18.3 Flashcards
what is the morphology associated w/ toxicity due to acetaminophen use
massive necrosis (hepatocellular necrosis)
CYP P450 makes toxic metabolite in acinus zone 3. In severe injury the zone injury extends to the periportal hepatocytes → acute hepatic failure
what is the morphology associated w/ toxicity due to anabolic steroid use
bland hepatocellular cholestasis w/o inflam (cholestatic);
peliosis hepatis: blood filled cavities, not lined by endothelial cells (vascular lesion)
hepatocellular adenoma
what is the morphology associated w/ toxicity due to aspirin
(reye syndrome) - microvesicular steatosis (diffuse small droplets fat)
what agents are associated with the development of
hepatocellular adenoma
HCC
cholangiocarcinoma
angiosarcoma
Hepatocellular adenoma: oral contraceptives, anabolic steroid
HCC: EtOH, thorotrast
Cholangiocarcinoma: thorotrast
Angiosarcoma: thorotrast; vinyl chloride
what is the pathogenesis of alc related liver dz
alcohol is a major cause of liver dz in western countries and often leads to death and disability early in life
alc dehydrogenase in the cytosol usually metabolize alc
in high levels - the ethanol-ozidizing system (CYP2E1) located in the SER plays a role –> the alc competes w/ other metabolites and delays the catabolism of other drugs and potentiate its defects
how does steatosis present in alc related liver dz
hepatomegaly w/ minimal symptom; mildly increased bili
how does steatohepatitis present in alc related liver dz
tender hepatomegaly, +/- cholestasis, increased bili;
ast:alt 2:1 (<300-400), increased ALP, nonspecific sxs
how does steatofibrosis/cirrhosis present in alc related liver dz
hepatic dysfxn seen via labs, hypoproteinemia, coag abnormalities: activation of sinusoidal stellate cells and portal fibroblasts → fibrosis
what determines long term survivial for alc liver dz
Survival is up 90% if you stop drinking and don’t have jaundice, ascites or hematemesis
but if continued it drops to 50-60%
Pts w/ advance dz die from hepatic coma, massive GI hemorrhage, intercurrent infxn, hepatorenal syndrome and HCC.
what are the symptoms of acute alcoholism
associated w/ CNS effects but could lead to hepatic and gastric changes
reversible if stopped drinking
how does chronic alcoholims present
affects the liver and stomach but also the GI tract, CNS, CV, pancreas. Liver is the main site of chronic injury.
The alimentary tract can be affected too
B1 def and cause peripheral neuropathy and wernicke-korsakoff syndrome - risk of many other nutrition deficits as well.
Cerebral atrophy, cerebellar degeneration, optic neuropathy.
CV injury is in the myocardium and may cause dilated congestive cardiomyopathy.
risk for acute/chronic pancreatitis
if pregnant the baby is in danger of fetal alcohol syndrome.
increased risk for oral, esophagus and liver CA and also breast CA in women.
what are the criteria for metabolic syndrome
what is NAFLD
how can it progress
MC CLD in USA
more prevalent in hispanics
NAFLD entails the presence of hepatic steatosis in pts who do not drink or do not have other causes that could lead to 2ndary hepatic steatosis.
associated w/ metabolic dz
how does NAFLD present histologically
>5% hepatocytes - fat droplets accumulate
NASH, which has significant overlap with the histology of alcoholic hepatitis
NAFLD presents differently in children, who may have more diffuse steatosis and portal fibrosis and ballooned hepatocytes may not be present
what can help determine the clinical management of NAFLD
Fibrosis –> around central V as “spider webs’ ‘ of pericellular collagen deposition (it’s also referred to as chicken wire pattern) - seen on trichrome stain
can progress to bridging fibrosis and then cirrhosis
Cirrhosis is often subclinical for years and the steatosis/ballooned hepatocytes may be reduced/absent
how does NAFLD present
often asymp w/ metabolic syndromes only
NASH is also asymp but has elevated LFT and nonspecific signs of malaise, RUQ fullness/discomfort. These pts may pass due to cardiac death
what is hemochromatosis
excess iron abs
abnormal regulation of intestinal abs of dietary fats which leads to increase in total iron poo (could get up to >50 g)
build up in parenchymal organs like the liver (most), pancreas, heart, joints and endocrine organs
It may be hereditary or 2ndary to another cause
prevalent in caucasain, M pts >40 yo
what is the mechanism of liver injury in hemochromatosis
manifests after 20 g has accumulated
The mechanism of injury to the liver includes:
- Lipid peroxidation via iron-catalyzed free radical rxns
- Stimulation of collagen formation by activation of hepatic stellate cells
- Interaction of ROS and iron w/ DNA - lead to lethal cell injury and predisposition to HCC
what is cellular mechanism of hemochromatosis
Iron abs is regulated by hepcidin (encoded by HAMP gene, produced and secreted by the liver). The adult form of hemochromatosis is due to HFE gene mutation, MC C282Y
what is the presentation of hemochromatosis
The pt will present w/ hepatomegaly, abd pain, skin pigment change, DM (destruction of islet cells) or unstable glucose levels, cardiac dysfxn (arrhythmias/cardiomyopathy) and atypical arthritis (fully developed cases have micronodular cirrhosis).
hypogonadism: F - amenorrhea and M - impotence and loss of libido
what diagnositic tools will help diagnose hemochromatosis
very high levels of iron and ferritin (w/o 2ndary cause)
liver bx (quantitative hepatic iron- no longer necessary)
**It is imp to screen family members for probands.
(prissian blue-stain can help to see accumulation of hepatocellular iron)
what is wilson dz
AR mutation of ATP7B gene–> abnormal excretion of copper into bile and failure to incorporate copper into ceruloplasmin.
increase levels of copper in the liver, brain and eyes (but also kidneys, bone, joints, parathyroid gland)
toxic to RBC –> hemolytic anemia.
age range 6-40 yo
how will wilsons dz present
The pt will present w/ acute/chronic liver dz,
parkinson like sxs (psychiatric and behavioral - tremor, poor coordination, chorea or choeroathetosis or rigid dystonia= spastic dystonia, masklike facies, rigidty and gait problems. )
Kayser-fleischer rings in the eye
how do you dx wilsons dz
based on biochemical presence of decreased serum ceruloplasmin
increased hepatic copper (most sensitive/accurate)
increased urinary excretion of copper (most specific)
what is a1-antitrypsin def
autosomal codominant: d/o bc low levels of a1AT leading to problem in protein folding –>apoptosis
homozygous PIZZ mutation- mutation (GLU372 → LYS342)
formation of pulmonary emphysema bc the activity of destructive protease is not inhibited
liver dz is due to the accumulation of misfolded protein in the hepatocytes
what is the fxn of a1-antitrypsin
what goes wrong if there is a def
imp for the inhibition of proteases, esp elastase, cathepsin G and proteinase 3 which are released from neutrophils at sites of inflam
if def –> a1-AT is folded incorrectly in these pts and polymerized, this creates ER stress and triggers unfolded protein response which signals apoptosis
how will a1-AT def present
MC in N european descent and diagnosed
MC in infants and children bc of the early presentation- neonate will present w/ severe dz and rapid progression to cirrhosis
Teens will have hepatitis, cirrhosis and lung dz
pt in mid-late life will have cirrhosis +/- HCC
what is the morphology of a1-AT def
PAS stain after diastase diversion of the liver show magenta cytoplasmic granules (characteristic) and electron micrograph show ER dilated by groups of misfolded protein
