Alpha-1-antitrypsin (AAT) is an acute phase secretory glycoprotein that inhibits neutrophil proteases like elastase and is considered as the archetype of a family of structurally related serine-protease inhibitors termed serpins. Serum AAT predominantly originates from liver and increases three to five fold during host response to tissue injury and inflammation. The AAT deficiency is unique among the protein-misfolding diseases in that it causes target organ injury by both loss-of-function and gain-of-toxic function mechanisms. Lack of its antiprotease activity is associated with premature development of pulmonary emphysema and loss-of-function due to accumulation of resultant aggregates in chronic obstructive pulmonary disease (COPD). This' in turn' markedly reduces the amount of AAT that is available to protect lungs against proteolytic attack by the enzyme neutrophil elastase. The coalescence of AAT deficiency, its reduced efficacy, and cigarette smoking or poor ventilation conditions have devastating effect on lung function. On the other hand, the accumulation of retained mutant proteins in the endoplasmic reticulum of hepatocytes in a polymerized form rather than secreted into the blood in its monomeric form is associated with chronic liver disease and predisposition to hepatocellular carcinoma (HCC) by gain- of- toxic function. Liver injury resulting from this gain-of-toxic function mechanism in which mutant AAT retained in the ER initiates a series of pathologic events, eventually culminating at liver cirrhosis and HCC. Here in this review, we underline the structural, genetic, polymorphic, biochemical and pathological advances made in the field of AAT deficiency and further comprehensively emphasize on the therapeutic interventions available for the patient.

Alpha-1-antitrypsin deficiency: Genetic variations, clinical manifestations and therapeutic interventions.

Neutrophilic panniculitis associated with alpha-1-antitrypsin deficiency (AATD) is a very rare disease. Its estimated prevalence is 1 in 1000 subjects with severe AATD (usually white individuals with a Pi*ZZ genotype). It is manifested clinically by painful recurrent ulcerating subcutaneous nodules, and characterized histologically by dense infiltrates of neutrophils in the deep dermis and connective-tissue septae, with secondary lobular panniculitis. It may be the only clinical manifestation of AATD, although it can also occur together with the classical pulmonary or hepatic manifestations of the disease. AATD-associated panniculitis is not only very rare but may also be significantly underdiagnosed. The physician managing a case of panniculitis with a clinical presentation suggestive of AATD and a compatible skin biopsy should measure serum AAT concentration and, if low, determine the AAT phenotype by isoelectric focusing. If uncertainty remains, the SERPINA1 gene should be sequenced to identify the genotype. If AATD is diagnosed, AATD testing of first-degree family members should be performed in order to take appropriate preventive and therapeutic measures, including genetic counselling, education on inheritance, risk arising from tobacco smoke, occupational exposure to pollutants and hepatotoxic substances, and the provision of information on clinical management. Cases of panniculitis in which conventional therapy with dapsone has failed may be managed with intravenous augmentative therapy using human AAT. The current manuscript addresses the fundamental concepts of the pathogenesis of AATD-associated panniculitis and describes the clinical presentation and management of cases in order to reduce underdiagnosis and improve outcomes.

Neutrophilic panniculitis associated with alpha-1-antitrypsin deficiency: an update.

https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(10)61149-X.pdf

Cutaneous larva migrans

A 38-year-old woman (bipara; C-sections in 2001 and 2007) with increasing hepatic impairment was diagnosed with alpha-1 antitrypsin deficiency (phenotype PiMZ) in 2010. She subsequently developed cirrhosis (Child C), and underwent ligation of esophageal varices in 2013. In December 2013, the patient was admitted with numerous acute, confluent, and deep ulcers affecting the entire right lower leg. Primary lesions presented as rapidly ulcerating hemorrhagic nodules. Surrounded by highly erythematous borders, the ulcers involved the entire dermis and subcutis, extending down to the fascia. They were extremely painful and branched into the subcutis like a fox's den, to a large extent undermining dermis and epidermis; only narrow bridges of skin were focally present (Figure 1). Although never described in association with alpha-1 antitrypsin deficiency, given this striking clinical picture and the considerable pain associated with it, we first thought of an exceptionally extensive case of pyoderma gangrenosum. Albeit rarely, alpha-1 antitrypsin deficiency may occasionally be associated with large ulcers [1]. There were no systemic signs suggesting an acute bacterial infection (synergistic gangrene), and the onset of symptoms was too sudden to consider B-cell lymphoma (leg type). Artifacts seemed unlikely because of the extent and acuteness of the lesions. Lab tests revealed pancytopenia and considerable impairment of hepatic function, in particular coagulation parameters (prothrombin time, activated partial thromboplastin time). Although the wound smear yielded Escherichia coli, Klebsiella pneumoniae, and Staphylococcus aureus, we interpreted this colonization as a secondary phenomenon. Histology of a hemorrhagic nodule revealed large numbers of neutrophils in the dermis and subcutis, with septa and lobules equally affected. There was no evidence of vasculitis. This type of morphology may be found both in pyoderma gangrenosum and in necrotizing panniculitis associated with alpha-1 antitrypsin deficiency [1, 2]. Given that the dominant clinical findings, to wit, hemorrhagic nodules and deep ulcers that subsequently coalesce by undermining the tissue like a fox's den, may be observed in both disorders, establishing a conclusive diagnosis posed a major challenge [3–5]. Based on the patient's underlying disease, our working diagnosis was necrotizing panniculitis associated with alpha-1 antitrypsin deficiency. However, clinical findings and histology did not unequivocally rule out “deep” pyoderma gangrenosum at that time [2, 6, 7]. In order to counter the enzyme deficiency, we initiated treatment with an alpha-1 proteinase inhibitor (Prolastin®, 60 mg/kg/week IV). Antiinflammatory therapy included the short-term use of high-dose prednisolone (initially 1,000 mg every day IV, subsequently tapered); the patient also received ampicillin and sulbactam according to antibiogram. Although this therapy resulted in reduced inflammation, the skin lesions did not significantly improve. While the formation of granulation tissue was markedly slow, residual skin was “streaming” off of the lower leg as oily-necrotic debris (Figure 2). As dressing changes were extremely painful, they

Pyoderma gangrenosum-like necrotizing panniculitis associated with alpha-1 antitrypsin deficiency: a lethal course.

Total lower lip and chin reconstruction with radial forearm free flap: A novel approach.

Panniculitis is a recognized, but rare complication of α1-antitrypsin (A1AT) deficiency Less than 60 cases have been reported, mostly in the homozygous PiZZ variant We report the case of a 55-year old woman with A1AT panniculitis associated with the heterozygous phenotype PiMS and discrete reduction of A1AT serum levels In addition, the pathophysiology of the disease, clinical and histopathological features, and current treatment possibilities are briefly reviewed

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Alpha-1-antitrypsin deficiency-associated panniculitis: a case report.

A larva migrans cutânea representa uma das dermatoses mais frequentes nos turistas que regressam de pai- ses tropicais e sub-tropicais. O agente mais frequente e a larva Ancylostoma brasiliensis que habita no intestino de caes e gatos. Os humanos sao afetados quando contatam com solo contaminado com os excrementos de animais infetados. Apresentamos o caso de uma professora, 39 anos de idade, natural e residente em Portugal que, apos regressar de ferias no Nordeste do Brasil, refere dermatose localizada a 4a prega interdigital e porcao adjacente do dorso dos pes, constituida por varias lesoes eritematosas, pruriginosas, de trajecto serpiginoso, compativeis com larva migrans cutânea. O quadro regrediu apos terapeutica com Albendazol. Devido a maior frequencia de fluxos migratorios na atualidade, as dermatoses tropicais podem tornar-se mais fre- quentes nos paises de clima temperado. Salienta-se a importância do aconselhamento dos turistas para a prevencao desta dermatose, nomeadamente atraves do uso de calcado protetor. PALAVRAS-CHAVE – Larva migrans; Ancilostoma; Dermatoses tropicais.

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Larva migrans cutânea – a propósito de um caso clínico

Cutaneous squamous cell carcinomas are malignant neoplasms derived from epidermal keratinocytes. Because of their potential risk for metastasis, they account for the majority of the deaths attributable to nonmelanoma skin cancers [1]. Squamous cell carcinomas represent about 90 % of lower lip cancers, and although their incidence is low [2−5], they are very important because of the morphological and functional aspects involved. Surgery constitutes the gold standard treatment option, allowing histologic examination of the margins [6]. Because the lips are so important for functional, aesthetic and social aspects, surgical approach to this area represents a challenge for the dermatologic surgeon. Along with curing the tumor and attaining a good aesthetic result, another essential objective is to preserve the oral sphincter function. Multiple techniques have been described in the literature and, depending on the location, size and depth of the defect, the surgeon has many options to select the best reconstructive procedure.

Hagedorn rectangular flap for lower lip squamous cell carcinoma

Potential effects of pregnancy-associated hormones, endogenous and exogenous hormones on melanocytic nevi have been known for years. A 35-year-old man presented with a 6 month history of fast and simultaneous growth of previous, multiple melanocytic nevi located on the trunk, associated with increased levels of beta-human chorionic gonadotropin derived from testicular seminoma. After radical orchiectomy and adjuvant radiotherapy the tumor marker became undetectable. Without tumor relapse or further growth or other changes in skin lesion after 3 years of follow-up. We propose that in our patient, β-HCG derived from seminoma increased the growth pattern of previous nevi, a rarely described association.

Fast and simultaneous growth of multiple melanocytic nevi associated with seminoma

Secondary intention healing is a valid option for surgical wound management, allowing for excellent results and providing a clear advantage over other techniques in selected patients. The authors report the case of a 66-year-old Caucasian man who had squamous cell carcinoma excised from the concha that healed by secondary in- tention. Some aspects of this technique are reviewed.

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Alexandra Chaveiro

Papers

Alpha-1-antitrypsin deficiency-associated panniculitis: a case report.

Larva migrans cutânea – a propósito de um caso clínico

Hagedorn rectangular flap for lower lip squamous cell carcinoma

Fast and simultaneous growth of multiple melanocytic nevi associated with seminoma

Cicatrização por segunda intenção - a propósito de um caso clínico