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Flashcards in Metabolic Liver disease Deck (45):
1

How should you diagnose NASH?

ultrasound/CT for steatosis
-exclusion of EtOH and other liver diseases

2

Mutation in hemachromatosis? How is it inherited?

Mutation =C282Y in HFE gene OR H63D. Autosomal recessive

3

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

4

At what age do you typically see hematchromatosis?

1. Middle aged
2. Juvenile form

5

What labs would you see in HH?

1. transferrin saturation > 45%
2. High ferritin

6

What do you see in histology of HH?

1. High hepatic iron concentration--prussian blue stain will show iron

7

What is the gene involved in wilson's disease?

ATP7B

8

What is the pathophysiology of wilson's?

Less Cu-transporting ATPase. -->less Cu being pumped into the golgi
--Less Cu being packaged for excretion

9

What protein is cu bound to for secretion into the plasma?

Ceruloplasmin

10

When does wilson's disease present?

can be child or adult.
CHILD: Liver dz
ADULT: liver dz plus neuropsych symptoms usually

11

What lab findings would you see in Wilson's?

Low ceruloplasmin
Increased urinary copper
KF rings

12

What do you see on liver histology in wilsons?

Silver stain for copper is positive

13

What mutation do you have in alpha 1 AT?

Mutation in A1AT (ZZ, ZS alleles abnormal). MM is normal

14

How does a1AT deficiency actually cause disease?

Mutated A1AT accumulates in the liver
--Destruction of pulmonary CT matrix=interstitial lung dz

15

At what age does alpha 1 antitrypsin present?

Children or adults:
CHILD: more liver problems
ADULT: More pulmonary issues

16

What gene is responsible for A1AT protein?

SERPINA 1--results in a mutation of glutamine to lysine @ position 342

17

What is the normal role of A1AT?

inhibits proteases. Especially the damaging elastase produced by neutrophils

18

How can you diagnose A1AT?

1. protein phenotyping or genotyping
2. Low serum A1AT
3. Liver biopsy

19

What can you see on biopsy of A1AT?

PAS positive globules (hot pink)

20

Treatment for A1AT?

1. smoking cessation
2. Consider liver transplantation
3. Can also provide an A1AT analogue to the lungs

21

If you are deficient in A1AT, what other protease inhibitors might you be missing?

1. C1 inhibitor
2. Antithrombin III
3. A1-antichymotrypsin

22

Where is most of the body's iron stored?

In macrophages and hepatocytes

23

When might you have physiologically elevated levels of hepcidin?

During inflammation. It's an acute phase reactant

24

What does ferroportin do?

Main iron export protein. It's found on enterocytes, hepatocytes, and macrophages.

25

What does the HFE protein do?

It's a sensor of circulating iron that's found on hepatocytes

26

What does Hepcidin do?

It regulates the amount of ferroportin in cells. It does this by binding to ferroportin and degrading it.

27

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

28

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

29

When you have low hepcidin

Increase iron absorption nad deposition occurs.

30

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

31

Aside from HFE, what other mutations can lead to HH?

HJV, HAMP, TfR2 of a gain of function in ferroportin

32

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

33

Examples of non-hemachromatotic iron overload dzs

Feroportin loss of function
-Aceruloplasminemia
3. Atransferrinemia

34

Where does iron deposit in HH?

liver, heart, spleen, endocrine organs

35

If you are a patient with HH, what is the most likely cause of death?

HCC
Cirrhosis
--Less so cardiomyopathy or diabetes

36

A C282Y mutation (homozyg) puts you at increased risk of:

HCC and CRC

37

A H62D mutation (homozyg) puts you at increased risk of:

HNPCC

38

What levels of iron do you want to aim for in HH?

50-100 Ig/L

39

What is the main transporter of Cu in the blood?

Ceruloplasmin

40

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.

41

If you make a diagnosis of wilson's...what follow up exam must you do?

Mandatory slit lamp eye exam for Kayser-Fleischer rings.

42

Are Kayser-Fleischer rings specific to Wilson's?

NO-->Can also see it generally in liver disease

43

What do you see on histology of wilson's disease?

Copper staining hepatocytes
--cirrhosis
-steatosis
--mitochondrial abnormalities

44

What is the clinical presentation of someone with wilson's?

Pretty variable:
1. Liver failure
2. Renal dysfunction
3. Cardiac problems
4. CNS issues
5. Kayser Fleischer rings
6. Hemolytic anemia

45

How do you treat wilsons?

1. D-penicillamine (an iron chelator)
2. Trientine and zinc