- Email: [email protected]
Seeing the light with celiac
Clinical Immunology 115 (2005) 236 – 239 www.elsevier.com/locate/yclim
Case Discussion
Seeing the light with celiac Carol E. Semrada, Alessio Fasanob, Antonio Picarellic, Luigi Sabbatellac, Kathleen Sullivand,T a
University of Chicago, Section of Gastroenterology, Chicago, Illinois, USA Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, M.D., USA c Department of Clinical Sciences, University La Sapienza, Rome, Italy d Division of Allergy and Immunology, Children’s Hospital of Philadelphia, USA
b
Received 15 November 2004; accepted with revision 4 February 2005 Available online 5 March 2005
Case A 26 year old young woman broke her wrist playing volleyball and was told in the emergency room that she appeared to have osteoporosis. A DEXA (dual energy X-ray absorptiometry) scan subsequently confirmed osteoporosis with a T score of 3.0. Her primary care physician obtained some additional studies which revealed a mild normocytic anemia and a normal erythrocyte sedimentation rate. She was given a prescription for iron. Several months later, she returned with fatigue and oral ulcers. She denied any other symptoms, however screening tests for celiac disease were sent as well as another blood count. IgG anti-gliadin antibodies were positive and IgG anti-endomyseal antibodies were positive. A biopsy demonstrated villous atrophy, however, the young woman refused a consultation with a dietician to provide guidance on maintaining a gluten-free diet. She felt that dietary changes were unnecessary given her lack of gastrointestinal symptoms.
Recommendations of Dr. Carol Semrad, MD Celiac disease (CD) is an inflammatory condition of the small bowel triggered by the ingestion of wheat, rye, or barley in the diet in genetically susceptible individuals [1,3,4]. It is a common genetic disease with a prevalence of about 1:250 in the United States and Europe. The alcohol-soluble fraction of wheat gluten, gliadin, and similar prolamines from rye and barley contain the toxic epitopes that trigger T-cell-mediated inflammation in the bowel. Virtually all individuals with CD T Corresponding author. E-mail address: [email protected] (K. Sullivan). 1521-6616/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clim.2005.02.002
have the HLA DQ2 or DQ8 haplotype. However, 30% of normal individuals have the DQ2 haplotype to suggest that other non-HLA genes are involved. CD most commonly presents in the first 2 years of life after wheat is introduced in the diet and in young adult life but can present at any age. The duodenum and proximal jejunum are the most affected but the entire small intestine, colon, and stomach can be involved. The severity and extent of small bowel inflammation determine the clinical presentation. Severe inflammation of much of the small bowel results in diarrhea due to malabsorptive (osmotic) and secretory mechanisms, whereas inflammation limited to the proximal duodenum and jejunum (sites of absorption of iron, calcium and folate) results in select nutrient deficiencies. Small intestinal biopsy findings suggestive of celiac disease include varying degrees of villous atrophy, crypt hyperplasia, increased intraepithelial lymphocytes, and increased lymphocytes and plasma cells in the lamina propria. However, these findings are not specific for celiac disease. Therefore, improvement on a gluten-free diet is required to confirm the diagnosis. This case exemplifies the biceberg phenomenaQ of the clinical presentation of CD in the United States. Only a small group of individuals presents with diarrhea. Most, as in this case, have no or nonspecific gastrointestinal symptoms and present with metabolic bone disease, iron deficiency anemia, skin rash (dermatitis herpetiformis), neurologic manifestations (peripheral neuropathy, ataxia, seizures), infertility, or autoimmune diseases. The anemia is refractory to iron therapy due to villous atrophy and poor iron absorption. As illustrated here, despite iron therapy, this young woman developed fatigue and oral ulcers (angular stomatitis), suggestive of worsening anemia. It is not unusual for young adults with celiac disease who participate in high impact sports, such as in this case, to
C.E. Semrad et. al. / Clinical Immunology 115 (2005) 236–239
present with fractures that lead to the discovery of osteoporosis. Metabolic bone disease is common in individuals with celiac disease [2,5,6]. About 70% have abnormal bone mineral density studies (osteopenia or osteoporosis). Serologic tests are useful to screen for celiac disease and are often the first clue to the diagnosis. This woman had positive anti-gliadin and anti-endomysial IgG antibodies to suggest celiac disease. Anti-gliadin antibodies are sensitive but not specific for celiac disease. Antiendomysial and tissue transglutaminase (the antigen recognized by endomysial antibodies) antibodies are highly specific for celiac disease but their sensitivity depends on experienced laboratory workers. The IgA subclass of antibodies is most commonly ordered, however these studies will be negative in individuals with IgA deficiency and celiac disease. In such cases, only the IgG subclass of antibodies may be positive. Although a positive antiendomysial or tissue transglutaminase antibody study supports the diagnosis of CD, small bowel biopsy remains the gold standard for diagnosis. Villous atrophy, as in this case, is a characteristic finding. The treatment for CD is a life-long strict gluten-free diet because even small amounts of gliadin (10 mg~1/8 teaspoon flour) can trigger bowel inflammation. On a gluten-free diet, intestinal villi regenerate and nutrient absorption returns to normal. This results in the resolution of gastrointestinal symptoms and anemia. Bone mineral density usually also improves on a strict gluten-free diet. However, some individuals do not recover to peak bone mass. This may be due to life-long asymptomatic disease, poor calcium absorption, and failure to reach peak bone mass or poor adherence to a strict gluten-free diet. A gluten-free diet is required for improvement in anemia, osteoporosis, and other conditions associated with celiac disease whether gastrointestinal symptoms are present or absent. A fall in serum antibodies is helpful in monitoring dietary adherence. It is easier to convince those with diarrhea or other symptoms to adhere to a strict gluten-free diet than asymptomatic individuals. Further education and the hope for a decrease in bone fracture risk should be incentive for this young woman to begin a gluten-free diet.
Recommendations of Dr. Alessio Fasano, MD Celiac disease (CD) is an immune-mediated enteropathy triggered by damage of the small intestinal mucosa caused by the gliadin fraction of wheat gluten and similar alcoholsoluble proteins (prolamines) of barley and rye in genetically susceptible subjects [1,3]. The presence of gluten in these subjects leads to self-perpetuating mucosal damage, while the elimination of gluten results in a full mucosal recovery. The clinical manifestations of CD are protean in nature and vary markedly with the age of the patient, the duration and extent of disease, and the presence of extra-intestinal pathology [1,3]. This variability is probably related to the
237
multifactorial nature of the disease whose clinical expression depends on both genetic and environmental factors. Once thought to be primarily a disease of the gastrointestinal tract, we now know that CD may present with signs and symptoms in many other organ systems [4]. The combination of osteoporosis in a pre-menopausal woman, anemia, fatigue, and aphthous ulcers is almost unique for CD. The relationship between CD and bone mass development has received considerable interest in recent years [2,5]. Defective absorption of calcium and vitamin D secondary to small intestinal mucosal damage is a wellknown complication of CD. Patients with CD may have skeletal diseases such as rickets or osteomalacia. Even more importantly, an undisputed relationship between untreated CD and osteoporosis in adult age has been shown [5]. In the past, osteoporosis was regarded as a condition affecting only adults. With the advent of accurate non-invasive methods for bone mass quantification, it has been shown that the condition has its inception during childhood and adolescence. DEXA is widely viewed as the preferred method to assess bone mineral content because of its speed, precision, and minimal radiation exposure. DEXA measures three components of body composition-bone mineral content, fat tissue mass, and lean tissue mass. DEXA bone determinations are based on a two-dimensional projection of a three-dimensional structure, and the values are a function of three skeletal parameters: the size of the bone being examined, the volume of the bone, and its mineral density. A number of studies initially demonstrated reduced bone mineral density in adults with CD, particularly in untreated cases and in those who fail to respond fully to a gluten-free diet. Both cross-sectional and longitudinal studies have also shown variable, although remarkable, improvement in bone mass in children and young adults after starting treatment with the diet [6,7]. The finding of a complete recovery of osteopenia in CD young subjects after just 1 year of a gluten-free diet is in contrast with the adult data in which recovery was infrequently achieved [8] and highlights the potential benefit of diagnosing CD before the peak bone mass is reached. A routine complete blood cell count may reveal many hematologic abnormalities in an untreated patient with CD. Anemia is the most frequent non-gastroenterological symptoms experienced by CD patients. The anemia is usually microcytic and hypochromic due to iron deficiency [9]. The diagnosis of CD can be suspected by positivity of sensitive serological tools, such as the IgA class antitransglutaminase and the antiendomysium antibodies. Despite the high sensitivity and specificity of the serologic tests, confirmation of CD diagnosis still requires a small intestinal biopsy [3]. Treatment of CD is based on the life-long exclusion of gluten-containing cereals from the diet, irrespective of the presence of gastrointestinal symptoms [1,3]. A healthy diet
238
C.E. Semrad et. al. / Clinical Immunology 115 (2005) 236–239
that includes vegetables, fruits, meats, eggs, and dairy products is perfectly safe. Meats need to be cooked without breading or gluten-containing seasonings. Alternatives to the gluten-containing grains, which can safely be used in cereals and in baking flours, include amaranth, bean flour, buckwheat (kasha), corn (maize), millet, nuts, potato, quinoa, rice, soybean, sorghum, teff, tapioca, and wild rice. In conclusion, CD is a common disorder in children as well in adults. The spectrum of clinical presentations is wide, and currently extra-intestinal manifestations (e.g. anemia or osteoporosis) are more common than the classical malabsorption symptoms. A high degree of awareness among health care professionals and a bliberalQ use of serological CD tests can help to identify many of the nonclassic cases.
Recommendations of Drs. Antonio Picarelli, MD and Luigi Sabbatella D.Sc. CD is the most common gastrointestinal autoimmune disease in the world, with an estimated prevalence of about 1:100 [1,3]. The first aspect which must be pointed out with regard to this case is the possibility that a person could have celiac disease without presenting any gastrointestinal symptom. In common clinical practice, these patients are defined as asymptomatic because of the presence of only extraintestinal signs or symptoms. These signs, such as that of this case, e.g. anemia, asthenia, oral ulcers, and osteoporosis, are not commonly considered suggestive of CD whereas, in our experience, patients presenting such symptoms should be considered symptomatic. This observation can prove useful in relation to previous classifications of CD that reported the existence of typical and atypical forms of the disease. In fact, the patient under discussion is a 26 year old woman who presented with villous atrophy and would traditionally be considered asymptomatic, even though she had osteoporosis as well as anemia. However, we would consider this patient who presented with the clinical aspects normally found in older women as strongly symptomatic. It is well known that symptoms are collected by physicians solely based on the declaration of the patients. It is common in our clinical practice to observe patients who do not declare any symptom suggestive of CD, but after a diagnosis and following a gluten-free diet the same patient declares a clear improvement and a well-being previously unknown. Therefore, we often have to consider the possibility that the patient is unaware of their symptoms. In this case report, the patient presented with villous atrophy in the absence of gastrointestinal symptoms. The patient underwent screening for CD and was found to have IgG anti-gliadin antibodies and IgG anti-endomysial antibodies (EMA). A biopsy was positive. With this knowledge, we think it is important to point out that the clinical
presentation of CD patients with EMA IgG positive is slightly different compared to that of EMA IgA positive patients, as we previously reported [10]. Normally, EMA IgG positive patients seem to be affected by a systemic pathology while EMA IgA positive patients seem to be primarily affected by gastrointestinal disease. The differences could be due to the natural characteristics of IgA and IgG themselves, the first localized and normally only mucosal, the second circulating in the blood. The patient under discussion had an unusual presentation of CD, with signs and symptoms suggestive of CD although in the absence of gastrointestinal symptoms normally considered to be the only typical signs of celiac disease. In our experience, this is typical for patients with EMA IgG positive. Furthermore, the patient presented with villous atrophy in which case CD can easily be diagnosed. It is important to highlight that often CD in patients with EMA IgG antibodies can occur without villous atrophy. In this situation, it can be useful to perform the organ culture of duodenal biopsy specimens. It has been reported that specimens from CD patients release and/or produce EMA in the culture medium that can be revealed the same as serum EMA [11,12]. This method, which is very easy to set up, seems to be extremely sensitive and together with the histological examination is helpful in the diagnostic armamentarium of CD, especially when histologic results are unclear. In conclusion, CD is no longer definable as a disease of organ pathology which only affects gastrointestinal tract, but it has to be defined as a systemic disorder with gastrointestinal specific (e.g. diarrhea, vomiting, abdominal pain) and non-gastrointestinal specific manifestations (e.g. anemia, aphthous ulcers, asthenia, osteoporosis) and autoimmune pathologies (e.g. dermatitis herpetiformis, insulindependent diabetes mellitus, thyroiditis). When physicians have to confront a situation such as this one, it is mandatory to stress the importance of starting a gluten-free diet as early as possible. This leads to an improvement in health as well as the possible prevention of further complaints.
Celiac antibodies reference guide Antibody
Positive in celiac disease
Notes
IgG endomysial antibody IgA endomysial antibody IgG gliadin antibody IgA gliadin antibody IgG tissue transglutaminase IgA tissue transglutaminase IgA reticulin
90%
May define patients with more systemic disease Decreases on gluten-free diet
90% 75% 80%
Decreases on gluten-free diet
95% 95% 60%
Not widely used
C.E. Semrad et. al. / Clinical Immunology 115 (2005) 236–239
IgA antibodies will be absent in patients who are IgA deficient. Approximately 10% of patients with celiac disease will be IgA deficient.
Discussants Carol E. Semrad, M.D. Associate Professor of Medicine University of Chicago Section of Gastroenterology Chicago, Illinois Alessio Fasano, M.D. Professor of Pediatrics, Medicine, and Physiology Director, Mucosal Biology Research Center University of Maryland School of Medicine Baltimore, MD Antonio Picarelli, MD Luigi Sabbatella, D.Sc. Dept. of Clinical Sciences University "La Sapienza", Rome. Italy
Case Report Kathleen E. Sullivan, MD PhD Division of Allergy and Immunology Children’s Hospital of Philadelphia
239
References [1] P.H.R. Green, B. Jabri, Coeliac disease, Lancet 362 (2003) 383 – 390. [2] C.E. Semrad, Bone mass and gastrointestinal disease, Ann. N. Y. Acad. Sci. 904 (2000) 564 – 570. [3] A. Fasano, C. Catassi, Current approaches to diagnosis and treatment of celiac disease: an evolving spectrum, Gastroenterology 120 (2001) 636 – 651. [4] A. Fasano, Celiac disease—How to handle a clinical chameleon, N. Engl. J. Med. 348 (2003) 2568 – 2570. [5] M.L. Bianchi, M.T. Bardella, Bone and celiac disease, Calcif. Tissue Int. 71 (2002) 465 – 471. [6] V.L. Sdepanian, C.N. de Mirunda Carvalho, M.B. de Morais, et al., Bone mineral density of the lumbar spine in children and adolescents with celiac disease on a gluten-free diet in Sao Paolo, Brazil, J. Pediatr. Gastroenterol. Nutr. 37 (2003) 571 – 576. [7] G. Barera, S. Beccio, M.C. Proverbio, S. Mora, Longitudinal changes in bone metabolism and bone mineral content in children with celiac disease during consumption of a gluten-free diet, Am. J. Clin. Nutr. 79 (2004) 148 – 154. [8] M.L. Moreno, H. Vazquez, R. Mazure, E. Smecuol, S. Niveloni, S. Pedreira, E. Sugai, E. Maurino, J.C. Gomez, J.C. Bai, Stratification of bone fracture risk in patients with celiac disease, Clin. Gastroenterol. Hepatol. 2 (2) (2004 Feb.) 127 – 134. [9] A. Carroccio, E. Iannitto, F. Cavataio, et al., Sideropenic anemia and celiac disease: one study, two points of view, Dig. Dis. Sci. 43 (1998) 673 – 678. [10] A. Picarelli, M. Di Tola, L. Sabbatella, et al., Identification of a new coeliac disease subgroup: antiendomysial and anti-transglutaminase antibodies of IgG class in the absence of selective IgA deficiency, J. Intern. Med. 249 (2001) 181 – 188. [11] A. Picarelli, L. Sabbatella, M. Di Tola, et al., Forty-eight hours of biopsy culture improve the sensitivity of the in vitro gliadin challenge in the diagnosis of celiac disease, Clin. Chem. 47 (2001) 1841 – 1843. [12] A. Carroccio, G. Iacono, D. D’Amico, et al., Production of antiendomysial antibodies in cultured duodenal mucosa: usefulness in coeliac disease diagnosis, Scand. J. Gastroenterol. 37 (2002) 32 – 38.
Case Discussion
Seeing the light with celiac Carol E. Semrada, Alessio Fasanob, Antonio Picarellic, Luigi Sabbatellac, Kathleen Sullivand,T a
University of Chicago, Section of Gastroenterology, Chicago, Illinois, USA Mucosal Biology Research Center, University of Maryland School of Medicine, Baltimore, M.D., USA c Department of Clinical Sciences, University La Sapienza, Rome, Italy d Division of Allergy and Immunology, Children’s Hospital of Philadelphia, USA
b
Received 15 November 2004; accepted with revision 4 February 2005 Available online 5 March 2005
Case A 26 year old young woman broke her wrist playing volleyball and was told in the emergency room that she appeared to have osteoporosis. A DEXA (dual energy X-ray absorptiometry) scan subsequently confirmed osteoporosis with a T score of 3.0. Her primary care physician obtained some additional studies which revealed a mild normocytic anemia and a normal erythrocyte sedimentation rate. She was given a prescription for iron. Several months later, she returned with fatigue and oral ulcers. She denied any other symptoms, however screening tests for celiac disease were sent as well as another blood count. IgG anti-gliadin antibodies were positive and IgG anti-endomyseal antibodies were positive. A biopsy demonstrated villous atrophy, however, the young woman refused a consultation with a dietician to provide guidance on maintaining a gluten-free diet. She felt that dietary changes were unnecessary given her lack of gastrointestinal symptoms.
Recommendations of Dr. Carol Semrad, MD Celiac disease (CD) is an inflammatory condition of the small bowel triggered by the ingestion of wheat, rye, or barley in the diet in genetically susceptible individuals [1,3,4]. It is a common genetic disease with a prevalence of about 1:250 in the United States and Europe. The alcohol-soluble fraction of wheat gluten, gliadin, and similar prolamines from rye and barley contain the toxic epitopes that trigger T-cell-mediated inflammation in the bowel. Virtually all individuals with CD T Corresponding author. E-mail address: [email protected] (K. Sullivan). 1521-6616/$ - see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.clim.2005.02.002
have the HLA DQ2 or DQ8 haplotype. However, 30% of normal individuals have the DQ2 haplotype to suggest that other non-HLA genes are involved. CD most commonly presents in the first 2 years of life after wheat is introduced in the diet and in young adult life but can present at any age. The duodenum and proximal jejunum are the most affected but the entire small intestine, colon, and stomach can be involved. The severity and extent of small bowel inflammation determine the clinical presentation. Severe inflammation of much of the small bowel results in diarrhea due to malabsorptive (osmotic) and secretory mechanisms, whereas inflammation limited to the proximal duodenum and jejunum (sites of absorption of iron, calcium and folate) results in select nutrient deficiencies. Small intestinal biopsy findings suggestive of celiac disease include varying degrees of villous atrophy, crypt hyperplasia, increased intraepithelial lymphocytes, and increased lymphocytes and plasma cells in the lamina propria. However, these findings are not specific for celiac disease. Therefore, improvement on a gluten-free diet is required to confirm the diagnosis. This case exemplifies the biceberg phenomenaQ of the clinical presentation of CD in the United States. Only a small group of individuals presents with diarrhea. Most, as in this case, have no or nonspecific gastrointestinal symptoms and present with metabolic bone disease, iron deficiency anemia, skin rash (dermatitis herpetiformis), neurologic manifestations (peripheral neuropathy, ataxia, seizures), infertility, or autoimmune diseases. The anemia is refractory to iron therapy due to villous atrophy and poor iron absorption. As illustrated here, despite iron therapy, this young woman developed fatigue and oral ulcers (angular stomatitis), suggestive of worsening anemia. It is not unusual for young adults with celiac disease who participate in high impact sports, such as in this case, to
C.E. Semrad et. al. / Clinical Immunology 115 (2005) 236–239
present with fractures that lead to the discovery of osteoporosis. Metabolic bone disease is common in individuals with celiac disease [2,5,6]. About 70% have abnormal bone mineral density studies (osteopenia or osteoporosis). Serologic tests are useful to screen for celiac disease and are often the first clue to the diagnosis. This woman had positive anti-gliadin and anti-endomysial IgG antibodies to suggest celiac disease. Anti-gliadin antibodies are sensitive but not specific for celiac disease. Antiendomysial and tissue transglutaminase (the antigen recognized by endomysial antibodies) antibodies are highly specific for celiac disease but their sensitivity depends on experienced laboratory workers. The IgA subclass of antibodies is most commonly ordered, however these studies will be negative in individuals with IgA deficiency and celiac disease. In such cases, only the IgG subclass of antibodies may be positive. Although a positive antiendomysial or tissue transglutaminase antibody study supports the diagnosis of CD, small bowel biopsy remains the gold standard for diagnosis. Villous atrophy, as in this case, is a characteristic finding. The treatment for CD is a life-long strict gluten-free diet because even small amounts of gliadin (10 mg~1/8 teaspoon flour) can trigger bowel inflammation. On a gluten-free diet, intestinal villi regenerate and nutrient absorption returns to normal. This results in the resolution of gastrointestinal symptoms and anemia. Bone mineral density usually also improves on a strict gluten-free diet. However, some individuals do not recover to peak bone mass. This may be due to life-long asymptomatic disease, poor calcium absorption, and failure to reach peak bone mass or poor adherence to a strict gluten-free diet. A gluten-free diet is required for improvement in anemia, osteoporosis, and other conditions associated with celiac disease whether gastrointestinal symptoms are present or absent. A fall in serum antibodies is helpful in monitoring dietary adherence. It is easier to convince those with diarrhea or other symptoms to adhere to a strict gluten-free diet than asymptomatic individuals. Further education and the hope for a decrease in bone fracture risk should be incentive for this young woman to begin a gluten-free diet.
Recommendations of Dr. Alessio Fasano, MD Celiac disease (CD) is an immune-mediated enteropathy triggered by damage of the small intestinal mucosa caused by the gliadin fraction of wheat gluten and similar alcoholsoluble proteins (prolamines) of barley and rye in genetically susceptible subjects [1,3]. The presence of gluten in these subjects leads to self-perpetuating mucosal damage, while the elimination of gluten results in a full mucosal recovery. The clinical manifestations of CD are protean in nature and vary markedly with the age of the patient, the duration and extent of disease, and the presence of extra-intestinal pathology [1,3]. This variability is probably related to the
237
multifactorial nature of the disease whose clinical expression depends on both genetic and environmental factors. Once thought to be primarily a disease of the gastrointestinal tract, we now know that CD may present with signs and symptoms in many other organ systems [4]. The combination of osteoporosis in a pre-menopausal woman, anemia, fatigue, and aphthous ulcers is almost unique for CD. The relationship between CD and bone mass development has received considerable interest in recent years [2,5]. Defective absorption of calcium and vitamin D secondary to small intestinal mucosal damage is a wellknown complication of CD. Patients with CD may have skeletal diseases such as rickets or osteomalacia. Even more importantly, an undisputed relationship between untreated CD and osteoporosis in adult age has been shown [5]. In the past, osteoporosis was regarded as a condition affecting only adults. With the advent of accurate non-invasive methods for bone mass quantification, it has been shown that the condition has its inception during childhood and adolescence. DEXA is widely viewed as the preferred method to assess bone mineral content because of its speed, precision, and minimal radiation exposure. DEXA measures three components of body composition-bone mineral content, fat tissue mass, and lean tissue mass. DEXA bone determinations are based on a two-dimensional projection of a three-dimensional structure, and the values are a function of three skeletal parameters: the size of the bone being examined, the volume of the bone, and its mineral density. A number of studies initially demonstrated reduced bone mineral density in adults with CD, particularly in untreated cases and in those who fail to respond fully to a gluten-free diet. Both cross-sectional and longitudinal studies have also shown variable, although remarkable, improvement in bone mass in children and young adults after starting treatment with the diet [6,7]. The finding of a complete recovery of osteopenia in CD young subjects after just 1 year of a gluten-free diet is in contrast with the adult data in which recovery was infrequently achieved [8] and highlights the potential benefit of diagnosing CD before the peak bone mass is reached. A routine complete blood cell count may reveal many hematologic abnormalities in an untreated patient with CD. Anemia is the most frequent non-gastroenterological symptoms experienced by CD patients. The anemia is usually microcytic and hypochromic due to iron deficiency [9]. The diagnosis of CD can be suspected by positivity of sensitive serological tools, such as the IgA class antitransglutaminase and the antiendomysium antibodies. Despite the high sensitivity and specificity of the serologic tests, confirmation of CD diagnosis still requires a small intestinal biopsy [3]. Treatment of CD is based on the life-long exclusion of gluten-containing cereals from the diet, irrespective of the presence of gastrointestinal symptoms [1,3]. A healthy diet
238
C.E. Semrad et. al. / Clinical Immunology 115 (2005) 236–239
that includes vegetables, fruits, meats, eggs, and dairy products is perfectly safe. Meats need to be cooked without breading or gluten-containing seasonings. Alternatives to the gluten-containing grains, which can safely be used in cereals and in baking flours, include amaranth, bean flour, buckwheat (kasha), corn (maize), millet, nuts, potato, quinoa, rice, soybean, sorghum, teff, tapioca, and wild rice. In conclusion, CD is a common disorder in children as well in adults. The spectrum of clinical presentations is wide, and currently extra-intestinal manifestations (e.g. anemia or osteoporosis) are more common than the classical malabsorption symptoms. A high degree of awareness among health care professionals and a bliberalQ use of serological CD tests can help to identify many of the nonclassic cases.
Recommendations of Drs. Antonio Picarelli, MD and Luigi Sabbatella D.Sc. CD is the most common gastrointestinal autoimmune disease in the world, with an estimated prevalence of about 1:100 [1,3]. The first aspect which must be pointed out with regard to this case is the possibility that a person could have celiac disease without presenting any gastrointestinal symptom. In common clinical practice, these patients are defined as asymptomatic because of the presence of only extraintestinal signs or symptoms. These signs, such as that of this case, e.g. anemia, asthenia, oral ulcers, and osteoporosis, are not commonly considered suggestive of CD whereas, in our experience, patients presenting such symptoms should be considered symptomatic. This observation can prove useful in relation to previous classifications of CD that reported the existence of typical and atypical forms of the disease. In fact, the patient under discussion is a 26 year old woman who presented with villous atrophy and would traditionally be considered asymptomatic, even though she had osteoporosis as well as anemia. However, we would consider this patient who presented with the clinical aspects normally found in older women as strongly symptomatic. It is well known that symptoms are collected by physicians solely based on the declaration of the patients. It is common in our clinical practice to observe patients who do not declare any symptom suggestive of CD, but after a diagnosis and following a gluten-free diet the same patient declares a clear improvement and a well-being previously unknown. Therefore, we often have to consider the possibility that the patient is unaware of their symptoms. In this case report, the patient presented with villous atrophy in the absence of gastrointestinal symptoms. The patient underwent screening for CD and was found to have IgG anti-gliadin antibodies and IgG anti-endomysial antibodies (EMA). A biopsy was positive. With this knowledge, we think it is important to point out that the clinical
presentation of CD patients with EMA IgG positive is slightly different compared to that of EMA IgA positive patients, as we previously reported [10]. Normally, EMA IgG positive patients seem to be affected by a systemic pathology while EMA IgA positive patients seem to be primarily affected by gastrointestinal disease. The differences could be due to the natural characteristics of IgA and IgG themselves, the first localized and normally only mucosal, the second circulating in the blood. The patient under discussion had an unusual presentation of CD, with signs and symptoms suggestive of CD although in the absence of gastrointestinal symptoms normally considered to be the only typical signs of celiac disease. In our experience, this is typical for patients with EMA IgG positive. Furthermore, the patient presented with villous atrophy in which case CD can easily be diagnosed. It is important to highlight that often CD in patients with EMA IgG antibodies can occur without villous atrophy. In this situation, it can be useful to perform the organ culture of duodenal biopsy specimens. It has been reported that specimens from CD patients release and/or produce EMA in the culture medium that can be revealed the same as serum EMA [11,12]. This method, which is very easy to set up, seems to be extremely sensitive and together with the histological examination is helpful in the diagnostic armamentarium of CD, especially when histologic results are unclear. In conclusion, CD is no longer definable as a disease of organ pathology which only affects gastrointestinal tract, but it has to be defined as a systemic disorder with gastrointestinal specific (e.g. diarrhea, vomiting, abdominal pain) and non-gastrointestinal specific manifestations (e.g. anemia, aphthous ulcers, asthenia, osteoporosis) and autoimmune pathologies (e.g. dermatitis herpetiformis, insulindependent diabetes mellitus, thyroiditis). When physicians have to confront a situation such as this one, it is mandatory to stress the importance of starting a gluten-free diet as early as possible. This leads to an improvement in health as well as the possible prevention of further complaints.
Celiac antibodies reference guide Antibody
Positive in celiac disease
Notes
IgG endomysial antibody IgA endomysial antibody IgG gliadin antibody IgA gliadin antibody IgG tissue transglutaminase IgA tissue transglutaminase IgA reticulin
90%
May define patients with more systemic disease Decreases on gluten-free diet
90% 75% 80%
Decreases on gluten-free diet
95% 95% 60%
Not widely used
C.E. Semrad et. al. / Clinical Immunology 115 (2005) 236–239
IgA antibodies will be absent in patients who are IgA deficient. Approximately 10% of patients with celiac disease will be IgA deficient.
Discussants Carol E. Semrad, M.D. Associate Professor of Medicine University of Chicago Section of Gastroenterology Chicago, Illinois Alessio Fasano, M.D. Professor of Pediatrics, Medicine, and Physiology Director, Mucosal Biology Research Center University of Maryland School of Medicine Baltimore, MD Antonio Picarelli, MD Luigi Sabbatella, D.Sc. Dept. of Clinical Sciences University "La Sapienza", Rome. Italy
Case Report Kathleen E. Sullivan, MD PhD Division of Allergy and Immunology Children’s Hospital of Philadelphia
239
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