GeneticsTier 1Medical Sciences concept

Alpha-1 antitrypsin deficiency - mechanism of liver vs lung disease (polymer accumulation vs protease-antiprotease imbalance)

Core concept

SERPINA1, chromosome 14q32 - alpha-1 antitrypsin is a serine protease inhibitor made in the hepatocyte and secreted; codominant expression (PI, "protease inhibitor" nomenclature)
Two entirely different mechanisms in the same patient

Lung = LOSS of function

dec circulating AAT -> unopposed neutrophil elastase (and proteinase 3, cathepsin G)
- -> destruction of alveolar elastin -> panacinar emphysema
- Cigarette smoke oxidises the reactive-centre methionine -> inactivates the residual AAT and recruits neutrophils
- -> smoking shortens life by ~20 years in PiZZ - the single most important intervention

Liver = toxic GAIN of function

Z variant (Glu342Lys) misfolds and polymerises by loop-sheet insertion
- -> polymers retained in hepatocyte ER -> ER stress, apoptosis, regeneration
- -> PAS-positive, diastase-resistant globules in periportal hepatocytes - the histological signature
- -> neonatal cholestasis, childhood or adult cirrhosis and hepatocellular carcinoma
The null-null genotype proves the split: no protein made at all -> emphysema but NO liver disease, because there is nothing to accumulate
- This dissociation is the point the exam tests

Genotypes

Phenotype	AAT level (% normal)	Lung	Liver
PiMM	100%	-	-
PiMZ	~55-60%	Slight inc risk if smoker	Modifier - inc risk of cirrhosis with NAFLD, alcohol, viral hepatitis
PiSZ	~40%	Modest risk	Small risk
PiZZ	~10-15%	Emphysema in most, esp. smokers	Cirrhosis in ~10-15% of adults
Null-null	0	Severe emphysema	None
PiF, PiI	Normal level	Functionally defective protein - level alone misses these	-

Protective threshold ~11 micromol/L (~0.5 g/L) - below this, emphysema risk rises steeply
AAT is an acute-phase reactant -> a "normal" level during infection or inflammation can conceal deficiency; always check CRP and confirm with phenotyping (isoelectric focusing) or genotyping
~1 in 2,000-5,000 Northern Europeans are PiZZ; the great majority are never diagnosed

Clinical picture

Emphysema that is early (4th-5th decade), panacinar and BASAL-predominant - the opposite of smoking-related centrilobular apical emphysema
- Basal predominance reflects greater lower-zone blood flow and neutrophil delivery
Also: bronchiectasis, panniculitis (necrotising, neutrophilic), and an association with granulomatosis with polyangiitis / PR3-ANCA vasculitis (proteinase 3 is an AAT target)

Test for AAT deficiency in: emphysema/COPD <45 y or with minimal smoking, basal-predominant emphysema, unexplained bronchiectasis, unexplained liver disease at any age, necrotising panniculitis, family history, ANCA vasculitis
- WHO and ATS/ERS advise testing every adult with fixed airflow obstruction at least once
Management splits by organ, and the two do not share a treatment
- Lung - smoking cessation above all, standard COPD therapy, vaccination, pulmonary rehab; IV pooled AAT augmentation (60 mg/kg weekly) slows CT densitometric decline in PiZZ with FEV1 ~30-65%; lung transplant
  - Augmentation raises the plasma level; it does nothing for the liver
- Liver - no specific therapy; surveillance for cirrhosis and 6-monthly HCC screening; avoid alcohol and treat metabolic risk factors; liver transplant is curative for both organs (the graft has the donor's SERPINA1)
- RNA interference (fazirsiran) reduces hepatic Z-polymer accumulation - investigational, and logically would worsen the lung deficit, so it is a liver-only strategy
Counsel family - test siblings and children; PiMZ relatives need smoking and alcohol advice rather than augmentation

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