Alpha-1 antitrypsin deficiency panniculitis

What is alpha-1 antitrypsin deficiency disease?

Alpha-1 antitrypsin is a serine protease inhibitor. Alpha-1 antitrypsin deficiency disease is an inherited metabolic disorder in which this protein is absent or defective.

Alpha-1 antitrypsin deficiency disease most often presents as lung disease (emphysema) or gastrointestinal disease (liver cirrhosis) It can also rarely affect the skin.

Alpha-1 antitrypsin deficiency is abbreviated as A1AD.

What is it panniculitis?

Panniculitis refers to a group of disorders that cause inflammation of the subcutaneous adipose tissue (the fat under the skin).

Panniculitis due to alpha-1 antitrypsin deficiency is rare.

* Image courtesy of Genetics 4 Medics

Who gets alpha-1 antitrypsin deficiency panniculitis?

Alpha-1-antitrypsin deficiency is more predominant in Caucasians of European and North American descent.

Men and women of any age are equally affected by panniculitis associated with alpha-1 antitrypsin deficiency, and it may rarely arise in children.

Since alpha-1-antitrypsin deficiency is not correctly diagnosed, the true predominance of panniculitis due to alpha-1-antitrypsin deficiency is difficult to determine. One study reported that panniculitis affected 0.9% of ZZ homozygotes for alpha-1-antitrypsin deficiency.

Panniculitis may be preceded by trauma. This is because an injury causes greater activation of the protease and a cascade of inflammatory events aimed at healing the wound.

What causes alpha-1 antitrypsin deficiency?

Genetics

Alpha-1-antitrypsin deficiency is usually due to a mutation in chromosome 14)

Alpha-1-antitrypsin deficiency is a autosomal co-dominant disorder, meaning that two different versions (alleles) of a gene They are expressed in an individual. Each allele makes a slightly different protein. Both alleles influence the characteristics and severity of the deficiency disease.

There are more than 90 known mutant alleles of the alpha-1-antitrypsin gene, and they are classified based on their acidic starch. gel mobility (F = fast, M = medium, S = slow, Z = very slow). A normal level of a variant enzyme with altered activity it can also cause clinical disease.

the genotype (of a person genetic makeup) and its combination of these genes Determine the degree of the deficiency. The normal genotype is “MM” has a normal level of alpha-1-antitrypsin. Patients with two “ZZ” genes (homozygous) have an 85% alpha-1-antitrypsin deficiency. This type is the most commonly associated with emphysema.

Pathogenesis

Alpha-1-antitrypsin is produced primarily in the liver and regulates several proteolytic enzymes including trypsin, elastase, chymotrypsin, factor VIII, collagenase and kallikrein. Lack of alpha-1 antitrypsin leads to increased activity of these enzymes and located Destruction of tissues.

What are the clinical features of alpha-1 antitrypsin deficiency?

Alpha one antitrypsin deficiency leads to inflammation and necrosis in various organs

Lung disease

• Alpha-1-antitrypsin generally protects the lungs from elastase enzymes produced by neutrophils.
• When alpha 1 antitrypsin is deficient, elastase enzymes can damage and scar lung tissue that causes emphysema.
• Asthma, bronchiectasis and chronic obstructive pulmonary Illnesses are also more frequent.
• Lung disease is much more severe in smokers than in non-smokers with alpha-1 antitrypsin deficiency.

Liver disease

• The abnormal alpha-1-antitrypsin protein builds up inside liver cells (hepatocytes) and can cause hepatitis.
• Hepatitis may present with a swollen abdomen, leg edema or jaundice.
• Liver disease is accelerated by drinking alcohol.
• Later, cirrhosis (scarring of the liver) occurs.
• This increases the risk of hepatocellular carcinoma.

Pancreatic disease

• Elastase is a pancreatic enzyme.
• Increased elastase due to alpha-1-antitrypsin deficiency can cause chronic pancreatitis.
• Chronic pancreatitis leads to steatorrhea, malabsorption, vitamin deficiency (A, D, E, K, B₁₂), diabetes and weight loss.

kidney disease

• Membranoproliferative glomerulonephritis

Panniculitis

In alpha-1-antitrypsin deficiency disease:

• Panniculitis is due to unopposed enzyme action and breakdown of proteins within the skin.

• Initially erythematous plates and nodules develop in the trunk or proximal extremities
• The nodules can be extended on the legs, arms, trunk or face.
• The nodules may ulcerate, bleed, and leak oily material.
• The patient may be febrile.

Panniculitis associated with alpha-1-antitrypsin deficiency does not improve with antibiotics or systemic steroids

How is alpha-1-antitrypsin deficiency and associated panniculitis diagnosed?

Diagnosis of alpha-1-antitrypsin deficiency

Alpha-1-antitrypsin deficiency disease may be suspected by clinical features, especially emphysema, chronic hepatitis, and liquefaction panniculitis. Various tests may be arranged to confirm the diagnosis.

Serum alpha-1-antitrypsin levels

• Serum alpha-1-antitrypsin levels can confirm whether a patient is deficient or not.
• Note that alpha-1-antitrypsin can be misleadingly elevated during an inflammatory state, as it is a acute protein phase.

Alpha-1-antitrypsin phenotype and genotyping

• If the disease is highly suspicious and alpha-1-antitrypsin levels are normal, an iso-electrophoretic mobility study (alpha-1-antitrypsin phenotype) may be useful.
• Genotyping can detect abnormal alleles in an individual.

Respiratory investigations

• Lung function tests can help determine if emphysema is present.
• Chest x-ray may show characteristic lung changes (emphysema at the lung bases).
• High resolution Connecticut Scanning (HRCT) can help identify basal emphysema and bronchiectasis

Diagnosis of panniculitis associated with alpha-1-antitrypsin deficiency

Blood test

• Inflammatory markers (erythrocytes sedimentation rate and C-reactive protein) may be elevated.
• Antinuclear antibodies and rheumatoid factor may be present in low titers.
• Chronic disease can cause normocytosis anemia and hypoalbuminemia.

Skin biopsy

Skin biopsy of panniculitis should include deep adipose tissue. Specific characteristics of alpha-1-antitrypsin deficiency panniculitis in histopathology include:

• Predominantly lobar inflammation, with some septal involvement and extensive tissue destruction.
• In early disease, neutrophils infiltrate Between collagen packages in the lattice dermis.
• The collagen in the dermis gradually dissolves and the epidermis can be liquefied
• Spread of neutrophils may progress to involve fibrous septa and lobules of subcutaneous fat.
• In later stages, histiocytes and lipophages are seen, sometimes with giant cell accumulation.
• Leukocytoclastic and lymphocytic vasculitis can arise in areas of dense inflammation, as well as in phlebothrombosis and hemorrhage.
• Skip areas of normal fat next to necrotic Areas of fat may be a feature.
• The areas heal with fibrosis and sometimes dystrophic calcification.
• Direct immunofluorescence can detect intravascular deposits of complement C3 and IgM in the dermis of uncertain significance.

What is the treatment for alpha-1-antitrypsin deficiency and its associated panniculitis?

General measures

• Avoid trauma and surgery to the area if possible.
• It is essential to avoid smoking and alcohol.
• Avoid occupational exposures that may increase the risk of respiratory tract illnesses (e.g., mining, construction work)
• Annual influenza vaccination is recommended.

Oral medications

• Tetracycline antibiotics (doxycycline, minocycline) may be effective for mild panniculitis. It is believed that the anticollagenase activity of tetracyclines may help restore the balance between protease and antiprotease enzymes.

• Dapsone and colchicine can reduce the inflammation associated with panniculitis.

Systemic corticosteroids, antimalarials, immunosuppressants, and danazol are ineffective in alpha-1-antitrypsin deficiency disease.

Enzyme replacement therapy.

Enzyme replacement therapy with exogenous Alpha-1 antitrypsin concentrate (Prolastin®) infused intravenously has been reported to be effective. The recommended starting dose of 60 mg/kg once a week can be adjusted according to response. The required dose and duration of treatment vary according to case reports. Its use may be limited by high cost and limited availability.

Other measures

• Plasma to exchange
• Genetically modified alpha-1-antitrypsin
• Organ transplant (lungs/liver) for patients with advanced disease

What is the result of alpha-1-antitrypsin deficiency and its associated panniculitis?

the forecast and the life expectancy of a patient with alpha-1 antitrypsin deficiency depends on the phenotype, the level of enzyme deficiency, and associated factors. hepatic and lung damage.

Complete resolution of panniculitis associated with alpha-1-antitrypsin deficiency has been described within four weeks of treatment with enzyme replacement therapy. It may recur, in which case indefinite treatment may be necessary.

Chronic ulceration can complicate associated panniculitis, and when the areas finally heal they can form atrophic scars