α1-Antitrypsin deficiency panniculitis (A1ADP) is a rare form of panniculitis that affects children and adults. Clinical and histologic features, precipitating actors, and treatments are discussed.
α1-Antitrypsin, a serine protease inhibitor synthesized in the liver, regulates the action of proteolytic enzymes including trypsin, collagenase, elastase, factor VIII, chymotrypsin, and kallikrein. A deficiency of this protein is hypothesized to lead to
inadequate inhibition of proteases released by neutrophils and monocytes, which in turn results in unchecked inflammation and tissue necrosis.1 The systemic sequelae of this phenomenon include panacinar emphysema, hepatitis, cirrhosis, hemorrhagic diathesis, and panniculitis.2 Panniculitis most commonly occurs in patients with the severe homozygous deficiency PiZZ phenotype, resulting in serum α1-antitrypsin levels that are 10% of normal. The lesions may mimic cellulitis and are most frequently found on the trunk and proximal extremities. Characteristic microscopic features include neutrophils between collagen bundles in
reticular dermis, septal panniculitis with liquefactive necrosis, and collagenolysis with large areas of normal fat lobules adjacent to necrotic fat.3
Case Report
After falling down the stairs at home, a previously healthy 40-year-old woman presented to the emergency department with a tender edematous 25-cm hematoma on the right lateral thigh. The patient was treated empirically for an infected hematoma; use of oral antibiotics resulted in partial improvement. Subsequently, atraumatic indurated plaques and nodules developed on the
extremities; these plaques and nodules were minimally responsive to oral and intravenous antibiotics. The hematoma was incised and drained. Culture results were negative for bacterial and fungal growth. Serous fluid drained from a left-buttock nodule that had spontaneously ulcerated. The patient was admitted to our hospital for further diagnosis and management.
The patient was comfortable and nontoxic. Her temperature was 99.8ºF, and her heart rate was 88 bpm. Distributed over the right axilla, the medial area of the left elbow, the left ankle, the distal area of the right tibia, and the lateral area of the right thigh were multiple, deep, red, tender, indurated, 4- to 25-cm nodules and plaques (Figure 1). On the left buttock was an ulcerated 5-cm nodule.
A biopsy of the right axillary lesion was performed. Results of histologic examination showed normal epidermis and dermis. Mixed lobular and septal panniculitis included normal fat lobules adjacent to necrotic fat lobules (Figure 2). The infiltrate was composed of lymphocytes, histiocytes, and pools of neutrophils with suppuration, liquefactive necrosis, and collagenolysis (Figure 3). Neutrophils were splayed between collagen bundles (Figure 4). Granulomata were not evident, and there was no evidence of vasculitis. Periodic acid–Schiff, Gram, and acid-fast bacillus stains were negative for microorganisms. Refractile material was not evident under polariscopic examination. The microscopic differential diagnosis included infections, factitial panniculitis, subcutaneous Sweet syndrome, pancreatic fat necrosis, and α1-antitrypsin deficiency panniculitis (A1ADP).
Levels of antineutrophil cytoplasmic antibodies (p-ANCA, c-ANCA), C3, C4, and CH50 were normal. Cryoglobulins were not detected. Complete blood cell count and amylase and lipase levels were normal. Erythrocyte sedimentation rate was
elevated (52 mm/h).
Serum α1-antitrypsin level was 37.0 mg/dL (reference range, 84–218 mg/dL) with a ZZ phenotype. Results of a chest radiograph, liver function tests, and pulmonary function tests were normal. Given the clinical and pathologic findings and the results from the genetic α1 phenotyping, α1-antitrypsin deficiency was diagnosed. The patient, treated with dapsone, improved dramatically.
Comment
α1-Antitrypsin, a polypeptide glycoprotein synthesized by hepatocytes, inhibits collagenase, elastase, factor VIII, chymotrypsin, and kallikrein.1 α1-Antitrypsin is an acute-phase reactant that increases in serum concentration with stress from illness or trauma. Protease activation in the absence of α1-antitrypsin may trigger a cascade of inflammatory events that ultimately damage the tissues they are
meant to protect.2 Speculation is that absence of α1-antitrypsin allows inflammation to continue unabated and thus leads to panniculitis.
α1-Antitrypsin deficiency most frequently causes severe and rapidly progressive panacinar emphysema. This deficiency also is associated with hepatitis, cirrhosis,
vasculitis, acquired angioedema, Marshall syndrome, and severe psoriasis.4 Recently, α1-antitrypsin deficiency was used as a model for conformational
diseases (including liver cirrhosis) and neurodegenerative disorders (including Alzheimer disease and spongiform encephalopathies).5
Serum concentration of α1-antitrypsin is determined by inheritance of autosomal codominant alleles—M, S, and Z being the most common.6 Most cases of A1ADP occur in individuals with a severe homozygous deficiency (ZZ phenotype).3
Ninety-five percent of the US population shares the normal protease inhibitor MM phenotype designated type M. SZ heterozygotes have one third of the normal inhibitor level and a relatively low risk of developing emphysema.6 Prevalence of
the SZ phenotype ranges from 1 in 180 to 1 in 2500 individuals, depending on geographic location.7 Type Z, an α1-antitrypsin variant, differs from the M protein by a single amino acid substitution (lysine for glutamic acid).1 This substitution
results in a changed conformation leading to inhibition of α1-antitrypsin release from hepatocytes and decreased serum levels in patients with the protease inhibitor ZZ phenotype. Homozygous deficiency occurs in about 1 in 2500 individuals; heterozygous deficiency occurs in about 1 in 50.