Mak Flashcards
(221 cards)
1
Q
variant
A
general term for any change regardless of frequency
2
Q
polymorphism
A
variant allele/DNA sequence that is present in greater than one percent of the allelic population
3
Q
single gene (or monogenic) inheritance
A
trait/disease phenotype in these cases is dictated by one gene (i.e. cell surface antigens, dystrophin, phenylalanine hydroxylase)
4
Q
simplest case of inheritance
A
**single gene** having two different alleles in a population
5
Q
Allelic constitution
A
configuration of alleles at a given locus
6
Q
heteroallelic
A
two defective alleles are present
7
Q
Allelic heterogeneity
A
different alleles at the same locus which gives rise to the same or similar disease (i.e. CF, Muscular Dystrophy)
8
Q
Locus heterogeneity
A
genes at different loci that cause the same or similar disease (i.e. PKU)
9
Q
polygenetic inheritance
A
number of genes interact to render phenotype
10
Q
Genetic Background
A
all other genes that influence the action of the gene in question
11
Q
multifactorial inheritance
A
***most human traits/disorders*** Environmental and genetic factors combine to produce a phenotype
12
Q
Fragile X syndrome
A
purely allelic heterogeneity, no multifactorial CGG repeat on FMR1 most common hereditary form of MR
13
Q
Penetrance
A
***either/or*** the probability of manifesting a trait given the presence of an allele or set of alleles
14
Q
what determines the outcome of penetrance?
A
modifier gene
15
Q
incomplete penetrance
A
only possible in Dominant inheritance ***polydactyly, Fragile X***
16
Q
complete penetrance examples
A
homozygous CF, Huntingtons disease
17
Q
%penetrance
A
cases with pheno / # cases with geno
18
Q
retinitis pigmentosa
A
true polygenic inheritance peripherin and ROM1
19
Q
fragile X in men
A
moderately retarded, have large testes (macroorchidism), large heads, large protruding ears, prominent jaw and stubby hands. Speech development is delayed
20
Q
fragile X in women
A
tend to be shy and show some learning disorders
21
Q
****fragile X phenotypic variation in women due to***
A
***extreme lionization***
22
Q
what inheritance is Fragile X
A
X-dominant with incomplete penetrance
23
Q
Sherman paradox
A
seen in FragX position in the pedigree in part determines the risk of developing the syndrome (sister less chance than granddaughter)
24
Q
premutation alleles
A
of repeats in genotypically affected individual that allows them to be phenotypically normal ( btwn 50-200 in Fragile X)
25
highest range of repeats correlates well with
absence of the FMR1 mRNA and the presence of clinical disease.
26
\*\*\*\*there is a correlation between\*\*\*\*
increased repeats in permutation alleles and frequency of expansion to full mutation
27
nonpenetrant transmitting male (NTM)
pheno normal man who passes disease on
28
where is FMR1 abundant
brain and testes
29
anticipation
apparent worsening of the diseases over several generations (huntingtons, myotonic dystrophy)
30
variable expressivity
the \*\*\*range\*\*\* of phenotypic manifestations of the same genetic disorder (or of the same genotype)
31
expressivity versus penetrance
expressivity refers to the \*\*\*type or degree of manifestation\*\*\* of a gene that is a penetrant
32
variable expressivity example
neurofibromatosis (polygenic inheritance) \*\*\*variable phenotype even in those with same mutation\*\*\*
33
uniparental disomy
resulting zygote will have a euploid chromosome number but (at least) two chromosomes (e.g. two maternal chromosome 15s) were \*\*\*inherited from the same parent\*\*\*
34
genomic imprinting
genes activated or inactivated in a sex-specific manner (prader willi, angelman sx)
35
genomic imprinting can cause
uniparental disomy leading to a gene being present in either 2 active or inactive doses which can lead to functional imbalance
36
prader-willi sx
obesity, hypogonadism, \*\*maternal 15q\*\*
37
angelman sx
severe MR, spasticity, \*\*\*paternal 15q\*\*\*
38
multifactorial traits (complex traits)
have both a genetic and an environmental basis
39
quantitative traits
continuous spectrum of phenotypes that are measured by numerical biometry methods.
40
normal human traits affected by number of genes and environ factors
skin and hair color, height, weight, blood pressure, intelligence
41
threshold traits
only occur when a threshold is reached, doesn't appear to follow bell curve pyloric stenosis, neural tube defects, CVD, cleft lip, a1-antitrypsin deficiency rltd lung disease
42
key features of multifactorial disease #1 (MFD)
family studies suggest inheritance, but no mendelian relation
43
lambda(r)
disease prevalence in relatives / disease prevalence in gen pop
44
key features of multifactorial disease #2
risk to 1\* family member is square root of gen pop frequency
45
key features of multifactorial disease #3
risk declines rapidly for more remote relatives (versus AD where it only declines by half)
46
key features of multifactorial disease #4
for traits with sex-dependent liabilities, the recurrence risk is higher when the \*\*\*less commonly affected sibling\*\*\* is the \*\*\*proband\*\*\* (bc has higher level of genetic liability)
47
MFD examples
alzheimers
48
Alzheimers path
\*\*\*locus heterogeneity\*\*\* mutations in presenilins and APP lead to overprod. of AB peptide and the early onset forms of the disease
49
phenotypic variance equation
Vp = Vg + Ve (g= genotype; e= environment)
50
heritability
proportion of the observed variance due to genes Hb= Vg/Vp
51
concordance form of heritability (dichotomous traits)
(percentMZ - perDZ) / (100- perDZ)
52
population genetics
study of the distribution of alleles in populations and the factors that maintain or alter allele frequencies.
53
Hardy-Weinberg equation
p2 + 2pq + q2 = 1 p = BB q= bb
54
Hardy-Weinberg equation use
freq. of given genotype from the freq. of alleles at given locus
55
allele freq. equation
num of specific allele / total number of all diff. alleles
56
Hardy-Weinberg law
genotypes will be distributed in a population based on the allele frequencies and the genotype frequencies will remain constant from generation to generation
57
Hardy-Weinberg requirements
random mating, large population, neglible mutation rate/amnt of migration/slection
58
Consanguineous matings
nonrandom mating resulting in increased homozygous genotypes
59
stratified population
one having subgroups that do not intermarry. (Basis can be culture, economic status, race, religion etc)
60
assortative mating
choice of mate based on phenotype (intelligence, stature, skin color, musical talent etc); inc homozygous
61
random matings versus nonrandom frequencies
random: AA = p2 = 0.25, Aa = 2pq = 0.50, aa q2 = 0.25 nonrandom: AA = 0.50, Aa = 0, aa = 0.50
62
why does it need to be a large population
dec. chance of only one allele being passed down (genetic drift)
63
genetic fitness
probability of transmitting one's genes to the next generation
64
spontaneous mutation rate
m= (s)(q)
65
genetic drift
est. of new alleles or frequencies that can cause formation of subpop in gen pop
66
selective disadvantage (s)
1-f f= fitness
67
founder effect
group of colonists do not have the same allele frequencies as their original population or the population they move into
68
principle of toxicology
dose dictates toxicity
69
Which LD50 is more toxic? 0.5 or 50?
0.5
lower the LD, more toxic
70
carbon monoxide sources
car exhauts, fires, cigarettes, biotransformation of paint removers (methylene chloride)
71
CO method of tox
CO binds Fe2+ to form carboxyhemoglobin
**cherry red color in mucus membranes**
72
target organ of CO poisoning?
globus pallidus in cerebellum
73
cyanide exposure
all physical forms
occupational, bitter almonds, fruit pits, fires
74
cyanide mechanism of toxicity
mitochondrial toxin, inhibiting ETC
binds **ferric (Fe3+) iron** of mito cytochrome oxidase
75
CN sx
very rapid, convulstions, etc
76
CN tx STEP 1
administor nitrite to create additional Fe3+ (methemoglobin)
77
CN tx step 2
administor thiosulfate to create SCN, which is easily excreted
78
methemglobinemia tx
methylene blue
79
organophosphate insecticides
diazinon, malathion
80
organophosphate mech of tox
inhibit acetyhlcholine esterase
**S**alivation, **L**acrimation, **U**rination, **D**efectation
Miosis, wheezing
81
organophosphate nicotinic sx
muscle twitching, elevated HR/BP
82
organophosphate tx vs. carbamate tx
Atropine for both
**PAM-2** **only for organophosphates**
83
carbamate (carbaryl) toxicity
inhibits acetylcholine esterase but clears faster in water than organophosphates
84
paraquat toxicity
free radicals and lipid peroxidation
causing **chronic** **pulmonary fibrosis**
_death is multi-organ failure_
85
paraquat dx
qualitative test of sodium dithionite in 2N NaOH **turns blue**
86
benzene toxicity
cns depression and cancer
87
why is toluene preferred
methyl group prevents future cancer risk
88
which type of PKU requires both dietary restriction and neurotransmitter precursor replacement
Type II (DHPR deficiency) and III (biopterin deficiency)
89
which diseases are treated at the protein level?
hemophilia and AAT
90
modification of somatic genome through bone marrow transplantion diseases
gaucher, hunter, hurler's syndromes
91
autoimmune hepatitis definition
chronic, progressive idiopathic hepatitis that if untreated can lead to cirrhosis
responds well to immunosupression
92
autoimmune hepatitis lab results
elevated ALT, AST
serum autoantibodies
necroinflammatory activity on liver biopsy
93
who does autoimmune hepatitis affect?
white northern european females
94
Type 1 autoimmune hepatitis
middle aged, most common US
ANA, ASMA
95
Type II automimmune hepatitis
kids, S. Europe
Anti-LKM-1
96
PBC
primary biliary cirrhosis
97
PSC
primary sclerosing cholangitis
98
Overlap syndrome
clinical and histologic features of both AIH and (PBC or PSC)
99
AIH sx
acute hepatitis, concurrent autoimmune conditions (i.e. thyroid, arthritis), fulminant with encephalopathy
100
What should you see on histology of AIH?
rosette formation, plasma cells, bridging necrosis
101
AIH tx
immunosuppression (80% remission)
liver transplant (75%)
102
cholestatic xenobiotic
contraceptive
103
hepatocellular necrosis xenobiotic
acetaminophen
104
fatty liver disease xenobiotic
ethanol, methotrexate
105
steatohepatitis with **mallory denk bodies**
ethanol
106
fibrosis and cirrhosis xenobiotics
alcohol and methotrexate
107
hepatocellular adenoma xenobiotic
oral contraceptives
108
hepatocellular carcinoma
alcohol
109
acetaminophen
predictable hepatotoxin
most common of acute liver failure needing transplantation
**coagulative necrosis and ballooning degeneration**
110
oral contraceptives
feathery degeneration
111
leading cause of liver disease?
alcoholic liver disease
112
alchoholic hepatic steatosis
enlarged, greasy liver with macro- and micro-vesicular fat changes
increased synthesis of lipids and peripheral fat catabolism; abnormal LPLs
113
mallory denk bodies
**alcoholic hepatitis**
thick, ropy perinuclear eosinophilic inclusions (cytokerating IFs)
114
alcoholic hepatitis neutrophilic rxn
infiltrate in areas of hepatic necrosis
## Footnote
**produce free radicals**
115
alcoholic hepatocellular steatosis
shunting of normal substrates towards lipid synthesis instead of catabolism
W/ increased PERPH catabolism of FAT
116
NAFLD (non alcoholic fatty liver)
most common chronic liver disease
## Footnote
**dx by liver biopsy**
117
explain the relationship btwn hepatic steatosis, hepatitis, and cirrhosis
see image
118
alcoholic cirrhosis gross/histo
gross: shruken, diffusely nodular, firm
micro: nodules of hepatocytes surrounded by fibrous bands
119
alcoholic labs (chronic)
elevated bilirubin, ALP and neutrophilia
## Footnote
**AST/ALT 2:1 or more**
120
alcoholic steatofibrosis
**most important consequence of injury**
**"chicken wire" fibrosis** (perisinusoidal, pericellular fibrosis)
121
grade vs. stage of NAFLD
grade: deg. of inflammation, necrosis, steatosis
stage: degree of fibrosis
122
NASH (non-alcoholic steatohepatitis)
see in NAFLD
**most common cause of elevated liver enzymes today**
most rapidly progressing version
123
NAFLD steatosis
greater than 5% fat cells
elevated liver enzymes
**no inflammation, cell death, or fibrosis**
124
NAFLD histo
ballooned hepatocytes, macrovesicular steatosis
125
NAFLD sx and labs
fatigue, URQ pain w/ NO hx of excess alcohol consumption
**AST/ALT ratio less than 1**
126
NAFLD 2 hit hypo
**first hit: insulin resistance**
⇒
hepatic stenosis
**second hit: hepatocellular oxidative injury**
⇒
NAFLD
127
Insulin Resistance changes
decreased adiponectin, increased cytokines, fat cell apoptosis
128
pediatric NAFLD
more diffuse steatosis, portal fibrosis, **mononuclear** inflammatory cells
129
cholelithiasis risk factor
forty, fertile, female, fat
130
cholesterol stones
**only in GB**
**radiolucent if pure cholesterol!!!**
**native americans**
131
pigment stones
non-western countries
bacterial infections
**inorganic Ca + unconjugated bilirubin**
132
biliary colic
after meal, stones pushed against outlet of GB
RUQ, epigastric pain radiating to shoulder
133
acute cholecystitis
stone obstruction, **emergent cholecystectomy**
## Footnote
**serosa w/ fibrinous exudate**
**Acalculous cholecystitis (no stones inv.)- may occur in severly ill**
134
acute cholecystitis sx
RUQ, epigastric pain \>6 hours, fever, n/v, tachycardia, diaphoresis,
No jaundice, **if +, common bile duct is obstructed = sign. location for stones/obstruction!!**
135
chronic cholecystitis
subserosal fibrosis, gray-white wall
chronic inflamm w lymphoid follicle formation
**Rotinkansky-Aschoff Sinuses!!!**
136
**porcelain gallbladder!?**
white/crunchy due to dystrophic calcifications
## Footnote
**cancer risk!!**
137
von meyenberg complexes
hamartomas of ductal structures in hyalinized stroma
assoc. with **PCLD**
138
caroli's disease
congenital, non obstructive, multifocal segmental dilatation of intrahepatic ducts
**cholangiocarcinoma risk**
139
caroli's syndrome
disease + congenital hepatic fibrosis
140
Caroli's disease sx
late childhood
chronic recurrent fever, pain, jaundice
**incr. ESR, biliary enzymes**
141
explanted liver
caroli disease
subcapsular dilated bile duct (bottom arrow)
142
cholangitis
caroli disease
dilated bile duct, concretion, debris
143
Alagille Syndrome
rare AD, JAG1/Notch2 mutations
syndromic **paucity** of interlobular bile ducts due to deficient bile flow
tx with liver transplant
144
Alagille Syndrome sx and labs
cholestasis, pruritus, xanthomas @ 6 mo to 5 yrs
**conjugated** hyperbilirubinemia
CGT/ALP elevation
HLP
145
Hepatic Artery compromise
infarcts of liver
coagulative necrosis + inflamed, hyperemic borders
146
hepatic infarct of zahn
atrophy and hemostasis with **no necrosis**
147
portal HTN
cirrhosis w/ assoc. esophageal or periumbilical varices
148
Rt sided cardiac decomp
congestion of liver and centrilolobular sinusoids
atrophic liver cell plates
149
lt sided decomp
centrilobular necrosis, ischemic coagulative necrosis
150
systemic circulatory decomp
like left sided + **nutmeg liver**
151
nutmeg liver
central vein red, parenchyma tan brown
152
peliosis hepatis
due to impaired flow w/in liver due to toxins
blood filled cysts, incomplete endothelial lining
153
Budd-Chiari syndrome
thrombosis of **2 or more major** hepatic veins or IVC
due to increased tendency to clot (genetic or pregnancy)
154
sinusoidal obstruction syndrome
fibrotic occlusion of small hepatic veins with endothelial injury due to herbal teas
155
focal nodular hyperplasia
vascular malformation of AV anastomoses w/ localized overgrowth of liver components
**central stellate scar w/ blood vessels**
*no malignant potential!*
156
nodular regenerative hyperplasia
transformation of entire liver into mult. nodules **without** fibrous septa bwn them
due to heterogeneous microcirculation
157
hepatocellular adenoma
benign, women on OC
solitary yellow w/ sheets and cords of normal liver cells
158
liver cavernous hemangioma
most common benign
discrete subcap red-blue soft nodules
vasc lesion
159
Kasabach merritt syndrome
microangiopathic anemia with consumption coagulopathy and liver cavernous hemangioma
160
hepatocellular carcinoma
AFP increased
## Footnote
**propensity for vascular invasion ► intrahepatic metastasis**
161
fibrolamellar HCC
better outcome, no underlying disease/cirrhosis
younger people
162
liver cholangiocarcinoma
**thorotrast RF**
located at hilar (**Klatskin tumor**), cause biliary obstruction sx
163
hepatoblastoma
most common in kids
assoc. Beckwith-Wiedemman, FAP
164
what viral infection is worsened in pregnant women?
HEV
165
preeclampsia
maternal HTN, proteinuria, edema, clotting abnorm
166
eclampsia
preeclampsia + hyperreflexia and convulsions
167
H.EL.LP syndrome
hemolysis, elev. liver enzymes, low platelets
168
acute fatty liver in pregnancy
defect in mito FA b-oxidation
**microvesicular steatosis**, scant inflammation, necrosis
169
intrahepatic cholestasis of pregnancy
***pruritus + marked inc bile salts***, darkening urine, lightening stools
**centrilobar cholestasis**
170
what order are HBV serologic antigens detected?
1. Hb**s**Ag
2. Hb**e**Ag (chronic, *vertical transmission to baby possible)*
3. anti- HB**c** (*IgM (acute) IgG (chronic)*)
4. anti-HB**e** (*_window period)_*
5. anti-hb**S** (***_lifelong, vaccine)_***
171
teenage girl with depression and brown-ringed corneas
Wilson's disease
**Kayser-Fleischer ring** is diagnostic
172
What is this?
onion skin fibrosis
PRIMARY SCLEROSING CHOLANGITIS
173
What is this?
apoptotic body
## Footnote
**hepatitis**
174
what is this?
interface hepatitis (spillover of portal inflammatory cells beyond limiting plate, into lobule)
175
what is this?
macrovesicular fatty change
alcoholic or nonalcholic steatohepatitis
176
what is this?
mallory denk bodies
alcoholic hepatitis
177
most common reason for liver transplanation in kids?
biliary atresia (one or more bile ducts are abnormally narrow, blocked, or absent)
178
most common metastases to liver
colon
(secondary much more common than primary liver ca)
179
most common cause of hepatitis
viral hepatitis
180
young categories
1. neonate: 0-4 weeks
2. perinatal: 26th week gestation to 1 month postpartum
3. infant: 5-52 weeks post birth
1. child: greater than 1 yo
181
neonate/infant subq/IM injections
absorption dependent on perfusion, low muscle mass
182
neonate/infant enteral distribution
within hrs of birth, significant changes in gastric pH
first 2 days, gastric emptying is delayed
183
altered oral drug absorption in neonate/infant
congential HD, RDS, CHF, short bowel syndrome, thyroid disease
184
neonate/infant renal function
GFR is much less than in adults. adult levels 6+ months
185
neonate drug metabolism
depends on drug tx or environ. exposure of mom
P450 decreased initially
conjugation rxns diminished (**glucuronide)**
186
neonate/infant plasma protein binding
decreased plasma protein binding (**affinity for acidic anionic drugs**)
displacement of drugs by bilirubin (**phenytoin, indamethicin**)
187
why is there problems during tx of the elderly?
change in pharmacokinetics and pharmacodynamics
188
elderly absorption changes
dec gastric acid secretion: dec abs. of ferrous sulfate and ketoconazole
antacids: dec abs of cimetidine, digitalis, tetracycline, phenytoin
189
Vd changes in elderly
Vd lipid soluble, half life: **increased** (*amiodarone, diazepam*)
Vd water soluble, Vd muscle binding: **decreased** (*ethanol, digoxin*)
190
drug clearance in elderly
**decreased** if Phase **I** dependent
**no change** if Phase **II** dependent
191
elderly pharmacodynamic changes
changes in receptor binding, receptor number, or altered receptor-initiated translations
192
digoxin
**lower renal elimination** in elderly,
+diuretics worsen
193
diuretics
greater risk of electrolyte depletion
194
psychoactive drugs
atypical and typical dopamine antagonists **black box warning**
195
Why are heavy metals dangerous?
\*\*\*accumulation\*\*\*, extremely long half lives so toxic in small, repeated doses
196
**Ca** disodium EDTA
**IV and IM inj.**
**lead encephalopathy** and cadmium
**contraindicated in renal disease**
197
**disodium EDTA**
used for **hyper**calcemia
198
succimer (meso-2,3-dimercaptosuccinic acid)
sulfur groups bind, PO, lead
tastes bad, nausea
199
dimercaprol (BAL)
lead, arsenic, **inorganic mercury**
admin IM w/ **peanut oil**
**contraindicated in liver disease**
***_both urine AND BILE excretion_***
200
penicillamine
PO, dont use in renal
## Footnote
**Wilson's disease tx**
**ADR: agranulocytosis**
201
what do you test for lead poisoning
**whole blood** not plasma!
\>75% of lead bound to Hb
202
lead poisoning sx
**lead colic, lead palsy, lead encephalopathy (cerebral edema)**
microcytic anemia, muscle weakness, memory loss
203
what's the most sensitive indicator of lead toxicity and why?
**hematologic**
**lead inhibits heme synthesis ► binds _d-aminolevulinate dehydratase_ *_in cytsol_*** and _**ferrochelatase *in mitochondria***_
204
how is mercury toxic/
**binds sulfhydryl groups**
205
Minamata disease
**methylmercury** toxicity leading to **permanent weakness, visual field constriction, ataxia and numbness**
**inorganic** mercury taken up by algae ►fish
206
what is contraindicated in **methyl** mercury poisoning
dimercapol, increases brain levels
207
arsenic toxicity sx
**rice water diarrhea (loss of albumin ► gelatinous diarrhea)**
208
chronic arsenic toxicity
**hyperkeratosis, arrythmia, hepatomegaly, garlic odor, mee's lines on nails (*horizontal*)**
209
cadmium sx
**emphysema due to inhalation**
210
cadmium tx
**disodium EDTA**
***BAL contraindicated, increases renal toxicity***
211
cadmium monitoring
**monitor urinary B2-microglobulin due to occupational exposure**
212
itai itai disease
**accidental ingestion of cadmium**
213
wilson's disease
high copper levels due to ATP7B defect
## Footnote
**penicillamine**
214
absorption
drug/drug or drug/food can cause altered pH, transport, chelation, or metabolism
## Footnote
**consider staggering dose**
215
antacid absorption interactions
prevents tetracycline absorption
216
cholestyramine interactions
digoxin, warfarin
217
gastric transit time
**changes rate, but not extent**
***shift in peak NOT in bioavailabilty***
218
h2 antagonists
decrease ketoconazole and intraconazole absorption
219
PPI
dec. atazanavir, and -conazole absorptions
220
PGP
ATP dep. mol. transport, "gatekeeper of metabolism"
## Footnote
***inhibited by ketoconozaole, emycin, grapefruit, cmycin***
221
