148 DERMATOLOGY, VENEREOLOGY Zdrav Vestn |May – June 2025 | Volume 94 | https://doi.org/10.6016/ZdravVestn.3587 Copyright (c) 2025 Slovenian Medical Journal. This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License. Alpha-1 antitrypsin deficiency-associated panniculitis: a case report Panikulitis pri pomanjkanju alfa-1 antitripsina: prikaz primera Špela But, 1 Maja Jerše, 2 Pij Bogomir Marko 3 Abstract Alpha-1 antitrypsin deficiency is a hereditary disorder with predominantly pulmonary but also extrapulmonary manifes- tations. In the skin, it is associated with panniculitis, a necrotizing neutrophilic inflammation in the subcutis. Clinically, it presents with tender, erythematous, oedematous, recurrent, and potentially ulcerative nodules, most often located on the extremities or the trunk. The entity is often unrecognized, though it can greatly affect the patient’s quality of life and is poten- tially lethal. Clinical suspicion is supported by deep-skin biopsy, the concentration of alpha-1 antitrypsin in the serum, and electrophoresis, or, if possible, by genotype or phenotype characterization. Currently, the most widely accepted treatment options include dapsone, doxycycline, and augmentation therapy. We report a case of a young Caucasian man with alpha-1 antitrypsin deficiency that manifested with recurring and extremely painful nodules on his legs and gluteal area. The diagno- sis was established based on the patient’s history, a low serum level of alpha-1 antitrypsin, and the findings of the deep-skin biopsy, which were suggestive of neutrophilic panniculitis. Total remission was achieved with dapsone, and the therapy was well-tolerated. Izvleček Pomanjkanje encima alfa-1 antitripsina je dedna bolezen, ki največkrat prizadene pljuča, jetra, redkeje pa kožo, kjer pa se izrazi kot panikulitis. Panikulitis je nekrotizirajoče nevtrofilno vnetje podkožnega maščevja. Kaže se z bolečimi, eritemastimi in edemastimi vozliči na udih in trupu, ki se pogosto ponavljajo ter lahko ulcerirajo. Bolezen se pogosto spregleda oziroma se prepozna prepozno, čeprav pomembno vpliva na kakovost bolnikovega življenja in je lahko smrtna. Pri postavitvi diagnoze so v pomoč: histopatološki izvid globoke biopsije kože, določanje koncentracije alfa-1-antitripsina v serumu, elektroforeza serumskih beljakovin in genotipizacija ter fenotipizacija. Možnosti zdravljenja vključujejo: dapson, doksiciklin in intraven- sko nadomeščanje alfa-1-antitripsina. S kliničnim primerom predstavljamo mladega moškega s panikulitisom in znanim po- manjkanjem alfa-1-antitripsina. Diagnozo smo potrdili z znižano koncentracijo alfa-1-antitripsina v serumu in nevtrofilnim panikulitisom v patohistološki preiskavi biopta kože. Po uvedbi dapsona pa je prišlo do popolne remisije bolezni. 1 Department of Dermatovenereology, University Medical Centre Ljubljana, Ljubljana, Slovenia 2 Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia 3 Department of Dermatology and Venereal Diseases, University Medical Centre Maribor, Maribor, Slovenia Correspondence / Korespondenca: Špela But, e: spela.but@gmail.com Keywords: panniculitis; neutrophilic panniculitis; alpha-1 antitrypsin; alpha-1 antitrypsin deficiency; dapsone Ključne besede: panikulitis; nevtrofilni panikulitis; alfa-1 antitripsin; pomanjkanje alfa-1 antitripsina; dapson Received / Prispelo: 25. 11. 2024 | Accepted / Sprejeto: 25. 4. 2025 Cite as / Citirajte kot: But Š, Jerše M, Marko PB. Alpha-1 antitrypsin deficiency-associated panniculitis: a case report. Zdrav Vestn. 2025;94(5–6):148–54. DOI: https://doi.org/10.6016/ZdravVestn.3587 eng slo element en article-lang 10.6016/ZdravVestn.3587 doi 25.11.2024 date-received 25.4.2025 date-accepted Dermatology, venereology Dermatologija, venereologija discipline Case report Klinični primer article-type Alpha-1 antitrypsin deficiency-associated panniculitis: a case report Panikulitis pri pomanjkanju alfa-1 antitripsina: prikaz primera article-title Alpha-1 antitrypsin deficiency-associated panniculitis Panikulitis pri pomanjkanju alfa-1 antitripsina alt-title panniculitis, neutrophilic panniculitis, alpha-1 antitrypsin, alpha-1 antitrypsin deficiency, dapsone panikulitis, nevtrofilni panikulitis, alfa-1 anti- tripsin, pomanjkanje alfa-1 antitripsina, dapson kwd-group The authors declare that there are no conflicts of interest present. Avtorji so izjavili, da ne obstajajo nobeni konkurenčni interesi. conflict year volume first month last month first page last page 2025 94 5 6 148 154 name surname aff email Špela But Špela But 1 email name surname aff Maja Jerše 2 Marko Marko 3 eng slo aff-id Department of Dermatovenereology, University Medical Centre Ljubljana, Ljubljana, Slovenia Dermatovenerološka klinika, Univerzitetni klinični center Ljubljana, Ljubljana, Slovenija 1 Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia Inštitut za Patologijo, Medicinska fakulteta, Univerza v Ljubljani, Ljubljana, Slovenija 2 Department of Dermatology and Venereal Diseases, University Medical Centre Maribor, Maribor, Slovenia Oddelek za kožne in spolne bolezni, Univerzitetni klinični center Maribor, Maribor, Slovenija 3 Slovenian Medical Journal Slovenian Medical Journal 149 CASE REPORT Alpha-1 antitrypsin deficiency-associated panniculitis: a case report 1 Introduction Panniculitis is an inflammation of the subcutaneous fat that presents non-specifically through various disor- ders (1). It is also a rare extrapulmonary manifestation of alpha-1 antitrypsin (AAT) deficiency (AATD). Pan- niculitis in AATD is estimated to affect 1 in 1000 indi- viduals (2), although the actual prevalence remains un- known as it is often misdiagnosed (3,4). Epidemiological characteristics include European ancestry and female gender, with the condition most frequently occurring in the fourth decade of life (4-6). In general, panniculitis develops spontaneously and is less commonly triggered by trauma or iatrogenic procedures (2,4). Clinically, it presents with tender, red, oedematous, and potentially ulcerative subcutaneous nodules with oily discharge. The nodules often recur and predominantly appear on the extremities, though the abdomen, trunk, gluteal ar- ea, and face can also be affected (3,4,6,7). In the initial stages, skin lesions can mimic cellulitis and may later heal with atrophic scars (6,7). Histopathologically, pan- niculitis in AATD is neutrophilic. For a correct diag- nosis, the distribution of the inflammatory infiltrate, potential septal thickening, and especially the type of fat necrosis need to be evaluated. The characteristic features include “floating fat” and neutrophil splaying (2,8). The biopsy findings should be considered in con- junction with the patient’s clinical picture, history, and analytical data (6,7). Timely diagnosis is crucial, while improper management can be potentially life-threaten- ing (9). 2 Case report A 34-year-old Caucasian man presented with a 5 x 3 cm indurated, tender, dry, and non-fluctuating oede- ma in the left popliteal fossa. It was circumscribed by a 10 x 6 mm erythematous area and mimicked celluli- tis (Figure 1). In addition, multiple tender, erythema- tous nodules appeared on the medial side of the right thigh and calf (Figure 2), as well as on the soles of both feet (Figure 3). The skin lesions developed simultane- ously, acutely, and spontaneously without prior ma- nipulation, injury, or insect bites to the affected sites. No systemic symptoms were present. Over the past six months, the patient has experienced several outbreaks of similar skin lesions on the lower extremities, some- times accompanied by oral ulcers. He did not have any prescribed medications and was allergic to naproxen. His medical history revealed that he has AATD (PiZZ genotype) with known liver damage (liver steatosis). First, deep vein thrombosis was ruled out with Doppler Ultrasonography. Then, based on the clinical picture and patient’s history, AATD-associated panniculitis was suspected. While waiting for the laboratory and histopathologic results, the patient was started on doxycycline for three weeks. However, the response to the treatment was not satisfactory, as new nodules began to appear alongside the existing ones. These new nodules developed in the Figure 1: Cellulitis-like oedema in the left popliteal fossa. Source: archive of the Department of Dermatology and Venereal Diseases, University Medical Centre Maribor. 150 DERMATOLOGY, VENEREOLOGY Zdrav Vestn | May – June 2025 | Volume 94 | https://doi.org/10.6016/ZdravVestn.3587 left gluteal region and were so painful that the patient had trouble sitting, significantly affecting his quality of life. The blood analysis showed a decreased concentration of AAT in the serum (0,29 g/L) and a reduced alpha-1 globin band on protein electrophoresis (2,5%), alongside lymphocytopenia (14,7%), an elevated concentration of CRP in the serum (41 mg/L), and a high sedimentation rate (34 mm/h). All other markers in the extensive lab- oratory panel (complete blood count with differential, biochemical markers of kidney and liver function, elec- trolytes, lipids, most common tumour markers, specific antibody tests, urinalysis), including the concentration of glucose-6-phosphatase in the serum, were within the normal range. The deep skin biopsy revealed extensive lobular and focally septal panniculitis with the replace- ment of fat lobules by dense neutrophilic infiltration in the subcutis. Additionally, focal necrosis admixed with lymphocytes, eosinophilic granulocytes, neutro- phils, histiocytes, and some lipophages, accompanied by collagenolysis and elastolysis were observed. The lesion was relatively sharply delineated and even jux- taposed with areas of relatively normal fat (Figures 4 and 5). There was also no evidence of leukocytoclastic vasculitis. In the next step, direct immunofluorescence (DIF) was performed. DIF revealed granular deposits of complement component 3 (C3) at the dermo-epider- mal junction and in the vessel walls of the subcutaneous layer. Only a few globules of immunoglobulin (Ig) A, IgG, and IgM were identified in the papillary dermis, and dense deposits of fibrin/fibrinogen were found in Figure 2: Tender, erythematous nodule on the medial and posterior side of the right calf. Source: archive of the Department of Dermatology and Venereal Diseases, University Medical Centre Maribor. Figure 3: Tender, erythematous nodule on the sole of the right foot. Source: archive of the Department of Dermatology and Venereal Diseases, University Medical Centre Maribor. 151 CASE REPORT Alpha-1 antitrypsin deficiency-associated panniculitis: a case report the vessel walls of the superficial layer of the dermis. The histopathologic findings suggested neutrophilic panniculitis, while erythema nodosum, pancreatic, and possibly infective panniculitis were considered in the differential diagnosis. DIF excluded potential vasculitis or autoimmune disease. Based on the clinical picture, patient history, and low serum AAT levels, the diagnosis of AATD-associated panniculitis was established. Then, considering the unsatisfactory response to doxycycline, the patient was administered a gradu- ally increasing dose of dapsone. Total remission was achieved with a maximum daily dose of 100 mg after two months of treatment. Following careful monitoring of the clinical picture, potential side effects, and labo- ratory marker values, dapsone was gradually decreased and discontinued six months after initiation. No re- gression was observed throughout this period, and the treatment was well-tolerated by the patient. 3 Discussion AATD is a genetic disorder of autosomal codomi- nant inheritance, primarily manifesting as a disease of the lungs, liver, and, rarely, the skin or blood vessels. It is characterized by decreased levels of AAT protein in the serum. AAT is an enzyme, a serine protease inhib- itor, with a crucial role in protecting tissues from pro- teolytic damage (2-4). It is primarily synthesized in the liver and, to a lesser extent, in the lungs, colon, pancre- as (3,5), and cornea (5). After being secreted into the serum, the enzyme is distributed throughout the body. AAT is most recognized for neutralizing neutrophil elastase in the lungs, although it also inhibits several other proteases, such as trypsin, proteinase-3, pancre- atic elastase, thrombin, plasmin, etc. (2,3). Additional- ly, it has been identified as relevant in modulating the Figure 4: Deep skin biopsy with lobular panniculitis of the subcutis and adipose tissue (A). The affected fat lobules are necrotic, replaced with an intense neutrophilic infiltrate admixed with lymphocytes, eosinophilic granulocytes, neutrophils, histiocytes, and some lipophages (B - the composition of the infiltrate in higher magnification). Typical histopathological features of vasculitis are absent (C - the vessel wall without neutrophils and inflammation) (hematoxylin-eosin, original magnification x4). Source: archive of the Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. Legend: * It must be taken into account that the most prevalent manifestations are pulmonary, followed by liver disease. Affected organ Clinical manifestation Lungs COPD, emphysema, bronchiectasis Liver Cirrhosis, cholestasis, hepatocarcinoma Skin Panniculitis Blood vessels Systemic vasculitis, aneurysms Table 1: *Most common clinical manifestations of alpha-1 antitrypsin deficiency (2-4,10). 152 DERMATOLOGY, VENEREOLOGY Zdrav Vestn | May – June 2025 | Volume 94 | https://doi.org/10.6016/ZdravVestn.3587 Figure 5: Weigert-Van Gieson staining, based on the affinity towards elastic fibers, better visualized the presence of collagenolysis and elastolysis, with “floating fat” separated from the reticular dermis (Weigert-Van Gieson, original magnification x10). Source: archive of the Institute of Pathology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. activity of certain immune cells (2) and pro-inflamma- tory cytokines, such as interleukin-8, tumour necrosis factor-α, and leukotriene B4 (4). AATD is caused by mutations in the SERPINA1 gene, which codes for the AAT protein. These mutations result in the production of dysfunctional AAT, predis- posing individuals to the development of several diseas- es (Table 1). Most commonly, antiprotease insufficien- cy manifests as a lung disease. The unopposed action of neutrophil elastase, an enzyme that degrades elastin and other components of connective tissue, can result in emphysema, early-onset chronic obstructive pulmo- nary disease, and even bronchiectasis. The accumu- lation of the defective enzyme in the liver may lead to neonatal cholestasis, cirrhosis in children or adults, and even hepatocarcinoma in adults (2-4). Due to its po- tential role in accelerating the degradation of the aortic wall, AATD has also been linked to systemic c-ANCA (anti-neutrophil cytoplasmic antibody) vasculitis and aneurysmal disease (10). The disorder has also been associated with panniculitis, although the exact patho- physiology remains unclear. Presumably, the lack of the enzyme’s protective functions promotes an exaggerated neutrophilic response and increased proteolytic damage to the subcutis (2,4). One of the hypothesized mecha- nisms includes the role of the complement system, as some evidence suggests that the degradation product of C3 is increased in AAT-deficient individuals (4). AAT deficiency may also be associated with other cutane- ous disorders, including psoriasis, chronic urticaria, acquired angioedema (3,7), prurigo nodularis, atopic dermatitis, and Marshall’s syndrome (7). However, the underlying mechanisms are not proven (3,7). 153 CASE REPORT Alpha-1 antitrypsin deficiency-associated panniculitis: a case report The clinical manifestation of AATD depends on the individual’s genotype and the concentration of the af- fected enzyme in the serum. Panniculitis is particularly common in individuals with the most severely deficient genotype PiZZ, characterized by markedly decreased levels of AAT (1,4). In such individuals, the serum con- centration of AAT is usually below 0.5 g/L, whereas it normally ranges from 1 to 2.0 g/L (2-4,6). Panniculitis can be the sole manifestation of AATD, or it develops alongside other associated pulmonary or hepatic condi- tions. Most frequently, it occurs in individuals without a previous diagnosis of AATD, whereas prior pulmonary or liver dysfunction has been documented in almost a third or 10% of cases respectively (4). However, the pa- tient’s age at presentation and smoking status must al- so be considered. In addition, Elsensohn et al. reported panniculitis as part of a systemic illness, along with ana- sarca, pulmonary embolus, and hypogammaglobulin- emia (11). Clinical suspicion of AATD-associated panniculitis is supported by deep-skin biopsy and complemented by the serum concentration of AAT or protein electropho- resis (12). The histopathological features of panniculitis in AATD include predominantly lobular inflammation of the subcutaneous fat, accompanied by fat necrosis and dense neutrophilic infiltration, which is typical of neu- trophilic panniculitis (1,4,8). Neutrophilic panniculitis is a heterogeneous group of inflammatory and infectious skin disorders. The differential diagnosis is wide and in- cludes pancreatic panniculitis, infective panniculitis, subcutaneous Sweet syndrome, panniculitis associated with rheumatoid arthritis, erythema induratum, and er- ythema nodosum. The characteristic histologic findings of AATD-associated panniculitis are collagenolysis and elastolysis, which lead to the development of “floating fat” that is detached from the adjacent reticular dermis and septa. One of the diagnostic hints of early-stage dis- ease is also the identification of neutrophils dispersed among collagen bundles of the deep reticular dermis (2,4,8). Furthermore, while primary vasculitis is not ob- served in AATD-associated panniculitis (2), secondary leukocytoclastic vasculitis has been reported, although it is not a typical feature of the disease. In such cases, DIF showed vascular deposits of C3 and IgM in the der- mal layer (2,4,7). Nevertheless, the findings of deep-skin biopsy are not diagnostic and can be quite variable. The correct diagnosis should be established based on clinical and laboratory data, most commonly the serum concen- tration of AAT (6,7). Still, AAT is an acute-phase reac- tant, much like C-reactive protein (CRP), and hence, its levels could be augmented during acute inflammation (2,3). The likelihood of a falsely negative result, meaning a normal AAT value in the serum, could be overcome by simultaneous quantification of CRP and AAT. In ad- dition, the reduction or absence of the AAT (alpha-1 globulin) band in electrophoresis may be helpful (7), although it is no longer commonly used (12). Ultimate- ly, phenotype or genotype characterization is preferred (4,12). Once the diagnosis of AATD-associated panniculitis is established, the entity must be managed appropriately, as the outcome can be potentially lethal (9). Over the years, various types of drugs and their combinations have been tested in pursuit of the best management strategy. Currently, most clinicians administer dapsone as a first- line treatment (4,5). It is usually administered orally in daily doses of 50-100 mg and remains the most proven, readily available, and affordable treatment. According to a systematic review, dapsone achieves clinical remis- sion in 62% of cases. However, patients may not tolerate it well due to its side effects (5). Before administering dapsone, it is imperative to exclude glucose-6-phosphate dehydrogenase deficiency to avoid haemolytic anaemia (4). Furthermore, tetracyclines, typically doxycycline, could also be effective as monotherapy, with tetracy- clines reportedly achieving clinical remission in 33% of cases (5). Hence, they might be a reasonable option of- fered as an adjuvant to the first-line or as a second-line treatment (4,5). Finally, the most effective treatment for AATD-associated panniculitis proves to be augmen- tation therapy. The intravenous administration of hu- man-purified AAT was reported to reach total remission in 100% of cases (5). IV-AAT is safe and well-tolerated (2), although it is rather costly, as repeated intermittent or maintenance administration may be required (5). In practice, augmentation therapy is usually used when dapsone, with or without doxycycline, fails to achieve satisfactory remission (2,4,5). Additionally, panniculitis remains an off-label indication for IV-AAT (4). Alter- native treatment options include liver transplantation and plasma exchange (5,7). Furthermore, there has been some contradictory evidence regarding the effectiveness of colchicine (13), whereas most antibiotics, immuno- suppressants, non-steroidal anti-inflammatory drugs, and conservative therapy all failed to elicit a satisfactory response. All in all, further scientific evidence and de- tailed research into disease pathophysiology are needed to establish better cost-effective treatments (2,4,5). In conclusion, a major limitation of our report is that it presents a single case, making generalization to a broader population difficult, if not impossible. Nev- ertheless, we believe it highlights a potential diagnostic 154 DERMATOLOGY, VENEREOLOGY Zdrav Vestn | May – June 2025 | Volume 94 | https://doi.org/10.6016/ZdravVestn.3587 and management approach for such patients, though the strategy should be tailored to each patient individually. Furthermore, patients diagnosed with AATD should be closely monitored for associated conditions, particularly pulmonary and liver manifestations. More detailed rec- ommendations on diagnostic algorithms and treatment can be found in the literature (14). 4 Conclusion AATD-associated panniculitis is rare and often mis- diagnosed, although proper management remains cru- cial, even lifesaving. The diagnosis should be established considering the clinical picture, the biopsy findings, and analytical data. It could be demanding to suspect the dis- ease even in patients with previously recognized AATD. However, it should be kept in mind that panniculitis can also be the first clinical manifestation of the disorder. Had this been the case with our patient, the appropriate diagnosis would have most likely been established com- paratively later, unfortunately at the cost of the patient’s physical and mental well-being. Everything considered, we hope that this case report raises awareness and aids clinicians in reaching a timely diagnosis should they ev- er encounter panniculitis in AATD. Ethics approval and consent to participate The authors complied with the ethical requirements of their institutions. Consent for publication Written informed consent for publication of this case report and any accompanying images was obtained from the patient. Conflict of interest None declared. Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Acknowledgements Not applicable. References 1. Wick MR. Panniculitis: A summary. Semin Diagn Pathol. 2017;34(3):261- 72. DOI: 10.1053/j.semdp.2016.12.004 PMID: 28129926 2. American Thoracic Society; European Respiratory SocietyAmerican Thoracic Society/European Respiratory Society statement: standards for the diagnosis and management of individuals with alpha-1 antitrypsin deficiency. 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