Severe deficiency of alpha1-antitrypsin associated with cutaneous vasculitis, rapidly progressive glomerulonephritis, and colitis

CASE REPORTS

Severe Deficiency of Alpha,-Antitrypsin Associated with Cutaneous Vasculitis, Rapidly Progressive Glomerulonephritis, and Colitis MICHAEL LEWIS, M.B.B.Ch., F.C.P.(S.A.)* JEREMY KALLENBACH, M.B.B.Ch., M.R.C.P. MATHEW ZALTZMAN, M.B.B.Ch., F.C.P.(S.A.) HOWARD LEVY, M.B.B.Ch. DAVID LURIE, M.B.B.Ch. ROY BAYNES, M.B.B.Ch. PETER KING, M.B.B.Ch., M.R.C.Path. ANTHONY MEYERS, M.B.B.Ch., F.C.P.(S.A.) Johannesburg,

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The association of vasculitis with severe deficiency of alpha,antitrypsin is rare. This report describes a 44-year-old man with severe deficiency of alpha,-antitrypsin associated with diffuse vasculitis involving skin, kidney (rapidly progressive glomerulonephrltis), and colon (colitis). Colitis has not previously been reported In association with deficiency of alpha,-antitrypsin. Other reported cases are reviewed and the possible immunologic mechanisms underlying the association are discussed. Severe deficiency of the protease inhibitor alpha,-antitrypsin is clearly associated with the development of panlobular emphysema and various hepatic disorders [ 11. Its association with cutaneous vasculitis [2] and glomerulonephritis [3,4], however, has been only sporadically reported. We describe a 44-year-old man with alpha,-antitrypsin deficiency (phenotype PiZZ) associated with severe emphysema in whom disseminated vasculitis involving skin, kidney (crescentic glomerulonephritis), and colon developed. Colitis has not been previously reported in association with alpha,-antitrypsin deficiency. CASE REPORT Emphysema associated with alpha,-antitrypsin deficiency (phenotype PiZZ) was first diagnosed in 44-year-old man in 1978. The serum level of alpha,

antitrypsin was 50 mg/dl (normal 200 to 400 mg/dl). He had smoked heavily for 23 years (40 cigarettes per day). Chest radiography showed hyperinflation,

From the Department of Medicine, Johannesburg Hospital and University of the Witwatersrand, and the Department of Anatomic Pathology, School of Pathology, Johannesburg, South Africa. Manuscript accepted July 6, 1964. Current address and address for reprint requests: Cii of Hope National Medical Center, Department of Respiratory Diseases, 1500 East Duane Road, Duane, California 91010. l

and pulmonary function tests confirmed the presence of severe airflow limitation with arterial hypoxia (one-second forced expiratory volume = 0.85 liter, one-second forced expiratory volume/forced vital capacity ratio = 40 percent, arterial oxygen tension = 58 mm Hg). Apart from albuterol (by inhalation), he took no other regular medications. The patient was relatively well until February 1982 when he was admitted to the Johannesburg Hospital with arthralgia, myalgia, watery diarrhea (which subsequently became bloody), and a hemorrhagic rash on the extremities. Skin biopsy showed evidence of leukocytoclastic vasculitis with bullae and epidermal necrosis (Figure 1). lmmunofluorescence showed granular deposits of IgG, IgM, C3, and fibrinogen within the walls of the small dermal vessels. Sigmoidoscopy revealed the presence of inflamed friable mucosa, and a barium enema performed two weeks later showed features of nonspecific colitis. Colonoscopy performed after eight weeks revealed granular friable mucosa in the transverse and descending colon and the recta-sigmoid region. Random biopsy specimens showed no specific abnormality. Relevant laboratory investigations at the time of admission demonstrated a hemoglobin level of 16.6 g/dl, a white blood cell count of 23,400/mm3, and a platelet count of 461,000/mm3. The differential count showed 71 percent neutrophils, 13 percent lymphocytes, 7 percent monocytes, and 9 percent

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Figure 1. Skin showing leukocflociastic vasculitis in the dermis {hematoxylin and eosin stain; original magnification X 198, reduced by 30 percent).

eosinophils. Subsequent serial differential counts showed predominant neutrophilia with no eosinophilia. The Westergren erylhrocyte sedimentation rate was 33 mm per hour. The prothrombin index was 71 percent and the partial thromboplastin time was 37 seconds (control 38 seconds). The blood urea nitrogen level was mildly elevated with a normal serum creatinine level (urea nitrogen = 29 mg/dl; creatinine = 1 mg/dl), thought to be explicable on the basis of gastrointestinal bleeding. A 24-hour collection of urine contained 0.1 g/liter of protein and a normal urinary sediment. Antinuclear antibody was present in the serum (titer 1:80), but rheumatoid factor, LE cells, anti-DNA antibodies, and cryoglobulins were absent. Serum levels of total complement, C3, and C4 were normal. Extensive microbiologic studies of blood, urine, and stool revealed no bacteria or parasites. Results of all serologic studies of viruses, fungi, rickettsiae, brucella, typhoid, yersinia, and schistosomiasis were negative. Hepatitis B surface antigen was not detected in the serum. After a protracted course requiring multiple blood transfusions because of continual bleeding from the large bowel, the patient eventually showed improvement following the administration of high-dose corficosteroids and sulfasalazine. He was discharged from the hospital receiving prednisone 40 mg daily and sulfasalazine 1.5 g daily. The patient remained relatively well and returned to work. One year later, he was readmitted to the hospital because of deteriorating renal function (which had been noted over the previous three months) and the development of new erythematous papular lesions of the extremities. The blood urea nitrogen level was 64.3 mg/dl with a serum creatinine level of 3.6 mg/dl. The urine contained 2-I protein with a red blood

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cell count of 675,00O/ml and numerous granular casts. Antinuclear antibodies were not present in the serum, and serum levels of total complement, C3, and C4 were normal. Levels of immune complexes measured in fresh serum on two separate occasions were markedly elevated (40 and 371 pug/ml; normal less than 7.76 pg/ml; Clq binding assay). Skin biopsy again showed leukocytoclastic vasculitis. lmmunofluorescence showed granular deposits of IgG, C3, and fibrinogen in the walls of the dermal blood vessels. The prednisone dosage was increased to 60 mg per day. The patient appeared to have a clinical response to the increased dosage and was discharged following a fortnight stay in the hospital. He was readmitted after three days with hypotension and respiratory failure due to extensive pneumonic consolidation of the right lung. Despite mechanical ventilation, broad-spectrum antibiotics, plasma infusion, and inotropic therapy, he died a few hours after admission. Autopsy Findings. Kidneys: The kidneys appeared normal macroscopically. Multiple histologic sections showed the presence of epithelial crescents occurring in approximately 97 percent of the glomeruli (Figure 2). Many of the glomerular capillaries contained fibrin thrombi (Figure 3). In some areas, complete global sclerosis as well as normal basement membranes were noted. No immune deposits were seen. Evidence of leukocytoclastic vasculitis was found in one area of the renal pelvis, the appearance being similar to that seen in the skin biopsy specimens the previous year (Figure 4). lmmunofluorescence studies showed no immunoglobulins, complement, or fibrinogen. Large bowel: Macroscopic inspection revealed scattered small areas of thickened bowel wall in the descending

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Figure 2. Glomerulus showing epithelial crescent formation (hematoxylin and eosin stain; original magnification X 330, reduced by 30 percent).

Figure 3. Glomerulus with fibrin exudation in capillaries and into Bowman’s space (hematoxylin and eosin stain; original magnification X 330, reduced by 30 percent). colon, the changes being maximal at the recta-sigmoid junction and in the rectum. Histologic sections of these areas showed inflammatory changes in the arterioles and small muscular arteries. The vascular lumina were occluded by organizing fibrin-platelet thrombi. The walls of the vessels as well as the perivascular connective tissue were infiltrated by lymphocytes, histiocytes, and a few eosinophils (Figure

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5). Results of immunofluorescence studies of the colon were negative. The histologic appearances were thought to be consistent with healing vasculitis. Lungs: Bronchopneumonic consolidation was evident throughout the right lung. Histologic sections revealed the presence of invasive aspergillosis. A whole left lung section showed the presence of panlobular emphysema.

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Figure 4. Arteriole in renal pelvis showing leukocytoclastic vasculitis (hemotoxylin and eosin stain; original magnification X 30, reduced by 30 percent).

Figure 5. Colon showing organizing thrombus in submucosal arteriole with associated inflammatory infiltrate (hematoxylin and eosin stain; original magnification X 13 7, reduced by 30 percent).

Liver: Sections of the liver demonstrated normal hapatic architecture. The hepatocytes contained periodic acidSchiff-positive and diastase-resistant intracytoplasmic globules. Transmission electron microscopy showed the presence of moderately electron-dense material in the dilated endoplasmic reticulum and large, moderately electron-dense globules in the cytoplasm consistent with the ultrastructural 6). findings in alpha,-antitrypsin deficiency (Figure

The association of severe deficiency of alpha,-antitrypsin with renal disease has been rarely reported. In 1969, Miller and Kuschner [4] described a case of “subacute glomerulonephritis with focal glomerular necrosis,” with varying degrees of proliferative change extending to crescent formation and necrotizing angiitis

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Figure 6. Electron micrograph of liver showing intracytoplasmic globules of alpha, -antitrypsin (original magnification x 7,000, reduced by 30 percent).

(involving lungs, skeletal muscles, peri-pleural nerves, testes, kidney, and skin), in a 48-year-old man with marked deficiency of alpha,-antitrypsin (PiZZ). Moroz et al [3] reported the occurrence of membranoproliferative glomerulonephritis in three alphat-antitrypsindeficient children (PiZZ) who had died of cirrhosis. Immunofluoresence studies were performed in only one of the children and showed subendothelial deposits of alpha,-antitrypsin, immunoglobulins, and complement on the glomerular basement membranes. Membranous glomerulonephritis [5] has recently been reported in a child with cirrhosis who had a PiSZ phenotype. Immunofluorescence studies in this case, although demonstrating the presence of immunoglobulins and complement within the glomeruli, failed to show the presence of alpha,-antitrypsin. Persistent cutaneous vasculitis has recently been reported in a 2-year-old child with PiZZ phenotype and neonatal liver disease [ 21. lmmunofluorscence studies of the skin revealed the presence of alpha,-antitrypsin, October

IgG, C3, and fibrinogen within the dermal vessel walls. Generalized vasculitis involving skin, kidney, and colon and resulting in rapidly progressive (crescentic) glomerulonephritis and colitis developed in our patient with severe deficiency of alpha,-antitrypsin. The clinical and pathologic renal findings in this report compliment those of Miller and Kuschner [4], who first described the association of rapidly progressive (crescentic) glomerulonephritis with severe deficiency of alpha,antitrypsin. Colitis has not been previously reported in association with alpha,-antitrypsin deficiency. When considering the possible pathogenetic mechanisms underlying the association of alpha,antitrypsin deficiency with a generalized vasculitic illness, it is worthy to note that alpha,-antitrypsin is an important regulatory protein involved in the suppression of immunologic and inflammatory processes [6]. Recent evidence has suggested that even midly deficient phenotypes are associated with a number of immuno1995

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logic and inflammatory disorders including anterior uveitis [7], rheumatoid arthritis [8], systemic lupus erythematosus [6], and juvenile chronic polyarthritis [9]. Experimental data suggest that deficiency of the antiprotease is associated with various abnormalities in the regulation of immune and inflammatory responses. Enhanced lymphocyte responses to phytohemagglutinin have been demonstrated in patients with marked deficiency of alpha,-antitrypsin, suggesting that the enzyme normally has a role in the regulation of lymphocyte activation and transformation [lo]. Alpha,-antitrypsin may also influence the complement cascade [6] by inhibiting neutrophil protease that can activate the cascade, by a direct inhibitory action on some of the complement proteins [6], and by acting as a receptor for C3 [ 111. The enzyme may also modulate neutrophil migration by inhibiting the chemotactic factors, C3a and C5a [ 121, and it has been demonstrated that deficient patients have enhanced serum chemotactic activity [ 131. The protease inhibitor may attenuate the damaging effects of various neutrophil and macrophage enzymes. Finally, alpha,-antitrypsin may

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inhibit some aspects of coagulation and fibrinolysis [ 14,151. Thus, deficient patients may have a propensity for exaggerated immunologic and inflammatory responses. In some of the reports linking glomerulonephritis and skin lesions with severe deficiency of alphal-antitrypsin, it has been postulated that the abnormal Z protein may act as an antigen leading to the formation of circulating immune complexes, which cause damage in these areas. The finding of alphalantitrypsin in the glomeruli and skin of some described patients [2,3] supports this possibility. The presence of immunoglobulins, C3, and fibrinogen on skin immunofluorescence on two occasions and the high serum titers of circulating immune complexes support the likelihood that the vasculitis in our patient was mediated by immune mechanisms. It is possible that the abnormal alpha,-antitrypsin might either have been part of an immune complex or have predisposed to a disorder of immune regulation by virtue of its functional defect. The renal and colonic lesions were probably caused by ischemic damage associated with the vasculitis.

REFERENCES

1. MorseJO: Alpha,-antitrypsindeficiency.N EnglJ Med 1978; 299: 1099-1105. 2. BrandupF, OstergaardPA:Alpha,-antitrypsindeficiencyassociated with persistentcutaneousvasculitis.Arch Dermatol 1978; 114:921-924. 3. Moroz SP, Cutz E, Williamson Balfe J, Sass-KortsakA: Membranoproliferativeglomerulonephritis in childhood cirrhosis associated with alpha,-antitrypsin deficiency. 4.

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Pediatrics 1976; 57: 232-238. Miller F, Kuschner M: Apha,-antitrypsin deficiency, emphysema, necrotizing angiitis and glomerulonephritis. Am J Med 1969; 46: 615-623. Rodriquez-Soriano J, Fidalgo I, Camarero C, Vallo A, Oliveros R: Juvenile cirrhosis and membranous glomerulonephritis in a child with alpha,-antitrypsin deficiency Pi SZ. Acta Paediatr Stand 1978; 67; 793-796. Breit SN, Penny R: Role of protease inhibitor (a,-antitrypsin) in the regulation of immunologic and inflammatory reactions. Aust NZ J Med 1980; 10: 449-453. Brewer-ton DA, Webly M, Murphy AH, Mildord-Ward A: The antitrypsin phenotype MZ in acute anterior uveitis (letter). Lancet 1978; I: 1103. Cox DW, Huber 0: Rheumatoid arthritis and alpha,-antittypsin. Lancet 1976; I: 1216-1217.

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Arnaud P, Galbraitn RM, Faulk WP, Ansell BM: Increased frequency of the MZ phenotype of alpha, protease inhibitor in juvenile chronic polyarthritis. J Clin Invest 1977; 60: 1442-1444. Breit SN, Robinson JP, Luckhurst E, Clark P, Penny R: Immunoregulation by alpha,-antitrypsin. J Lab Clin lmmunol 1982; 7: 127-131. Landen B, Schmitt M, Dierich MP: Alpha,-antitrypsin serves as a C3 receptor molecule (abstr). Fed Proc 1979; 38: 1467. Goetzl EJ: Modulation of human neutrophil polymorphonuclear leukocyte migration by human plasma alpha globulin inhibitors and synthetic esterase inhibitors. Immunology 1975; 29: 163-174. Ward PA, Talamo RC: Deficiency of chemotactic factor inactivator in human serum with alpha,-antitrypsin deficiency. J Clin Invest 1973; 52: 516-519. Heck LW, Kaplan AP: Substrates of Hageman factor 1. lsolation and characterization of human factor Xl (PTA) and inhibition of the activated enzyme by alpha,-antitrypsin. J Exp Med 1974; 140: 1615-1630. Borsodi AD, Bradshaw RA, Rughani IK, Bruce RM: Structural and functional relationships of human antithrombin Ill and alphal-antiiin. Adv Exp Med Biil 1974; 52: 249-253.