Metabolic/ Storage Diseases of Liver

Question 1

alpha 1-antitrypsin deficiency

Answer 1

autosomal recessive

Question 2

mutation the is most pathological in alpha-1-antitrypsin deficiency

Answer 2

Pi ZZ variant: glutamine to lysine at position 342

Question 3

A1AT deficiency - presentation in newborns/children

Answer 3

• liver related complications (more than adults)
• sx: neonatal jaundice, hepatomegaly, FTT, acute liver failure
• elevated liver enzymes in 25%

Question 4

A1AT deficiency - adult presentation

Answer 4

• 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

Question 5

Answer 5

less common manifestation of A1AT deficiency: necrotizing panniculitis - painful necrosis of subq fat

(can also get anti-proteinase-3-positive vasculilits)

Question 6

why might you see high or normal levels of A1AT in pts who truly have A1AT deficiency?

Answer 6

can be elevated in inflammation (acute phase reactant)

Question 7

Answer 7

A1AT deficiency

Question 8

tx for A1AT deficiency - liver

Answer 8

liver transplant = cure

smoking cessation!

b/c this is the only place that alpha-1 antitrypsin is made

Question 9

what problems are related to deficieny in each of these:

• C1 inhibitor
• antithrombin III
• alpha-1-antichymotrypsin

Answer 9

• C1 inhibitor: angioedema
• antithrombin III: thrombosis
• alpha-1-antichymotrypsin: COPD

Question 10

function of hepcidin

Answer 10

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

Question 11

how is iron regulated?

Answer 11

circulating iron detected by enterocytes –> stim hepcidin formation –> hepcidin effects ferroportin in enterocytes and macrophages –> more ferroportin internalized –> less iron absorbed and available

Question 12

HFE protein

Answer 12

found on hepatocytes

sensor of circulating iron

Question 13

features of HFE iron overload

Answer 13

• impaired synthesis or function of hepcidin
• lots of iron in plasma –> elevated transferrin saturation
• normal erythropoiesis
• responds to phlebotomy

Question 14

features of non-HFE iron overload

Answer 14

• not assoc w/ hepcidin function or level
• transferrin sat slightly high or LOW
• iron in RES and cells (not plasma
• phlebotomy doesn’t help

Question 15

hereditary hemochromatosis pathogenesis

Answer 15

mutation in HFE –> decreased hepcidin –> increased iron absorption and levels –> increased transferrin saturation –> deposition of iron in liver, heart, spleen and endocrine organs

Question 16

natural hx of hereditary hemochromatosis

Answer 16

1. genetic predisposition (sometimes disease does not develop)
2. iron overload but no sx
3. early sx: lethargy, arthropathy
4. organ damage: cirrhosis, HCC, cardiomyopathy, diabetes

Question 17

what organ systems are effected by HH?

Answer 17

Question 18

2 genotypes assoc w/ increased cancer risk in pts w/ HCC

Answer 18

C282Y homozygous – HCC!!!, CRC, breast cancer

H63D homozygous + MMR mutation – HNPCC

Question 19

tx for HH

Answer 19

phlebotomy weekly or biweekly - aim for ferritin 50-100g/L

avoid increase in iron + vit C

screen family members

Question 20

Answer 20

iron buildup in tissue - HH

Question 21

Answer 21

liver darker than normal b/c full of iron

Question 22

genetic mutation - Wilson’s disease

Answer 22

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)

Question 23

genetic inheritance of Wilson’s disease

Answer 23

autosomal recessive

Question 24

pathogenesis of Wilson’s disease

Answer 24

defective biliary excretion of copper –> accumulation in organs (liver, brain, cornea, kidneys)

Question 25

two typical ways that wilson presents

Answer 25

1. fulminant hepatic failure (esp in young person) 2. hemolytic anemia (Coombs-negative hemolytic anemia)

Question 26

Wilson's Disease - sx

Answer 26

* Kay-Fleisher Rings * Liver damage * CNS sx: neuropsych sx * hemolysis * renal damage * bone: arthritis, ricketts

Question 27

what is this? ddx?

Answer 27

sunflower cataracts Ddx: * Wilson's * Primary biliary cirrhosis * primary sclerosing cholangitis * autoimmune hepatitis * cholestatic disease

Question 28

Answer 28

steatosis w/ Mallory bodies in Wilson's disease

Question 29

liver histology in Wilson's disease

Answer 29

* steatosis * mallory hyaline bodies: glycogenated nuclei in hepatocytes * focal necrosis, nodular cirrhosis * Cu staining * mitochondrial abnormalities

Question 30

Wilson's disease tx

Answer 30

* D-penicillamine * trientine * zinc: prevents uptake of Cu into small bowel * Liver transplant * diet: avoid Cu containing foods and water supply

Question 31

dx Wilson's disease

Answer 31

* low ceruplasmin * slit-lamp eye exam for KF rings * 24 hr urine Cu level * liver biopsy * molecular testing (for mutation)

Question 32

Crigler-Najjer syndrome

Answer 32

children defect in conjugation of bilirubin (via glucoronyl transferase) sx: unconj hyperbilirubinemia

Question 33

Dubin-Johnson and Rotor Syndrome

Answer 33

defect in excretion of bilirubin sx: conj hyperbilirubinemia

Question 34

non-hemolytic anemia should make you thing of....

Answer 34

Wilson's disease

Question 35

replacing A1AT in A1AT deficiency helps w....

Answer 35

lungs but not liver