Metabolic causes of liver disease

Question 1

Examples of metabolic causes of liver disease

Answer 1

Haemochromatosis
Wilson’s disease
Alpha-1-antitrypsin deficiency

Question 2

What is haemochromatosis

Answer 2

Deficiency of the iron regulatory hormone hepcidin -> iron overload

Question 3

*What mutations cause haemochromatosis

Answer 3

HFE mutations - 2 types/genes:
C282Y
H63D

Question 4

Haemochromatosis clinical presentation

Answer 4

Often asymptomatic until later stags.
Usually presents between 40-60.
Fatigue, weakness, arthropathy, heart problems.

Question 5

Clinical presentation of advancing haemochromatosis

Answer 5

Also Bronzing of the skin,
Diabetes,
Hepatomegaly,
Arthropathy

Question 6

Haemochromatosis pathophysiology

Answer 6

Depends on the aetiology
In hereditary; increased intestinal absorption of iron causes accumulation in tissues, particularly in the liver, leading to fibrosis and functional organ failure

Question 7

Aetiology of haemochromatosis

Answer 7

Often hereditary in autosomal recessive pattern of HFE gene (responsible for regulating iron uptake).

Question 8

Epidemiology of haemochromatosis

Answer 8

C282Y is more common in white populations

Question 9

Diagnosis of haemochromatosis

Answer 9

Screening not advised;
penetrance very low.
Consider genetic analysis in unexplained chronic liver disease.
Total Iron Binding capacity reduced, serum iron raised.
LFTs can be normal

Question 10

Treatment of haemochromatosis

Answer 10

Phlebotomy; removing 400-500ml of blood every 2 weeks.

Tends to require insulin

Question 11

Complications of haemochromatosis

Answer 11

Liver fibrosis
Liver failure
Cirrhosis
Hepatocellular carcinoma
Diabetes is deposition in the pancreas

Question 12

What is Wilson’s disease

Answer 12

Disorder of copper metabolism -> Copper build up in the liver

Question 13

Wilson’s disease clinical presentation

Answer 13

Hepatic = acute liver failure; chronic hepatitis
Psychological = behavioural problems common, might lead to diagnosis
Eyes = Kayser-Fleischer ring and/or sunflower cataracts on examination with a slit lamp

Question 14

Wilsons disease pathophysiology

Answer 14

ATP7B codes for a P type ATPase, which acts in hepatocytes to move copper across intracellular membranes.
Copper transporting action directly supports production of ferroxidase caeruloplasmin, as well as excretion of copper into bile.
Serum levels of copper are low.
Hepatic retention of copper develops, which causes liver injury (cirrhosis, failure)

Question 15

Wilsons disease, what gene codes for which protein that allows copper to move into hepatocytes

Answer 15

ATP7B codes for P type ATPase

Question 16

What are the purposes of copper once undergone transporting action into hepatocytes

Answer 16

Supports production of Ferroxidase Caeruloplasmin.

Excretion of copper into bile.

Question 17

Wilsons disease aetiology

Answer 17

Mutation in ATP7B - over 500 identified.

Autosomal recessive

Question 18

Wilsons disease epidemiology

Answer 18

Rare -difficult to diagnose.

Affects 1/30,000 to 1/100,000

Question 19

Wilsons disease diagnosis

Answer 19

Slit lamp analysis of eyes
Detect Kayser-Fleischer rings (bronze rings of the cornea)
Low serum caeruloplasmin.

Question 20

Wilsons disease treatment

Answer 20

Avoid alcohol.
Prevent intestinal copper absorption - Chelation agents such as Zinc (lifelong)
Hepatic = about 5% of patients with liver failure will need a transplant
Neuro = deep brain stimulation

Question 21

Wilsons disease complications

Answer 21

Cirrhosis -> liver failure.

Fatal if untreated

Question 22

What is Alpha-1-antitrypsin deficiency

Answer 22

Deficiency of serine protease inhibitor alpha-1-antitrypsin

Question 23

Clinical presentation of Alpha-1-antitrypsin deficiency

Answer 23

Lung symptoms present between 30-50 (this is earlier in smokers). COPD life symptoms, early onset emphysema
Liver: Not always present here. Neonates may present jaundice and hepatitis. Possibly cirrhosis and liver failure

Question 24

Pathophysiology of Alpha-1-antitrypsin deficiency

Answer 24

A1AT inhibits the action of neutrophil-protease enzymes in the lung, produced in presences of inflammation, infection or smoking.
In deficiency, elastase can break down elastin without inhibition, so destroys alveolar walls and causes emphysematous change

Question 25

What is the function of Alpha-1-antitrypsin

Answer 25

Inhibits the action of neutrophil-protease enzymes in the lung, produced in presences of inflammation, infection or smoking

Question 26

Aetiology of Alpha-1-antitrypsin deficiency

Answer 26

Mutation in the SERPINA1 gene
Autosomal recessive
Relatively low penetrance
Many possible mutations

Question 27

Epidemiology of Alpha-1-antitrypsin deficiency

Answer 27

Commonest amongst white people.
1/4000 present
Underdiagnosed since not always exhibits problems

Question 28

Diagnosis of Alpha-1-antitrypsin deficiency

Answer 28

A1AT serum levels

Question 29

Treatment of Alpha-1-antitrypsin deficiency

Answer 29

Lung = (as COPD) cessate smoking, corticosteroids, bronchodilators, treat infection.
Liver = cessate drinking. In liver failure, possibly transplant

Question 30

Complications of Alpha-1-antitrypsin deficiency

Answer 30

Variable prognosis.

Untreated can lead to liver failre