Clinicopathology of Hereditary liver disease Flashcards
Hereditary hemochromatosis presentation
- very tanned (tan in wintertime)
- abnormal LFTs
- increased ferritin levels
primary iron overload
Hereditary hemochromatosis
secondary iron overload
alcohol or NAFLD/NASH, transfusion related
Hemochromatosis
disorder of iron metabolism that leads to iron overload
Hereditary hemochromatosis mechansism
body absorbs too much iron from the diet, excess iron stored in the liver, skin, heart, pancreas, testes and joints, severe tissue damage
where is iron deposited in HH
liver, skin, heart, pancreas, testes and joints
histology of HH
iron overload, fibrosis, cirrhosis
total body iron stores by age in HH
men present earlier than women
women have menstrual cycle which naturally decreases iron stores - will present about 15 years later
how do we detect iron overload?
can see on MRI
which organ does not acculumate iron?
spleen - therefore color can be used as a reference on MRI imaging
hepatocytes with Fe overload
yellowish brown, refractive granules
what stain tests for iron?
Prussian blue
HH histology
low power: areas of brownish discoloration over the liver
high power: portal area in the central portion of the field, periportal hepatocytes with refeactile yellow brown pigment
where does iron deposition in the liver start?
periportal areas - zone 1!!!! other disease are zone 3 due to lack of blood flow, but zone 1 here because liver thinks it wants the iron
untreated HH can lead to
cirrhosis
which cancer can arise from hemochromatosis with cirrhosis?
hepatocellular carcinoma - common because iron is toxic, so it can cause mutations
pathology can show larger nodules with no accumulation of iron, with cellular atypic and thicker cell plates
do hepatocellular carcinomas accumulate iron?
no because cirrhotic regenerative nodule has not had time to accumulate iron
non-genetic mechanism for iron overload
secondary
transfusion associated iron overload, or patients on chronic transfusion regiments (sickle cell, hemolytic anemias, etc)
difference between primary iron deposits and secondary iron deposits
primary includes iron deposits in the liver cell hepatocytes
secondary has iron in the kupferr cell macrophages, trying to clear it out, and then progresses to hepatocytes as overload increases
difference between primary iron deposits and secondary iron deposits
primary includes iron deposits in the liver cell hepatocytes
secondary has iron in the kupferr cell macrophages, trying to clear it out, and then progresses to hepatocytes as overload increases
what is the hepatic iron index
it normalizes to a patients age to determine if there is a hereditary cause or not
how can you tell if patient has hemolytic anemia on liver biopsy?
abnormal shaped cells in sinusoidal spaces (sickle cell)
hemochromatosis treatment
phlebotomy - removal of iron to deplete stores
unless patient is anemia or has a blood disorder - chelating agents
prime protein of iron absorption
hepcidin
dietary iron is taken up by the ____ and stored within the cell as ____
enterocytes
ferritin
ferroportin
iron can be absorbed through the basolateral membrane by ferroportin
hepcidin is made where
liver
HFE protein makes
hepcidin, hemojuveline, and transferrin receptor 2 (TFR2)
hepcidin causes ____ iron release from cells when it binds to _____
decreased
ferroportin
HFE mutation
leads to downregulation of hepcidin and therefore uncontrolled release of iron from enterocyte and macrophages
hepcidin binds ____ to prevent ____ release into blood stream
ferroportin
iron
_____ hepcidin levels leads to decreased serum iron
increased
how does iron cause damage to tissues?
iron causes injury and inflammation by reactive O2 species
what organs can iron overload deposit? what conditions are then caused?
liver - cirrhosis - high risk for HCC
heart - cardiac dysfunction/restrictive cardiomyopathy, HFPEF
pituitary - hypergonadotropism, infertility
pancreas - diabetes mellitus
joints - arthropathy
skin - increased pigmentation
inheritance pattern of HH
autosomal recessive disorder, HFE gene mutation on chromosome 6
principal missense mutations in hereditary hemochromatosis
major mutation C282Y
minor mutation H63D
phenotypes associated with HH
C282y/C282y homozygous (primary driver for HH)
compound heterozygote - C282Y/H63FD - will not result in full-blown disease and may not lead to cirrhosis `
what is bronze diabetes
skin pigmentation, liver cirrhosis, diabetes
how does HH cause diabetes?
pancreatic iron deposition damages islet cells
leads to increased insulin resistance
are organ Fe deposits reversible?
cardiac is reversible with treatment
goal ferritin level
< 50 ng/ml or hemoglobin <11
iron chelators
desferoxamine, deferasirox, oral deferiprone
Wilson’s disease
- genetic disorder of copper metabolism
- failure of hepatocytes to excrete excess dietary copper into biliary canaliculi
Wilson’s disease histology
accumulation of copper starting in periportal hepatocytes
effects of Wilsons disease on liver
acute liver failure, chronic hepatitis, fibrosis, cirrhosis
how is excess copper normally excreted?
through bile from the liver
where will copper accumulate?
liver, kidneys, brain, joints, cornea with damage to these organs
how does Wilson’s disease present?
usually with neuropsychiatric or liver symptoms
which zone is affected by Wilsons disease?
zone 2
genetics of Wilson’s disease
mutation of ATP7B - encodes copper transporting ATPase
organ systems affected and how
liver - chronic hepatitis, cirrhosis or fulminant hepatic failure by age 30-40
heme - hemolytic anemia (esp if fulminant)
neuro - psychosis, seizures, ataxia, tremors, behavior changes if Cu deposits in brain
renal - proximal rental tubular acidosis, nephrolitiasis
Kayser-Fleishcer rings
golden brown pigment deposits around periphery of pupil (Wilsons)
lab results in Wilson’s disease
- high serum copper > 10 mcg/dL
- high urine copper >100 mcg/24 hrs (can’t be excreted from bile so urinated out)
- low serum ceruloplasmin
- relatively low alk phos in setting of high total bilirubin (ALP: TBili <4)
ceruloplasmin
protein that binds free copper, if overload - low levels since excess copper is binding it all up
Wilson’s disease treatment
copper chelation
liver transplantation for fulminant hepatic failure or decompensated cirrhosis
copper chelating agents
d-penicillamine, Tridentine, zinc (competitively binds for intestinal absorption of copper)
alpha 1 antitrypsin deficiency
- genetic metabolic disorder, predisposes to chronic pulmonary and liver disease
A1AT deficiency imaging
consistent with cirrhosis and portal hypertension,
hyperinflation of lungs
gene mutation in A1AT deficiency
SERPINA1 gene encodes A1AT protein
- serine protease inhibitor, creates altered structure that prevents export from hepatocytes
histology of A1AT Deficiency
variably sized eosinophilic, PAS positive granules within the cytoplasm of periportal hepatocytes
non specific inflammatory changes, including fibrosis leading to cirrhosis
polymerized aggregates of A1AT visible in hepatocyte cytoplasm as variably sized eosinophilic globules
what stain do we use in A1AT deficiency?
PAS because its cheaper than the actual AIAT stain
most common mutation to gene that regulates A1AT deficiency
SERPINA gene most common mutation is PiZZ
treatment for A1AT deficiency
liver transplantation
enzyme replacement can help pulmonary disease but not liver dysfunction
inheritance pattern of A1AT deficiency
autosomal co-dominant
normal phenotype of A1AT
PiMM
so abnormal is S, Z, or null
no A1AT protein made at all and disease implications
Pi-null/null - all will get emphysema but none will get cirrhosis!
