Metabolic Liver Diseases (3): Alpha 1 Antitrypsin Deficiency, Hereditary Haemochromatosis and Wilson’s disease Flashcards
Name 3 metabolic disorders that can cause liver disease.
- Haemochromatosis - iron overload.
- Alpha 1 anti-trypsin deficiency.
- Wilson’s disease - disorder of copper metabolism.
What is alpha-1-antitrypsin?
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.
Define alpha-1-antitrypsin deficiency.
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.
Explain the pathophysiology of alpha-1-antitrypsin deficiency.
- 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. - 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.
What diseases does deficiency of alpha-1-antitrypsin causes?
- Emphysema
- COPD
- Chronic liver disease
- Hepatocellular carcinoma (HCC)
What are the different genotypes you can inherit for alpha-1-antitrypsin?
Which one brings about symptomatic disease?
PiMM - normal (M = medium)
PiZZ - homozymgous, symptomatic (Z = very slow)
PiMZ - heterozygous (slow)
Give the clinical features of alpha-1-antitrypsin deficiency.
Symptoms:
- COPD like symptoms – dyspnoea (emphysema), chronic cough, sputum production
- Cirrhosis
Signs:
- Cholestatic jaundice
How would you diagnose alpha-1-antitrypsin deficiency?
- Low serum A1A levels = screening test of choice
- Liver biopsy = shows cirrhosis
- Shows cirrhosis
- Shows acid-Schiff-positive staining globules (this stain highlights the mutant alpha-1-antitrypsin proteins) in hepatocytes - Genetic testing / genotyping for A1AT gene
- High resolution CT thorax
- Diagnoses bronchiectasis and emphysema
Management of alpha-1-antitrypsin deficiency.
- No treatment
- Treat complications of liver disease
- Stop smoking
- Those with hepatic decompensation should be assessed for liver transplant
- Manage emphysema
What stain would you use on a liver biopsy in alpha1-antitrypsin deficiency?
What would you see?
Periodic Acid Schiff (PAS).
PAS +ve globules.
What is the curative treatment of alpha-1-antitrypsin deficiency?
Liver transplant
Define haemachromatosis.
A genetic, iron storage disorder that results in excessive total body iron and deposition of iron in tissues.
Haemochromatosis is a genetic disorder. How is it inherited?
Autosomal recessive inheritance.
What causes hereditary haemachromatosis?
Autosomal recessive inheritance with a mutation in the HFE gene (chromosome 6).
Mostly affects middle aged men.
What is the defining feature of hereditary haemachromatosis?
Increased intestinal iron absorption leading to excess iron deposition in organs.