NV Flashcards
Blood supply to liver?
2/3 from Portal v.-deoxygenated, rich in nutrients; 1/3 from hepatic a. - provides O2 to liver cells
Fxns of the liver?
Metabolism (carbs, lipids, AAs), Synthesis (albumin, clotting factors, VLDL, LDL, HDL, cholesterol, glycogen), Catabolism (ammonia–>urea; hormones, detoxifies foreign cmpds/drugs/chemicals), Storage (glycogen, TGs, Fe++, Cu++, fat-sol. vits), Excretion (bile, endogenous waste), Blood reservoir, Endocrine
Enzymes involved in AA metab., present in cytosol of hepatocytes, are elevated in hepatic injury
AST, ALT (serum transaminases)
ALP
enzyme removes PO4 groups, found in liver, bone and intestines as diff. isoenzymes, in bile duct/liver cells, elevated in cholestatic disorders
Most sensitive enzyme indicator of liver disease?
GGT (gamma glutamyl transpeptidase)- enzyme inv. in glutathione metab., and drug detox
When GGT and ALP are elevated together this indicates?
Hepatobiliary disease
Get decreased serum levels of this protein in liver disease but level does NOT correlate with severity of disease?
Albumin (protein produced by liver, maintains normal oncotic pressure)
Etiologies of Acute Hepatitis ?
Viral (72%), Acetaminophen OD, response to meds (ie Cipro), excess alcohol, Autoimmune, Metabolic disorders, circulatory disorders
Clinical Manif. of Severe Acute Hepatitis
Acute encephalopathy, coagulopathy, ARF, GI bleeding, Infection/Sepsis, Resp. failure, Cardiovascular collapse
Poss. outcomes of Acute hepatitis?
May: 1) Resolve w/ supportive therapy,
2) Proceed to Acute Liver Failure,
3) Develop into Chronic Hepatitis
(liver has large regen. capacity, hepatocytes divide even during necrosis/chronic injury)
What serum measurements are markers of Biliary exretory fxn?
Bilirubin, ALP, GGT
Histo features they look for when evaluating for liver hepatitis?
Spotty/lytic necrosis, Ballooning degen., Interface hepatitis, Confluent necrosis, bridging necrosis
Acute Hepatic Failure is clinical syndrome that results from?
inadequate liver fxn due to either diminished # of hepatocytes or impaired fxn; MC due to chronic liver disease, may result from compensated chronic disease w/ sudden flare of activity (acute-on-chronic LF)
Acute Hepatic Failure (AHF) → Hyperammonemia →?
Hepatic encephalopathy (behavioral changes, rigidity, hyperreflexia, Asterixis, EEG changes)
how does AHF → Coagulopathy?
decreased production of clotting factors →bleeding diathesis and incr PTT,
hypersplenism/marrow suppression → Thrombocytopenia,
liver fails to clear activated factors from circ → DIC
Microvesicular steatosis?
multiple tiny droplets of fat that do NOT displase the nucleus- seen in acute fatty liver of pregnancy and toxic rxn to drugs (such as tetracycline, valproate)
Lab findings of AHF?
elevated serum AST, ALT, hyperammonemia, hypoalbuminemia
Hepatorenal syndrome?
Functional RF w/o intrinsic morphologic abnormalities, decr renal perfusion, systemic vasodilation →compensatory renal vasoconstriction→ decr GFR,
Renal fxn normalizes if liver fxn returns to normal
Def of Chronic Liver Disease?
Various liver diseases + abnormal tests lasting 6+ months assoc. w/ progressive fibrosis, ultimately → cirrhosis
Pathogenesis of Liver Cirrhosis?!
Stimulation of Ito/stellate cell by ROS, Gfs, IL-1 produced by damaged hepatocyte→ myofibroblast-like cell: produces smooth m. actin, GFAP →→ collagen deposited→ fibrosis →cirrhosis
Etiologies of Chronic liver disease?
NAFLD, Hep B/C, Alcoholic LD, Hereditary hemochromatosis, alpha-1 antitrypsin deficiency, Wilson’s disease, PBC/PSC, Autoimmune hepatitis
Pathophys changes in liver cirrhosis that →alterations on microvasculature architecture ?!
Loss of Sinusoidal cell fenestrations, Shunt development, High-pressure, fast-flowing vessels WITHOUT solute exchange, loss of functional integrity
Regenerative nodules?
micro (<3mm) and macro (3+ mm) from regeneration of liver cells in canals of Hering (progenitors of parenchymal and bile duct cells), seen in Cirrhosis
Morph of Cirrhosis
Bridging fibrous septa: fibrosis c/o delicate bands or broad scars surrounding multiple adjacent lobules,
Disruption of ENTIRE liver architecture by fibrous scars,
Regenerative nodules,
alterations in microvasculature
Clinical manif of Cirrhosis
Silent or nonspecific Sx: weakness, anorexia, weight loss;
In advanced disease: progressive LF, Portal HTN
Cirrhosis is the MC cause of Portal HTN which → what major consequences?
Ascites, portosystemic venous shunts (→esophageal varices, hemorrhoids, caput medusae), Congestive splenomegaly, Hepatic encephalopathy
Fxns of bile?
Bile acids are needed for emulsification/ micelle formation for absorption of dietary fat, provides bicarb for neutralizing gastric acid, inv. in elimination of cholest., organic molecules, heavy metals, lipophilic drug metabolites
Unconjugated form of bilirubin?
water insoluble (cannot be excreted in urine), toxic, crosses BBB in infants→ kernicterus (presents as neurologic deficits/seizures)
Conjugated form of bilirubin?
water soluble, nontoxic, excreted in urine
Bile Salts? fxn?
are Bile Acids conjugated w/ taurine or glycine = Cholic acid, Chenodeoxycholic acid ;
Detergents - solubilize H2O-insoluble lipids
accum. of substances normally excreted in bile (ie. bilirubin, cholesterol, bile acids)/ bile pigment in hepatic parenchyma due to decr bile flow or impaired bile formation
Cholestasis (causes may be extrahepatic/intrahepatic obstruction of bile ducts, OR defects in hepatocyte bile secretion)
Histo feature seen in Cholestasis?
“Feathery degen.’ -clear cytoplasm w/ wispy cytoplasmic threads,
if intracellular- see bile in cytosol,
Bile plugs in dilated canaliculi
Clinical manif of Cholestasis
- Incr serum bilirubin→Jaundice
- Serum bile acids→ Pruritis,
- Malabsorp. of fats/fat-sol vits→ Steatorrhea, hemorrhage, clotting disorders,
- Incr serum cholesterol→ Xanthomas of skin
- Elevated ALP and GGT
Phagiocephaly?
Assymetric head, deformation, can occur pre- or post- natally, can be corrected by helmets/positioning
Dysmorphic individual?
one who shows a problem w. generalized growth and/or in the growth/formation of atleast one structure of the body
what % of all newborns have a recognizable major congenital anomaly?
what % of these are due to a syndrome?
3%
(but will be seen in up to 7% of all births if followed to age 6);
25%
Defects that require medical or surgical intervention and will have a sign. impact on the health of the infant known as?
Major anomalies (ex: neural tube defects, cleft lip/palate)
(3+ minor anomalies incr suspicion of a poss. major anomaly)
3 Types of problems in morphogenesis that → congenital anomalies?
Malformation, Deformation, Disruption
Malformation?
Mechs?
exs?
Intrinsically abnormal developmental process→primary structural defect;
altered tissue formation, growth or differentiation due to genetic, enviornmental or a combo of factors ;
cleft lip, polydactyly
Deformation?
Mechs?
exs?
an abnormality of morphogenesis due to extrinsic force on a normally developing structure;
can be extrinsic (Fetal constraint) or intrinsic (fetal akinesia);
Clubfoot, plagiocephaly
What situations pre-dispose to deformations?
Uterine malformations or pathology (ie Bicornuate uterus, fibroid cysts), multiple fetuses, Breech position
Disruption?
Mechs?
Abnormality of morphogenesis due to destructive force acting upon the developing structure;
Cell death or tissue destruction due to vascular, infectious or mechanical force (trauma, compression, tearing)
MC cause of Disruption we see?
Amniotic bands that → vascular occlusion, another common cause of vascular disruption is cocaine abuse
(most disruptions are assymetrical!)
Gastroschisis is due to what type of congenital anomalie?
Disruption- occlusion of the omphalomesenteric a. → body wall defect w. herniation (get high AFP)
(young mothers who smoke at incr risk)
What are some vascular causes of Disruption?
Aberrant vessels, Vascular occlusion, hypoperfusion, vasoactive drugs (cocaine, amphetamines)
Porencephaly?
Congenital disorder due to vascular accident/disruption, occlusion of a cerebral a. → porencephalic cyst in the brain
Poland Anomaly ?
Subclavian a. disruption →absent pectoral m. defect and ipsilateral limb defects (reduced digits), MC on R side (if on L see heart defects), seen when mother is Diabetic
A cascade of effects stemming from a single localized abnormality in early morphogen. – the 1st defect may be a malformation, disruption or deformation?
Sequence
Holoprosencephaly is due to?
Malformation sequence - 1° malformation→ incomp. cleavage of prosencephalon and faulty bifacial devel. (most severe form: cyclopia w. proboscis)
Why are women on cholesterol lowering meds at a much higher risk of having baby w. brain anomalies?
Cholesterol activates ‘Shh’ which is a transcription promoting factor that needs to fxn properly to get normal brain devel.
Robin Sequence?
Sequence of anomalies initiated by either malformation (hypoplastic mandible) or deformation(mandibular constraint) → abnormal tongue position, U-shaped cleft palate, possible airway obstruction, Micrognathia
Potter Sequence?
Initiated by lack of amniotic fluid due to renal agenesis or from amniotic rupture (disruption) →fetal compression→ pulmonary hypoplasia, potter facies, positioning defects, breech position, growth deficiency
A combo of anomalies that occur together more frequently than by chance alone but underlying etiology is unknown, most cases sporadic?
Associations
Coloboma of eye, Heart defects, Choanal atresia, retardation of growth/devel., genital and ear anomalies?
CHARGE Syndrome from gene mutation on Chr 8
VATER?
an association c/o vertebral defects, imperforate anus, T-EF, renal or radial ray defects
MURCS
an association c/o Mullerian duct, Renal and Cervical vertebral defects
Anomalies of several diff. structures, all of which lie in the same body region during embryogenesis?
Ex of this?
Complex ;
OEIS complex= Omphalocele, exstrophy, imperforate anus, spinal defects
Multiple structural defects in one or more tissues thought to be due to a particular chromosomal, genetic, teratogenic or unknown insult that impairs mulriple tissues
Syndrome
See short stature, mental retardation, limb defects, classic facies (unibrow)
Cornealia de Lange Syndrome, caused by mutations in gene (NIPBL) on Chr 5
Multiple structural defects in one or more tissues thought to be due to a particular chromosomal, genetic, teratogenic, or unknown insult that impairs multiple tissues
Syndrome
Retinoic acid embryopathy?
Syndrome that results from maternal use of retenoids (MC Accutane) → ear/facial anomalies, CNS defects etc
Drug that disrupts growth of neural axons → Limb defects (Phocomelia)
Thalidomide
Steps inv in the work-up of the genetic pt.?
collect history (of pt., of pregnancy, FH),
examine pt., Testing, est. Dx, counseling for pt./family
FH of a genetics pt. should inc?
Generate a fam pedigree for 3 gens. -record miscarriages and causes of death, Ask about Consanguinity and ethnic origins
Pregnancy history of a genetics pt. should inc?
medical history should inc?
weight gained, fetal mvmt, any testing prior/during;
review labor/delivery, feeding history, medical probs, devel. milestones -ask about regression (which could be sign of a metabolic disorder that needs prompt Tx)
explain Free cell DNA testing
fetal DNA leaks into maternal circ. and is methylated diff. than adult DNA, so you can get a ratio of methyleted vs not, that should be 1:1 if baby has correct # of Chr.
pretty accurate, not perfect but much better than maternal serum screenings
PE of a genetics pt should inc?
observation- look for asymmetry, estimate devel. age,
Measurements- growth parameters, head size (inc. parents), anything else that look abnormal (ex: Canthal measurements)
Canthal measurements: What are some different findings?
Telecanthus: inner canthi is incr and outer canthi is normal, marker of FAS and Waardenburg Sx;
Hypertelorism: both measurements are incr, seen in a lot of disorders;
Hypotelorism: need to image brain for holoprosencephaly
If child has disorder/intelectual delays but you do not recognize a specific syndrome what testing should you start w.
Chr Microarray
When should a fam/individual be referred for genetic counseling?
Prior to conception when there is a FH or other risk factor that incr chance for an abnormal offspring and ASAP for newly diagnosed pts
What must you have to provide genetic counseling?
what info will be covered in session?
accurate Dx, complete FH, current info on condition, unbiased approach;
basic info on condition, inheritance, risk for others, options available (prenatal testing etc), prognosis, Tx options
Diff ways to communicate risk to pts in genetic counseling?
Mendelian trait (calculated risk), Polygenic/multifactorial traits- emperic risk (observed), and Bayes Theorem (use of both calc. risk w/ observed data)
what systemic viral infections can cause hepatitis?
EBV (infectious mono), CMV, HSV, Adenovirus (neonates, IC), yellow fever
Which hepatotropic viruses never cause chronic hepatitis?
HAV, HEV
(“vowels A,E = only AcuteE hepatitis, except HEV in IC/pregnant women)
(“Consonants B, C, D- cause Chronic disease)
HBV genome structure?
HBV 3 types of viral particles?
relaxed (noncovalently closed) circular, partially ds DNA, Polymerase attached to 5’ end of the - strand, RNA primer attached to 5’ end of the + strand, overlapping open reading frames;
complete spherical infectious virion (Dane particle), 2 types of noninfectious- filamentous/spherical particles have only envelope structure
How is HBV transmitted?
by “Blood, Birthing and Bonking”
only hepatotropic v. that is more often chronic than not, is almost never detected in acute form, 80+% develop chronic hep., 20% of whom develop cirrhosis?
HCV
Typical course of acute viral hepatitis?
- Incubation period: ASx
- Symptomatic Pre-icteric: malaise, fatigue, nausea, fever, 2wks post-exposure
- Icteric phase: jaundice, dark urine, clay-colored stools, hepatomegaly, 1-2wks after prodrome, lasts up to 6wks
- Covalescence: diminishing jaundice, 6-8wks post-exposure
when are pts w/ acute viral hepatitis most infectious?
last ASx days of INCUBATION period
Labs in acute viral hepatitis?
high levels of transaminases (>1000 U/L),
Hyperbilirubinemia (due to cholestatic jaundice/cholestasis),
Viral serology
Def of Chronic viral hepatitis
Symptomatic, biochemical or serological evidence of continuing/relapsing disease for longer than 6mos (26wks)
Carrier state of viral hepatitis
Harbors organisms without S/Sx, either +/- liver damage → reservoirs for future infection
Hepatocellular damage in viral hepatitis is due to?!
Host’s adaptive immune response to viral proteins expressed by infected cells- T-cells are activated after recognition → Necroinflamm. activity, Apoptosis (Immunopathology)
(NOT due to direct viral cytopthic effect)
HAV general features?
Fam=Picornaviridae, Genus- Hepatovirus,
small, naked, +sense, ss-RNA w/ a single ORF that encodes a single polypeptide- proteolysis of this →structural/regulatory proteins,
5’ non-coding region has an IRES for cap-indep. translation (No cap!),
3’ end has poly-A tail,
usually benign, self-limited course
HAV transmission?
fecal-oral, via contaminated food/H2O, contaminated shellfish concentrates virus- can infect if undercooked, (or blood transmission=minor route),
heat stable, acid and detergent (ie 1% SDS) resistant;
HAV shed in feces 2-3 weeks before, and 1 wk after the start of jaundice (can spread to close contacts during this time)
HAV prevalence/epidemiology?
endemic in developing countries (Asia, Africa, SA) w/ poor sanitation- kids under 6 affected, ASx/mild clinical disease, many have Abs by age 10;
in developed- better socioeconomy/hygeine but no herd immunity, older age group affected, more severe Sx, incidence very low in US due to vaccine
HAV serology?
IgM: rises w onset of Sx, marker of acute infection,
IgG: rises after months, when IgM declines, persists, confers lifelong immunity against reinfection w. all strains (no direct detection og IgG must measure total then subtract IgM to get IgG)
HBV gen features?
Hepadnavirus, spherical double shelled, partially ds relaxed circular DNA, very resistant to extreme temp/humidity, “Dane particle”=complete infectious virion, 4 open-reading frames:
Nucleocapsid core, capsid shell is made of: HbcAg
envelope glycoproteins (surface): HbsAg
Polymerase (Pol) w. DNA Pol and reverse transcriptase activity
HBx protein
HBV, serum markers of active replication?
HBV-DNA, HBsAg, HBeAg
(HBeAg is marker of active infection and infectivity)
Appears during peak Sx of Hep B, implies waning of acute infection?
Anti-HBe
HBV mode of transmission?
Contact w. contaminated body fluids (serum, urine, saliva…),
depends on geographics: high prevalence areas (ie Asia)- MC route is perinatal infection (both horizontal/vertical) - early childhood infection→HIGH rate of chronicity
Horizontal in intermediate prev. areas,
in low prev. areas (US): Sexual/IV drugs -low rate of chronicity
Clinical outcomes of Hepatitis B ?
Most cases (~90%)- self-limited, spontaneous resolution/recovery, majority w/ no Sx or jaundice, some w acute disease,
Chronic disease (5-10%)- may progress to cirrhosis +/- develop HCC,
Fulminant/acute liver failure (<0.5%)
What predicts chronicity of Hepatitis B?
Age at time of infection, younger= more likely to become chronic (ie vertical transm from mother→baby)
Why is complete cure of chronic Hepatitis B hard to achieve?
Virus inserts itself into host DNA →host cannot mount effective response via production of HbsAb→virus persists
(so Tx invs limiting progress of disease/damage to liver -prevent cirrhosis/HCC)
What determines disease outcome of Hepatitis B?
Host immune response, in early stage innate immune response (NK cells, IFN) protects, resolution if CD4+/CD8+ produce IFN-gamma, etc and clear infected cells;
If weak immune response: some infected cells not killed→CHRONICITY
Why is it difficult to make vaccine against HCV?!?
due to genomic instability, Ag variability, RNA Pol- poor fidelity in copying, thus many genotypes/subtypes (even in same pt.- quasispecies)
HCV gen features?
Flaviviridae, Small, + ssRNA virus, RNA codes for only 1 polyprotein- processed into fxnal proteins, E2 envelope protein (target of anti-HCV Abs) is the most VARIABLE region of genome, new virus strains can escape neutralizing Abs!
Why is there a HIGH RATE of chronicity of Hepatitis C?!
Anti-HCV IgG produced after infection does NOT confer immunity! → recurrent reactivation of preexisting infection or emergence of newly mutated strain
Why has there been such a dramatic decr in annual incidence of Hepatitis C infections?
mostly due to decr in transfusion-assoc infection
(blood transfusion and Factor VIII -no longer major routes)
Hepatitis C Risk Factors
IV drug abuse, multiple sex partners, surgery in last 6mos, needle stick [(1.8%= higher risk than HIV (0.3%)], multiple contacts, work in medical/dental fields
~1/3 of pts have unknown etiology
HCV clinical manif
Incubation period: 4-26wks, most pts ASx (85%)-bc there is weak/delayed immune responses (more mild than HBV), HCV RNA is detected in blood for 1-3wks together w/ incr AST/ALT ;
Majority develop chronic Hepatitis, Cirrhosis in up to 20% (HCV RNA remains in blood, AST/ALT never normalize)
HCV Serology
HCV-RNA- marker of acute infection w/ resolution or remains in blood in chronic disease despite presence of Anti-HCV
(Anti-HCV is just diagnostic, does NOT confer immunity)
HCV Tx? what does response depend on?!?
(usually a Q)
Pegylated IFN-alpha, ribavirin;
HCV genotype- 2, 3 best response!!,
and host genotype- IL28B gene (encodes IF-lambda)
HDV infection?
it is a defective “satellite virus”/viroid- requires HBV as helper for infection, both self-limited EXCEPT in IV drug abusers→ acute liver failure, can be: co-infection of HBV and HDV at same time- acute, self-limited, OR
Superinfection: when HBV carrier gets HDV → severe acute hepatitis
HDV gen features?
very small, covalently circular, - ss RNA, uses host’s RNA Pol to replicate via RNA-directed RNA syntheis, Delta Ag (HDAg) protein produced by virus
(HBsAg on both HBV and HDV)
HEV mnemonic?
“Pregnant Pigs in EEndia”
in India- more sporadic HEV cases than HAV,
In Pig farms in developed world,
Unique: high mortality rate (up to 20%) in Pregnant women
HEV features/clinical manif
naked, + ss RNA, Hepevirus, MC form of hepatitis in endemic regions, Virions shed during acute illnes,
Fecal-oral route, HEV RNA and virions in stool/serum before Sx appear,
S/Sx: elevated AST, ALT, IgM anti-HEV at same time, self-limited
Along w/ clinical info and serology, assess hepatitis via biopsy which can?
Confirm clinical Dx, exclude simultaneous conditions, Grade extent of inflamm./injury, Stage the degree of fibrosis, monitor Tx effectiveness
(EXCEPTION: biopsy not done for Hep A)
Characteristic Morph of Hep C?! (KNOW)
Lymphoid aggregates or follicles in portal tract!!
Characteristic Morph of Hep B?! (KNOW)
Hepatocytes look like “Ground Glass”/ granular periphery of cell, ER is stuffed full of HbsAg)
Which demographic has longest life expectancy?
lowest?
Hispanic women
Non-hispanic black males
Homeostenosis?
Decr in reserve capacity w/ aging- as we age we egage more of our physiological reserves just to maintain homeostasis thus there are less reserves left to address challenges; A medical issue of aging
Normal physiologic body composition changes w aging?
Loss of lean body mass, decr in skeletal m. mass, decr in bone mass, Incr in total body adipose tissue→accum. in mm. and organs- more fat but not necessarily more weight
Importance of body composition changes w aging?
has major implications on prescribing meds- t1/2 of lipophilic drugs increases dramatically!, serious complications can arise from “normal” drug doses
Normal physiologic changes seen in aging?
Temp: incr risk for both hyper-/hypo-thermia, difficulty mounting a fever in response to infection! (all conditions causing fever in young pts may present WITHOUT fever in elderly)
Body fluid: TBW decr, thirst sensation diminished,
BP: higher BPs or orthostatic hypotension,
Senses: Dark adaptation decr, near vision declines, high frequ hearing declines, sense of smell declines after 50yo
Normal cardio changes seen in aging?
incr vessel wall thickness+ decr elastin= stiff vessels (makes it difficult to get accurate BP reading), incr BP but normally below threshold for HTN, adipose infiltration, decr pacemaker cells, calcifications of heart →murmurs, epi/NE levels are higher but tissue response to beta-adrenergic stimulation is decr
Normal Neuro changes seen in aging?
slower encoding, slowed recall. decr ability to multi-task, decr #/size of motor neurons, decr sensation in feet, lack of ankle reflexes
Normal Resp changes seen in aging?
GI changes?
decr elasticity, FEV1 and O2 sat ;
presbyesophagus may occur, hepatic metabolic fxn may decline
Normal Renal changes seen in aging?
steady decline in most but not all, affects drug metabolism!!, must review all meds/adjust doses
Normal Immune changes seen in aging?
Thymic involution- less naÏve lymphocytes to respond to new threats, decr T cell response, decr in some cytokines, decr Ab response to vaccines
Normal skeletal changes seen in aging?
Loss of cortical thickness, incr in cortical porositym thinning of trabeculae w loss of connections ;
Why do ppl get shorter?
Wear of discs btwn bones, changes in posture- ususally due to arthritis but can be from osteoporosis (NOT NORMAL AGING but diseases)
So normal aging is heterogenous and marked by??
Decr in reserve capacity (homeostenosis) and diminished ability to respond to stress
⇒ Incr vulnerability!
BPH leads to Sx of urinary frequ, hesitancy, dribbling, should avoid what type of drugs that will make this worse?
alpha-agonists (Decongestants)
Diseases manifest themselves diff in elderly, which →
exs?
atypical presentation= incr risk of advers outcomes and delayed Dx→ incr morbidity/mortality;
expect more vague complaints such as acute confusion/delerium, “weak and dizzy”, refuse to eat/drink, malaise, fatigue, falling
When an elderly pt. complains of pain, why must it be considered more urgent ?
HA is relatively uncommon as a new complaint and may be a sign of what in elderly?
Blunting of sensation of pain may occur, many elderly pts will minimize their complaints, and abdominal pain is much more likely to be due to a life threatening disease!;
temporal arteritis, trigeminal neuralgia, HZV, subdural hematoma, metastatic disease
Anorexia/weight loss considerations in elderly?
malignancy/inflamm. disorders at top of list but also consider CHF, chronic lung disease, drug ADRs, depression, memory loss, hyperthyroidism
Weakness/fatigue considerations in elderly?
Apathetic hyperthyroidism, true m. weakness represents specific disease, expect weakness for up to 3 wks after a period of immobility like a hospital stay- takes awhile to get back to baseline
Common barriers for effective communication w elderly?!
Ageism, sensory problems ie hearing, cognitive problems, dementia
(tips- consider pts health literacy skills/cultural beliefs, RESPECT, dedicate time w. each pt., write down instructions, address pt w last name)
Risk factors for HAV?
low socioeconomic status (poor sanitation),
Travel to endemic areas,
MSM,
Illicit drug use
HAV liver tropism is attributed to?
1) Hepatocellular asiaglycoprotein receptor-mediated uptake of IgA-HAV cmplx,
2) Intracellular factors favoring viral replication
HAV mechs of infection
Hosts: humans ans nonhuman primates,
Cellular receptor: HAVcr1/TIM1 (class 1 integral glycoprotein),
Auxiliary factor: IgA1-lambda- facilitates infection =special ligand of HAVcr1/TIM1, forms IgA-HAV cmplx and enhances receptors intxn w/ HAV
Cellular Immune responses to HAV?
in acute phase- CD8 CTLs are the main lymphocytes in liver, NK cells may also lyse HAV infected hepatocytes;
Anti-HAV CD4 T cell response imp. for recovery- CD4 Tcells become main lymphocytes in liver in the covalescent/recovery phase
HUMORAL Immune responses to HAV?
Abs against the conformational epitope formed by VP1 and VP3 are protective against infection→ life long immunity after recovery, no chronic disease; Vaccination very effective for prevention!
HBV is an enveloped DNA virus, the envelope consists of?
3 types of surface Ags (HBsAg):
- The long form: (LHBsAg)- contains pre S1, pre S2, and S domains
- Medium form (MHBsAg)- Pre S2 and S domains
- Short form (SHBsAg)- contains S domain only
Describe HBV entry into target cells
HBsAgs bind to receptor→ nuclear capsid released into cells by receptor mediated endocytosis, loss of envelope →transport of core particle to cell nuclear mem. → uncoating/release of RC DNA into nucleus
Next step after HBV RC DNA is released into host cell’s nucleus?
RC DNA cnvtd to covalently closed circular DNA (cccDNA) by removal of viral Pol, RNA form RC DNA then DNA synthesis/ligation by cellular enzymes → formation of viral minichromosome (where transcription occurs)
Viral variants of HBV due to?
HB Pol lacks proof reading capacity →genome prone to mutation
Thus exists in host as Quasi-species- a mixture of genetic variants
What is the key determinant for vertical transmission of HBV?
HBeAg and HBV DNA levels in infected woman
(90% for HBeAg + vs 32% for HBeAg neg women)
(Breastfeeding is NOT a sign. mode of transmission)
Humoral Immune response to HBV?
Anti-HBsAg Abs are protective
Cellular immune responses to AHB?
- noncytolytic clearance (drop of viral titers)- occurs after peak repl./before onset of hepatitis, Mediated by viral specific CTL-produced cytokines: IFN-y, TNF-alpha, IFN-alpha/beta
- Inflamm. cell-mediated liver damage: High levels of CD4/CD8 T cell responses detected in blood, massive liver infiltration of T cells, NK cells and neutrophils
HCV infection invs interaction btwn?
HCV E1, E2 heterodimer w/ multiple cellular surface proteins which can bind to E2 to form cmplx
How is HDV transmitted?
Parenteral routes- drug addicts and hemophiliacs at high risk
How is Anencephaly diagnosed?
prenatally by elevation of maternal AFP and fetal US,
usually go post-term, polyhydramnios
Encephalocele
Defect in cranial vault→herniation of brain/meninges
Rachischisis
worst form of spina bifida, neural tube never even forms you just have neural tissue
where does HBV RNA transcription occur?
list HBV Subgenomic transcripts (and the proteins they form)
Viral RNA- is transcribed from viral miniChr then exported out of the nucleus for protein synthesis/genome repl.
Pre-S1 RNA (LHBsAg)
Pre-S2/S RNA (MHBsAg, SHBsAg)
X RNA (HBxAg)
fxns of HBV pgRNA ?
=pregenomic RNA- encodes viral Pol and HBcAg and serves as template for genomic repl. (lacks the start codon for HBeAg)
what catalyzes cnvsn of unconjugated to conjugated bilirubin in the liver?
UDPGT
Physiologic jaundice is due to?
immature conjugation/excretion mechs in babies liver till 2 weeks of age (low UDPGT activity and low levels of ligandin binding protein), can also get more bilirubin b/c: shorter RBC lifespan, high RBC mass, birth trauma
Physiologic jaundice Tx?
Phototherapy- cnvts to H2O soluble isomers that can be excreted into bile w/o conjugation→ excreted into stool/urine (most resolve in 2-3wks)
Breastmilk Jaundice?
Tx?
lasts longer than physiologic jaundice, breastmilk has beta-glucuronidase that deconjugates conjug’d bilirubin;
tempor. stop breastfeeding
Kernicterus
brain damage in baby due to excessive levels of unconjug’d bilirubin that crosses BBB, toxic to brain, due to Neonatal hyperbilirubinemia, G6PD deficiency, spherocytosis
hereditary disorders that →Unconjug’d hyperbilirubinemia?
Crigler-Najjar Syndromes type 1 and II, Gilbert syndrome
hereditary disorders that → Conjug’d hyperbilirubinemia?
Dubin-Johnson and Rotor syndromes
(both AR)
Hereditary hyperbilirubinemia due to absent UGT1A1 (gene for UDGPT) activity→ kernicterus and FATAL w/o liver transplant
Crigler-Najjar Syndrome type 1 (AR)
(see Sx of Kernicterus- hypotonia, deafness, oculomotor palsy, lethargy)
Dubin-Johnson Syndrome
(Sxs, labs, gross morph?)
AR, due to mutated gene for MRP2 (transports conjug’d bilirubin from liver cells to canaliculi)→ benign relapsing conjug’d hyperbilirubinemia, non-pruritic jaundice in teens or ASx, normal AST/ALT, gross path: BLACK PIGMENTED LIVER , non-iron (melanin) pigment
Hereditary hyperbilirubinemia due to decreased UGT1A1 activity→ mild jaundice, non-fatal ?
Dx by? Tx?
Crigler-Najjar Syndrome type II (only one that is AD!!!);
by HPLC/liver biopsy enzyme assay;
lifelong phototherapy or transplant in some
Hereditary hyperbilirubinemia due to decr (30% of nml) UDPGT activity, no Tx needed- ASx or mild jaundice only w/ stress, infection, or fasting?
Lab findings?
Gilbert Syndrome (AR);
incr in Unconjug’d bilirubin, incr in ratio of urinary coproporphyrin I:III
Causes of large Bile Duct obstruction → Cholestasis?
Tx?
Gallstones (extrahepatic), Malignancies of biliary tree/head of pancreas, strictures from surgery;
surgery to reverse extrahepatic obstruction to avoid biliary cirrhosis, but if cause is intrahepatic surgery is NOT helpful (unless transplant)
Ascending cholangitis?
Subtotal/intermittent obstruction→ secondary bacterial infection by Coliforms/enterococci from gut → F/C, abd pain, jaundice,
severe form= Suppurative- bile pus fills bile ducts, SEPSIS dominates
Sepsis-assoc. cholestasis?
response to microbial products in blood, esp in systemic G– infection, 2 types: Canalicular and Ductular
Sepsis-assoc. Canalicular cholestasis morph.
centrilobular canalicular bile plugs, Kupffer cell activation, mild portal inflamm., scant/absent hepatocyte necrosis
Sepsis-assoc. Ductular cholestasis morph?
Dilated canals of Hering and Bile ductules, bile plugs, septic shock
(worse path than canalicular)
Prolonged conjug’d hyperbilirubinemia in newborn that needs to be evaluated for if jaundice lasts beyond 2-3wks?
Causes?
Neonatal Cholestasis;
Neonatal hepatitis (toxic, metabolic, infectious or idiopathic), Cholangiopathies- biliary atresia..
Neonatal hepatitis (which can→ cholestasis) is due to ?
pathogenesis?
can clinically determine etiology as either toxic, metabolic or infectious 90% of the time, need Bx 10%, 10-15% idiopathic;
immature bile synthesis/secretion pathways decompensated by injury
Neonatal Hepatitis- liver biopsy will show?!?
Necrosis, GIANT CELL transformation- multinucleated giant Hepatocytes!!! unique response of young liver to injury so only occurs in infants!!;
micro: apoptotic/acidophil bodies, extramedullary hematopoiesis
Fetal/embryonal form (20%) of Biliary atresia ?
aberrant intrauterine devel. of extrahepatic biliary tree→obstruction, assoc w other anomalies (of abd organs, polysplenia, etc)
Perinatal form (80%) of biliary atresia?
presumably normally developed biliary tree is destroyed at birth, invs. Viruses (rota-, reo-, echo- viruses, CMV) →continual inflamm/ obstruction
Gross morph of liver cholestasis due to biliary atresia?
micro?
enlarged, dark green, hard liver, micronodular cirrhosis, dilated intrahepatic bile ducts w. inspissated bile ;
fibrosis (stains blue w trichrome stain), incr ductules, neutrophils, bile plugs in ductules
Tx of Liver cholestasis due to biliary atresia?!
Kasai procedure (hepatoportoenterostomy)- bypasses atretic ducts to achieve bile flow, OR transplant - It is the MC reason for liver transplantation in kids!
Iron overload in tissues and organs such as liver due to AR genetic mutations ?
Primary hemochromatosis
Iron accumulates in body due to known sources of excess iron ie. multiple transfusions, ineffective erythropoiesis (thalassemias, sideroblastic anemia), incr iron intake (Bantu siderosis), cirrhosis, chronic liver disease
Secondary hemochromatosis
HFE hemochromatosis?
due to mutation in HFE gene → decr hepcidin→ incr iron absorption/ defect in regulation of intestinal absorption→ more iron in blood/deposited in tissues
(MC is C282Y mutation)
HFE hemochromatosis clinical manif?
classic triad: hepatomegaly, slate grey skin, DM, …plus pancreas fibrosis, cardiac dysfxn, abd pain, death due to cirrhosis/ cardiac failure, but normal life expec. w Tx= phlebotomy
have 200x risk of HCC (not dec by Tx)
AR disorder due to mutation of ATP7B gene→defective ATPase→ impaired Cu++ excretion into bile/failure to incorporate into ceruloplasmin → accum of Cu++ at toxic levels in liver, brain, eye, etc
Wilson’s Disease
Dx of Wilson’s Disease?
Liver Bx- qunatitation of Cu++,
Lab: urinary Cu++ excretion, serum ceruloplasmin,
easily missed clinically- presents in teens/20s w neuropsychiatric, liver, neuro, and eye abnormalities
KAYSER-FLEISHER RINGS (brown ring around cornea)
(many diverse mutations so no genetic testing)
Wilson’s disease (AKA Hepatolenticular degen.) path?
Tx?
Glycogenated nuclei, Cu++ granules- stain red w. rhodanine stain
(liver changes resemble viral hepatitis and fatty changes);
Copper chelation or transplant
Alpha-1 antitrypsin (AAT) deficiency?
AR disorder, mutated SERPINA1 gene on Chr 14→ low levels of AAT (a serine protease inhibitor)→uncontrolled proteases→ COPD, cirrhotic liver w. accum. of A1AT-Z in cytoplasmic globules (stain w PAS), poss HCC
3 intrahepatic Biliary tract diseases?
- Primary Biliary Cirrhosis,
- Secondary Biliary Cirrhosis (due to prolonged obstruction of extrahepatic biliary tree)
- primary sclerosing cholangitis
Autoimmune non-suppurative inflamm./destruction of med-sized intrahepatic bile ducts⇒ chronic progressive, often fatal cholestatic liver disease, may be ASx but with incr ALP or present w biliary cirrhosis?
assoc w.?!
Primary Biliary Cirrhosis (90% in females);
Celiac, Sjogren’s, MS, Raynaud’s !
4 stages of Primary Biliary Cirrhosis?
- Portal: portal inflamm., BD damage, +/- florid duct lesion
- Peripheral: ductular prolif, periportal inflamm, fibrosis
- Septal: bridging fibrosis, ductopenia
- Cirrhosis: Biliary cirrhosis
(histo: fibrotic or granulomatous inflamm.)
Primary Biliary Cirrhosis Dx?
Tx?
Liver Bx, labs will show elevated serum ALP, GGT and AMA!!!!(antimitochondrial Abs);
Ursodiol or transplant if advanced
Chronic cholestatic disorder char. by inflamm./fibrosis that obliterates intra-and extra-hepatic BDs up to ampulla of vater, w/ dilation of preserved segments? how does this appear on imaging?
coexists w.?
primary sclerosing cholangitis (PSC);
“Beading”
IBD esp. UC;
primary sclerosing cholangitis clinical manif?
persistent ASx elevated ALP, Cholestatic Sx (jaundice, pruritis- Tx w cholestyramine), CHD (weight loss, ascites, varices, enceph.)
primary sclerosing cholangitis pathogen?
activated T-cells in GIT (assoc w. UC) go to liver and cross-react w. Ag in BD →immune-mediated injury to BDs, CONCENTRIC PERIDUCTAL FIBROSIS → fibrous obliteration of ducts, “ONION SKIN” scar
primary sclerosing cholangitis gross morph?
pts at risk for developing?
Nodules of cirrhosis, areas of hypertrophy/hyperplasia, Fibrotic ;
cholangiocarcinoma, HCC, chronic/autoimmune pancreatitis (incr IgG4)
Deaths from acute poisoning are due to ?
cardiovascular complications, depressed respiration -hypoxia (further decr. by mixing barbs, opiates, benzos or alcohol)
so supporrtive careis essential to maintain resp. and circulation
MC poisonings in kids less than 5yo?
vits w. IRON, OTC meds, cleaning supplies, pesticides
MC poisonings of adults due to?
analgesics, drugs of abuse, antidepressants, sedatives, anti-anxiety meds, alcohol, or combo of these
Iron toxicity: primarily occurs in? .. from?
toxic dose is calc. based on?!
toxic amt is?!
young kids, multi-vits w/ iron;
elemental Fe content!
20+ Mg/Kg Elemental Fe!
Syrup of Ipecac?!
Emetic, stimulates CTZ in brain and has direct effect on stomach → vomiting. good for terminating exposure to MANY DRUGS ie acetaminophen, antihistamines, vits, coldremedies, benzos, pesticides (paraquat)
When is emesis (syrup of ipecac) contraindicated?
corrosive agents, loss of gag reflex, comatose, sharp objects, agents assoc w seizure (strychnine, TCAs, GHB), ingestion of hydrocarbons if risk of aspiration is greater than risk of systemic toxicity
Activated charcoal -added to lavage fluid to enhance removal of toxins, what agents are well adsorbed by it?
acetaminophen, aspirin, amphetamines, benzos, digoxin, opiates, malathion, Nicotine, syrup of ipecac
it can be used in comatose pts., ineffective for acids, alkalis, most metals, petroleum distillates, do NOT use for corrosive/caustic agents
what antagonist can be used for opiate overdose ?!
NALOXONE! = competitive reversible antagonist at opiate (mu) receptor, reverses resp. depression of opiate
what antagonist can be used for Benzodiazepine overdose ?!
FLUMAZENIL! - competitive reversible antagonist, reverses resp. depression
(benzos are the “-pam” drugs- diazepam, oxazepam..)
N-acetyl-benzoquinoneimine (NAPQI) ?!
Acetaminophen is metabolized by P450s to this hepatotoxic metabolite, NAPQI is detoxified by binding to glutathione, liver damage occurs when hepatic glutathione depletion occurs → NAPQI binding to proteins
how does SODIUM BICARBONATE enhance excretion?!
alkalinizes urine to enhance excretion of ACIDIC drugs (ie. barbs, aspirin)
Major toxicity of Petroleum distillates (gasoline, furniture polish, kerosene..)?
Aspiration and chemical pneumonitis
Risk of aspiration of an agent depends on?
- Viscosity, surface tension, volatality
- low viscosity incrs potential to flow into airways
- low surface tens allows rapid spread from mouth to trachea
- high volatality→ rapid displacement of O2 from alveoli→hypoxia
BEST determinant of aspiration potential of petroleum distillates?
VISCOSITY! (expressed as SUS units)
low viscosity= high aspiration risk !!
Most deaths from abuse of aerosol propellants (huffing) due to?
huffing while pregnant causes ?
Cardiac arrest or hypoxia;
decr birth weight, incr fetal death, nerve damge in baby,
there’s no antidote or Tx
What are the long term effects from abusing the aerosol propellant Toluene? (in whiteout)
ophthalmic and auditory n. damage - BLINDNESS and HEARING LOSS
What are the long term effects from abusing the aerosol propellant Benzene- which is in gasoline?
LEUKEMIA
Iron toxicity Tx?!
emesis if caught early, bicarb lavage to decr absorption, or if plasma iron 350µg/dl - Chelation therapy with Deferoxamine!
there is an Excellent correlation of acetaminophen blood levels with?
time expired since ingestion, and prediction of toxicity
(thus can use a Nomogram to evaluate risk of toxicity)
Antidote used for Acetaminophen toxicity!?
n-ACETYLCYSTEINE- taken up by the cell, provides CYS for glutathione synthesis
advantage of giving this orally is 100% goes to liver but it is not pleasant so can be given IV if necessary
Salicylates follow what order kinetics?
1st order at HA dose, zero order at doses taken for arthritis/toxic doses
mechs of Salicylate toxicity?!
- Aspirin directly stimulates resp. centers in medulla→Hyperventilation →resp. alkalosis
- toxic levels uncouple oxidative phosphorylation which stimulates CO2 production, increases ketones, lactic and pyruvic acid → metabolic acidosis (usually only in kids)
S/Sx of Salicylate toxicity?
HA, tinnitus, sweating, hyperventilation, drowsiness, fever (MC in kids), acid-base and electrolyte imbalance, dehydration, low serum K+ levels (renal excretion of bicarb and organic acids)
Can use nomogram to predict severity of Salicylate toxicity since it has good correlation with the time of ingestion and ?!?
PLASMA SALICYLATE concentration
Tx of Salicylate toxicity?!
emesis, lavage, +/- activated charcoal, alkalinize urine to enhance salicylic acid excretion 4-fold by giving IV bicarb, makes drug more ionized so less of it can get to brain,
for kids also need to- correct electrolytes/fluids, return body temp to nml
Methanol toxicity!?
irreversible toxicity to eye- photophobia and BLINDNESS
methanol metabolized by alcohol dehydrogenase to the toxic metabolites formaldehyde and formic acid, formic acid →met. acidosis and BLINDNESS
this alcohol induces inebriation/nausea, targets kidney → RF, oliguria, and obstruction due to?
what Tx is only used for this alcohol?
Ethylene glycol,
oxalate crystals deposit in lumen of kidney;
Fomepizole (inhibitor of alcohol dehydrogenase, used as an alternative to ethanol)
Tx for both Ethylene glycol and methanol toxicity?
IV Ethanol -competes for alcohol dehydrogenase, has greater affinity than other alcohols
why should we care about herbal agents?
~1/2 of US pop. uses some form, some agents have active ingredients that: are assoc. w drug-herbal intxns, may be palliative, may have sign. adverse effects
Gov regulation of herbal products?
considered dietary supplements (NOT drugs), thus do NOT have to be proven safe oe effective
Herb labeling
- no std. for efficacy, safety or validation
- Standardized- certain conc. is consistent btwn batches
- NF on label, meets NF std. for purity, strength of marker cmpd and labeling
- can NOT be marketed for prevention/Tx of a disease
Garlic: is marketed for?
its effects?
lowering cholesterol, preventing heart attack ;
- Lowers cholesterol (HMG CoA reductase inhibitor)
- Inhibits platelet aggregation via Ajoene (Allicin metab.) and Diallyl trisulfide - inhibit platelet cyclooxygenase, reduce platelet TXA2
Garlic: Cautions?
- avoid high doses w/ antiplatelet drugs
- Avoid prior to surgery!
- Must store chopped garlic in oil in fridge or → Clostridium infection
Active ingredients og Horse Chestnut and their action
- Escin (good cmpnt) decreases: leg pain (4fold), swelling, and vascular permeability of venous capillaries!!
- Aesculin cmpnt that incr risk of bleeding (gums, nose, etc), similar to Warfarin
Horse Chestnut CIs?
- Anticoagulants, aspirirn, NSAIDs (since it enhances bleeding)
- Pregnancy (category X)
- Breast feeding
- Avoid before surgery
Ginko Biloba actions?
- improves perfusion of capillaries/ blood flow in skin,
- Kaemferol: anti-oxidant, reduces free redical damage, may slow aging/ improve mental focus, improves utilization of ATP and glucose in brain
- Kaemferol and Apigenin: inhibitors of MAO-A/B
Ginko Biloba standardized for?
ginko flavonglycosides: quercetin, kaempferol, isorhamnetine
Ginko Biloba Adverse effects?
- BLEEDING times can double!
- drug intxns w/ incr risk of bleeding: inhibits PAF, aspirin, NSAIDs, Warfarin, heparin, Platelet IIb/IIIa receptor antagonsits (clopidogrel)
- Lethal ingestion of ginko seeds (contain ginko toxin- antivit. B6, interferes w/ AA metab)→ seizures/death
St. John’s Wort: standardized for?
Adverse effects/ drug rxns?!
should contain min. of: 0.3% Hypericin and 3% Hyperforin;
HA, loss of appetite, induces P450 isozyme Cyp 3A4 so may need to incr dose of OCs, theophylline, warfarin and avoid before surgery, should NOT be taken w/ MAO inhibitors or SSRIs
Poss. MOA of St. John’s Wort
- Hyperforin SSRI
- Hypericin and Hyperforin - MAO inhibitors (enhance mood)
- activation of GABA (they are inhibited by flumazenil), anti-anxiety action
- Alcohol extract: anti-depressant action (for mild depression, NOT mod/severe depression)
- cumulative effect mediated by more than 1 MOA
Valerian: used for? mech?
active ingredients?
Insomnia; binds to GABA-A receptor, opens Cl- channel→hyperpolarization/ decr neuronal activity (effect similar to benzos)
Valerenic acid, valtrate, Glutamine
Marketed to stimulate immune system but not much evidence for this, not effective to prevent colds but decr. cold Sx, no benefit in kids, avoid use w/ immunosuppresants
Echinacea
May block the translocation of the cytosol androgen receptor to the nucleus, inhibitor of 5alpha-reductase!! (compared to Finasteride)?
Saw Palmetto!
Ginesing decreases levels of cortisol/neurotransmitters during stress, may stimulate immune system and has what CV effects?
Active ingrediants?
Red ginseng may lower lipids and incr. HDLs,
Panax ginseng inhibits platelet aggregation,
Ginsenosides
This herbal med causes nervousness, avoid taking it w. coffee or before bed, abusing it → HTN, excitability, sleeplessness, nervousness, diarrhea in AM
Ginseng
KAVA is marketed for sedation/relaxation alternative to alcohol, MOA?
Adverse effects?
interacts w GABA receptor;
impairment of motor skills, sedation, yellow eyelids/nails (this is NOT jaundice), hepatic toxicity!!! (FDA warning, like a black box warning)
Herb marketed for migraines/arthritis pain- Inhibits phospholipase A2, inhibits platelet serotonin release;
Feverfew;
drosi-/dizzi-ness, postfeverfew syndrome of insomnia, joint pain, m. aches when discont. it, heavier flow, mouth ulceration, may incr. bleeding so avoid before surgery
6 Herbs to avoid prior to surgery?
Feverfew, Garlic, Ginko Biloba, Ginseng, Horse Chestnut, St. John’s Wort
Herbs to avoid mixing w/ alcohol?
Valerian, KAVA
Herbs to avoid mixing w MAO or serotonin re-uptake inhibitors?
St. John’s Wort, Valerian
90% of cases of Congenital Adrenal Hyperplasia (CAH) due to?
incidence is 1/14,000 births world wide (classic) but higher where?
Nonclassic form is much MC (1-2/1000)
21-hydroxylase deficiency (AR);
Alaska (Yupik Eskimos), Reunion Island ;
(nonclassic more common in NYC)
S/Sx of Classic CAH?
Large hyperplastic adrenals at birth, ambiguous genitalia (androgenital syndrome), high risk of adrenal insufficiency, early puberty, short stature;
Can be Simple/virilizing form (25%, have atleast 1% enzyme activity) or Salt-wasting form (75%, 0 enzyme activity)→Crisis- hypovolemic shock, hyperkalemia
S/Sx on Nonclassic CAH
(have 20-50% enzyme activity)
Mild, no genital ambiguity, onset usually in adolescence, No adrenal insufficiency, androgen excess→ Oligomenorrhea, Hirsuitism, Acne
Steroid biosynthetic pathway is a cascade that start w?
ends with?
Cjolesterol;
Mineralocorticoids (Aldo), Glucocorticoids, Gonadal steroids
21-hydroxylase genes are on Chr 6 and are tightly linked w/ HLA,
what genetic changes are seen in the most severe/salt-wasting form of CAH?
point mutations in 75%, gene deletion (12%), Large gene cnvsns (12%)
All states now screen newborns for 21-hydroxylase deficiency, can be effectively treated with?
Glucocorticoid and Mineralocorticoid Tx, genital reconstruction
IRB- approved protocol for prenatal Dx/Tx for 21-hydroxylase deficiency to prevent female virilization
Start Dexamethasone when pregnancy is confirmed in at risk pts.,
Chorionic villus sampling at 8-10wks,
Amniocentesis at 16wks,
if baby is found to be Male or is an unaffected female- stop dexamethosone, only cont. in affected females
MEN syndrome type 1
“3 Ps” Parathyroid neoplasia, Pituitary neoplasia, Pancreatic islet neoplasia, AD
MEN syndrome type 2?
Genetic testing is est. in the Dx/Tx and enables?
“TPP”- Thyrocalcitonin (medullary carcinoma), Pheochromocytoma, Parathyroid neoplasia ;
prophylactic thyroidectomy and saves family members extensive prospective testing
MEN 2A
genetics?
- Medullary thyroid Ca. 100%
- Pheochromocytoma 50%
- Parathyroid neoplasia 10-20%
Point mutations of RET Proto-oncogene on Chr 10q which interacts w GDNF, site of mutation determines disease
MEN 2A Variants?
- Familial Medullary thyroid Ca. (FMTC)
- MEN 2A w/ cutaneous lichen amyloidosis (MEN-2A/CLA)
- MEN 2A w. Hirschsprung disease
All pts with new medullary thyroid Ca. should be screened for??!
RET
MEN 2B
- Medullary thyroid Ca. 100% (early onset)
- Pheochromocytoma 50%
- No parathyroid disease
- Marfinoid habitus nearly 100%
- Intestinal ganglioneuromatosis and mucosal neuromas ~100%
Neoplasm of parafollicular (C) cells, secrete calcitonin, CEA (can be used as markers), starts as hyperplasia→ Nodular hyperplasia → MicroCa.→ MacroCa.;
indolent in 80%, the rest- very aggresive, can metastasize early to liver, bone, lung (can obstruct airway)
Medullary Thyroid Ca.
(70% sporadic or can be familial- MEN 2A, MEN 2B, FMTC)
MEN2B is most aggressive then sporadic=MEN2A>FMTC
Genetic testing for family members of pts w MEN 2A or familial medullary Thyroid Ca. (FMTC) w/ known mutation?
- Normal RET analysis- excludes w/ ~100% certainty, repeat analysis in 3-5yrs (No catecholamine or Ca++ screening)
- If they have RET mutation: Thyroidectomy before 5yo -OR- Annual Calcitonin and neck US until abnormal>thyroidectomy, cont. catecholamine and Ca++ screening
- Screen all possibly affected fam members
RET testing for FMTC?
no known RET mutation occurs in 5-8% of families so not finding mutation does not rule it out, need annual calcitonin and neck US, repeat genetic analysis when more mutations known
RET testing for Sporadic MTC?
absence of FH does NOT exclude mutation, 6% germline mutation, If no mutation- hereditary excluded w 99% certainty, somatic mutations in 25%
