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Difficulty: MediumPathology and Biopsy Interpretation

A 41-year-old previously healthy man comes to the physician because of progressive exertional dyspnea over the last 14 months. He is a lifetime non-smoker and reports rare alcohol consumption. Physical examination is notable for decreased breath sounds at the lung bases and mild hepatomegaly. Initial laboratory testing reveals elevated serum aspartate aminotransferase and alanine aminotransferase levels. To further investigate the hepatic findings, a percutaneous liver biopsy is obtained. Histopathologic examination of the specimen demonstrates intracytoplasmic, round, eosinophilic globules predominantly within periportal hepatocytes. Special staining reveals that these globular inclusions are strongly periodic acid-Schiff (PAS) positive and resist degradation when treated with diastase enzymes. Based on these biopsy findings, which of the following is the most likely diagnosis?

  1. Alpha-1 antitrypsin deficiencyAnswer
  2. B
    Glycogen storage disease type I
  3. C
    Alcoholic steatohepatitis
  4. D
    Hereditary hemochromatosis
  5. E
    Chronic hepatitis B

Answer

The correct diagnosis is alpha-1 antitrypsin deficiency.
The correct answer is alpha-1 antitrypsin (AAT) deficiency. The patient's clinical presentation of early-onset emphysema (suggested by dyspnea in a young non-smoker) and hepatomegaly is highly suspicious for AAT deficiency. The definitive histologic clue is the presence of eosinophilic, round inclusions in periportal hepatocytes. Because AAT is a glycoprotein, it stains strongly with periodic acid-Schiff (PAS). Furthermore, because it is not composed of glycogen, it resists enzymatic digestion by diastase, remaining distinctly visible (diastase-resistant).

Step-by-Step Solution

1
Analyze the clinical presentation.
A young, non-smoking male presents with unexplained lower-lobe predominant dyspnea (suggesting early-onset emphysema) and concurrent hepatic involvement.
To establish the systemic context of the disease process.
2
Evaluate the liver biopsy histochemical stains.
The periportal inclusions are PAS-positive and diastase-resistant.
Diastase is an enzyme that digests glycogen. Resistance indicates the accumulated substance is a glycoprotein, not glycogen.
3
Correlate pathology with the clinical syndrome.
The combination of early-onset lung disease and PAS-positive, diastase-resistant hepatic inclusions confirms the diagnosis of alpha-1 antitrypsin deficiency.
Misfolded alpha-1 antitrypsin glycoprotein abnormally accumulates in the rough endoplasmic reticulum of hepatocytes, leading to liver damage and systemic deficiency.

Key Concept

Histopathologic identification of alpha-1 antitrypsin deficiency relies on observing PAS-positive, diastase-resistant eosinophilic inclusions in periportal hepatocytes.
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Topics

Pathology and Biopsy Interpretation

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