This document discusses alpha-1 antitrypsin deficiency. It is an autosomal recessive disease causing deficiency of alpha-1 antitrypsin (AAT), which normally inhibits neutrophil elastase. This leads to lung emphysema and liver disease. In the lung, AAT deficiency results in panacinar emphysema due to uncontrolled neutrophil elastase activity. In the liver, AAT accumulates in hepatocytes, seen as PAS+ diastase-resistant inclusions. The disease presents in childhood with liver disease such as neonatal hepatitis or later with lung emphysema. Treatment involves AAT augmentation therapy for the lung. The pathology, clinical features, genetics and pathogenesis are described.

1. FLASHPATH
H a z e m A l i

2. ALPHA-1
ANTITRYPSIN
DEFICIENCY
H a z e m A l i

3. CLINICAL
• Autosomal recessive disease, causing deficiency and low serum level of
alpha-1-antitrypsin (AAT)
• Commonly presents with:
– Liver disease (neonatal hepatitis, Jaundice, cirrhosis)
– Lung disease (panacinar emphysema)
• AAT deficiency can also presents with:
– Cutaneous necrotizing panniculits
– MPGN and infantile nephrotic syndrome

4. CLINICAL
• Alpha-1-antitrypsin is an acute-phase plasma glycoprotein
– Serum level is elevated during infections and other inflammatory conditions
• AAT is functioning as a protease inhibitor (Pi), which inhibits proteases
released at sites of inflammation
– Mainly neutrophil elastase, cathepsin G, and proteinase 3
• It is synthesized mainly by liver cells
• It is encoded by SERPINA1 gene on chromosome 14
– (Serine Protease INhibitor A1)
– Previously known as Pi gene

5. CLINICAL
• About 75 allelic variants are identified and ordered alphabetically according
to their products’ migration pattern during electrophoresis
• Most of these variants are normal, the most common “normal” one is PiMM
(90% of individuals)
• The most common “deficiency” variant is PiZZ
• Due to amino acid substitution (lysine for glutamic acid at position 342)
• Low serum AAT level
• Heterozygous PiMZ shows milder disease than homozygous PiZZ
– This is called “autosomal codominant expression”
• Other less common “deficiency” variants
• Pi-null: No detectable serum AAT – Very aggressive disease
• Pi-S: moderate decrease in serum AAT – No clinical disease

6. PATHOGENESIS
• Due to missense mutation (amino acid substitution), causing abnormal
protein folding and resulting in:
– Blockage of protein transfer from the endoplasmic reticulum to Golgi apparatus
– Prevention of protein secretion into the circulation
• Accumulation of misfolded AAT in hepatocytes results in formation of
cytoplasmic inclusions and apoptosis
• Absent/low circulatory AAT results in unopposed leukocyte proteases activity
during any inflammatory process
– In lungs, destruction of connective tissues causes emphysema
• This can be aggravated by smoking (by increases the activation and influx of
neutrophils)

7. CLINICAL
Treatment
• Lung:
– "Augmentation therapy“
• infusion of purified AAT from pooled human plasma
– Avoid cigarette smoking
• Liver:
– Mainly symptomatic and supportive
–Liver transplantation in end-stage disease

8. GROSS
Lung:
• Panacinar emphysema (enlarged cystic lung)
Liver:
• Non-specific
• Advanced disease  cirrhosis

9. MICROSCOPY
Lung
• Characteristic feature:
– Abnormal enlargement of airspaces
– The whole acinus is involved (i.e. panacinar)
• Other features:
– Variable inflammation
– No or little fibrosis

10. MICROSCOPY
Liver
• Characteristic feature
– Round to oval intracytoplasmic eosinophilic inclusions
– Mainly seen in Periportal “zone 1” hepatocytes
– NOT seen in infants < 3 months
• Other features:
– Neonatal giant cell hepatitis
– Variable cholestasis, inflammation, ductular reaction
– Rare Mallory bodies and fatty change
• Advanced cases:
– Portal fibrosis and Cirrhosis – HCC

11. MICROSCOPY
Neonatal giant cell hepatitis
• An injury pattern seen in neonates
• Associated with wide variety of liver diseases
– The most frequently associated disorder is alpha-1 antitrypsin deficiency
• The hallmark is syncytial giant cell transformation of hepatocytes
– Thought to reflect hepatocyte cell fusion and/or mitotic inhibition
Ductular reaction is usually mild in AAT deficiency, but:
– in some case it may predominate (simulate biliary atresia)
– In other cases, there may be paucity of intrahepatic bile ducts

12. SPECIAL STUDIES
• Laboratory:
Detection of abnormal protein by electrophoresis
• Special stains:
Liver cytoplasmic inclusions are PAS positive and Diastase resistant
• IHC:
Liver cytoplasmic inclusions are AAT positive
• Electron microscopy:
Hepatocytes shows granular material “misfolded protein”
in dilated endoplasmic reticulum

13. SPECIAL STUDIES
Periodic acid – Schiff (PAS) can also stain:
• Glycogen – red
– E.g. Acinar carcinoma and pancreatic serous cystadenoma
– Also Alveolar soft parts sarcoma (PAS+ intracytoplasmic crystals)
– Also Ewing sarcoma/PNET and Rhabdomyosarcoma (DD from lymphomas)
• Basement membranes – red
– E.g. in Glomerular diseases
• Mucin – red
– E.g. metaplasia and adenocarcinoma
• Colloid – red
• Fungi – red

14. SPECIAL STUDIES
PAS conjugated with other stains/substances:
• PAS/Diastase:
– Glycogen is digested by diastase “diastase sensitive” (absence of red stain)
– Mucin is not digested by diastase “diastase resistant” (persistence of red stain)
– Also used to detect fungi (in glycogen-rich background e.g. skin)
• PAS/Alcian Blue:
– “pan-mucin” stain, used routinely in all GIT biopsies
– Stains both neutral mucin (PAS+ = red) and acid mucin (AB+ = blue)
• “neutral”  gastric mucin cell metaplasia in small intestine
• “acid”  intestinal metaplasia with goblet cells in stomach or Barrett’s esophagus
• PAS/Light Green:
– Stains fungi (red) and background (green)

15. SPECIAL STUDIES
Alpha 1-antitrypsin (AAT) is also positive in:
• Normal cells:
– Histiocytes and Liver cells
• Tumors:
– Histiocytic neoplasms
– Many GIT, liver and pancreas neoplasms
– Salivary gland neoplasms
– Yolk sac tumor
– Giant cell tumor of bone
Verylowspecificity

16. DIFFERENTIAL DIAGNOSIS
L u n g
• Other types of emphysema
• Other causes of obstructive lung diseases
• Other causes of congenital / cystic lung diseases

17. DIFFERENTIAL DIAGNOSIS
Chronic
bronchitis
Bronchiectasis Asthma
Small-airway
disease
“bronchiolitis”
Emphysema
Site B r o n c h u s Bronchioles Alveoli
Major
pathology
• Mucous gland
hyperplasia
• Excess mucus
• Inflammation
• Airway
dilation &
scarring
• Smooth
muscle
hyperplasia
• Excess mucus
• Inflammation
(eosinophils)
• Inflammatory
scarring &
obliteration
• Airspace
enlargement
• Wall
destruction
• No fibrosis
Other obstructive lung diseases:

18. DIFFERENTIAL DIAGNOSIS
O t h e r c o n g e n i t a l / c y s t i c l u n g d i s e a s e s :
• Congenital:
– Bronchogenic cysts
– Congenital pulmonary cysts
– Congenital pulmonary airway malformation
– Congenital lobar emphysema
– Pulmonary sequestration
• Acquired:
– Healed abscess
– Honeycombing
• Mixed:
– Cystic fibrosis
No destruction of alveoli
Fibrosis

19. DIFFERENTIAL DIAGNOSIS
L i v e r
• Other causes of giant cell transformation
• Other causes of neonatal cholestasis
• Other causes of cirrhosis
α1-Antitrypsin deficiency is one of the few liver diseases
that can still be diagnosed in an end-stage liver explant
because of the PAS-positive and diastase-resistant
globules that remain in the hepatocyte cytoplasm

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