Week 6 - E - Chronic Liver Disease (2) - Haemochromatosis, Wilson's, alpha-1-antitrypsin, Budd-Chairi, Drugs/cardiac cirrhosis

Question 1

Storage diseases that can cause chronic liver disease include * Haemochromatosis * Wilson’s disease * Alpha-1-antitrypsin deficiency What is haemochromatosis? It can be primary or secondary - what is the difference?

Answer 1

Haemochromatosis is when there is excess iron in the body leading to iron deposition in different organs * Primary haemochromatosis is known as hereditary haemochromotosis and it is a genetic condition resulting in increased iron absorption from the gut * Secondary haemochromatosis are from causes from the diet/treatement - eg iron overload from diet, transfusions or iron therapy

Question 2

Hereditary haemochromatosis What is the commonest gene mutation and what is the inheritance? What chromsome does this gene mutation take place on?

Answer 2

The most common gene mutation is in the HFE gene (High Fe2+) located on chromosome 6 - mutations occur most commonly in either the C282Y or H63D locations of the gene It is an autosomal recessive disease of iron overload

Question 3

What does the mutated HFE gene cause in hereditary haemochromatosis?

Answer 3

The mutated gene prevents the synthesis of hepcidin in the liver (this regulates iron absorption) A decrease in this means iron absorption from the enterocytes (small bowel) is increased The iron accumulation eventually leads to iron deposition in different organs - which is toxic

Question 4

What are the organs in which the iron usually deposits and what does this cause to these organs?

Answer 4

Iron often depositis in the joints, liver, heart, pancreas, adrenals and skin The deposition of iron in these different organs can be very toxic

Question 5

What are the presenting features of haemochromatosis?

Answer 5

Patient often has features such as * Arthralgia - joint pain * Decreased libido / impotence * Eventual cirrhosis due to fibrosis in the liver occurring * Cardiomyopathy * Pancreatic failure resulting in diabetes * Skin deposition + pancreatic failure results in the typical bronzed diabetic appearance

Question 6

How is hereditary haemochromatosis diagnosed?

Answer 6

Abnormal LFTs, increased ferritin and increased transferrin saturation should all trigger suspicion of HH Genetic testing is then carried out to confirm the diagnosis HFE genotyping - molecular genetic testing for the C282Y and H63D mutations in the HFE gene on chromsome 6

Question 7

Before genetic testing could be carried out, haemochromatosis was confirmed by liver biopsy What was seen on liver biopsy in these patients?

Answer 7

Increased iron deposits in the hepatocytes was confirmed by Perl’s staining of the liver biopsy

Question 8

What is the 1st line treatment of hereditary haemochromatosis? What is carried out if patient is intolerant of this?

Answer 8

1st line treatment is venesection (removal of blood) If patient is intolerant of venesection - then they are given an iron chelating agent eg desferrioxamine (binds to iron and increases its excretion in urine/faeces)

Question 9

What are the complications of haemochrmatosis (specific to the liver)?

Answer 9

Fibrosis of the liver leading to cirrhosis This increases the risk of hepatocellular cancer of the liver

Question 10

Wilson’s disease What is Wilson’s disease? What is the inheritance of the condition? What is there excess deposition of and where?

Answer 10

Wilson’s disease is an inherited autosomal recessive disorder of copper metabolism There is a disorder of copper excretion resulting in excess deposition in the liver and CNS (basal ganglia)

Question 11

What genetic abnormality is inherited that causes Wilson’s disease? What chromsome is it located on?

Answer 11

Wilson’s disease is due to an autosomal rcessive disorder of a copper transporting protein known as ATP7B (aka the Wilson’s disease gene) and is on chromosome 13 The gene codes for a P-type (cation transport enzyme) ATPase that transports copper into bile and incorporates it into ceruloplasmin

Question 12

Children usually present with liver disease whereas the first sign of disease in young adults is often neurological disease Features result from excessive copper deposition in the tissues, especially the brain, liver and cornea What are the presenting features of Wilson’s disease in the brain and liver?

Answer 12

Neurological features -speech, behavioural and psychiatric problems are often the first manifestations. Also: asterixis, chorea, dementia, parkinsonism Liver - features of hepatitis / cirrhosis / fulminant liver failure

Question 13

What is the sign seen either directly or on slit lamp around the cornea in Wilson’s disease? Which layer of the cornea do they deposit in?

Answer 13

Kayser–Fleischer rings (KF rings), a pathognomonic sign, may be visible in the cornea of the eyes, either directly or on slit lamp examination as deposits of copper in a ring around the cornea. They are due to copper deposition in one of the layers of the cornea (the descement membrane)

Question 14

How is Wilson’s disease diagnosed?

Answer 14

Diagnosis reduced serum caeruloplasmin reduced serum copper (counter-intuitive, but 95% of plasma copper is carried by ceruloplasmin) (ceruloplasmin is still secreted, but in a form that lacks copper (termed apoceruloplasmin) and is rapidly degraded in the bloodstream) increased 24hr urinary copper excretion After this, diagnosis is then confirmed by liver biopsy

Question 15

What is the treatment of Wilson’s disease?

Answer 15

Diet - avoid foods with high copper conent Generally, penicillamine is the first treatment used. This binds copper (chelation) and leads to excretion of copper in the urine

Question 16

Alpha-1-antitrypsin deficiency What is the cause of an A1AT deficiency? What is the inheritance?

Answer 16

Alpha-1 antitrypsin (A1AT) deficiency is an autosomal recessive inherited condition caused by a lack of a protease inhibitor (Pi) normally produced by the liver As A1AT is a Serine Protease INhibitor - this disease can be termed a serpinopathy

Question 17

What gene mutation leads to the A1AT deficiency? Which chromosome is it located on?

Answer 17

Serpin peptidase inhibitor, clade A, member 1 (SERPINA1) is the gene that encodes the protein alpha-1 antitrypsin. A mutation in the SERPINA1 gene results in not enough alpha-1 antitrypsin (A1AT) This gene is located on chromosome 14

Question 18

Which organs does A1AT deficiency tend to effect? What enzyme is importantly broken down by A1AT? Its levels increase in the A1AT deficiency

Answer 18

A1AT tends to affect the lungs and the liver * Emphysema in the lungs * Cirrhosis of the liver The role of A1AT is to protect cells from enzymes such as neutrophil elastase

Question 19

Why does A1AT deficiency cause Emphysema of the lungs? Cirrhosis of the liver?

Answer 19

Neutrophil elastase is excessively free to break down elastin, degrading the elasticity of the lungs, which results in respiratory complications, such as chronic obstructive pulmonary disease, in adults/young non-smokers Normally, A1AT leaves its site of origin, the liver, and joins the systemic circulation; defective A1AT can fail to do so, building up in the liver, which results in cirrhosis in either adults or children.

Question 20

What is the difference in the emphysema caused by A1AT deficiency to the emphysema seen in normal COPD?

Answer 20

Emphysema is most prominent in the lower lobes in A1AT deficiency In COPD, emphysema is most prominent in the upper lobes

Question 21

How is A1AT deficiency diagnosed?

Answer 21

Serum A1AT levels are usually decreased Carry out spirometry - shows an obstructive pattern

Question 22

What is the management of A1AT deficiency?

Answer 22

Smoking cessation is very important (this also causes an increase in neutrophil elastase activity) Supportive: bronchodilators, physiotherapy intravenous alpha1-antitrypsin protein concentrates * In severe disease lung transplantation may also be recommended. * In those with severe liver disease liver transplantation may be an option

Question 23

Budd-Chairi syndrome What is Budd-Chairi syndrome?

Answer 23

Budd-chairi syndrome (or hepatic vein thrombosis) - this is where there is thrombosis of the hepatic veins causing congestive ischaemia and hepatocyte damage

Question 24

What are the different causes of budd-chairi syndrome?

Answer 24

Causes include Congenital venous webs Hypercoagulable states - eg * combined OCP * pregnancy * malignancy * polycythaemia rubra vera * thrombophilia - protein C or protein S or antithrombin III deficiency

Question 25

What are the classic features of budd chairi syndrome? What is the very sensitive and initial test carried out?

Answer 25

Classifc featurs are * Sudden onset, severe abdominal pain * Ascites * Tender hepatomegaly Budd–Chiari syndrome is most commonly diagnosed using ultrasound studies of the abdomen and retrograde angiography.

Question 26

What is the treatment of Budd-Chairi syndrome?

Answer 26

Angioplasty or TIPS may be needed to revascularise the thrombosed hepatic vein Life-long anti-coagulant therapy is often required (unless there are varices)

Question 27

Immunerable drugs can damage the liver and may be dose related or idiosyncratic Which is methotrexate? What does it cause to the liver? What is the treatment?

Answer 27

Methotrexate is a dose dependent liver toxin - will cause progressive fibrosis Important to simply stop the drug treatment

Question 28

Cardiac cirrhosis What is cardiac cirrhosis and how does it occur?

Answer 28

Cardiac cirrhosis is a term used to include the spectrum of hepatic disorders that occur secondary to hepatic congestion due to cardiac dysfunction, especially the right heart chambers

Question 29

What are the different causes of cardiac cirrhosis?

Answer 29

High right heart pressures due to eg * Heart failure * Incompetent tricuspid valve * Rheumatic fever * Constrictive pericarditis

Question 30

What are the clinical features of cardiac cirrhosis?

Answer 30

The features of right sied heart failure * Elevated JVP * Ascites * Ankle oedema) * SOB when lying flat * Fatigue However the ascites is usually extreme and there are signs of liver impairment TREAT THE CARDIAC CONDITION