Liver & intrahepatic bile ducts
Metabolic diseases
Alpha-1 antitrypsin deficiency


Topic Completed: 28 July 2020

Minor changes: 28 July 2020

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PubMed Search: Alpha-1 antitrypsin deficiency[TI] liver[TI] free full text[sb]

See also: Lung nontumor chapter

Caroline I.M. Underwood, M.D.
Avani Pendse, M.D., Ph.D.
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Cite this page: Underwood C, Pendse A. Alpha-1 antitrypsin deficiency. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/liverAAT.html. Accessed September 23rd, 2020.
Definition / general
  • Genetic metabolic disorder causing deficiency of alpha-1 antitrypsin deficiency (AAT) and leading to disease in the lungs and liver
Essential features
  • Different phenotypes have different clinical presentations
  • Should be included in the differential diagnosis for all cases of early onset cirrhosis
  • PASD and AAT positive eosinophilic intracytoplasmic globules within hepatocytes
    • Absence does not rule out AAT deficiency
ICD coding
  • ICD-10: E88.01 - Alpha-1 antitrypsin deficiency
Epidemiology
Sites
Pathophysiology
  • AAT is a serine proteinase inhibitor
    • From the serpin superfamily
  • Secreted by hepatocytes (primary source) and also epithelial cells in the lung and GI tract, neutrophils and macrophages (Trends Mol Med 2014;20:116)
  • AAT structure = beta pleated sheets and alpha helices (Methods Mol Biol 2017;1639:9, Mutat Res 2017 Jul;773:14)
  • Normal process (Methods Mol Biol 2017;1639:9):
    • Folding and glycosylation occur in the endoplasmic reticulum, which allows for export from the cell
    • Reactive loop of AAT is cleaved by proteinase binding
    • Cleaved reactive loop binds to the beta sheet
  • Mutated process (Methods Mol Biol 2017;1639:9, Mutat Res 2017 Jul;773:14, Trends Mol Med 2014;20:116):
    • Mutation causes a change in the tertiary structure
    • Noncleaved reactive loops from AAT can bind to other beta sheets, resulting in molecular linkage
    • Process is called loop sheet polymerization
    • Misformed AAT cannot be exported from the cell
    • Leads to AAT accumulation and endoplasmic reticulum stress response
Etiology
  • AAT encoded by SERPINA1 gene located on chromosome 14 (Methods Mol Biol 2017;1639:9, Trends Mol Med 2014;20:116)
  • Multiple genetic variants:
  • 4 phenotypes (Methods Mol Biol 2017;1639:9, Orphanet J Rare Dis 2008;3:16):
    • Normal = normal function and plasma levels of AAT
      • "M" phenotype (PiMM)
      • Present in > 99% of world population
    • Deficient = abnormal function and low plasma levels of AAT
      • Mutant phenotype with "Z" or "S" alleles (PiSZ, PIZZ, etc.)
      • Present in < 1% of world population
    • Null = no detectable AAT in plasma
      • Proteins are truncated or unstable; leads to degradation
      • Very rarely causes liver disease and no hepatocyte inclusions will be present
      • Does cause lung disease
      • Present in < 0.1% of world population
    • Dysfunctional = normal plasma levels of AAT
      • AAT does not function correctly
      • Present in < 0.1% of world population
Clinical features
Diagnosis
Laboratory
Prognostic factors
  • Depends on the genetic phenotype (see also Etiology)
Case reports
Treatment
Gross description
Gross images

Contributed by Avani Pendse, M.D., Ph.D.

Cirrhotic liver

Microscopic (histologic) description
  • Adults: range of following findings (Aliment Pharmacol Ther 2018;47:877)
    • Eosinophilic intracytoplasmic globules in hepatocytes
      • Usually in zone 1, near portal triads
      • Most suggestive feature of AAT deficiency
    • Fibrosis: ranges from minimal periportal fibrosis to cirrhosis
    • Mild portal inflammation: predominantly lymphocytic
    • Mild steatosis: often in periportal hepatocytes
  • Neonates (Hepatology 1988;8:307, Am J Surg Pathol 2010;34:1498):
    • Intracytoplasmic globules may be absent or difficult to detect in neonates
    • Hepatitis
    • Extrahepatic biliary atresia like features including:
      • Lobular cholestasis
      • Bile ductular reaction
      • Giant cell transformation of hepatocytes
      • Variable fibrosis
Microscopic (histologic) images

Contributed by Avani Pendse, M.D., Ph.D.

Nodular cirrhosis

Trichrome

Intracytoplasmic globules

PASD


AAT

Neonatal biopsy changes

Giant cell change

Positive stains
  • Diastase resistant periodic acid Schiff (PAS) positive globules
  • AAT positive globules
    • Caution: inflamed and reactive hepatocytes may show background staining in the absence of AAT deficiency
Electron microscopy description
Sample pathology report
  • Liver biopsy in an adult with elevated transaminases and total bilirubin:
    • Liver, random, ultrasound guided needle core biopsy:
      • Hepatocytes with cytoplasmic PAS diastase positive globules compatible with alpha-1 antitrypsin deficiency
      • Cholestasis and mild portal chronic inflammation
      • Periportal fibrosis noted on trichrome stain
      • See comment and microscopic description
      • Comment: Immunohistochemistry for AAT is positive in the cytoplasmic globules and supports the diagnosis. Correlation with laboratory findings is recommended.
  • Hepatectomy at the time of transplant:
    • Liver, native, hepatectomy:
      • Liver with cirrhosis / stage 4 fibrosis
      • PAS positive, diastase resistant hepatocyte cytoplasmic globules present, consistent with patient's history of AAT deficiency
      • Negative for malignancy
Differential diagnosis
Board review style question #1

Which of the following is true of alpha-1 antitrypsin (AAT) deficiency in the liver?

  1. Electron microscopy would show intramitochondrial fibrillary inclusions
  2. Globules are negative for PASD and positive for AAT immunohistochemistry
  3. Globules represent misfolded protein within the endoplasmic reticulum
  4. Intracytoplasmic globules are the diagnostic feature
  5. Number of globules correlates with disease severity
Board review answer #1
C. Globules represent misfolded protein within the endoplasmic reticulum. Although the intracytoplasmic globules are highly suggestive of alpha-1 antitrypsin deficiency, they are not diagnostic. In fact, there are no definitive diagnostic criteria for this disease (Answer D). Additionally, the globules are variably present and may be absent in some cases. There is also no correlation between the number of globules and disease severity (Answer E). When present, the globules are positive for both PASD and AAT (Answer B). These globules represent collections of misfolded protein. On electron microscopy the fibrillary inclusions are located within the endoplasmic reticulum, not within the mitochondria (Answer A).

Reference: Alpha-1 antitrypsin deficiency

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Board review style question #2
Which of the following additional findings is most often seen associated with alpha-1 antitrypsin (AAT) deficiency in the liver of adult patients?

  1. Early onset cirrhosis
  2. Elevated tissue concentration of AAT
  3. High AST and low ALT
  4. Mild steatosis
  5. No detectable AAT in plasma
Board review answer #2
A. Early onset cirrhosis. Although AAT does indeed collect in the hepatocytes due to its inability to be released from the ER, tissue levels are not routinely tested (Answer B). Rather, AAT levels are measured in the plasma. An AAT deficient phenotype is most common and would have a low but still detectable plasma level of AAT. This phenotype has the mutant "z" or "s" alleles. A null phenotype is much rarer and no AAT can be detected in the plasma of such patients due to degradation of the protein entirely (Answer E). A dysfunctional phenotype is also rare, but although the protein does not function properly there are normal plasma levels of AAT. Other laboratory abnormalities would be elevations in both AST and ALT (Answer C) indicating hepatocyte stress. A sole elevation in AST would be more consistent with alcoholic liver injury. Histologically, hepatic steatosis may be present but this finding is variable and much less common than fibrosis or cirrhosis (Answer D). In fact, early onset cirrhosis should prompt suspicion and testing for alpha-1 antitrypsin deficiency.

Reference: Alpha-1 antitrypsin deficiency

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