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391 Cards in this Set

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what is the dual blood supply to the liver?
1. hepatic artery
2. portal vein
describe how blood exits the liver
central veins to hepatic vein to IVC
which zone of the liver gets more blood and nutrients: the periportal or the centrolobular?
periportal (peripheral)
(centrolobular is the most susceptible to anoxia)
what lies at the center of an acinus?
portal triad
describe the three zones of the liver and their respective blood supply
1. Zone 1 - surrounding portal triad
2. Zone 2 - middle portion
3. Zone 3 - periphery, recieves blood that is poorest in oxygen and nutrients
liver plates run between ? and ?
run between central veins and portal areas
Sinusoids are lined by?
endothelial cells and Kupffer cells
What is found in the space of Disse?
stellate cells (aka. cells of Ito)
define limiting plate
the layer of hepatocytes closest to portal areas
what is the most sensitive test for acute hepatocellular injury?
AST
which enzyme is elevated in cholestasis?
Alkaline phosphatase
which enzyme is a sensitive detector of chronic alcohol consumption?
Gamma glutamyl transpeptidase
(also a sensitive indicator of hepatobilary disease)
what does ceruloplasmin measure?
transport and maintenance levels of copper
describe copper levels in Wilson's disease
decreased
What is alpha-fetoprotein?
a tumor marker for hepatocellular carcinoma (also for germ cell tumors of ovary/testis)
what is the enzyme called that conjugates bilirubin in the liver?
UDP-glucuronyltransferase
what happens to conjugated bilirubin once it is excreted into bile?
it is decongugated by bacteria in the intestine and degraded to urobilin. 20% is reabsorbed, 80% is excreted
which type of bilirubin does the van den Bergh reaction measure?
direct (conjugated) bilirubin
(then alcohol is added and total bilirubin can be measured)
why does physiologic neonatal hyperbilirubinemia occur?
caused by:
- functional immaturity in bilirubin clearance
- increased bilirubin production
- intestinal absorption of unconjugated bilirubin
when do bilirubin levels peak in physiologic neonatal hyperbilirubinemia?
day 5
why is hyperbilirubinemia associated with breastfeeding?
How is this differentiated from physiologic neonatal hyperbilirubinemia?
breast milk contains an inhibitor of bilirubin conjugation.
here bilirubin levels peak at 10-20 days
what goes on in transient familial neonatal hyperbilirubinemia?
- inhibitor of bilirubin conjugation present in maternal serum
- peak bilirubin level w/i 4 days, may cause kernicterus
which two types of inherited disorders of bilirubin metabolism result in unconjugated hyperbilirubinemia?
1. Crigler-Najar syndromes I and II
2. Gilbert syndrome
which two inherited disorders of bilirubin metabolism result in conjugated hyperbilirubinemia?
1. Dubin-Johnson syndrome
2. Rotor syndrome
three classes of causes of conjugated hyperbilirubinemia?
1. biliary obstruction
2. parenchymal liver disease/cholestasis
3. metabolic disorders
describe the morphology of cholestasis (5)
- accumulation of bile pigment within hepatic parenchyma
- dilated bile canaliculi with bile plug
- feathery degeneration of hepatocytes
- bile lobes/infarcts
- portal tract fibrosis
lab test characteristic of cholestasis vs. hepatitis
(ALP, AST, ALT)
1. marked elevation of Alkaline Phosphatase
2. milder elevations of AST, ALT
(hepatitis has marked elevations of AST, ALT, rather than Alk. phos.)
extrahepatic causes of cholestatic liver disease (6)
1. gallstone in common bile duct
2. cholangiocarcinoma
3. bile duct stricture
4. sclerosing cholangitis (fibrosis of bile ducts)
5. carcinoma of ampulla of Vater
6. carcinoma of head of pancreas
intrahepatic causes of cholestatic liver disease?
1. hepatitis
2. drugs
3. primary biliary cirrhosis
causes of hepatitis other than viral? (3)
1. alcohol, drugs or both
2. metabolic liver disease (hemochromatosis, alpha-1 antitrypsin deficiency, wilson's disease)
3. autoimmune
what are the three major pathological mechanisms underlying cirrhosis?
1. cell death
2. fibrosis
3. regeneration
Top 3 causes of cirrhosis?
1. alcoholic liver disease
2. viral hepatitis
3. biliary disease
stimuli for stellate cell activation? (4)
1. Chronic inflammation (TNF, IL-1)
2. Cytokine production (TGF-B, PDGF)
3. disruption of cellular matrix
4. toxins
3 types of portal hypertension?
1. prehepatic
2. intrahepatic
3. posthepatic
Prehepatic causes of portal hypertension?
1. portal vein thrombosis
2. portal vein stenosis
3. splenomegaly
Posthepatic causes of portal hypertension?
1. R sided heart failure
2. constrictive pericarditis
3. hepatic vein obstruction
intrahepatic causes of portal hypertension? (6)
1. cirrhosis
2. schistosomiasis
3. granulomatous disease
4. steatosis
5. miliary TB
6. tumors
clinical consequences of portal hypertension? (4)
1. ascites
2. postsystemic venous shunts
3. congestive splenomegaly
4. hepatic encephalopathy
three theories behind the pathogenesis of ascites? (3)
1. cirrhosis causes vascular obstruction, which causes increased hydrostatic pressure in sinusoids, which leads to ascites
2. cirrhosis leads to decreased albumin in blood. this leads to decreased plasma oncotic pressure, leads to ascites
3. leakage from liver surface
in portal hypertension: thrombocytopenia and anemia suggest?
congestive splenomegaly
mortality of acute liver failure?
80-90%
what types of viral hepatitis may cause acute liver failure?
Hep A,B,C,D,E
herpes
which drug is notorious for causing acute liver failure?
acetaminophen
toxins causing acute liver failure (3)?
1. CCl4
2. Amanita phalloides
3. phosphorus
vascular causes of acute liver failure?
1. ischemia
2. veno-occlusive
3. malignant infiltration
4. Budd-Chiari syndrome
three miscellaneous causes of acute liver failure?
1. Wilson's disease
2. autoimmune hepatitis
3. acute fatty liver of pregnancy (AFLP)
what is hepatorenal syndrome?
kidney failure in patients with severely compromised liver function (w/o any other known causes of renal failure)
what is hepatopulmonary syndrome?
intrapulmonary microdilation (with liver disease or portal hypertension)
tx. - liver transplant
what causes hepatic encephalopathy?
portal blood enters the systemic circulation without being processed by the liver. appears to be associated with high ammonia levels
what are the three clinical phases of viral hepatitis?
1. prodrome
2. icteric phase (jaundiced, ill)
3. convalescent phase
what are some s/s of decompensated cirrhosis brought about by viral hepatitis?
portal HTN
hepatic encephalopathy
fulminant liver failure
lab indications of acute viral hepatitis?
extremely high levels of:
AST
ALT
describe the hepatic histological characteristics of acute viral hepatitis
1. hepatocyte injury or death
2. balloned hepatocytes
3. inflammatory infiltrate
4. bridging necrosis
5. Kupffer cell hyperplasia
6. portal tracts infiltrated with inflammation
7. may have cholestasis
describe the hepatic morphology in severe chronic viral hepatitis (5)
1. increased inflammation in portal areas
2. bile duct damage
3. bridging necrosis
4. fibrous tissue deposition
5. regenerative hepatic nodules
what is the predominant mode of transmission of HepA?
fecal-oral
where does the HepA virus replicate?
jejunum (before it is transported to the liver)
how is the HepA virus shed in the feces?
liver -> excreted in bile -> feces
(shedding occurs during the prodrome phase, before it is clinically apparent)
what is unique about a HepA infection?
no carrier state
does not lead to chronic disease
how long can relapsing HAV last?
~1yr
what type of virion is HepB
dsDNA
HepB belongs to which family of viruses?
Hepadnaviridae
mode of transmission of HepB?
parenteral
vertical
sexual
HepB is associated with increased risk of what cancer?
hepatocellular carcinoma
what is the incubation period of HepB?
4wks-6mo
is there a correlation between the severity of an acute HepB attack and the progression to chronicity?
the more severe the acute attack - the least likely to progess to chronicity
which HepB serum antigen reflects the core protein?
HBcAg
which HepB serum protein reflects the envelope glycoprotien?
HBsAg
what is the function of protein X in HepB?
virus replication
describe the appearance of HBsAG (levels throughout the infection)
*appears in serum weeks before clinical sx
*persists for a total of 3-4 months
HBsAg levels present for >6 months denotes?
carrier state
what is the significance of antibodies to HBsAg appearing?
indicates recovery as well as immunity
(appear a few weeks after the dissapearance of the antigen)
which antibody is a marker of hepB infection in the "window period" between the dissapearance of HBsAg and the appearance of anti-HBsAg?
Anti-HBcAg
in a HepB infection: which viral marker is closely correlated with viral infectivity?
HbeAg
which type of Hepatitis can only be seen in conjunction with a HepB infection?
HDV
type of genome of HDV?
RNA virion
why must HepD be associated with HepB?
HDV cannot replicate on its own - genome incomplete
clinical s/s of a patient with a HepB and HepD infection?
*severe course
*suspect in a patient with a worsening case of HBV
HepC belongs to which viral family?
Flaviviridae
structure of HepC genome?
ssRNA
HepC is associated with what cancer?
hepatocellular carcinoma
why is HepC often diagnosed when a person has been a chronic carrier for a while?
asymptomatic
often find incidentally
a chronic carrier of HCV often develops?
cirrhosis or HCC
transmission of HepE?
fecal-oral
can hepE become chronic?
NO
when is hepE unusually fatal?
during pregnancy (20%)
HGV belongs to which family of viruses?
Flaviviridae
transmission mode of HGV?
parenteral
(seen frequently in blood donors)
can HGV become a chronic infection?
yes, but not associated with mortality or HCC
hepatocellular carcinoma is almost always seen after?
cirrhosis of any kind
besides hepatitis viruses, what are three other viruses associated with hepatitis?
1. EBV
2. Yellow fever
3. HSV
bacteria known for causing hepatitis?
Salmonella typhi
what is the most common form of liver disease in the US?
Alcoholic liver disease
ETOH is metabolized into what intermediate?
acetaldehyde
effect of excess acetaldehyde?
produces excess NADH in liver mitochondria
*interferes with lipid metabolism, get fatty change
what would the ALT/AST ratio be in alcoholic liver disease?
>2
lab results of the following in alcoholic liver disease?
1. albumin
2. bilirubin
3. PTT
1. decreased
2. increased
3. prolonged
4 CBC abnormalities seen in alcoholic liver disease?
(WBC, platelet #s, RBC size etc)
1. leukocytosis
2. thrombocytopenia
3. mild anemia
4. increased MCV
levels of the following in alcoholic liver disease?
1. TAGs
2. uric acid
3. K+
4. Mg++
5. Phosphate
1. hypertrigliceridemia
2. hyperuricemia
3. hyperkalemia
4. hypomagnesemia
5. hypophosphatemia
consequences of a thiamine deficiency in an alcoholic?
Wernicke syndrome
Korsakoff syndrome
effects of alcoholism on the following:
1. heart
2. GI
3. reproductive
1. cardiomyopathy
2. chronic and acute pancreatitis, acute gastritis
3. testicular atrophy, increased spontaneous abortions
alcoholism is associated with a risk in what 4 GI/liver related cancers?
Oral
pharynx
esophagus
liver
is fatty change reversible?
yes
(with no more alcohol consumption)
alcoholic hepatitis is associated with accumulation of intracytoplasmic eosiniphilic hyaline inclusions known as?
Mallory bodies
is alcoholic cirrhosis reversible?
NO
microscopic characteristics of alcoholic cirrhosis? (4)
1. fibrous septae
2. regenerative micronodules or pseudonodules
3. Mallory bodies
4. steatosis
what is the difference between the following hepatotoxic agents?
1. intrinsic
2. idiosyncratic
1. predictable or true hepatotoxins
2. non-predictable toxicity (only toxic in a small proportion of people)
at which hepatic zone are the following drugs toxic:
1. acetaminophen
2. alhyformate
3. frusemide
4. halothane
1. zone 3
2. zone 3
3. zone 2
4. zone 3 (or massive)
tetracycline, phosphorous and ETOH are know to cause what kind of liver damage?
massive
which 2 drugs are notorious for causing hepatic vein thrombosis?
oral contraceptives
steroids
oral contraceptives also are known to cause what liver cancers?
adenoma
hematoma
HCC
cholangiosarcoma
thorotrast is known to cause what sorts of liver cancer?
HCC
cholangiosarcoma
angiosarcoma
how is autoimmune hepatitis clinically diagnosed?
hypergammaglobulinemia
anti-smooth muscle antibodies
(clinical s/s identical to other forms of chronic hepatitis so hard to distinguish)
what is primary biliary cirrhosis?
autoimmune liver disease
which sex is primary biliary cirrhosis more common in?
women
pathogenesis of primary biliary cirrhosis?
destruction of bile ducts by T lymphocytes
which type of antibodies are a key feature of primary biliary cirrhosis?
antimitochondrial antibodies (AMA)
what are some clinical s/s of primary biliary cirrhosis?
asymptomatic
pruritis
jaundice
cirrhosis/liver failure
lab tests used to diagnose primary biliary cirrhosis?
*cholestatic liver function tests
*AMA
*liver biopsy
four histological stages of primary biliary cirrhosis?
1. damage to intrahepatic ducts
2. ductal proliferation
3. scarring
4. cirrhosis
what is primary sclerosing cholangitis?
chronic inflammatory disease of the biliary tree - causes scarring which narrows and obstructs bile ducts
is primary sclerosing cholangitis more common in males or females?
males
(ages 30-50)
primary sclerosing cholangitis is associated with what other disease?
ulcerative colitis
clinical progression of primary sclerosing cholangitis?
pruritis -> cholangitis -> cirrhosis -> liver failure
what is a radiographic hallmark of primary sclerosing cholangitis?
"beading" of barium column in intrahepatic and extrahepatic bile ducts
two antibodies we can look for in the lab to help diagnose primary sclerosing cholangitis?
1. ANA
2. ANCA
which type of hyperplasia is associated with portal HTN?
nodular regenerative hyperplasia
which hepatic tumor is associated with OC and anabolic steroid use?
Hepatocellular adenoma
what is a rare malignant vascular hepatic tumor that is associated with toxic exposure vinyl chloride, thorotrast and arsenic?
angiosarcoma
prognosis of angiosarcomas?
metastasize widely
death w/i 1yr of diagnosis
what is the most frequent liver tumor in children?
hapatoblastoma
gross manifestations of hepatoblastoma?
single mass
what is the MC primary hepatic malignancy?
hepatocellular carcinoma (HCC)
what are some predisposing factors to HCC?
1. viral infections (HBV,HCV)
2. chronic alcoholism (cirrhosis)
3. food contaminants (aflatoxins)
connection between X protien and HCC?
X protein (found in HBV) may disrupt normal cell growth
(may activate proto oncogenes and disrupt the normal cell cycle)
laboratory studies that help us diagnose HCC?
increased alpha fetoprotein
CEA positive
which has a better prognosis - classic HCC or fibrolamellar HCC?
fibrolamellar HCC
cancer that arises from the biliary epithelium anywhere in the biliary tree is called?
cholangiosarcoma
(bile duct carcinoma)
where are some common places in the biliary tree for cholangiosarcoma to arise?
*convergence of L and R hepatic ducts
*intrahepatic ducts
*small bile ductules at periphery of hepatic lobule
types of cancer that like to metastasize to the liver?
breast
lung
colon
melanoma
pancreas
risk factor for gallstones?
1. increased age
2. female
3. high estrogen levels (obesity, multiparous, OCs)
pigment stones are the result of?
associated with?
precipitation of excess insoluble unconjugated bilirubin
(can be associated wtih bacterial infection or hemoytic anemia)
what makes up 96% of all cases of acute cholecystitis?
obstruction of the cystic duct by gallstones
what are some causes for acute acalculous cholecystitis?
major non-biliary surgery
multiple injury states
severe burns, sepsis
recent childbirth
parenteral nutrition
mechanical ventilation
effect of opiates on acute cholecystitis?
increase the tone in the sphincter of Oddi - make it worse
one of the complications of gallstones is an empyema. what is it?
"pus filled gallbladder"
(usually see following an infection)
what are three gas forming bacteria that are known to cause an emphysematous gallbladder?
1. E.coli
2. Clostridium welchii
3. anaerobic streptococcus
what is the most common type of clinical gallbladder disease?
chronic cholecystitis (calculous)
are most tumors of the gallbladder benign or malignant?
malignant
(benign are rare)
what makes up the majority of gall bladder carcinomas?
adenocarcinomas
neoplasms of the gall bladder are more common in which race?
Native Americans
prognosis for gall bladder cancer?
Poor -- mean survival time is 6mo from diagnosis
(most have metastasized by the time they are diagnosed)
what is a Klatskin tumor?
a cholangiocarcinoma that arises from the bifurcation of the main hepatic ducts
(may mimic biliary cirrhosis and obstructive jaundice)
are thromboses more common in the hepatic artery or portal vein?
portal vein
events that could cause a portal vein thrombosis?
sepsis
trauma
portal HTN
thrombogenic disorders
pancreatitis
what is Budd-Chiari syndrome?
hepatic vein thrombosis/IVC thrombosis
clinical s/s of Budd/Chiari?
hepatomegaly
abdominal pain
ascites
Budd/Chiari syndrome is MC associated with what other disorders? (4)
1. polycythemia vera
2. HCC
3. other abdominal neoplasms
4. complication of pregnancy
what condition causes a nutmeg liver?
right sided CHF
what genetic mutation is associated with alpha-1-antitrypsin deficiency?
*inheritance pattern?
P1ZZ
autosomal recessive
hepatic manifestations of a homozygous P1ZZ mutation?
defective secretion of alpha-1-antitrypsin from the liver
(it's stuck in ER of hepatocyte, causes liver injury)
function of normal working alpha-1-antitrypsin?
inhibits neutrophil protease and elastase
manifestations of an alpha-1-antitrypsin deficiency in:
1. adults
2. children
1. emphysema
2. liver disease (cirrhosis)
clinical features of alpha-1-antitrypsin deficiency in newborns?
*persistent neonatal jaundice
*may present with portal HTN, esophageal bleeding, hypersplenism
*progresses to acute fulminant liver failure
hepatic clinical features of alpha-1-antitrypsin deficiency in adults?
chronic hepatitis
cirrhosis
portal HTN
HCC
lab values that assist in diagnosis of alpha-1-antitrypsin deficiency?
increased:
serum aminotransferase
GGT
what is the classic histological hallmark of alpha-1-antitrypsin deficiency?
PAS positive (represents retained alpha-1-antitrypsin in hepatocytes)
what is the most severe form of alpha-1-antitrypsin deficiency?
ZZ
(there is a Z-, but it is incompatible with life)
what is the mildest form of alpha-1-antitrypsin deficiency?
MM
what is Wilson's disease?
impaired copper excretion by liver
(followed by copper deposition in other organs)
where is the site of the biochemical defect seen in Wilson's disease?
liver membrane
(mutation in ATP7B on chrom.13)
when are most diagnoses of Wilson's disease made?
after 5yrs old
(Copper needs time to accumulate)
inheritance pattern of Wilson's disease?
autosomal recessive
what are the serum ceruloplasmin levels in a patient with Wilson's disease?
decreased
(ceruloplasmin is a copper binding protein-decreased levels mean it is all bound to copper)
where does excess copper accumulate?
liver
kidney
brain
cornea
Kayser-Fleischer rings are deposits of copper in?
Descemet's membrane circumscribing the cornea
treatment for wilsons disease?
chelation of copper
liver transplant
what stain can be used to see the copper deposits in the liver?
Rhodamine stain
what is hemochromatosis?
iron storage disease
(1/3 of stored iron is in the liver)
where in the GI is iron absorbed?
duodenum and proximal jejunum
when iron cannot be absorbed where does it accumulate?
liver
(end result is cirrhosis and/or HCC)
mutation of which protein leads to hemochromatosis?
HFE
(results in impaired transferrin)
what is the "classic triad" seen in iron storage diseases?
1. pigment cirrhosis with hepatomegaly
2. skin pigmentation
3. diabetes mellitus
in which population is iron storage diseases most prevalent?
people of northern european ancestry
diagnostic tests used to look for iron storage diseases?
1. transferritin saturation
2. unsaturated iron binding capacity
3. serum ferritin
4. liver biopsy
5. hepatic iron concentration/index
which mutation would be looked for in genetic testing for hemochromatosis?
C282Y mutation for HFE
what is choledocholithiasis?
presence of stones within the bile ducts of the biliary tree (stones migrated from gallbladder)
where do stones tend to impact in choledocholithiasis?
ampulla of Vater
complications of choledocholithiasis? (4)
1. pancreatitis
2. cholangitis
3. hepatic abscess
4. biliary cirrhosis
clinical s/s of choledocholithiasis? (3)
1. fever
2. pain
3. acute jaundice
what is cholangitis?
inflammation of the bile ducts resulting from any obstruction of bile flow
(commonly from an ascending bacterial infection of the bile ducts)
common infecting bacteria causing cholangitis? (5)
1. E.coli
2. Klebsiella
3. enterococci
4. clostridium
5. enteric gram neg. anaerobes
what are the 2 forms of extrahepatic biliary atresia?
1. embryonic (fetal) type
2. perinatal form (most)
*manifests 4-8 wks following a jaundice free period*
what is the location of the following types of biliary atresia?
1. type 1
2. type 2
3. type 3
1. common bile duct
2. hepatic bile ducts
3. above porta hepatis
what two things control (exocrine) pancreatic secretions?
secretin
cck
4 major enzymes released by exocrine pancreas?
1. amylase (CHO)
2. lipase (TAGs)
3. Trypsin
4. Chymotrypsin
which lab value is followed to diagnose acute pancreatitis?
serum amylase
(95% specificity first 24hrs)
what are the causes of death in acute severe pancreatitis? (4)
1. shock
2. DIC
3. ARDS
4. septic pancreatic abscesses
why is hypocalcemia seen in acute pancreatitis?
circulating Ca++ is precipitated into calcium-fatty acid soaps
two MC predisposing conditions for pancreatitis?
excessive alcohol intake
gallstones
what characterizes chronic pancreatitis?
progressive parenchymal FIBROSIS and CALCIFICATION
MC cause of chronic pancreatitis?
alcoholism
are pancreatic pseudocysts associated with acute or chronic pancreatitis?
chronic
what is the difference between a pancreatic cyst and a pancreatic pseudocyst?
pseudocyst - lacks epithelial lining, solitary
cyst - anomaly of pancreatic duct
4 risk factors for pancreatic cancer?
1. smoking (2-3x)
2. chemical carcinogens (nitrosamines, polycycline hydrocarbons)
3. hi-fat diet
4. DM
MC pancreatic cancer?
adenocarcinoma
where do most pancreatic carcinomas arise?
head of pancreas
(cause obstructive jaundice)
which cells do most pancreatic carcinomas arise from?
ductal cells (99%)
prognosis for pancreatic carcinoma?
usually results in death within 1 yr
(diagnosis is very late)
where is ETOH absorbed?
stomach (20%)
intestine (80%)
which enzyme metabolizes 90% of alcohol in the liver and GI?
alcohol dehydrogenase
what type of kinetics does alcohol metabolism have?
significance?
zero order kinetics
(always at a rate of 1drink/hr)
*drink any more than that - goes to serum*
which would have a greater intoxication effect:
4 drinks in 1 hr
4 drinks over 4 hrs
4 drinks in one hour
when would the MEOS kick in ?
when the BAC >0.1
what is one possible reason for the increased tolerance to ETOH?
Induction of the MEOS can occur
ETOH is metabolized by either alcohol dehydrogenase or MEOS into?
Acetaldehyde
what happens to acetaldehyde?
aldehyde dehydrogenase converts it to acetic acid, then to acetyl CoA, then to CO2 and H2O
ETOH has what effect on the CNS?
depressant
the first part of the CNS to be affected by alcohol is?
then what is affected by higher doses?
highly integrated functions
higher doses affect motor function
ETOH and dopamine together have what effect?
ETOH increases DA mediated pleasurable effects
effect of ETOH increasing the release of NE?
contributes to enlivening and activating "party" effects of alcohol
effect of ETOH on GABA activity?
potentiates GABA activity through the GABA A receptor
(amnesia and sedation effects)
effect of ETOH on glutamate receptors?
blocks excitatory NMDA receptor
(amnesia and other cerebral depressant effects)
what antidepressant drug is associated with N/V when taken with alcohol?
Serotonin stimulation
(SSRIs)
which effect is responsible for the warm, flushed feeling experienced with alcohol intake?
vasodilation
(loss of central vasomotor control)
cardiac manifestations of alcoholism? (2)
hypertension
cardiomyopathy
effects of ETOH on gastric secretions?
increased with low BAC
decreased with high BAC
effect of ETOH on sphincter of oddi? significance?
increased secretion and spasm - causes pancreatitis
chronic alcoholism results in induction of which enzyme (responsible for some of the tolerance effects)
CYP2E1
excessive alcohol intake inhibits gluconeogenesis. consequences?
hypoglycemia
poor nourishment
mechanism of acetaldehyde causing hepatotoxicity?
acetaldehyde precipitates oxidative stress (ROS) which leads to tissue damage
Renal effects of ETOH?
diuresis due to reduction of ADH
(dose dependant)
what is the significance of less total body water in women vs. men?
women have a higher BAC because of this
describe the effects at the following BACs
1. 0.03%
2. 0.06%
3. 0.09%
1. feel relaxed, light feeling of exhileration
2. warmth and relaxation; decrease of fine motor skills
3. reaction time slowed, muscle control poor, speech slurred, legs wobbly
describe the effects at the following BACs:
1. 0.12%
2. 0.18%
3. 0.30%
4. >0.50%
1. judgement clouded, inhibitions lessened, impaired reason and logical decision making
2. behavior impaired, difficult to stay awake
3. semi stupor or deep sleep
4. coma and danger of death; breathing center paralyzed
what would the interaction of ETOH be with other drugs that utilize the CYP 450 system? (ie. clearance rates of the drugs)
increases clearance of these drugs
where does disulfiram act?
inhibits aldehyde dehydrogenase
besides disulfiram, what are some other inhibitors of aldehyde dehydrogenase?
metronidazole
cephalosporins
sulfonureas
in ETOH withdrawal, when is the onset of symptoms?
6-8 hrs after d/c alcohol
In ETOH w/d: when are peak syptoms experienced?
24-36 hrs after d/c
what is the significance of having increased excitatory NMDA (glutamate) receptor levels at the time of stopping alcohol?
causes large intracellular Ca++ influx, hyperexcitability and cell death. this results in a sudden decrease in ETOH mediated inhibitory actions via GABA - "excitatory overdrive"
which neurotransmitter mediates the "excitatory overdrive"?
NE
(autonomic hyperactivity)
what is the most serious stage of alcohol withdrawal syndrome?
Delerium Tremens (DT)
untreated, DT has a mortality of?
up to 15%
4 drugs used to treat ETOH withdrawal (not DTs)
1. benzodiazapenes
2. anticonvulsants
3. carbamezapine
4. B-Blockers or clinidine
give some examples of benzodiazapenes used to treat ETOH w/d
1. chlordiazepoxide
2. diazepam
3. oxazepam
4. lorazepam
would anticonvulsants be used prophylactically?
NO
only use if prolonged or frequent seizures occur
why are beta blockers beneficial in treating ETOH w/d
block sympathetic nervous system activity
(reduces hyperacticity)
what is normally administered to treat DTs?
large doses of benzodiazapenes
*if not controlled, use pentobarbital or propofol*
which two benzodiazapenes are "long duration of action" agents?
diazepam
chlordiazepoxide
which benzodiazapene is considered a short action of duration agent and is therefore "safer" in elderly or liver disease?
lorazepam
why are benzodiazepenes so successful in controlling agitation QUICKLY?
they are the most rapid drugs to cross the BBB
which benzodiazepine is known for having good IM absorption?
Lorazepam
(others are IV or oral)
which is more effective for treatment of ETOH w/d with BZD: symptom triggered or fixed schedule?
similar effectiveness
what is the classical triad seen in Wernicke's encephalopathy?
ataxia
confusion
opthalmoplegia
Describe Korsakoff psychosis
amnestic syndrome - (impaired recent memory and relatively intact intellectual function)
what can be administered to prevent Wernicke-Korsakoff syndrome?
Thiamine
why does a thiamine deficiency result in CNS damage?
the CNS is sensitive to the B vitamin dependant metabolism of glucose
MOA of disulfiram?
irreversible inhibition of aldehyde dehydrogenase
*increased acetaldehyde
*persists as long as ETOH is being metabolized
how long after ETOH ingestion should disulfiram not be administered?
12h
effects of excess acetaldehyde?
N/V
headache
Hypotension
disulfiram has what notable side effects?
* hepatotoxicity (follow with LFT tests)
* CNS - fatigue, headache, restlessness
MOA of naltrexone?
Antagonizes endogenous opioid receptors - reduces pleasurable effects of ETOH, but no adversive effects...
adverse effects of naltrexone?
nausea
dizziness
rare hepatitis at unusual doses (monitor LFTs, contraindicated in liver disease)
MOA of acamprosate calcium (Campral)
structural similarity to GABA - decreases glutaminergic transmission and modulates neuronal hyperexcitability --> reduces alcohol craving
which adversive agent is more affective: naltrexone or acamprosat calcium?
similar in effectiveness
MOA of topiramate in maintaining sobriety?
inhibits alcohol-induced release of DA in the midbrain - reduces rewarding effects of alcohol.
define a pharmaceutical drug interaction
occurs between two drugs (ie. IV additives)
define a pharmacokinetic drug interaction
interaction of 2 or more agents that lowers or elevates concentrations
(via altered absorption, distribution, metabolism, excretion)
define a pharmacodyamic drug interaction
1 drug increases or reduces the activity of another
(synergy, antagonistic, additive effects)
what are disease drug interactions?
*disease alters kinetics or dynamics of a drug (ie. renal failure prolongs the 1/2 life of digoxin)
-or-
*drug alters the disease (ie. beta blockers causing bronchoconstriction in asthma)
two classic drug food interactions involving:
1. tetracyclines
2. CCBs
1. don't mix with dairy products
2. don't mix with grapefruit juice
diuretics altering the serum K+ lab value is an example of what kind of drug interaction?
drug-lab interaction
which GI alteration are anticholinergics, opioids and food known for?
promoting slowed gastric emptying
which GI "speed" alterations are erythromycin, cisapride, metoclopramide known for?
promoting accelerated gastric emptying
What happens to serum [digoxin] when certain antibiotics are taken at the same time?
increases
effect of antacids on tetracyclins and quinolones?
antacids chelate them, cause reduced plasma concentration
possible interaction between TMP/SMX and methotrexate?
altered renal excretion (TMP/SMX reduces elimination of methotrexate)
diuretics reduce the renal excretion of what CNS drug?
lithium
probenecid inhibits the tubular secretion of what antibiotic?
penicillin
what do the following agents have in common?
lidocaine
acetaminophen
diazepam
theophylline
only or mostly hepatic clearance
what is the main function of the liver in regards to metabolism of lipophilic drugs?
conversion to water soluble metabolites
which system most commonly mediates the Phase I reaction of hepatic drug metabolism?
CYP450
biochemically, how is a lipophilic drug converted to a water soluble one?
a polar functional group is added or unmasked
(increased polarity promotes excretion)
what types of biochemical reactions can a phase I reaction be? (4)
1. oxidation
2. reduction
3. hydrolysis
4. deamination
in a phase I rxn, the goal is activation or inactivation. What is the main goal in a phase II rxn?
inactivation of drug
what general reaction type occurs in a phase II rxn?
conjugation (via transferases)
what specific biochemical rxns. take place in a phase II reaction? (4)
1. acetylation
2. glucuronidation
3. sulfation
4. methylation
once drugs have gone through the phase II rxn, how are they eliminated?
renally
(very water soluble)
T/F: some drugs can directly enter phase II metabolism (and bypass phase I)
true
the study of inheritance in the individual variation in drug response is termed?
pharmacogenomics
what are the 4 phenotypes for CYP450 isoenzymes?
1. poor metabolizers (PMs)
2. intermediary metabolizers (IMs)
3. extensive metabolizers (EMx)
4. Ultrarapid metabolizers (UMs)
which CYP enzyme is responsible for >50% of total hepatic CYP450 isoenzymes and is therefore responsible for many drug interactions?
CYP3A
are most drugs metabolized by one or multiple CYP450 isoenzymes?
one
describe the inhibition mechanism of CYP450 drug interactions
decreased metabolism of drugs
=accumulation
=potential for toxicity
describe the induction mechanism of CYP450 drug interactions
increased metabolism
=potential for reduced activity
what is autoinduction of CYP450?
when a drug increases the synthesis of CYP450 enzymes responsible for metabolizing itself.
which has a longer onset: induction or inhibition of CYP450?
induction (days or wks)
(vs. inhibition: hrs to days)
does ETOH act as a CYP450 inducer or inhibitor?
inducer
is rifampin a CYP450 inducer or inhibitor?
inducer
are CCBs CYP450 inducers or inhibitors?
inhibitor
what do the following have in common as far as their metabolism goes:
acetaminophen
amitriptyline
caffeine
propanolol
theophylline
substrates for CYP1A2
what do the following have in common:
cimetidine
CCBs
Erythromycin
Quinolones
SSRIs
inhibitors of CYP1A2
action of grapefruit juice on CYP450 system?
inhibitor
(specifically CYP1A2)
undetoxified NAPQI, formed by the metabolism of acetaminophen, results in what?
hepatic necrosis
what action do SSRIs have on CYP450 metabolism?
inhibitors
what action do FQs have on the CYP450 metabolism?
inhibitors
(specifically CYP1A2)
significance of a patient on cipro and warfarin?
cipro will inhibit warfarin metabolism (CYP1A2 inhibitor)
ketoconazole has what action on CYP3A4?
competitively inhibits
azole antifungals interact with what other drugs?(the three he gave in lecture)
lovastatin
alprazolam
carbamazapine
effect of antacids, Ca, Zn, Mg, Fe on absorption of FQs?
reduce
effect of azole antifungals on warfarin absorption?
decreased
(increased warfarin INR when simultanously on azoles)
which macrolide antibiotic doesn't have any CYP activity?
azithromycin
erythromycin inhibits CYP metabolism. is this reversible or irreversible inhibition?
irreversible
(effects last until new enzyme is synthesized)
which three statins are not metabolized by CYP3A4 (or have minimal CYP3A4 metabolism)?
1. fluvastatin (NONE)
2. pravastatin (little to none)
3. rosuvastatin (little to none)
why are increased serum levels of statins a concern?
increased risk of myopathy
what is the biological chemical that is found in grapefruit juice?
(this chemical binds to and inhibits CYP450)
bioflavonoids
(more specifically: naringenin & quercetin)
how long do the CYP inhibition effects of grapefruit juice last?
up to 24 hrs
two drugs not to take with warfarin because they cause CYP2C9 inhibition?
metronidazole
amiodarone
what two effects does phenytoin have on warfarin metabolism?
1. induction (causes increased INR)
2. inhibition (causes decreased INR)
effect of phenytoin on vitamin K synthesis?
reduces Vit K synthesis
significance of warfarin and cranberry juice together?
Cranberry juice has antioxidants that inhibit CYP. Causes increase in INR
besides the hepatitis viruses, what are two other viruses that cause mild hepatitis?
CMV
EBV
besides the hepatitis viruses: two viruses that cause SEVERE hepatitis?
coxsakie viruses (disseminated form)
herpes simplex (disseminated form)
which two hepatitis viruses cause acute hepatitis only and never progress to a chronic infection?
HAV
HEV
does immunity to one strain of hepatitis render immunity to the other strains?
NO
HAV belongs to which viral family?
picornavirus
how many serotypes does HAV have?
one
transmission mode of HAV?
mainly fecal-oral
when does the HAV virus shed in comparison the the onset of clinical s/s
shedding occurs 1-2 wks prior to onset of clinical s/s
where does HAV intitially replicate?
intestinal epithelial cells
how does HAV get from the intestine to the liver?
via blood
if HAV lives in the liver, how is it excreted in the feces?
the virus is shed into the bile ducts
in the course of an HAV infection, when does most of the hepatocyte damage occur?
occurs at the time of a detectable immune response
which cells are thought to mediate liver cell damage?
cytotoxic T cells
how rapidly after an HAV infection does the liver return to normal? (via hepatocyte regeneration)
8-12 wks (rapid)
describe the preicteric phase of an HAV infection
1-7 days long
prodrome of weakness, malaise, N/V
describe the icteric phase of an HAV infection
abrupt onset
dark urine, jaundice
rise in aminotransferases and bilirubin.
*characterized by hepatic tenderness and hepatosplenomegaly
are there extrahepatic manifestations in an HAV infection?
NO!
no chronic disease = no extrahepatic manifestations
what is fulminant HAV infection associated with?
coagulation disorders
encephalopathy
(fatality rate >50% in fulminant hepatitis)
how is HAV diagnosed?
anti-HAV IgM
(using EIA)
specific therapy for HAV?
none at present
what, when administered, renders passive immunity to HAV?
immunoglobulin (HA-Ig)
*must be administered within 2 wks of exposure to virus
reccomendations of HAV vaccine?
1. travelers/(persons >2yrs) traveling to endemic areas
2. MSM, illegal drug users
3. chronic liver disease, clotting factor disorders
4. occupational risk
what family does HBV belong to?
calcivirus
HEV has the highest prevalence in what age group?
young adults
which has a higher mortality rate: HAV or HEV?
HEV (10x higher, but still only 1-3%)
why is an HEV infection so bad in pregnant women?
15-25% fatality rate
which has a longer incubation time: HAV or HEV?
HEV
in an HEV infection which occurs first: presence of symptoms or shedding of viral particles in the feces?
shedding of viral particles in the feces
treatment for HEV?
supportive
is there a vaccine available for HEV?
NO
HBV belongs to which viral family?
hepadnaviridae
what is unique about the HBV genome?
it is the only human hepatitis virus with a DNA genome
what three things is the core of HBV made up of?
incomplete dsDNA genome
reverse transcriptase
HBV core antigen (HBcAg, HBeAg)
what two things are found in the envelope of HBV?
lipid bilayer
HBV surface antigen (HBsAg)
what is the Dane particle?
the normal HBV virion
in HBV, what is the major antigen found in subviral particles?
HBsAg
describe, in a nutshell, the replication process of HBV
*HBV is uncoated, then transported to nucleus
*converted into complete DNA circle
*dsDNA circle is template for host RNA pol, which transcribes to form a greater-than-full-length mRNA called pgRNA
*mRNAs are translated in cytoplasm, viral proteins are made
*pgRNA is encapsidated to form "core"
*RT then converts pgRNA into partial dsDNA genome
what is the age correlation between progression of HBV to a chronic infection?
newborns - highest rate of progression to chronic infection
teenagers, adults - lowest rates
does an HBV infection tend to asymptomatic in the young or old patient?
in the young (ie. newborn)
what mediates the actual cell destruction in an HBV infection?
cytotoxic T-cells
(and cytotoxic by-products of the inflammatory response)
which enzyme levels would be elevated in an acute HBV infection?
serum bilirubin
aminotranferases
extrahepatic manifestations of HBV?
arthralgias
rashes
serum-sickness syndrome
in an HBV infection, which occurs first: symptoms or jaundice?
symptoms
what are 3 viral markers we can use to detect an HBV infection?
HBeAg
HBsAg
HBV DNA
(all appear at the onset of symptoms)
which antibody is only seen once the HBs antigen is gone (signifiying beginning of recovery)
Anti-HBs
what two things can chronic HBV infection lead to?
1. cirrhosis
2. HCC
which HBV antigen is used to detect replicating virus?
HBeAg
which antibody never shows up in a chronic HBV infection?
Anti-HBs
(chronic infx - still producing Ag)
interpret the following based on HBV serology:
HBsAg (+)
HBeAg (-)
AntiHBs (-)
AntiHBc (-)
early HBV infection
interpret the following based on HBV serology:
HBsAg (+)
HBeAg (+)
AntiHBs (-)
AntiHBc (+)
acute or chronic HBV infection with high infectivity
interpret the following based on HBV serology:
HBsAg (-)
HBeAg (-)
AntiHBs (+)
AntiHBc (+)
previous infection, immune to HBV
a vaccine response would see an increase in which HBV serology marker?
Anti-HBs
three treatments for an HBV infection?
1. interferon alpha
2. RT inhibitors
3. liver transplant (end stages)
if a patient in liver failure due to chronic HBV gets a liver transplant is he cured?
NO
virus never goes away, liver problems will return
how can passive immunity to HBV be achieved?
HBV immune globulin (HBIB)
when would HBV immune globulin (HBIB)be indicated?
for prophylaxis in people that think they have had an HBV exposure
which HBV antigen is the only one found in the HBV vaccine?
HBsAg
describe the genome of HDV
defective RNA virus
(requires HBV for replication)
give three RT inhibitors used to treat HBV
1. lamiduvine
2. adefovir
3. entecavir
what exactly makes up the delta antigen?
in HDV: the RNA genome associated with a structural protein (the HDV virion=delta antigen)
what serological marker is used to detect HDV?
Delta antigen
what is the significance of a concurrent HBV and HDV infection?
increased chance of developing fulminant hepatitis
what is the prophylactic treatment for an HDV infection?
HBV vaccine
HCV belongs to which family of viruses?
flavaviridae
why is there a problem developing an HCV vaccine?
9 genotypes, each with multiple serotypes
*also high mutation rates
which 3 groups are at risk for developing HCV?
1. IV drug users
2. recipients of blood or blood products
3. healthcare workers
complications of HCV?
1. chronic HCV infection
2. cirrhosis
3. HCC
*HCV is leading indicator for liver transplantation*
3 extrahepatic manifestations of HCV?
1. essential mixed cryoglobulinemia
2. membranoproliferative glomerularnephritis
3. porphyria cutanea tarda (photosensitive lesions on skin)
which marker is used to detect HCV infection?
Anti-HCV antibodies
(or can look for viral RNA via RT-PCR)
two drugs approved for the treatment of HCV?
1. interferon alpha
2. ribavirin