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PEDIATRICS Vol. 107 No. 6 June 2001, p. e93

ELECTRONIC ARTICLE:
Macroamylasemia Attributable to Gluten-Related Amylase Autoantibodies: A Case Report

Received Jul 3, 2000; accepted Jan 17, 2001.

Graziano Barera*, Elena BazzigaluppiDagger , Matteo Viscardi*, Federica Renzetti*, Cesare Bianchi*, Giuseppe Chiumello*, and Emanuele BosiDagger

From the Departments of * Pediatrics and Dagger  Medicine, Scientific Institute H San Raffaele, University of Milan, Milan, Italy.

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.  Key words:  childhood, celiac disease, thyroiditis, antiendomysium antibodies, antitransglutaminase antibodies, autoantigens, enzyme-immunoglobulin complex.