FLASHPATHH a z e m A l i

ALPHA-1 ANTITRYPSI

N DEFICIENCY

H a z e m A l i

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

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

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

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)

CLINICALTreatment• 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

GROSS

Lung:• Panacinar emphysema (enlarged cystic lung)

Liver:• Non-specific• Advanced disease cirrhosis

MICROSCOPYLung• Characteristic feature:

– Abnormal enlargement of airspaces– The whole acinus is involved (i.e. panacinar)

• Other features:– Variable inflammation– No or little fibrosis

MICROSCOPYLiver• 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

MICROSCOPYNeonatal 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

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

SPECIAL STUDIESPeriodic 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

SPECIAL STUDIESPAS 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)

SPECIAL STUDIESAlpha 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 Ve

ry lo

w s

peci

ficit

y

DIFFERENTIAL DIAGNOSISL u n g• Other types of emphysema

• Other causes of obstructive lung diseases

• Other causes of congenital / cystic lung diseases

DIFFERENTIAL DIAGNOSIS

Chronic bronchitis

Bronchiectasis Asthma

Small-airway disease

“bronchiolitis”

Emphysema

Site B r o n c h u s Bronchioles AlveoliMajor

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:

DIFFERENTIAL DIAGNOSISO 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

DIFFERENTIAL DIAGNOSISL i v e r• Other causes of giant cell transformation

• Other causes of neonatal cholestasis

• Other causes of cirrhosisα1-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

WWW.

DO NOT FORGET TO SEARCH FOR MORE PICS AND VIRTUAL SLIDES

THANK YOUH a z e m A l i