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To the Editor: Alpha-1-antitrypsin (AAT) deficiency is considered to be a rare monogenic disorder affecting mainly the lungs and the liver. Several mutations in the AAT gene may underlie the disorder, although the Pi*ZZ allele is most frequently associated with low serum AAT levels and severe clinical manifestations.1 Liver disease may occur in early childhood or adulthood,2 whereas lung disease occurs after the third decade of life. However, estimates of the prevalence of the Pi*ZZ genotype suggest that the mutation does not always lead to clinical manifestations or that the disease is often unrecognized.3,4

CASE REPORT

  1. Top of page
  2. CASE REPORT
  3. DISCUSSION
  4. ACKNOWLEDGMENTS
  5. REFERENCES

A 78-year-old woman was admitted to Geneva University Hospital on December 8, 2008, presenting with fatigue and a 2-month history of progressively worsening peripheral edema, abdominal distention, and exertional dyspnea. Her personal medical history and family history were unremarkable. She was unmarried, without children, and lived independently at home. She was a nonsmoker, drank no alcohol, and took no regular medication. On physical examination, the presence of severe ascites and peripheral edema was confirmed. Diminished breath sounds and dullness on percussion were noted at both lung bases. No jaundice, hemorrhoids, or other indirect signs of chronic liver disease were found. The neurological examination was unremarkable; the Mini Mental State Examination score was 28 out of 30.

The laboratory findings revealed anemia (hemoglobin 10.9 g/dL), thrombocytopenia (platelet count 135,000/μL), abnormal liver function tests (aspartate aminotransferase 111 IU/L, alanine aminotransferase 60 IU/L, γ-glutamyl transferase 61 IU/L, total bilirubin 4.5 mg/dL, conjugated bilirubin 1.95 mg/dL), severe hypoalbuminemia (1.9 g/dL), and abnormal coagulation (prothrombin time 41%, partial thromboplastin time 33.7 seconds, factor V activity 65%, and factor VII to X activity 33%). Abdominal ultrasound and computed tomography scan revealed the presence of voluminous ascites and abnormal liver architecture, suggesting liver cirrhosis; hepatic and portal veins were patent. Ascites fluid albumin (0.6 g/dL, vs serum albumin 1.9 g/dL) suggested portal hypertension. No tumor cells were found on cytological analysis. Endoscopic gastroscopy showed gastroesophageal varices Stage I to II and portal hypertensive gastropathy. An echocardiography showed normal left ventricular size and systolic function, without pericardial effusion. These findings indicated a likely diagnosis of severe liver cirrhosis with portal hypertension.

Clinical history excluded alcoholic or drug-induced cirrhosis. Appropriate laboratory tests gave no indication of viral or autoimmune hepatitis, primary biliary cirrhosis, hemochromatosis, or Wilson's disease. Liver imaging gave no indication for Budd-Chiari syndrome. In the absence of any obvious clinical diagnosis, a transjugular liver biopsy was performed. Histological examination confirmed the presence of liver cirrhosis (Figure 1A). Identification of numerous periodic acid-Schiff–positive, diastase-resistant intracytoplasmic globules suggested AAT deficiency (Figure 1B).

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Figure 1.  Histology of liver biopsy. (A) A low-magnification view showed liver cirrhosis, with nodular fragmentation and surrounding fibrous bands (arrow). Mild perisinusoidal fibrosis is also seen (arrowhead) (Masson trichrome staining, original magnification × 100). (b) Periodic acid-Schiff staining after diastase digestion identified intracytoplasmic hyaline globules of varied size (arrowheads), some of which were larger than hepatocyte nuclei (arrow) (original magnification × 400).

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Low AAT serum levels, measured twice (0.22 g/L and 0.23 g/L, normal range 0.92–2 g/L), confirmed AAT deficiency. Finally, genotyping revealed a homozygous Pi*ZZ mutation of the SERPINA1 gene. Thus, clinical, morphological, biochemical, and genetic data led to a final diagnosis of isolated Child C12 liver cirrhosis secondary to AAT deficiency. The patient was successfully treated with two ascites punctures, beta-blockers, and diuretics (spironolactone and furosemide) and was able to return home after functional recovery. After treatment, a control chest X-ray showed no lung pathology, and pulmonary function tests showed no evidence of chronic obstructive pulmonary disease.

DISCUSSION

  1. Top of page
  2. CASE REPORT
  3. DISCUSSION
  4. ACKNOWLEDGMENTS
  5. REFERENCES

The natural history of AAT deficiency is poorly defined. AAT deficiency is defined as the inheritance of two severe deficiency alleles at the AAT locus, the SERPINA1 gene. Lung emphysema is attributed to unopposed elastase activity, leading to acinar tissue destruction. It usually occurs in adulthood and is modulated by active or passive smoking or possibly other pollutants or genetic modifiers.1,5 Liver disease is attributed to improper folding and intracellular accumulation of the mutated AAT protein, causing liver damage by poorly defined mechanisms.6 Although a minority of affected children present with severe liver disease, causing death or requiring liver transplantation, the majority enter adulthood with little or no liver function test abnormalities.2,3 Subsequent development of liver cirrhosis may occur at any age, with or without concomitant lung disease.7,8 The reasons for this heterogeneous clinical course remain unknown. These observations strongly suggest that there is a large “reservoir” of patients with Pi*ZZ mutations and a poorly defined, probably often quite benign, natural course, but the current case indicates that liver cirrhosis due to AAT deficiency can occur even in old age, in the absence of lung disease. AAT deficiency must therefore be considered in the differential diagnosis of liver cirrhosis in older adults. Even in geriatric practice, this “rare” genetic disorder deserves to be considered and confirmed using appropriate genetic testing.

ACKNOWLEDGMENTS

  1. Top of page
  2. CASE REPORT
  3. DISCUSSION
  4. ACKNOWLEDGMENTS
  5. REFERENCES

Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper.

Author Contributions: Each author participated in data collection, presentation of the results, and writing and correcting the letter.

Sponsor's Role: None.

REFERENCES

  1. Top of page
  2. CASE REPORT
  3. DISCUSSION
  4. ACKNOWLEDGMENTS
  5. REFERENCES