Metabolic/ Storage Diseases of Liver Flashcards
alpha 1-antitrypsin deficiency
autosomal recessive
mutation the is most pathological in alpha-1-antitrypsin deficiency
Pi ZZ variant: glutamine to lysine at position 342
A1AT deficiency - presentation in newborns/children
- liver related complications (more than adults)
- sx: neonatal jaundice, hepatomegaly, FTT, acute liver failure
- elevated liver enzymes in 25%
A1AT deficiency - adult presentation
- varying, but lung > liver
- greater risk of cirrhosis and HCC
- usually pts w/ cirrhosis or lier involvement have another identifiable cause of liver disease
- COPD and emphysema
less common manifestation of A1AT deficiency: necrotizing panniculitis - painful necrosis of subq fat
(can also get anti-proteinase-3-positive vasculilits)
why might you see high or normal levels of A1AT in pts who truly have A1AT deficiency?
can be elevated in inflammation (acute phase reactant)
A1AT deficiency
tx for A1AT deficiency - liver
liver transplant = cure
smoking cessation!
b/c this is the only place that alpha-1 antitrypsin is made
what problems are related to deficieny in each of these:
- C1 inhibitor
- antithrombin III
- alpha-1-antichymotrypsin
- C1 inhibitor: angioedema
- antithrombin III: thrombosis
- alpha-1-antichymotrypsin: COPD
function of hepcidin
expressed in hepatocytes, secreted into circulation
binds ferroportin (macrophages and basolateral side of enterocytes) –> more internalization and degradation of ferroportin, which INHIBITS iron export –> less iron in circ
how is iron regulated?
circulating iron detected by enterocytes –> stim hepcidin formation –> hepcidin effects ferroportin in enterocytes and macrophages –> more ferroportin internalized –> less iron absorbed and available
HFE protein
found on hepatocytes
sensor of circulating iron
features of HFE iron overload
- impaired synthesis or function of hepcidin
- lots of iron in plasma –> elevated transferrin saturation
- normal erythropoiesis
- responds to phlebotomy
features of non-HFE iron overload
- not assoc w/ hepcidin function or level
- transferrin sat slightly high or LOW
- iron in RES and cells (not plasma
- phlebotomy doesn’t help
hereditary hemochromatosis pathogenesis
mutation in HFE –> decreased hepcidin –> increased iron absorption and levels –> increased transferrin saturation –> deposition of iron in liver, heart, spleen and endocrine organs
natural hx of hereditary hemochromatosis
- genetic predisposition (sometimes disease does not develop)
- iron overload but no sx
- early sx: lethargy, arthropathy
- organ damage: cirrhosis, HCC, cardiomyopathy, diabetes
what organ systems are effected by HH?
2 genotypes assoc w/ increased cancer risk in pts w/ HCC
C282Y homozygous – HCC!!!, CRC, breast cancer
H63D homozygous + MMR mutation – HNPCC
tx for HH
phlebotomy weekly or biweekly - aim for ferritin 50-100g/L
avoid increase in iron + vit C
screen family members
iron buildup in tissue - HH
liver darker than normal b/c full of iron
genetic mutation - Wilson’s disease
ATP7B gene: encodes Cu-transporting P-type ATPase
responsible for transporting Cu from intracellular chaperone proteins into secretory pathways (excretion into bile and binding to apo-ceruloplasmin to form ceruplasmin)
genetic inheritance of Wilson’s disease
autosomal recessive
pathogenesis of Wilson’s disease
defective biliary excretion of copper –> accumulation in organs (liver, brain, cornea, kidneys)
two typical ways that wilson presents
- fulminant hepatic failure (esp in young person)
- hemolytic anemia (Coombs-negative hemolytic anemia)
Wilson’s Disease - sx
- Kay-Fleisher Rings
- Liver damage
- CNS sx: neuropsych sx
- hemolysis
- renal damage
- bone: arthritis, ricketts
what is this?
ddx?
sunflower cataracts
Ddx:
- Wilson’s
- Primary biliary cirrhosis
- primary sclerosing cholangitis
- autoimmune hepatitis
- cholestatic disease
steatosis w/ Mallory bodies in Wilson’s disease
liver histology in Wilson’s disease
- steatosis
- mallory hyaline bodies: glycogenated nuclei in hepatocytes
- focal necrosis, nodular cirrhosis
- Cu staining
- mitochondrial abnormalities
Wilson’s disease tx
- D-penicillamine
- trientine
- zinc: prevents uptake of Cu into small bowel
- Liver transplant
- diet: avoid Cu containing foods and water supply
dx Wilson’s disease
- low ceruplasmin
- slit-lamp eye exam for KF rings
- 24 hr urine Cu level
- liver biopsy
- molecular testing (for mutation)
Crigler-Najjer syndrome
children
defect in conjugation of bilirubin (via glucoronyl transferase)
sx: unconj hyperbilirubinemia
Dubin-Johnson and Rotor Syndrome
defect in excretion of bilirubin
sx: conj hyperbilirubinemia
non-hemolytic anemia should make you thing of….
Wilson’s disease
replacing A1AT in A1AT deficiency helps w….
lungs but not liver
