Hepatology - Inherited liver diseases

Question 1

What is the definition of haemochromotosis?

Answer 1

In haemochromotosis, total body iron is increased and excess iron is deposited in and damages several organs, including the liver. It may be primary or secondary to iatrogenic or dietary iron overload or other rare diseases.

Question 2

What is the definition of hereditary haemochromotosis?

Answer 2

Hereditary haemochromotosis is an autosomal recessive condition that results in increased absorption of dietary iron such that body iron may reach 20-60g (normally 4g).

Question 3

What is the epidemiology of HHC?

Answer 3

Hereditary haemochromotosis is an autosomal recessive condition. It has a prevalence in the Caucasian population of 1 in 400, with approximately 10% of the population be carriers.

Question 4

What is the aetiology of HHC?

Answer 4

Approximately 90% of patients have a single point mutation in a protein (hefestin, HFE) on the short arm of chromosome 6. The normal HFE protein is expressed in the small intestine and plays a role in the regulation of iron absorption.

Two missense mutations in the HFE gene account for most patients with HHC: a change of cysteine at position 282 for tyrosine or a change of histidine at position 63 to aspartate. HLA-A3, B7 or B14 occur with increased frequency in patients with HHC compared with the general population.

Question 5

What are the clinical features of HHC?

Answer 5

Most patients are diagnosed when elevated serum iron or ferritin levels are noted on routine biochemistry, or screening is performed for a relative with HHC. Presentation may also be with symptoms and signs of iron loading in parenchymal organs. The classic presentation is “bronzed diabetes” with hepatomegaly, new onset diabetes, and skin hyperpigmentation. Cardiac failure or dysrhythmia may also occur.

There is reduced incidence of overt disease in women because of extra iron losses associated with menstruation and a smaller dietary intake of iron.

Question 6

How do I investigate HHC?

Answer 6

1) LFTs: often normal even with cirrhosis

2) Iron studies:
i) Serum iron is elevated and total iron binding capacity (TIBC) is reduced. Transferrin saturation (serum iron/ TIBC) is >45%
ii) Serum ferritin reflects iron stores and is usually greatly elevated

3) Genotyping (by PCR using whole blood samples) for mutation analysis of the HFE gene is performed in patients with elevated ferritin and transferrin saturations
4) Liver biopsy - not always needed, performed in patients with abnormal LFTs and incr. serum ferritin

Question 7

What conditions cause secondary haemochromotosis?

Answer 7

Chronic haemolytic anaemia
Sideroblastic anaemia
Conditions requiring multiple blood transfusion
Porphyria
Dietary iron overload
Alcoholic cirrhosis (iron stores increase, mechanism unknown, but the levels do not reach those found in HHC)

Question 8

How do I manage haemochromotosis?

Answer 8

Excess tissue iron is removed by venesection: 500mL of blood are removed twice weekly until iron stores are normalised as assessed by serum ferritin and transferrin saturation. Ensure adequate hydration beforehand.

Before the initiation of phlebotomy, patients with HFE-HC should be assessed for complications (including diabetes mellitus, joint disease, endocrine deficiency (hypothyroidism), heart failure, porphyria cutanea tarda and osteoporosis), which should be managed regardless of whether or not HC is the underlying cause and whether there is symptomatic relief or improvement during phlebotomy.

To minimise the risk of additional complications, patients with HFE-HC could be immunised against hepatitis A and B while iron-overloaded.

Question 9

When should liver transplantation be considered in patients with haemochromotosis?

Answer 9

Transplantation is indicated in hepatic decompensation with ascites, spontaneous bacterial peritonitis, encephalopathy, variceal haemorrhage and early small tumour formation may require assessment for liver transplantation.
Early reports on the outcome of HFE-HC after liver transplantation for HFE-HC have found that survival may be lower than in other groups. Survival for transplant patients is around 64% after one year and 34% after five years.

Question 10

How should patients with haemochromotosis be monitored?

Answer 10

Serum ferritin is the main investigation because it correlates with symptoms and the risk of complications.
When serum ferritin is less than 1000 μg/L the risk of serious liver damage is below 1%. Serum ferritin levels above 1000 μg/L are an indication for liver biopsy because of the risk of cirrhosis.
When a liver biopsy shows cirrhosis, periodic screening for hepatocellular carcinoma, using echography or magnetic resonance imaging, is essential.

Question 11

What is the definition of Wilson’s disease?

Answer 11

This is a rare but important inherited liver disease, also known as hepatolenitcular degeneration. It is a disorder of hepatic copper disposition caused by mutations in the gene ATP7B, located on chromosome 13. Around 500 gene mutations are currently known.

Question 12

What is the aetiology of Wilson’s disease?

Answer 12

The ATP7B gene encodes a P-type adenosine triphosphatase (ATPase), known as Wilson’s ATPase, which functions within hepatocytes to move copper across intracellular membranes. The copper-transporting action directly supports production of the ferroxidase caeruloplasmin, in which copper is incorporated, as well as excretion of copper into bile. Consequently, in Wilson’s disease, serum concentrations of copper are low and hepatic retention of copper develops, leading to liver injury. There is a variation in the symptoms in patients with Wilson’s disease.

Question 13

What is the epidemiology of Wilson’s disease?

Answer 13

Wilson’s disease is inherited as an autosomal recessive trait. It is a rare condition and can often be difficult to diagnose.

Wilson’s disease affects between 1 in 30,000 and 1 in 100,000 individuals.

A Slavic type has a late age of onset and predominantly neurological features.

There is a juvenile type, which occurs in Western Europeans and several other ethnic groups. This has onset before age 16 years and mainly affects the liver.

Question 14

What is the history in Wilson’s disease?

Answer 14

A high index of suspicion is required for prompt diagnosis. Wilson’s disease should be considered in ANY child or young adult with unexplained liver abnormalities and also in patients with movement disorders.

The typical age of onset is during the second and third decades of life. Wilson’s disease usually presents as liver disease in children and adolescents, and as neuropsychiatric illness in young adults. However, younger children and older adults can also present with this condition.

Most patients who present with neurological features already have cirrhosis.

Wilson’s disease can cause liver, psychiatric, neurological, ophthalmological and other clinical features.

Question 15

What are the hepatic features of Wilson’s disease?

Answer 15

Hepatic disease due to Wilson’s disease is varied. Patients may present with persistent asymptomatic hepatomegaly or elevation of serum aminotransferases. The major patterns of hepatic involvement are:

• acute liver failure
• chronic hepatitis and cirrhosis
• severe chronic liver disease with small, shrunken liver, ascites and splenomegaly
• fulminant hepatic failure +/- haemolytic anaemia

Question 16

What are the psychiatric features of Wilson’s disease?

Answer 16

Psychiatric disorders and behavioural problems are common and may be the main clinical feature. Severe depression or various neurotic behavioural patterns are the most common presentations.

Question 17

What neurological features can be present in Wilson’s disease?

Answer 17

The most common early neurological sign is an asymmetrical tremor, in about half of patients.
The character of the tremor is variable and may be predominantly resting, postural or kinetic.
Other early symptoms include difficulty speaking, excessive salivation, ataxia, mask-like facies, clumsiness with the hands and personality changes. Some of these features are suggestive of Parkinson’s disease.
There may be choreiform movements that can be accompanied by gait disturbances, dysarthria and pseudobulbar palsy.

Question 18

What is the characteristic ophthalmological feature of Wilson’s disease?

Answer 18

The characteristic ophthalmological feature of this disease is the Kayser-Fleischer ring that is present in up to 95% of those with symptomatic (especially neurological) disease:

• A greenish gold or brown ring on the cornea may be visible to the naked eye or via the ophthalmoscope but usually a slit-lamp examination is required.
• This feature is NOT pathognomonic of Wilson’s disease, as it may occur in partial biliary atresia, primary biliary cirrhosis, primary sclerosing cholangitis, and cryptogenic cirrhosis.

The other characteristic feature is ‘sunflower cataracts’. They are brilliantly multi-coloured but visible only by slit-lamp examination. They do not impair vision.
Less common findings include night blindness, exotropic strabismus, optic neuritis and optic disc pallor.

Question 19

How can the kidneys be affected by Wilson’s disease?

Answer 19

A renal Fanconi’s syndrome may occur with hypercalciuria and nephrocalcinosis along with renal loss of amino acids, glucose, phosphate and excess uric acid.

Question 20

How do I investigate Wilson’s disease? Is genetic analysis helpful?

Answer 20

There is no single test that is reliable in isolation. Wilson’s disease should be considered in any patient, at any age, presenting with unusual liver or neurological abnormalities:

• presence of Kayser-Fleischer rings plus a low caerulolplasmin is sufficient to make the diagnosis
• biochemical findings include low serum caeruloplasmin, elevated basal 24-hour urinary excretion of copper and increased hepatic parenchymal copper concentration.
• genetic diagnosis remains limited, largely because most patients are compound heterozygotes. Almost all the known mutations have a low prevalence.

Family screening of first-degree relatives should occur, as the chance of a sibling being homozygous (and therefore developing clinical symptoms) is 25%. This is done by genetic analysis of the ATP7B gene, especially in patients with indeterminate clinical and biochemical features.

Question 21

When is a liver biopsy required in Wilson’s disease?

Answer 21

Liver biopsy is often diagnostic but is only required if clinical signs and non-invasive tests do not allow definitive diagnosis or if there is suspicion of additional liver pathology.

Question 22

What general measures are part of the management of Wilson’s disease?

Answer 22

Unlike many genetic disorders, Wilson’s disease is treatable. The goal of treatment is to remove toxic levels of copper from the body and prevent copper from re-accumulating.

General measures include:

• monitor hepatic and renal function, FBC and clotting
• avoid alcohol and drugs that are possibly hepatotoxic
• patients should avoid food high in copper, such as liver, chocolate, nuts, mushrooms, legumes and shellfish, especially lobster
• annual slit-lamp examination of Kayser-Fleischer rings should document fading or disappearance if copper is being adequately removed. If the rings return, it suggests poor compliance with treatment
• all patients need lifelong follow-up by specialist units to monitor progress, both clinical and biochemical, and to be alert to the side-effects of drugs, and encourage compliance

Question 23

What pharmacological strategies are available in Wilson’s disease?

Answer 23

The efficacy of the commonly used drugs is satisfactory for hepatic disease, but disappointing in patients with neurological disease, including the risk of neurological deterioration after the initiation of chelation therapy. The mainstay of treatment for Wilson’s disease is the use of chelating agents and medications to block copper absorption from the gastrointestinal tract. Currently available treatments, including zinc acetate and trientine, are generally well tolerated and effective:

1) Penicillamine forms soluble complexes with metals and is excreted in urine. About one third of patients treated with penicillamine have to change to trientine or zinc because of major adverse effects, including skin disorders, protein-losing nephropathy, lupus-like systemic inflammatory conditions and bone marrow suppression. About 15-20% of patients with neurological Wilson’s disease experience severe, although usually transient, worsening of their neurological symptoms when starting treatment with penicillamine.
2) Zinc prevents the absorption of copper but chelation should continue for two to three weeks after it has been started, as the onset is slow.
3) Trientine was initially used for the treatment of Wilson’s disease only in patients intolerant of penicillamine but it is now gaining acceptance as first-line therapy for hepatic and neurological disease. It may be the best option and it may be even more effective when used in combination with zinc.

Question 24

How should pregnant women with Wilson’s disease be counselled?

Answer 24

Women with Wilson’s disease who become pregnant require anti-copper therapy during their pregnancy.
Counselling should include that the chance that offspring will be homozygous is 0.5%
The major goal of treatment is to protect the mother from copper toxicity while protecting the fetus from possible teratogenesis due to low copper levels.
There is no contra-indication to pregnancy in women with Wilson’s disease in the maintenance phase of treatment except if liver function is poor.
Treatment should not be stopped during pregnancy, although conversion to zinc treatment may be advantageous since D-penicillamine is classified as a teratogen

Question 25

When is liver transplantation required for Wilson’s disease?

Answer 25

Liver transplantation is indicated for the approximately 5% of patients with acute liver failure as the first presentation of disease, most commonly in the second decade of life, or those who present with end-stage liver disease and severe hepatic insufficiency, most commonly in the third and fourth decades.

Liver transplantation restores normal biliary copper excretion (and so prevents disease recurrence) and promotes removal of copper from extrahepatic sites. Outcomes of liver transplantation are excellent, from both cadaveric and living donors.

Question 26

What is alpha 1 anti-trypsin?

Answer 26

Alpha-1 antitrypsin (A1AT) is a glycoprotein which is largely produced in the liver. It is is a serine protease inhibitor. Its main function is to balance the action of neutrophil-protease enzymes in the lungs - eg, neutrophil elastase produced by neutrophils in the presence of inflammation, infection or smoking.

If there is a deficiency of A1AT then elastase can break down elastin unchecked; in the lungs this can lead to the destruction of alveolar walls and emphysematous change.

Question 27

What is the definition of alpha 1 anti-trypsin deficiency?

Answer 27

A1AT deficiency is an inherited condition. In those with A1AT deficiency, the protein is still produced but the genetic defect means that the A1AT molecule configuration is changed. As a result, it cannot pass out of the liver into the bloodstream and so cannot pass to the lungs and the rest of the body. Some people with A1AT deficiency develop liver disease. This results from the congestion of A1AT in the liver cells, leading to cell destruction.

Serum concentration of A1AT below 15-20% of normal is very suggestive of homozygous A1AT deficiency.

Question 28

What is the aetiology of alpha 1 anti-trypsin deficiency?

Answer 28

There is a mutation in the SERPINA1 gene (previously known as the Pi gene) on chromosome 14. Over 100 different allelic variants of the A1AT gene have been described. M alleles are the normal variants of the gene. Other common variants are S and Z.

As a result of these different allelic variants, over 20 different variants of the A1AT molecule have been identified, all inherited as co-dominant alleles. Humans have two copies of the A1AT gene and can be homozygous or heterozygous.

Someone who is homozygous MM, will produce normal amounts of A1AT. Common genotypes for people with A1AT deficiency are SS, ZZ, MS, MZ, SZ. However, not everyone with A1AT deficiency develops clinically significant disease. The different genotypes will lead to different serum levels of A1AT. It is the serum level of A1AT that will determine the likelihood of developing clinically significant disease. Most patients with clinical disease are homozygous SS or ZZ. They have the lowest serum levels of A1AT.

A heterozygote MS or MZ will be a carrier of the disease. They produce lower than normal levels of A1AT (around 35% of normal). Evidence has shown an increased risk of liver and lung disease for people who are heterozygous for A1AT deficiency. Studies have shown that A1AT heterozygosity can be an important co-factor in the aetiology of chronic liver disease and a modifier for hepatitis C virus, end-stage liver disease, cirrhosis and hepatocellular carcinoma.

Question 29

What is the presentation of liver disease in alpha 1 anti-trypsin deficiency?

Answer 29

Not everyone with A1AT deficiency will develop liver disease.
Neonates with A1AT deficiency may present with neonatal jaundice and hepatitis; older children may develop hepatitis, cirrhosis and liver failure due to A1AT deficiency.
Many adults with A1AT deficiency will show some signs of abnormalities in LFTs but, in some, the build-up of A1AT in the liver can lead to hepatitis, fibrosis, cirrhosis and liver failure. With cirrhosis there is a risk of hepatocellular carcinoma.

Question 30

How should liver disease be managed in alpha 1 anti-trypsin deficiency?

Answer 30

Liver function should be monitored and liver disease treated as for liver disease and cirrhosis of other causes. See separate Cirrhosis and Liver Failure articles.
Hepatocellular carcinoma screening is also needed (more common in males than in females).
Liver failure may require transplantation.

Where the diagnosis is made in the absence of symptoms there should be advice about not smoking and referral to a chest clinic for the assessment of possible occult disease.
Many advise restraint with regard to alcohol consumption. However, one study suggests that neither alcohol nor viral hepatitis predisposes to advanced liver disease; however, two factors that do are obesity and being male.