Metabolic Liver disease

Question 1

How should you diagnose NASH?

Answer 1

ultrasound/CT for steatosis

-exclusion of EtOH and other liver diseases

Question 2

Mutation in hemachromatosis? How is it inherited?

Answer 2

Mutation =C282Y in HFE gene OR H63D. Autosomal recessive

Question 3

Describe the pathophysiology behind hemachromatosis

Answer 3

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

Question 4

At what age do you typically see hematchromatosis?

Answer 4

1. Middle aged

2. Juvenile form

Question 5

What labs would you see in HH?

Answer 5

1. transferrin saturation > 45%

2. High ferritin

Question 6

What do you see in histology of HH?

Answer 6

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

Question 7

What is the gene involved in wilson’s disease?

Answer 7

ATP7B

Question 8

What is the pathophysiology of wilson’s?

Answer 8

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

Question 9

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

Answer 9

Ceruloplasmin

Question 10

When does wilson’s disease present?

Answer 10

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

Question 11

What lab findings would you see in Wilson’s?

Answer 11

Low ceruloplasmin
Increased urinary copper
KF rings

Question 12

What do you see on liver histology in wilsons?

Answer 12

Silver stain for copper is positive

Question 13

What mutation do you have in alpha 1 AT?

Answer 13

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

Question 14

How does a1AT deficiency actually cause disease?

Answer 14

Mutated A1AT accumulates in the liver

–Destruction of pulmonary CT matrix=interstitial lung dz

Question 15

At what age does alpha 1 antitrypsin present?

Answer 15

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

Question 16

What gene is responsible for A1AT protein?

Answer 16

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

Question 17

What is the normal role of A1AT?

Answer 17

inhibits proteases. Especially the damaging elastase produced by neutrophils

Question 18

How can you diagnose A1AT?

Answer 18

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

Question 19

What can you see on biopsy of A1AT?

Answer 19

PAS positive globules (hot pink)

Question 20

Treatment for A1AT?

Answer 20

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

Question 21

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

Answer 21

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

Question 22

Where is most of the body’s iron stored?

Answer 22

In macrophages and hepatocytes

Question 23

When might you have physiologically elevated levels of hepcidin?

Answer 23

During inflammation. It’s an acute phase reactant

Question 24

What does ferroportin do?

Answer 24

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

Question 25

What does the HFE protein do?

Answer 25

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

Question 26

What does Hepcidin do?

Answer 26

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

Question 27

Describe the pathway of iron absorption and storage starting with iron absorption in the gut

Answer 27

1. Iron absorbed in intestine 2. Excreted into blood through ferroportin on basolateral side 3. Binds to apotransferrin in blood 4. Absorbed by macrophages

Question 28

Describe the pathway for iron homeostasis

Answer 28

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

Question 29

When you have low hepcidin

Answer 29

Increase iron absorption nad deposition occurs.

Question 30

How does HFE mutation result in HH?

Answer 30

HFE is a sensor of iron levels. Without it, hepcidin cannot be synthesized, causing high ferroportin and lots of iron export

Question 31

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

Answer 31

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

Question 32

What is different about non-HFE iron overload?

Answer 32

It's NOT associated with hepcidin function or level. Transferrin saturation is not high - --Iron in RES - -Not responsive to phlebotomy

Question 33

Examples of non-hemachromatotic iron overload dzs

Answer 33

Feroportin loss of function - Aceruloplasminemia 3. Atransferrinemia

Question 34

Where does iron deposit in HH?

Answer 34

liver, heart, spleen, endocrine organs

Question 35

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

Answer 35

HCC Cirrhosis --Less so cardiomyopathy or diabetes

Question 36

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

Answer 36

HCC and CRC

Question 37

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

Answer 37

HNPCC

Question 38

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

Answer 38

50-100 Ig/L

Question 39

What is the main transporter of Cu in the blood?

Answer 39

Ceruloplasmin

Question 40

What does the ATP7B protein do?

Answer 40

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.

Question 41

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

Answer 41

Mandatory slit lamp eye exam for Kayser-Fleischer rings.

Question 42

Are Kayser-Fleischer rings specific to Wilson's?

Answer 42

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

Question 43

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

Answer 43

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

Question 44

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

Answer 44

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

Question 45

How do you treat wilsons?

Answer 45

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