Front 58

what are Zebra bodies?

Back 58

seen on EM in some LSDs (e.g Niemann-Pick)

concentric "myelin" figures

Front 59

clinical presentation of Niemann-Pick?

Back 59

present by 6 mo (maybe at birth)
protuberant abd, fail to thrive, organomegaly, deteriorating motor fxn, skin xanthomas (chol, lipid in skin macs), "cherry red spot" (30-50%)
death by 3 yo

Front 60

when can Niemann Pick be detected?

Back 60

antenatally (like Tay Sachs)

present clinically at birth or by 6 months

Front 61

what's the deficient enzyme in Gaucher's dz?

accumulated substrate?

Back 61

glucocerebrosidase (cleaves glu from ceramide)

glucocerebroside

Front 62

what organs are majorly affected by Gaucher's Dz?

Back 62

Reticuloendothelial cells in spleen, LNs, marrow (sometimes neurons of brain too)

Front 63

what's the histology seen w/ Gaucher's Dz?

Back 63

"Gaucher's cells" in spleen, liver, marrow
NOT vacuolated (unlike other LSDs)
have fibrillary cytoplasm (crinkled tissue paper)

on EM: stacks of lipid in lysosomes

Front 64

What are the 3 clinical subtypes of Gaucher's?

Back 64

I (Classic): adult, non cerebral, spleen and bone, 80% jews, decreased enzyme, longevity shortened somewhat
type II: infantile, mostly cerebral, no jews, NO enzyme detectable, early death
type III: intermed b/w 1,2; juveniles w/ systemic like I but CNS by 2nd/3rd decade. intermediate enzyme level

Front 65

what's the cause of mucopolysaccharidoses (MPS)?

How many clinical variants are there?

Back 65

deficient enzymes to degrade GAGs (ground substance)

MPS I to VII

MPS I= Hurlers syndrome

Front 66

what's the deficient enzyme of mucopolysaccharidoses?

accumulated substrate?

major organs affected?

Back 66

alpha-L-iduronidase

heparan and dermatan sulfate

liver, spleen, brain, heart, blood vessels

Front 67

what's the histology look like w/ mucopolysaccharidoses?

Back 67

"balloon cells"
MPS in phagocytes, endothelium, sm musc cells, neurons, fibroblasts

EM: lamellated structures in neurons (Zebra bodies - like Niemann Pick)

Front 68

what's the clinical syndrome seen w/ mucopolysaccharidoses?

Back 68

hepatosplenomegaly, skeletal deformities, cardiac valvular lesions, coronary artery deposits, brain lesions

death by MI or cardiac decompensation

prenatal dx possible

Front 69

what causes glycogenoses?

Back 69

a deficiency in any of the enzymes involved in glycogen catabolism:
1. hepatic form
2. myopathic form
3. Pompe's dz

Front 70

Hepatic form of glycogenoses?

what's a major dz?

Back 70

liver key organ for glycogen metab
deficient glu-6 phophatase causes Von Gierke's dz
glycogen accumulates in all tissues
hepatomegaly and hypoglycemia
50% mortality

Front 71

myopathic form of glycogenoses?

Back 71

glycogen imp't for musc energy. enzyme def means muscle weakness

McArdle's Dz: def muscle phosphorylase--causes pain/cramps w/ exercise; no elevated lactate levels
nl longevity

Front 72

Pompe's dz?

Back 72

lysosomal enzyme def of acid maltase (alpha glucosidase)
widespread glycogen depostion in all organs
cardiomegaly most prominent
cardiorespir. failure in 2 yrs
milder adult form--sk musc only and chronic myopathy

Front 73

name the cause of the following dz's:
1. Von Gierke's dz
2. McArdle's
3. Pompe's

Back 73

all glycogenolyses:
1. glu-6 phosphatase deficiency; hepatomegaly and hypoglycemia
2. musc phosphorylase def; cramps,pain w/ exercise, no lactate levels
3. def acid maltase; cardiomegaly and failure in 2 yrs

Front 74

what does the precipitation of monosodium urate crystals cause in:
1. joint fluid
2. soft tissue
3. kidney

Back 74

gout:
1. acute and chronic arthritis
2. tophi
3. urate nephropathy nephrolithiasis

Front 75

what's gout?

Back 75

disorder of uric acid metabolism leading to hyperuricemia and precipitation of monosodium urate crystals in joints, soft tissue, and kidneys

Front 76

who is most often affected by gout?

Back 76

middle aged and older males
postmenopausal women

rare in children

Front 77

what's primary gout?

Back 77

basic metabolic defect causing hyperuricemia and gout unknown
(90% of all cases)

secondary: due to known genetic or acquired disorder

Front 78

what are 3 mechanisms leading to hyperuricemia?

Back 78

1. overproduce UA w/ nl excretion
2. overproduce UA w/ increased excretion
3. nl production of UA w/ under excretion

xs production 2/3 of pts

Front 79

lesch-nyhan syndrome

Back 79

deficiency of HGPRT (salvage pathway of purine synth)
results in hyperuricemia
x.s. excretion of UA

severe neuro impairment and self mutilation

Front 80

secondary gout

Back 80

due to known genetic or acquired disorder (10%):
usually caused by incr production of UA due to incr turnover (secondary to leuk, lymphoma, etc) or chronic renal dz (decr excretion)

Front 81

3 major features of gout?

Back 81

1. acute arthritis
2. chronic arthritis
3. tophus

Front 82

pathology of acute arthritis caused by gout

Back 82

inflammatory synovitis caused by UA crystal depostion and phagocytosis by polys which relase hydrolytic enzymes, cytokines
great toe (90% of pts)

Front 83

pathology of chronic arthritis caused by gout

Back 83

from repeated bouts of acute arthritis
articular cartilage becomes encrusted w/ UA crystals: progressive erosion of cart/bone
synovium proliferates: pannus formation and joint deformity

Front 84

pathology of tophus caused by gout?

Back 84

mass of urates, crystalline and amorphous, surrounded by intense IR of macs, lymphs, fibros, giant cells
mostly in the ear, olecranon, patellar bursae, periarticular ligs
involve skin, nasal cart, aorta, cardiac valves LESS common
NOT in CNS (urate can't X BBB)

Front 85

how is the kidney involved w/ gout

Back 85

1. acute UA nephropathy--intratubular deposits of free UA cause obstruction
2. nephrolithiasis-stones in collecting ducts (excrete >1100mg/d)
3. chronic urate nephropathy-urates in interstitium of kidney (medulla) cause microtophi

Front 86

3 clinical stages of gout?

Back 86

1. asymptomatic hyperuricemia
2. acute gouty arthritis- flare up then remission (months to yrs)
3. chronic tophaceous gout- peristent, disabling joint dz after many acute attacks

~20% of pts w/ chronic gout die of renal failure

Front 87

what's the prognosis for pts w/ chronic gout?

Back 87

~20 pts w/ chronic gout die of renal failure

Front 88

what kind of systemic amyloid is seen in the context of MM or B cell lymphoma?

fibril?

source?

Back 88

primary (idiopathic)

AL

immunoglobulin light chains

Front 89

what kind of systemic amyloidosis is seen in the context of chronic infection?

fibril?

source?

Back 89

secondary (reactive)

AA fibril

from SAA

Front 90

what kind of systemic amyloidosis is seen in the context of familial amyloidotic polyneuropathy?

source?

Back 90

heredo-familial (type of systemic amyloidosis)

from trans-thyretin

Front 91

what kind of systemic amyloidosis is seen in the context of long-term dialysis (carpal tunnel syndrome)?

Source?

Back 91

hemo-dialysis type systemic amyloidosis

from beta-2 microglobulin

Front 92

what are the 4 types of systemic amyloidosis?

Back 92

1. primary (idiopathic): AL from Ig
2. Secondary (reactive): AA from SAA
3. heredo-familial: from trans-thyretin
4. hemo-dialysis: from beta-2 microglobulin

Front 93

what are the 3 types of localized amyloidosis?

Back 93

1. senile (cardiac): from trans-thyretin
2. senile (cerebral): from beta-2 amyloid protein
3. endocrine: from calcitonin, insulin, or glucagon

Front 94

what type of localized amyloidosis is seen in the heart?

source?

Back 94

senile (cardiac)

from trans-thyretin

Front 95

what type of localized amyloidosis is seen as deposits in the brain/alzheimers?

source?

Back 95

senile (cerebral)

from beta-2 amyloid protein

Front 96

what type of LOCALIZED amyloidosis is seen in the context of endocrine tumors?

source?

Back 96

endocrine type localized amyloidosis

from calcitonin, insulin, glucagon