Inherited liver disease

Question 1

Which are the more common of the inherited liver diseases and how are they inherited? (what pattern of inheritance?)

Answer 1

The four most common conditions are haemochromatosis (carrier 1:14), alpha-1-antitrypsin deficiency (carrier 1:20), cystic fibrosis (1:25) and Wilson’s disease (1:85)

Question 2

What is Wilson’s disease?

Answer 2

This is a condition associated with a block in the excretion of copper into the cannuliculi. Therefore the tissue copper is elevated, but the bile and serum copper is decreased.

Question 3

Which chromosome is Wilson’s disease located on?

Answer 3

I just can’t believe that they would want us to learn this.

Chromosome 13

Question 4

What is the mechanism of Wilson’s disease

Answer 4

It is an abnormality in the copper-transporting ATPase, but there are like >200 mutations recognised.

Question 5

What are the blood test and urinary findings in this disease?

Answer 5

Firstly, there is decreased copper in the serum, and decreased caeruloplasmin.

Secondly there is increased urinary copper

Don’t forget good ol’ KF rings in the eye

Question 6

How do we screen family members for Wilson’s disease?

Answer 6

This is important - because there are so many mutations, there is no single DNA test.

Instead, the screening relies on “microsatellite (flanking) markers”

If you already have a high level of suspicion you could just do a urine sample or serum copper/caeruloplasmin

Question 7

What is the primary change in cystic fibrosis? (the underlying mechanism)

Answer 7

There is a mutation in the chloride transport channel.

IT IS ON CHROMOSOME 7

Question 8

What are the more common manifestations of cystic fibrosis?

Answer 8

paranasal sinus opacification (90-100%)
bronchiectasis (80%)

the most common GI manifestation is pancreatic insufficiency (85%)
about 20% get liver disease

Infertility is the most common manifestation for men with 95% males suffering, and almost 100% absence of the vas deferens

Question 9

What is the most common mutation for CF? Which chromosome?

Answer 9

Once again, it’s chromosome 7

the most common mutation is deletion F508

Question 10

What is alpha 1 antitrypsin deficiency?

Answer 10

This is an autosomal recessive condition from chromosome 14.

In the liver it is the failure of formation and excretion of alpha1 antitrypsin

In the lungs, the pathophysiology is different. Here the defective (or insufficient enzyme) fails to protect from the action of neutrophil elastase

Question 11

What is haemochromatosis and which chromosome is it on?

Answer 11

CHROMOSOME 6!

It is an iron accumulation disorder

It is associated with many many problems including heart disease, diabetes, M-C joint arthritis and infertility. There is skin colour change (associated with pituitary deposition, leading to MSH release) and cirrhosis and HCC development

Question 12

What is the characteristic arthritic changes with haemochromatosis?

Answer 12

Metacarpo-phalyngeal joint arthritis - JOINT SPACE NARROWING

there is also a propensity for pseudogout

Question 13

Why do haemochromatosis suffers get testicular atrophy?

Answer 13

This is most likely related to pituitary deposition, rather than testicular iron deposition.

Question 14

How do we make the diagnosis of haemochromatosis?

Answer 14

This is interesting and a developing field.

Firstly, there is a genetic diagnosis of the predisposition for the condition, and this is confirmed by testing for C282Y and H63D.

HOWEVER:

established haemochromatosis is defined as:

1. stainable hepatic iron grade 3 or 4
2. hepatic iron concentration of >80 micromol/gram
3. hepatic iron index > 1.9
4. > 5g iron removed by phlebotomy

Question 15

What is hepcidin? What is ferroportin?

Answer 15

Interesting question!

Hepcidin’s overall role is to inhibit iron absorption.

It binds to ferroportin and inhibits enterocyte iron release at the basolateral membrane.

Question 16

How would you screen for haemochromatosis?

Answer 16

The first thing would be to perform a transferrin saturation.

If this is >45%, then repeat when fasting.

If still >45%, then perform HFE gene testing.

If these come back as C282Y +/+ or C282Y/H63D +/+, then do LFTs and ferritin.

Biopsy is essential for diagnosis.

Question 17

If you’ve just diagnosed someone with haemochromatosis, what do we have to warn them about not getting?

Answer 17

Don’t drink heavily.
Don’t get fat (NASH)
Don’t get hepatitis.

Also, be aware of porphyria cutanea tarda

Usually we should be doing 6 monthly USS and AFP

Question 18

What is Gilbert’s syndrome?

Answer 18

this is a benign condition of mild unconjugated hyperbilirubinaemia.

Basically in times of increased stress, there is an inability of the liver to increase its metabolism of the bilirubin

This condition is A. Recessive

Question 19

What is Dubin-Johnson syndrome?

Answer 19

This is familial hyper-conjugated bilirubinaemia

It is autosomal recessive.

The ALP is normal. The process is about excretion.

Question 20

There are a few familial cholestatic syndromes. Do you know their names at least?

Answer 20

First up is benign recurrent intra-hepatic cholestasis.

This autosomal recessive condition is all about a defect in the biliary canalicular transporters

Next is progressive familial intra-hepatic cholestasis.
These are also autosomal recessive and are all treated with OLT

Question 21

Have you heard of Crigler-Najjar syndrome?

Answer 21

this is a SEVERE unconjugated hyperbilirubinaemia.

it is treated with phototherapy and OLT

Question 22

How does vitamin C help with the absorption of iron?

And where does iron get absorbed?

Answer 22

Ascorbic acid helps to change iron from Fe3+ (ferric) to Fe2+ (ferrous). It also helps to keep iron soluble

it’s absorbed at the proximal duodenum

Question 23

With respect to HBV infection, what is the YMDD mutant?

Answer 23

Found different answers on this, but Lawrie Powell has said that this occurs following lamovudine treatment.

UTD says it is a mutation associated with reverse transcriptase.

Question 24

What are the best tests of liver synthetic function?

Answer 24

albumin and prothrombin time (following vitamin K administration)