Macroamylasemia attributable to gluten-related amylase autoantibodies: A case report
Macroamylasemia attributable to gluten-related amylase autoantibodies: A case report
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DOI：
10.1542/peds.107.6.e93
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发表时间：
2001-06-01
期刊：
影响因子：
8
通讯作者：
Bosi, E
中科院分区：
文献类型：
--
作者：
Barera, G;Bazzigaluppi, E;Bosi, E
背景。大淀粉酶血症（MA）是一种良性疾病，由胰腺或唾液淀粉酶与血浆蛋白结合的循环大淀粉酶复合物引起，不能被肾小球清除。在大多数情况下，大分子淀粉酶是正常淀粉酶和免疫球蛋白a或G的复合物，可能是一种特异性抗原-抗体复合物。乳糜泻（CD）是一种对摄入谷蛋白的永久性不耐受，导致免疫介导的小肠黏膜炎症损伤。最近几项以人群为基础的血清学调查显示，乳糜泻是一种常见的疾病，在大多数被研究的国家，可能每200至250人中就有1人患有乳糜泻，包括美国，在那里显性乳糜泻很少见，这表明亚临床疾病的比例很高。乳糜泻的诊断目前取决于小肠特征性病变的组织学表现以及随后对引入无谷蛋白饮食的临床反应。与乳糜泻相关的MA已在成人患者中得到描述，在少数情况下，在严格的无麸质饮食后，MA减少或消失。儿童时期曾有少数MA病例，但至今未见与乳糜泻相关的报道。我们报告了一个患有乳糜泻，自身免疫性甲状腺炎和MA的女孩，其中乳糜泻相关的淀粉酶抗体和外分泌胰腺组织抗体通过无麸质饮食得到解决。病例报告。一个11岁的女孩被转介慢性腹痛和生长迟缓与持续性高淀粉酶血症和疑似慢性胰腺炎。我们证实血清淀粉酶升高，血清脂肪酶正常，24小时尿淀粉酶和淀粉酶清除率/肌酐清除率非常低，与MA一致。乳糜泻血清学检查呈阳性，小肠活检显示绒毛大部萎缩，证实了诊断。甲状腺功能检查显示明显的甲状腺功能减退，伴有高滴度的甲状腺微粒体抗体和甲状腺球蛋白抗体。其他自身抗体的筛查，包括抗核抗体、胰岛细胞抗体、谷氨酸脱羧酶、蛋白酪氨酸磷酸酶胰岛抗原512抗体、肾上腺抗体和细胞质中性粒细胞抗体，均为阴性。诊断为CD， MA和甲状腺功能减退可归因于自身免疫性甲状腺炎。临床改善后开始无麸质饮食和口服l -甲状腺素替代。血清淀粉酶和淀粉酶清除率/肌酐清除率正常化，与MA的消退一致。研究设计与方法。患者的血清样本在乳糜泻诊断时以及在实行无麸质饮食后3个月和12个月获得。10名连续未治疗的乳糜泻儿童的血清样本作为疾病对照，39名无胃肠道症状和无乳糜泻家族史的参与者作为健康对照。通过与循环免疫球蛋白的淀粉酶复合物测定MA的来源，在与蛋白A Sepharose或聚乙二醇沉淀免疫复合物后，通过测量上清上的淀粉酶来测试。淀粉酶活性沉淀bbb60 %与MA的存在一致。以猪淀粉酶为抗原，采用新开发的酶联免疫吸附法（ELISA）检测血清中对淀粉酶的免疫球蛋白G （IgG）和免疫球蛋白A （IgA）循环抗体。结果以任意单位（AUs）表示。对未配对数据采用Student’st检验进行统计分析。采用间接免疫荧光法在人胰腺冷冻切片上检测外分泌胰腺组织IgA和IgG抗体。蛋白A Sepharose或聚乙二醇的血清免疫沉淀使淀粉酶活性从1698降至89 U/L（94.8%）和75 U/L(95.6%)，在对照血清样品中仅略有降低。在诊断为乳糜泻的患者血清样本中，ELISA检测到高值的自身淀粉酶抗体IgA （3531 AU）和IgG （1855 AU）。健康对照组IgA自身抗体（平均+/-标准差）为3.4 +/- 2.5 AU，乳糜泻对照组为2.1 +/- 1.2 AU；健康对照组IgG自身抗体分别为10 +/- 4.8 AU和8.5 +/- 3.2 AU。在诊断为乳糜泻时，患者血清中有针对外分泌胰腺组织的自身抗体，包括IgA和IgG，但对照组中没有。在酶联免疫吸附试验（ELISA）中，患者血清中α -淀粉酶过量预孵育特异性抑制抗体与包被淀粉酶的结合，部分抑制外分泌胰腺的免疫反应性。无麸质饮食后，乳糜泻患者的α -淀粉酶和外分泌胰腺自身抗体下降。在儿童中很少有MA病例被描述，在所有病例中，淀粉酶测定是腹痛或创伤的临床研究的一部分。我们描述了第一例小儿病例报告MA与乳糜泻和自身免疫性甲状腺炎。外分泌胰腺组织自身免疫与乳糜泻的关系是有趣的。乳糜泻常与胰岛细胞自身免疫和临床1型糖尿病有关。在我们的病例中，内分泌胰腺似乎不受自身免疫过程的影响，因为我们无法证明胰岛细胞和胰岛特异性自身抗体。胰腺自身免疫与乳糜泻之间的关系是由停药后乳糜泻和胰腺自身抗体的平行下降和消失所提示的。这些发现与越来越多的人认识到自身抗体是乳糜泻的一种表现以及无谷蛋白饮食治疗后这些抗体的消退是一致的。乳糜泻中MA的形成机制和淀粉酶结合抗体的产生位点一直不明确，只能假设。可能在肠道水平，与谷蛋白相关抗原或其他抗原发生交叉反应，导致胰腺血清淀粉酶的自身抗体形成。然而，我们的研究结果表明乳糜泻和乳糜泻之间存在相关性，因为无麸质饮食的建立解决了这一问题。由于乳糜泻可能无症状且未确诊，我们建议对MA患者进行筛查。
Background. Macroamylasemia (MA) is a benign condition caused by circulating macroamylase complexes of pancreatic or salivary amylase bound to plasma proteins, which cannot be cleared by the renal glomeruli. In most cases, the macromolecular amylase represents a complex of normal amylase and either immunoglobulin A or G and may be a specific antigen-antibody complex. Celiac disease (CD) is a permanent intolerance to ingested gluten that results in immunologically mediated inflammatory damage of the small intestinal mucosa. Several recent population-based serologic surveys have shown CD to be a common disorder, possibly affecting 1 in 200 to 250 individuals in most countries studied, including the United States, where overt CD is rare, indicating a high proportion of subclinical disease. The diagnosis of CD currently rests on the histological demonstration of the characteristic lesion in the small intestine and the subsequent clinical response to the introduction of a gluten-free diet. MA associated with CD has been described in adult patients, and in a few cases, MA decreased or resolved after a strict gluten-free diet. A few single cases of MA have been described in childhood, but no association with CD has been reported so far. We report a girl with CD, autoimmune thyroiditis, and MA, in whom CD-related antibodies to amylase and to exocrine pancreas tissue resolved with a gluten-free diet.Case Report. An 11-year-old girl was referred for chronic abdominal pain and growth retardation associated with persistent hyperamylasemia and suspected chronic pancreatitis. We confirmed elevated serum amylase, normal serum lipase, and very low 24-hour urine amylase and amylase clearance/creatinine clearance ratio, consistent with MA. Serologic tests for CD were positive, and the diagnosis was confirmed by small bowel biopsy showing subtotal villous atrophy. Thyroid function tests showed a pronounced hypothyroidism, associated with high titers of thyroid microsomal and thyroglobulin antibodies. Screening for other autoantibodies-including antinuclear, islet cell, glutamic acid decarboxylase, protein tyrosine phosphatase islet antigen 512, adrenal gland, and cytoplasmic neutrophil granulocyte antibodies-was negative. A diagnosis of CD, MA, and hypothyroidism attributable to autoimmune thyroiditis was made. A gluten-free diet and oral replacement with L-thyroxine was started with clinical improvement. Serum amylase and amylase clearance/creatinine clearance ratio normalized, consistent with resolution of MA.Study Design and Methods. The patient's serum samples were obtained at the time of CD diagnosis and at 3 and 12 months after instituting a gluten-free diet. Serum samples from 10 consecutive untreated celiac children were disease controls, and 39 participants with no gastrointestinal symptoms and no family history of CD served as healthy controls. The origin of MA as determined by complexes of amylase with circulating immunoglobulins was tested by the measurement of amylase on supernatants after precipitation of immune complexes with either protein A Sepharose or polyethylene glycol. The precipitation of >60% of amylase activity was consistent with the presence of MA. Immunoglobulin G (IgG) and immunoglobulin A (IgA) circulating autoantibodies to amylase were measured using recently developed enzyme-linked immunosorbent assay (ELISA), using porcine amylase as antigen. Results were expressed as arbitrary units (AUs). Statistical analysis was performed by Student's t test for unpaired data. IgA and IgG antibodies to exocrine pancreas tissue were detected by indirect immunofluorescence on human pancreas cryosections.Results. Serum immunoprecipitation with either protein A Sepharose or polyethylene glycol reduced amylase activity from 1698 to 89 U/L (94.8%) and to 75 U/L (95.6%), with only marginal reduction in control serum samples. The ELISA for autoantibodies to amylase detected high values, both IgA (3531 AU) and IgG (1855 AU), in the serum sample from the patient at CD diagnosis. IgA autoantibodies (mean +/- standard deviation) were 3.4 +/- 2.5 AU in healthy controls, and 2.1 +/- 1.2 AU in celiac controls; IgG autoantibodies were 10 +/- 4.8 AU in healthy controls and 8.5 +/- 3.2 AU, respectively. Autoantibodies to exocrine pancreas tissue were documented in patient sera at the time of CD diagnosis, both IgA and IgG, but not in control groups. Preincubation of patient's serum with excess of alpha -amylase specifically inhibited antibody binding to coated amylase in the ELISA, and partially inhibited immunoreactivity to exocrine pancreas. Autoantibodies to alpha -amylase and to exocrine pancreas declined in CD patients after institution of a gluten-free diet.Conclusions. Few cases of MA have been described in children, and in all amylase determination was part of the clinical investigation for abdominal pain or trauma. We describe the first pediatric case report of MA associated with CD and autoimmune thyroiditis. The association of autoimmunity to exocrine pancreas tissue with CD is intriguing. CD is frequently found in association with pancreatic islet cell autoimmunity and with clinical type 1 diabetes. In our case, endocrine pancreas seemed to be spared by the autoimmune process, because we could not demonstrate islet cell and islet-specific autoantibodies. A relationship of pancreatic autoimmunity and CD is suggested by the parallel decline and disappearance of both CD and pancreas autoantibodies after gluten withdrawal. These finding are consistent with the increasing recognition of autoantibodies as a manifestation of CD and regression of these antibodies with treatment of a gluten-free diet. The mechanisms underlying the formation of MA in CD and the site of production of amylase-binding antibodies have been poorly defined and can only be hypothesized. It is possible that at the intestinal level, crossreactivity either with gluten-related or other antigens occurs, resulting in autoantibody formation to pancreas serum amylase. Nevertheless, our findings suggest a correlation between CD and MA, because it resolved with institution of a gluten-free diet. Because CD may be silent and undiagnosed, we suggest screening for the disease in patients with MA.