Flashcards in Metabolic Liver disease Deck (45):
How should you diagnose NASH?
ultrasound/CT for steatosis
-exclusion of EtOH and other liver diseases
Mutation in hemachromatosis? How is it inherited?
Mutation =C282Y in HFE gene OR H63D. Autosomal recessive
Describe the pathophysiology behind hemachromatosis
1. Decreased hepcidin activity
2. Hepcidin cannot bind transportin
3. high levels of transportin=extrusion of iron out of macrophages and enterocytes
4. Increased GI absorption of iron which deposits into organs
At what age do you typically see hematchromatosis?
1. Middle aged
2. Juvenile form
What labs would you see in HH?
1. transferrin saturation > 45%
2. High ferritin
What do you see in histology of HH?
1. High hepatic iron concentration--prussian blue stain will show iron
What is the gene involved in wilson's disease?
What is the pathophysiology of wilson's?
Less Cu-transporting ATPase. -->less Cu being pumped into the golgi
--Less Cu being packaged for excretion
What protein is cu bound to for secretion into the plasma?
When does wilson's disease present?
can be child or adult.
CHILD: Liver dz
ADULT: liver dz plus neuropsych symptoms usually
What lab findings would you see in Wilson's?
Increased urinary copper
What do you see on liver histology in wilsons?
Silver stain for copper is positive
What mutation do you have in alpha 1 AT?
Mutation in A1AT (ZZ, ZS alleles abnormal). MM is normal
How does a1AT deficiency actually cause disease?
Mutated A1AT accumulates in the liver
--Destruction of pulmonary CT matrix=interstitial lung dz
At what age does alpha 1 antitrypsin present?
Children or adults:
CHILD: more liver problems
ADULT: More pulmonary issues
What gene is responsible for A1AT protein?
SERPINA 1--results in a mutation of glutamine to lysine @ position 342
What is the normal role of A1AT?
inhibits proteases. Especially the damaging elastase produced by neutrophils
How can you diagnose A1AT?
1. protein phenotyping or genotyping
2. Low serum A1AT
3. Liver biopsy
What can you see on biopsy of A1AT?
PAS positive globules (hot pink)
Treatment for A1AT?
1. smoking cessation
2. Consider liver transplantation
3. Can also provide an A1AT analogue to the lungs
If you are deficient in A1AT, what other protease inhibitors might you be missing?
1. C1 inhibitor
2. Antithrombin III
Where is most of the body's iron stored?
In macrophages and hepatocytes
When might you have physiologically elevated levels of hepcidin?
During inflammation. It's an acute phase reactant
What does ferroportin do?
Main iron export protein. It's found on enterocytes, hepatocytes, and macrophages.
What does the HFE protein do?
It's a sensor of circulating iron that's found on hepatocytes
What does Hepcidin do?
It regulates the amount of ferroportin in cells. It does this by binding to ferroportin and degrading it.
Describe the pathway of iron absorption and storage starting with iron absorption in the gut
1. Iron absorbed in intestine
2. Excreted into blood through ferroportin on basolateral side
3. Binds to apotransferrin in blood
4. Absorbed by macrophages
Describe the pathway for iron homeostasis
1. Iron levels sensed in blood by HFE on hepatocytes and kupffer cells
2. Hepcidin synthesized
3. Enterocytes decrease Fe absorption
4. Macrophages decrease iron export
5. Plasma Fe drops
When you have low hepcidin
Increase iron absorption nad deposition occurs.
How does HFE mutation result in HH?
HFE is a sensor of iron levels. Without it, hepcidin cannot be synthesized, causing high ferroportin and lots of iron export
Aside from HFE, what other mutations can lead to HH?
HJV, HAMP, TfR2 of a gain of function in ferroportin
What is different about non-HFE iron overload?
It's NOT associated with hepcidin function or level. Transferrin saturation is not high
---Iron in RES
--Not responsive to phlebotomy
Examples of non-hemachromatotic iron overload dzs
Feroportin loss of function
Where does iron deposit in HH?
liver, heart, spleen, endocrine organs
If you are a patient with HH, what is the most likely cause of death?
--Less so cardiomyopathy or diabetes
A C282Y mutation (homozyg) puts you at increased risk of:
HCC and CRC
A H62D mutation (homozyg) puts you at increased risk of:
What levels of iron do you want to aim for in HH?
What is the main transporter of Cu in the blood?
What does the ATP7B protein do?
Chaperones Cu from the cytoplasm to the golgi apparatus for secretion. Without it, Cu stays in the cytoplasm and can't be excreted in the bile.
If you make a diagnosis of wilson's...what follow up exam must you do?
Mandatory slit lamp eye exam for Kayser-Fleischer rings.
Are Kayser-Fleischer rings specific to Wilson's?
NO-->Can also see it generally in liver disease
What do you see on histology of wilson's disease?
Copper staining hepatocytes
What is the clinical presentation of someone with wilson's?
1. Liver failure
2. Renal dysfunction
3. Cardiac problems
4. CNS issues
5. Kayser Fleischer rings
6. Hemolytic anemia