Liver Manifestations of Alpha 1-Antitrypsin (A1AT) Deficiency

Joanna YehPeds GI Case Conference

Jan 2013

Objectives

• Discuss a patient with A1AT deficiency• Review genetics and pathophysiology of A1AT

deficiency• Understand clinical symptoms, diagnosis,

monitoring, and treatment of A1AT deficiency

Case

• 8 month old boy diagnosed with A1AT on screening because brother had A1AT

• Our patient presents with bloody emesis and transfer to UCLA from OSH

• Hct drop from 33 to 27• Patient also began to have melanotic stools• Transferred after stabilization

Case

• PMH: BH unknown, no past hospitalizations or surgeries

• SH: Lives with parents and brother • Brother is 7 years old who presented with

neonatal hepatitis which resolved but found to be ZZ for A1AT deficiency

• FH: negative for other types of liver disease• NKDA• Meds: none

Case

• Exam normal except for irritability and “Abdomen: Distended with shifting dullness. Spleen approximately 1cm to 2cm below the left costal margin. Liver approximately 3 to 4cm below right costal margin”

• Labs:– CBC 10/9/25/140– PTT 25.7 PT 10.9 INR 1.1 (after vitamin K)– Chem 132/5.2/106– Alb 2.6 ALT 143 AST 313 Tbili 0.7 Dbili 0.4– Cr 0.1 Bun 10

Hospital Course

• 5/29/1997 to 6/10/1997• Made NPO and put on octreotide• EGD: small esophageal varices, sclerotherapy not

indicated, no active bleeding; snakeskin stomach mucosa

• Started on nadolol, isosorbide, sucralfate, pepcid, and aldactone

• MR venogram was normal• US showed hyperechoic liver (likely cirrhotic),

splenomegaly, and ascites• Discharged home on low Na and fluid restriction

Case

• No liver biopsy done but put on transplant list• Received OLT on 10/24/1997• Liver explant showed:– bridging fibrosis– Bile duct proliferation– PAS stained globules / immunoperoxidase staining

for A1AT positive

Alpha 1-Antitrypsin

• Discovered in 1965 by Laurell and Eriksson• Most common genetic cause of liver disease in

children• Incidence of 1 in 2000-3000 in U.S.• All races can be affected but most common in

whites• Predisposes to chronic obstructive pulmonary

disease• Serum levels of A1AT protein reduced

Maurice, Clin Transl Sci, 2012

Function of A1AT

• Serine protease inhibitor (SERPIN)• Inhibits neutrophile elastase and other

protease• Mainly synthesized in liver

Genetics• Autosomal recessive • Classic form is homozygous ZZ • MM is the normal genotype (95% of population)• S allele expressed 50-60% of protein• Z allele expresses 10-20% of protein• Z allele is common in northern Europeans• MZ usually does not lead to liver disease• More than 100 allelic variants – Rare: Mmalton, Mduarte, null

PiSSPiSZPiZZ

Bornhorst, Chest, 201270,000 consecutive samples

Blanco, Hepatitis Monthly, 2012

Liver Disease in A1AT• Only 10% of homozygotes develop clinically

significant liver disease in first 3 decades• Just over 1/3 of ZZ adults develop clinically

significant liver disease• Progression of liver disease in variable• No way to predict• Abnormal protein (Z) accumulated in ER• Can predispose to malignancy

Maurice, Clin Transl Sci, 2012

Perlmutter, Ann Rev Med, 2011

Fairbanks, Am J Gastro, 2008

Diagnosis• Serum A1AT phenotype– ZZ phenotype, levels usually <50-60 mg/dL– A1AT is an acute phase reactant

• A1AT genotype

Teckman, Curr Gastro Reports, 2006

60 mg/dL = 11 uM/L

Symptoms

• Neonatal cholestasis• Neonatal hepatitis• Children: jaundice, abd distension, pruritus,

poor feeding, FTT, hepatomegaly, splenomegaly, ascites, bleeding

• Adults: chronic hepatitis or cirrhosis of unknown etiology

• Adults with portal HTN complicationsFairbanks, Am J Gastro, 2008

Teckman, Curr Gastro Reports, 2006

Sveger, NEJM, 1976

Population-based studies indicate that 80% of PIZZ patients presenting with neonatal cholestasis are healthy and free of chronic disease by the age of 18 years.

Fairbanks, Am J Gastro, 2008

Sveger, Hepatology, 1995

Only 2-3% of ZZ children progress to needing liver transplantation during childhood.

Mechanism of Disease• Mutant protein has altered

folding• Tendency to polymerize and

aggregate• Abnormal accumulation in

hepatocytes -> inflammation -> fibrosis

• Other genetic and/or environmental modifiers– Impaired autophagy– Infections? Viral hepatitis?

Alcohol?Perlmutter, Hepatology, 2007

Perlmutter, Hepatology, 2007

Teckman, Curr Gastro Reports, 2006

Lung Manifestations

• Emphysema develops in 60-70% of adults over 25 years old with peak in 4th and 5th decades

Associations

• Systemic vasculitis• Interstitial fibrosis in patients with RA• Relapsing panniculitis• Multiple sclerosis• Peripheral neuropathy• Intracranial aneurysms• ?IBD (studies weak)• Glomerulonephritis

Fairbanks, Am J Gastro, 2008

Histology• PAS (periodic acid Schiff)

stain accumulated protein in ER

• Globule devoid hepatocytes and malignancy

• Nonspecific: giant cell transformation, bile duct paucity, bile duct proliferation, lobular hepatitis, steatosis, fibrosis, necrosis

Fairbanks, Am J Gastro, 2008

Treatment

• No specific therapies for A1AT liver disease• Cholestasis– Fat soluble vitamins– MCT oil– Actigall

• Avoid smoking (including secondhand smoke) and environmental pollution

• Monitor for HCC (AFP, ultrasound)• OLT (also decreases or eliminates emphysema risk)• Lung: IV purified pooled human plasma A1AT

(augmentation therapy)

Novel Treatments

• Enhancing proteasome and lysosome degradation

• Cell based and gene therapy– Hepatocyte transplantation

(PiZ mouse model)– siRNA (small interfering) – miRNA (micro)

Maurice, Clin Transl Sci, 2012

Summary

• A1AT is a relatively common but under-recognized and under-diagnosed genetic disease.

• Liver disease progression is quite variable and not dependent on A1AT genotype alone.

• Liver disease mainly with ZZ and SZ (necessary but not sufficient).

• No “cure” beyond OLT. • Elucidation of pathophysiology of A1AT liver

disease is paving way to future therapies.

References• Blanco, et al, “A1AT gene frequency distribution using maps of the world,” Hepatitis Monthly,

2012.• Bornhorst, et al, “A1AT phenotypes and associated serum protein concentrations in a large

clinical population,” Chest, 2012.• Clark, et al, “Liver test results do not identify liver disease in adults with A1AT,” Clin Gastro Hep,

2012.• Fairbanks, “Liver disease in A1AT deficiency: a review,” Am J Gastro, 2008.• Maurice and Perlmutter, “Novel treatment strategies for liver disease due to alpha 1-antitrypsin

deficiency,” Clin Transl Sci, Jun 2012.• Nelson, et al, “Diagnosis and management of patients with A1AT,” Clin Gastroenterol Hepatol,

2012.• Perlmutter, “A1AT deficiency: importance of proteasomal and autophagic degradative pathways

in disposal of liver disease-associated protein aggregates,” Annu Rev Med, 2011. • Perlmutter, et al, “Molecular pathogenesis of A1AT deficiency associated liver disease,”

Hepatology 2007.• Sveger and Eriksson, “The liver in adolescents with A1AT deficiency,” Hepatology, 1995.• Sveger, “Liver disease in A1AT deficiency detected by screening 200,000 infants,” NEJM, 1976.• Teckman and Lindblad, “A1AT deficiency: diagnosis, pathophysiology, and management,” Curr

Gastro Reports, 2006.