Celiac Disease: Clinical Perspective Dig Dis 2015;33:147–154 DOI: 10.1159/000369541
Extraintestinal Manifestations of Celiac Disease María Inés Pinto-Sánchez a Premysl Bercik a Elena F. Verdu a Julio C. Bai b, c a
Farncombe Family Digestive Health Institute, McMaster University, Hamilton, Ont., Canada; b Gastroenterology, Universidad del Salvador, and c Dr. Carlos Bonorino Udaondo Gastroenterology Hospital, Buenos Aires, Argentina
Abstract Case finding for celiac disease (CD) is becoming increasingly common practice and is conducted in a wide range of clinical situations ranging from the presence of gastrointestinal symptoms to failure to thrive in children, prolonged fatigue, unexpected weight loss and anemia. Case finding is also performed in associated conditions, such as autoimmune thyroid disease, dermatitis herpetiformis and type 1 diabetes, as well as in patients with irritable bowel syndrome, unexplained neuropsychiatric disorders and first-degree relatives of patients with diagnosed CD. This aggressive active case finding has dramatically changed the clinical characteristics of newly diagnosed patients. For instance, higher numbers of patients who present with extraintestinal symptoms are now being diagnosed with CD. Current recommendations state that due to a high risk for complications if the disease remains undiagnosed, patients with extraintestinal symptoms due to CD require appropriate diagnosis and treatment. Despite criticism regarding the cost-effectiveness of case finding in CD, such an aggressive approach has been considered cost-effective for high-risk patients. The diagnosis of CD among patients with extraintestinal symptoms re-
© 2015 S. Karger AG, Basel 0257–2753/15/0332–0147$39.50/0 E-Mail [email protected] www.karger.com/ddi
quires a high degree of awareness of the clinical conditions that carry a high risk for underlying CD. Also, understanding the correct use of specific serology and duodenal histology is key for an appropriate diagnostic approach. Both procedures combined are able to confirm diagnosis in the vast majority of cases. However, in certain circumstances, serology and even duodenal histology cannot confirm or rule out CD. A common cause of negative IgA serology is IgA deficiency. For such eventuality, IgG-based serological tests can help confirm the diagnosis. Importantly, some histologically diagnosed cases still remain seronegative despite exclusion of IgA deficiency. On the other hand, duodenal histology may be normal despite the presence of CD-specific antibodies and active CD. This has been clearly demonstrated in some cases of untreated dermatitis herpetiformis, but may also be due to the patchy condition of CD or lesions that are not adequately recognized by nonexpert endoscopists and/or pathologists. The effectiveness of agluten-free diet depends on the clinical end point addressed. A good example is the outcome of bone loss. While risk for fracture normalizes after the first year of dietary treatment, bone parameters measured by densitometry may not be normalized in the long-term follow-up. Moreover, it is still unclear how far an early glutenfree diet will positively affect associated autoimmune diseases like type 1 diabetes and autoimmune thyroiditis. © 2015 S. Karger AG, Basel
Prof. Julio C. Bai Dr. Carlos Bonorino Udaondo Gastroenterology Hospital Av. Caseros 2061 Buenos Aires 1264 (Argentina) E-Mail jbai @ intramed.net
Downloaded by: NYU Medical Center Library 128.122.253.212 - 5/13/2015 2:30:18 AM
Key Words Celiac disease · Extraintestinal manifestations · Diagnosis
The ‘Oslo consensus’ has recently defined celiac disease (CD) as a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals [1]. Traditionally, patients with CD presented with malabsorption dominated by diarrhea, steatorrhea, weight loss or failure to thrive (‘classical CD’). However, the proportion of newly diagnosed patients with malabsorptive symptoms has decreased over time, and CD with ‘non-classical’ and even asymptomatic presentation is gaining prominence [2]. The current awareness of CD complications in combination with the advent of highly sensitive and specific serological tests has dramatically increased the identification of patients among subjects having a higher risk for the disorder [3]. Case finding is now becoming more common and is conducted in a wide range of clinical situations ranging from the presence of gastrointestinal symptoms (diarrhea, abdominal pain and distension), failure to thrive in children [4, 5], prolonged fatigue [6], unexpected weight loss, recurrent aphthous stomatitis, anemia [7], increased liver transaminases [8] and unexplained neuropsychiatric disorder [9]. Case finding is also recommended in conditions that associate with CD such as autoimmune thyroid disease, dermatitis herpetiformis (DH) and type 1 diabetes [7], and in patients with irritable bowel syndrome associated with diarrhea and first-degree relatives of celiacs [10, 11]. This aggressive active case finding introduced in the last decades has dramatically changed the clinical characteristics of newly diagnosed patients. In such context, increasing numbers of CD patients are now diagnosed who present with an extraintestinal phenotype and a diversity of symptoms affecting many different systems. The present review aims to analyze the most common extraintestinal manifestations of CD and proposes an appropriate diagnostic workup. We also discuss the effect of the gluten-free diet (GFD) on these extraintestinal manifestations of CD.
Hematologic Manifestations of CD
CD is a common systemic disorder that can present with multiple hematologic manifestations prior to receiving a diagnosis of CD [12]. Iron deficiency anemia (IDA) without other clinical clues of intestinal malabsorption, is one of the most common extraintestinal manifestations of the disorder being encountered in around 50% of pa148
Dig Dis 2015;33:147–154 DOI: 10.1159/000369541
tients with subclinical phenotype [13]. This is considered the most frequent extraintestinal feature of the condition [14]. Evidence suggests that IDA, as the leading symptom, is more frequent in adults than in children [13, 14], and it is usually due to either increased iron loss or impaired absorption of iron, folate or vitamin B12, although occult blood loss from the gastrointestinal tract may occur [13, 15]. Bergamaschi et al. [16] have suggested that anemia of chronic diseases is due to immune activation and defective production of endogenous erythropoietin in a significant proportion of patients at presentation. The treatment of anemia associated with CD is primarily a GFD. Iron supplementation is usually indicated for the treatment of IDA associated with CD until the iron stores have been restored, which could take up to 2 years [12]. Thrombocytosis is also frequently seen in CD, occurring in up to 60% of patients [12, 17, 18]. The presence of inflammatory mediators, iron deficiency and hyposplenism have all been proposed as contributing factors [12]. The thrombocytopenia associated with CD usually improves with specific treatment [12, 17]. Defective splenic function affects more than one third of adult patients with symptomatic CD, and it may predispose to a higher risk of infections by encapsulated bacteria and thromboembolic and autoimmune complications [19]. The prevalence of hyposplenism increases from 19% in CD to 80% in CD with premalignant or malignant complications, and it is associated with a poor prognosis factor in CD [19, 20]. However, the evaluation of splenic function is not considered as a regular procedure in the clinical management of patients with noncomplicated CD, and in patients with a high degree of hyposplenism or splenic atrophy the prophylactic immunization with specific vaccines against the polysaccharide antigens of encapsulated bacteria remains controversial [19]. As demonstrated by Corazza et al. [20], the splenic hypofunction measured by pitted cells improves at least partially in some CD patients and even reverts to normal after 3–12 months of GFD. IgA deficiency is the most common primary immunodeficiency in Caucasians that is strongly overrepresented among patients with CD accounting for ∼5% (CD) [12, 21]. The importance of the association is due to the fact that IgA-deficient individuals are prone to other enteric conditions such as inflammatory bowel disease or chronic parasite infections, especially giardiasis, and even to developing anaphylactic transfusion reactions that may be life-threatening [12]. The diagnosis of CD could be challenging in this population that by definition will show false-negative IgA type CD-specific antibodies. IgG antiPinto-Sánchez/Bercik/Verdu/Bai
Downloaded by: NYU Medical Center Library 128.122.253.212 - 5/13/2015 2:30:18 AM
Introduction
Table 1. Extraintestinal manifestations of CD
System affected Extraintestinal manifestation
Estimated Comments prevalence in CD
Hematological
~50%
Thrombocytosis Hyposplenism IgA deficiency Leukopenia/neutropenia/ thrombocytopenia Mucocutaneous DH Psoriasis AA Urticaria/atopic dermatitis
12 Most commonly secondary to iron deficiency but may be multifactorial in etiology; low serum levels of folate and vitamin B12 without anemia are frequently seen up to 60% Possibly secondary to iron deficiency or hyposplenism ~19% Possibly associated with increased risk for infections ~5 – 10% CD patients have 10-fold increased risk for IgA deficiency; IgA deficiency predisposes to other enteric conditions
Extraintestinal Manifestations of Celiac Disease María Inés Pinto-Sánchez a Premysl Bercik a Elena F. Verdu a Julio C. Bai b, c a
Farncombe Family Digestive Health Institute, McMaster University, Hamilton, Ont., Canada; b Gastroenterology, Universidad del Salvador, and c Dr. Carlos Bonorino Udaondo Gastroenterology Hospital, Buenos Aires, Argentina
Abstract Case finding for celiac disease (CD) is becoming increasingly common practice and is conducted in a wide range of clinical situations ranging from the presence of gastrointestinal symptoms to failure to thrive in children, prolonged fatigue, unexpected weight loss and anemia. Case finding is also performed in associated conditions, such as autoimmune thyroid disease, dermatitis herpetiformis and type 1 diabetes, as well as in patients with irritable bowel syndrome, unexplained neuropsychiatric disorders and first-degree relatives of patients with diagnosed CD. This aggressive active case finding has dramatically changed the clinical characteristics of newly diagnosed patients. For instance, higher numbers of patients who present with extraintestinal symptoms are now being diagnosed with CD. Current recommendations state that due to a high risk for complications if the disease remains undiagnosed, patients with extraintestinal symptoms due to CD require appropriate diagnosis and treatment. Despite criticism regarding the cost-effectiveness of case finding in CD, such an aggressive approach has been considered cost-effective for high-risk patients. The diagnosis of CD among patients with extraintestinal symptoms re-
© 2015 S. Karger AG, Basel 0257–2753/15/0332–0147$39.50/0 E-Mail [email protected] www.karger.com/ddi
quires a high degree of awareness of the clinical conditions that carry a high risk for underlying CD. Also, understanding the correct use of specific serology and duodenal histology is key for an appropriate diagnostic approach. Both procedures combined are able to confirm diagnosis in the vast majority of cases. However, in certain circumstances, serology and even duodenal histology cannot confirm or rule out CD. A common cause of negative IgA serology is IgA deficiency. For such eventuality, IgG-based serological tests can help confirm the diagnosis. Importantly, some histologically diagnosed cases still remain seronegative despite exclusion of IgA deficiency. On the other hand, duodenal histology may be normal despite the presence of CD-specific antibodies and active CD. This has been clearly demonstrated in some cases of untreated dermatitis herpetiformis, but may also be due to the patchy condition of CD or lesions that are not adequately recognized by nonexpert endoscopists and/or pathologists. The effectiveness of agluten-free diet depends on the clinical end point addressed. A good example is the outcome of bone loss. While risk for fracture normalizes after the first year of dietary treatment, bone parameters measured by densitometry may not be normalized in the long-term follow-up. Moreover, it is still unclear how far an early glutenfree diet will positively affect associated autoimmune diseases like type 1 diabetes and autoimmune thyroiditis. © 2015 S. Karger AG, Basel
Prof. Julio C. Bai Dr. Carlos Bonorino Udaondo Gastroenterology Hospital Av. Caseros 2061 Buenos Aires 1264 (Argentina) E-Mail jbai @ intramed.net
Downloaded by: NYU Medical Center Library 128.122.253.212 - 5/13/2015 2:30:18 AM
Key Words Celiac disease · Extraintestinal manifestations · Diagnosis
The ‘Oslo consensus’ has recently defined celiac disease (CD) as a chronic small intestinal immune-mediated enteropathy precipitated by exposure to dietary gluten in genetically predisposed individuals [1]. Traditionally, patients with CD presented with malabsorption dominated by diarrhea, steatorrhea, weight loss or failure to thrive (‘classical CD’). However, the proportion of newly diagnosed patients with malabsorptive symptoms has decreased over time, and CD with ‘non-classical’ and even asymptomatic presentation is gaining prominence [2]. The current awareness of CD complications in combination with the advent of highly sensitive and specific serological tests has dramatically increased the identification of patients among subjects having a higher risk for the disorder [3]. Case finding is now becoming more common and is conducted in a wide range of clinical situations ranging from the presence of gastrointestinal symptoms (diarrhea, abdominal pain and distension), failure to thrive in children [4, 5], prolonged fatigue [6], unexpected weight loss, recurrent aphthous stomatitis, anemia [7], increased liver transaminases [8] and unexplained neuropsychiatric disorder [9]. Case finding is also recommended in conditions that associate with CD such as autoimmune thyroid disease, dermatitis herpetiformis (DH) and type 1 diabetes [7], and in patients with irritable bowel syndrome associated with diarrhea and first-degree relatives of celiacs [10, 11]. This aggressive active case finding introduced in the last decades has dramatically changed the clinical characteristics of newly diagnosed patients. In such context, increasing numbers of CD patients are now diagnosed who present with an extraintestinal phenotype and a diversity of symptoms affecting many different systems. The present review aims to analyze the most common extraintestinal manifestations of CD and proposes an appropriate diagnostic workup. We also discuss the effect of the gluten-free diet (GFD) on these extraintestinal manifestations of CD.
Hematologic Manifestations of CD
CD is a common systemic disorder that can present with multiple hematologic manifestations prior to receiving a diagnosis of CD [12]. Iron deficiency anemia (IDA) without other clinical clues of intestinal malabsorption, is one of the most common extraintestinal manifestations of the disorder being encountered in around 50% of pa148
Dig Dis 2015;33:147–154 DOI: 10.1159/000369541
tients with subclinical phenotype [13]. This is considered the most frequent extraintestinal feature of the condition [14]. Evidence suggests that IDA, as the leading symptom, is more frequent in adults than in children [13, 14], and it is usually due to either increased iron loss or impaired absorption of iron, folate or vitamin B12, although occult blood loss from the gastrointestinal tract may occur [13, 15]. Bergamaschi et al. [16] have suggested that anemia of chronic diseases is due to immune activation and defective production of endogenous erythropoietin in a significant proportion of patients at presentation. The treatment of anemia associated with CD is primarily a GFD. Iron supplementation is usually indicated for the treatment of IDA associated with CD until the iron stores have been restored, which could take up to 2 years [12]. Thrombocytosis is also frequently seen in CD, occurring in up to 60% of patients [12, 17, 18]. The presence of inflammatory mediators, iron deficiency and hyposplenism have all been proposed as contributing factors [12]. The thrombocytopenia associated with CD usually improves with specific treatment [12, 17]. Defective splenic function affects more than one third of adult patients with symptomatic CD, and it may predispose to a higher risk of infections by encapsulated bacteria and thromboembolic and autoimmune complications [19]. The prevalence of hyposplenism increases from 19% in CD to 80% in CD with premalignant or malignant complications, and it is associated with a poor prognosis factor in CD [19, 20]. However, the evaluation of splenic function is not considered as a regular procedure in the clinical management of patients with noncomplicated CD, and in patients with a high degree of hyposplenism or splenic atrophy the prophylactic immunization with specific vaccines against the polysaccharide antigens of encapsulated bacteria remains controversial [19]. As demonstrated by Corazza et al. [20], the splenic hypofunction measured by pitted cells improves at least partially in some CD patients and even reverts to normal after 3–12 months of GFD. IgA deficiency is the most common primary immunodeficiency in Caucasians that is strongly overrepresented among patients with CD accounting for ∼5% (CD) [12, 21]. The importance of the association is due to the fact that IgA-deficient individuals are prone to other enteric conditions such as inflammatory bowel disease or chronic parasite infections, especially giardiasis, and even to developing anaphylactic transfusion reactions that may be life-threatening [12]. The diagnosis of CD could be challenging in this population that by definition will show false-negative IgA type CD-specific antibodies. IgG antiPinto-Sánchez/Bercik/Verdu/Bai
Downloaded by: NYU Medical Center Library 128.122.253.212 - 5/13/2015 2:30:18 AM
Introduction
Table 1. Extraintestinal manifestations of CD
System affected Extraintestinal manifestation
Estimated Comments prevalence in CD
Hematological
~50%
Thrombocytosis Hyposplenism IgA deficiency Leukopenia/neutropenia/ thrombocytopenia Mucocutaneous DH Psoriasis AA Urticaria/atopic dermatitis
12 Most commonly secondary to iron deficiency but may be multifactorial in etiology; low serum levels of folate and vitamin B12 without anemia are frequently seen up to 60% Possibly secondary to iron deficiency or hyposplenism ~19% Possibly associated with increased risk for infections ~5 – 10% CD patients have 10-fold increased risk for IgA deficiency; IgA deficiency predisposes to other enteric conditions
