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8. Liver & Co > Metabolic Liver Diseases (3): Alpha 1 Antitrypsin Deficiency, Hereditary Haemochromatosis and Wilson’s disease > Flashcards

Metabolic Liver Diseases (3): Alpha 1 Antitrypsin Deficiency, Hereditary Haemochromatosis and Wilson’s disease Flashcards

1
Q

Name 3 metabolic disorders that can cause liver disease.

A
  1. Haemochromatosis - iron overload.
  2. Alpha 1 anti-trypsin deficiency.
  3. Wilson’s disease - disorder of copper metabolism.
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2
Q

What is alpha-1-antitrypsin?

A

A glycoprotein that controls the inflammatory cascade.
Synthesised in the liver.
Role: protects lung tissue from damage by inhibiting the proteolytic enzyme, neutrophil elastase.

Alpha-1-antitrypsin gene is located on chromosome 14.

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3
Q

Define alpha-1-antitrypsin deficiency.

A

An inherited autosomal recessive conformational disease, caused by an abnormality in the gene for a protease inhibitor called alpha-1-antitrypsin, that can be fatal.

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4
Q

Explain the pathophysiology of alpha-1-antitrypsin deficiency.

A
  1. In the liver:
    - Alpha-1-antitrypsin is produced in the liver
    - Its main role is to inhibit the proteolytic enzyme - NEUTROPHIL ELASTASE.
    - An abnormal “mutant” version of this protein is produced, rather than the normal alpha-1-antitrypsin protein.
    - This mutant protein gets trapped in the liver, builds up, and causes liver damage.
  2. In the lung:
    - Alpha-1-antitrypsin protects against tissue damage from neutrophil elastase.
    - The lack of a normal, functioning alpha-1-antitrypsin protein leads to an excess of protease enzymes that attack the elastic fibres + connective tissue in the lungs.
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5
Q

What diseases does deficiency of alpha-1-antitrypsin causes?

A
  1. Emphysema
  2. COPD
  3. Chronic liver disease
  4. Hepatocellular carcinoma (HCC)
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6
Q

What are the different genotypes you can inherit for alpha-1-antitrypsin?

Which one brings about symptomatic disease?

A

PiMM - normal (M = medium)
PiZZ - homozymgous, symptomatic (Z = very slow)
PiMZ - heterozygous (slow)

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7
Q

Give the clinical features of alpha-1-antitrypsin deficiency.

A

Symptoms:
- COPD like symptoms – dyspnoea (emphysema), chronic cough, sputum production
- Cirrhosis

Signs:
- Cholestatic jaundice

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8
Q

How would you diagnose alpha-1-antitrypsin deficiency?

A
  1. Low serum A1A levels = screening test of choice
  2. Liver biopsy = shows cirrhosis
    - Shows cirrhosis
    - Shows acid-Schiff-positive staining globules (this stain highlights the mutant alpha-1-antitrypsin proteins) in hepatocytes
  3. Genetic testing / genotyping for A1AT gene
  4. High resolution CT thorax
    - Diagnoses bronchiectasis and emphysema
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9
Q

Management of alpha-1-antitrypsin deficiency.

A
  • No treatment
  • Treat complications of liver disease
  • Stop smoking
  • Those with hepatic decompensation should be assessed for liver transplant
  • Manage emphysema
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10
Q

What stain would you use on a liver biopsy in alpha1-antitrypsin deficiency?

What would you see?

A

Periodic Acid Schiff (PAS).

PAS +ve globules.

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11
Q

What is the curative treatment of alpha-1-antitrypsin deficiency?

A

Liver transplant

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12
Q

Define haemachromatosis.

A

A genetic, iron storage disorder that results in excessive total body iron and deposition of iron in tissues.

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13
Q

Haemochromatosis is a genetic disorder. How is it inherited?

A

Autosomal recessive inheritance.

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14
Q

What causes hereditary haemachromatosis?

A

Autosomal recessive inheritance with a mutation in the HFE gene (chromosome 6).

Mostly affects middle aged men.

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15
Q

What is the defining feature of hereditary haemachromatosis?

A

Increased intestinal iron absorption leading to excess iron deposition in organs.

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16
Q

90% of people with haemochromatosis have a mutation in which gene?

A

HFE.

17
Q

Describe the pathophysiology of haemochromatosis.

A

Uncontrolled intestinal iron absorption leads to deposition in the liver, heart and pancreas -> fibrosis -> organ failure.

  1. The HFE gene protein interacts with the transferrin receptor 1, which is a mediator in intestinal iron absorption.
  2. Iron is taken up by the mucosal cells of the small intestine inappropriately.
  3. EXCEEDING the binding capacity of transferrin.
  4. Hepcidin, a protein synthesise in the liver, is central to the control of iron absorption; it is increased in iron deficiency states and decreased with iron overload.
  5. Hepatic expression of the hepcidin gene is decreased in HFE
    haemochromatosis thereby facilitating iron overload.
  6. Excess iron is then gradually taken up by the liver and other tissue over a long period.
  7. The iron itself precipitates fibrosis.
  8. In symptomatic patients, the total body iron content is 20-40 g (compared with 3-4 g in a normal person).
  9. The iron content is particularly increased in the liver and pancreas but also in other organs e.g. heart, skin and endocrine glands.
  10. In established cases, the liver shows extensive iron deposition and fibrosis.
18
Q

Give 4 symptoms of hereditary haemochromatosis.

A

Symptoms:
1. Joint Pain
2. Fatigue and Weakness - chronic tiredness
3. Abdominal Pain
4. Loss of Sex Drive - erectile dysfunction
5. Cognitive symptoms (memory and mood disturbance)

19
Q

Give 3 signs of haemochromatosis.

A

Signs:
1. Slate Grey Skin hyperpigmentation
2. Irregular Heartbeats
3. Diabetes
4. Dilated cardiomyopathy
5. Hepatomegaly
6. Osteoporosis

20
Q

How might you diagnose someone with haemochromatosis?
Give 3 investigations.

A
  1. Bloods – ↑ serum Fe, serum ferritin, serum transferrin
  2. HFE gene genotyping
  3. Liver biopsy
21
Q

What would be the blood test results (iron, ferritin, total iron binding capacity) in hereditary haemachromatosis?

What disease is this the same as?

A

Increased iron and ferritin.

Low total iron binding capacity.

The same as sideroblastic anaemia.

22
Q

What staining would you use on liver biopsy in hereditary haemachromatosis?

A

Perl’s staining

23
Q

How would you treat hereditary haemachromatosis?

A
  1. Venesection
    - Once a week, then a few times a year
  2. Desferrioxamine (iron chelator) if can’t venesect
  3. Testosterone replacement
  4. Low iron diet
  5. Screen family members and geneic counselling
  6. Monitoring serum ferritin
  7. Avoid alcohol
  8. Monitoring and treatment of complications
24
Q

Define Wilson’s disease.

A

Rare autosomal recessive disorder resulting in impaired excretion of copper in bile and faeces, leading to toxic accumulation of copper in the liver and CNS (basal ganglia i.e. globus pallidus and putamen)

25
Q

What is Wilson’s disease caused by?

A

Autosomal recessive mutation of ATP7B copper-binding-protein (‘Wilson disease protein’) on Chromosome 13 = reduced removal of Cu in liver

26
Q

Describe pathophysiology of Wilson’s disease.

A
  1. Dietary copper is normally absorbed from the stomach + upper SI.
  2. Copper is transported to the liver loosely bound to albumin.
  3. Once in the liver, it is incorporated into a glycoprotein called CAERULOPLASMIN, synthesised in the liver and secreted into the blood.
  4. The remaining copper is normally excreted in the bile and excreted in faeces.
  5. Wilson’s disease is a very rare inborn error of copper metabolism that results in copper deposition in various organs, including the liver, the basal ganglia of the brain and the cornea.
  6. The precise mechanism for the FAILURE OF COPPER EXCRETION IS UNKNOWN.
  7. Liver histology is not diagnostic but varies from that of chronic hepatitis to macronodular cirrhosis.
  8. The basal ganglia are damaged and show cavitation, the kidneys show tubular degeneration and erosions are seen in the bones.
27
Q

What system, apart from the liver, is affected by Wilson’s disease?

How does this present?

A
  1. CNS
  • Basal ganglia degeneration
  • Depression
  • Labile emotions
  • Decreased libido
  • Personality changes
  • Tremor
  • Dysarthria
  • Dementia
  • Decreased memory/IQ
  • Delusions
28
Q

Describe the clinical presentation of Wilson’s disease.

A
  1. Jaundice
  2. Parkinsonism (Cu in Basal ganglia)
  3. Dystonia (a movement disorder that causes the muscles to contract involuntarily)
  4. Dysarthria (difficulty speaking caused by brain damage or brain changes later in life)
  5. Kayser-Fleischer Ring (Cu in cornea)
29
Q

What is a Kayser-Fleischer ring?

A

Copper deposition in cornea - see in eyes of Wilson’s disease patients

30
Q

What investigations would you carry out in Wilson’s disease?

What would they show?

A
  1. Serum Cu & caeruloplasmin = ↓
  2. Liver biopsy (Gold Standard)
    - Increased hepatic copper, hepatitis and cirrhosis - but note: high copper levels are also found in chronic cholestasis
  3. 24h Urine Cu Assay – elevated
  4. MRI
    - Show degeneration of basal ganglia and cerebellum
31
Q

How would you treat Wilson’s disease?

A
  1. Lifetime copper chelation using:
    - Penicillamine
    - Trientene
  2. Screen siblings
    - Asymptomatic homozygotes need treating
  3. Liver transplant, if severe

8. Liver & Co (18 decks)

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