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