Clinics and Research in Hepatology and Gastroenterology (2015) 39, e1—e4
Available online at
ScienceDirect www.sciencedirect.com
CASE REPORT
Shwachman-Diamond syndrome with autoimmune-like liver disease and enteropathy mimicking celiac disease Claudio Veropalumbo a, Angelo Campanozzi b, Fabiola De Gregorio a, Antonio Correra c, Valeria Raia a, Pietro Vajro d,e,∗ a
Pediatrics Section, University of Naples ‘‘Federico II’’, Naples, Italy Department of Scienze Mediche e del Lavoro, Pediatrics Section, University of Foggia, Foggia, Italy c Pediatric Hospital Santobono-Annunziata, Naples, Italy d Department of Medicine and Surgery, Chair of Pediatrics, University of Salerno, Baronissi-Salerno, Italy e European Laboratory for Food Induced Disease (ELFID), Naples, Italy b
Available online 14 August 2014
Summary Liver abnormalities that normalize during infancy as well an enteropathy are reported in Shwachman-Diamond syndrome (SDS). The pathogenesis of both conditions is unknown. We report two SDS cases with autoimmune-like (antismooth muscle and/or antinuclear antibody positivity) liver disease and antigliadin antibody positive inflammatory enteropathy. Hypertransaminasemia did not resolve after immunosuppressive therapy and/or a gluten-free diet. These transient autoimmune phenomena and gut-liver axis perturbations may have played a role in transient SDS hepatopathy and enteropathy. Our report may stimulate other studies to define the relationship between the SDS genetic defect and intestinal permeability as the pathogenic mechanism underlying SDS related liver and intestinal inflammation. © 2014 Published by Elsevier Masson SAS.
∗ Corresponding author at: Department of Medicine and Surgery, Chair of Pediatrics, University of Salerno, Via Allende, 84081 BaronissiSalerno, Italy. Tel.: +39 089 965016; +39 089 672409; Mobile: +39 339 236 1008. E-mail addresses: [email protected] (C. Veropalumbo), [email protected] (A. Campanozzi), [email protected] (F. De Gregorio), [email protected] (A. Correra), [email protected] (V. Raia), [email protected] (P. Vajro).
http://dx.doi.org/10.1016/j.clinre.2014.06.017 2210-7401/© 2014 Published by Elsevier Masson SAS.
e2
Introduction Shwachman-Diamond syndrome (SDS) is an autosomal recessive genetic syndrome with variable and pleiotropic phenotypes which may hamper its rapid recognition [1,2]. It is caused by mutations in the gene encoding Shwachman-Bodian-diamond syndrome protein (SBDS), involved in several pathways which deal with ribosomal RNA metabolism, apoptosis, and mitotic spindle stabilization. Transient hepatic injury of unknown origin may be an early SDS manifestation [2—4]. In this report we propose transient autoimmune phenomena and gut-liver axis perturbation as the etiologic cause.
Case report 1 C. was born from unrelated healthy parents after an uneventful pregnancy; birth weight (W) and length (L) were 2.9 kg and 47 cm, respectively. Weaning occurred at 4 months of age. At age 5 months hepatomegaly (lower edge 3 cm below the right costal margin), isolated hypertransaminasemia (aspartate aminotransferases [AST], and alanine aminotransferase [ALT] up to 4 and to 10 × UNV, respectively) (Fig. 1A) were noted during a routine visit. W, L, and head circumference (HC) were < 5th percentile with a W/L ratio at 50th percentile. Positive antigliadin antibodies (AGA) (IgA and IgG up to 400 AU and 277 AU, respectively; upper normal values [UNV] < 30), and abnormal intestinal histology (mild villus atrophy with normal intraepithelial lymphocytes count [16%]) without Giardia infestation suggested possible celiac disease (CD). However, anti-endomesial (EMA) and anti-transglutaminase antibodies (TGase) tested negative. After starting a gluten-free diet (GFD), at 8 months, serum transaminases did not improve, but AGA serum levels markedly decreased (AGA IgA × 2 UNV, AGA IgG × 3 UNV). Because DQ2/DQ8 haplotypes were absent, gluten was reintroduced at 14 months. AGA relapsed to initial values, while EMA and TGase remained persistently negative. Laboratory tests to exclude other viral, genetic-metabolic, autoimmune, and muscular causes of elevated transaminases [5] revealed hypergammaglobulinemia with mildly elevated IgG (13.2 g/dl, UNV < 10.7), 1:80 positive antismooth muscle antibodies (ASMA) and 1:80 antinuclear antibodies (ANA), suggesting a diagnosis of autoimmune hepatitis (AIH) type I. Liver biopsy showed a mild active hepatitis (Fig. 2A), and corticosteroids and azathioprine were started at age 9 months. Hepatic enzymes (Fig. 1A) nearly doubled initial values, so immunosuppressive treatment was prudently tapered, and then stopped after 4 months. Mild neutropenia appeared within 5 months after prednisone decrease. At age 12 months, low levels of serum amylase (10 mol/l, normal values 28—100) and fecal elastase were repeatedly noted. Sweat test was normal, while molecular analysis of SBDS gene revealed causative mutations (c.258+2T/c.258+2T + c.183—1847A> CT). X-rays and magnetic resonance imaging demonstrated SDS typical ribs abnormalities and pancreatic lipomatosis, respectively. Pancreatic enzyme supplements were prescribed. During follow-up, serum transaminases progressively decreased to complete and persistent normalization at age 4 years (Fig. 1A). Neutropenia progressed requiring granulocyte
C. Veropalumbo et al. colony stimulating factor (G-CSF) which was successfully stopped after 1 year, when values of neutrophils reached 1000/mm3 . Current neutrophil count (age 2) is 1300/mm3 .
Case report 2 F. was born from unrelated healthy parents after an uneventful pregnancy. Birth W and L were 2.550 kg, and 49 cm, respectively. Weaning occurred at 4 months of age. She was seen by pediatric gastroenterologists at age 10 months for longstanding failure to thrive, mild hepatomegaly, neutropenia (600 neutrophils/mm3 ), and isolated hypertransaminasemia (AST and ALT 5 × UNV and 10 × UNV, respectively) which began at 2 months of age (Fig. 1B). She was diagnosed with possible CD based on increased AGA values (IgA 115—741 AU, IgG 111—2727 AU [UNV < 30]), and subtotal villus atrophy and increased intraepithelial lymphocytes on intestinal histology, without Giardia ova or parasites. After starting a GFD, AGA normalized, but hypertransaminasemia did not resolve. Negative DQ2 and/or DQ8 haplotypes eliminated the initial CD diagnosis, and gluten was reintroduced into the diet. Screening for the most common causes of age related hypertransaminasemia was negative, but there were borderline-increased total serum IgG (12.2 g/l: UNV < 10.6), and positive ASMA (1:80). Liver histology showed mild steatohepatitis (Fig. 2B). AIH therapy with prednisone was started at age 12 months. After initial improvement, liver enzymes rose sharply necessitating discontinuation of prednisone therapy after 3.5 months. Bone marrow biopsy demonstrated a defect of maturation of neutrophils with erythrophagocytosis. Investigation of SBDS gene revealed causative mutations (c.258+2T>C+c.183—184TA>CT). X-Rays revealed subclinical SDS skeletal abnormalities, namely short ribs with flared and irregular metaphyseal ends. Fecal elastase was low and pancreatic enzyme supplementation was prescribed. Serum transaminases normalized over a period of 3 years. Neutrophil values improved after G-CSF therapy, which was continued up to 10 years of age. Currently, at age 19, neutrophils are 1900/mm3 , while AST and ALT, EMA and TGase, IgA values remain normal (Fig. 1B).
Discussion Our report describes 2 pediatric SDS cases presenting with hypertransaminasemia, mild hypergammaglobulinemia, positive autoantibodies (ASMA and/or ANA), and histological liver activity, resembling type I autoimmune hepatitis, unresponsive to corticosteroids (AIH scores 10 for both, i.e., possible AIH). Fifteen percent of SDS patients have hepatomegaly, and 50 to 75% have elevated serum transaminases, and increased serum bile acids [3], with a wide range of histopathologic hepatic patterns [2,6]. The pathogenesis of the liver involvement remains poorly understood. Accelerated hepatocyte apoptosis through the Fas-pathway has been proposed. Autoimmune phenomena has been associated in one instance with SDS, but not specifically with SDS related liver disease [7]. The true functional roles and diagnostic significance of autoantibody positivity
Shwachman-Diamond syndrome hepatopathy, autoimmunity and enteropathy
e3
Figure 1 Trend of AST and ALT serum values over time in patients C (Panel A) and patient F (Panel B). Periods of immunosuppressive (IS) therapy and of gluten-free diet are reported. AST: aspartate aminotransferase; ALT: alanine aminotransferase. Normal values of aminotransferases are indicated by marked horizontal line at 35 U/l.
Figure 2 A and B show histologically mild active hepatitis with mild steatosis, and portal inflammation in patient C and patient F, respectively (Hematoxylin Eosin staining).
observed in our patients are difficult to define since differentiating irrelevant autoimmune phenomena from substantial autoimmune disease at an early stage is not possible [8]. During the first year of life, both patients had received an erroneous diagnosis of CD, the result of varying degrees of duodenal inflammatory enteropathic features described in more than half of symptomatic children with SDS [9]. A recent report described a 2-year-old girl with hypertransaminasemia, and hyperimmunoglobulinemia G similar to our patients. She had a few endoscopic characteristics of CD, was unresponsive to a gluten-free diet, and four years later, low serum pancreatic enzyme levels led to the correct diagnosis of SDS [10]. In SDS a subtle link between impaired ribosomal RNA, translational arrest, gut epithelial damage and loss of the intestinal barrier with increased intestinal permeability
probably exist. An isolated increase of AGA levels as observed in our patients could be an indicator of CD in a child of less than 2 years old [11]. However, it could also indicate other intestinal alterations causing a nonspecific increased permeability to macromolecules. Impaired gutliver axis is currently an emerging factor involved in non alcoholic fatty liver disease/steatohepatitis through lipid and carbohydrate metabolism alterations, translocation of endotoxins and pro-inflammatory cytokines leakage from the gut to the portal venous system [12] which are associated with progression from hepatic steatosis to hepatitis, which were both present in one of our patients. Further studies are required to support this hypothesis. We suggest that a high index of suspicion for SDS is necessary in a young child who presents with ‘‘autoimmune’’ hepatic and/or intestinal phenomena, requiring an accurate search for more typical SDS signs like neutropenia or pancreatic insufficiency or
e4 subclinical skeletal abnormalities to avoid misdiagnoses and potentially harmful therapies [2].
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements We are grateful to Professor Olivier Bernard (Bicêtre, France) and Professor Phil Rosenthal (San Francisco, California, USA) for helpful discussion in preparing the manuscript.
References [1] Shwachman-Diamond syndrome. Online mendelian inheritance in man, OMIM® . Baltimore, MD: Johns Hopkins University; 2010 [MIM Number: 260400; http://omim.org/]. [2] Dror Y, Donadieu J, Koglmeier J, Dodge J, Toiviainen-Salo S, Makitie O, et al. Draft consensus guidelines for diagnosis and treatment of Shwachman-Diamond syndrome. Ann N Y Acad Sci 2011;1242:40—55. [3] Toiviainen-Salo S, Durie PR, Numminen K, Heikkilä P, Marttinen E, Savilahti E, et al. The natural history of Shwachman-Diamond syndrome-associated liver disease from childhood to adulthood. J Pediatr 2009;155:807—11.
C. Veropalumbo et al. [4] Revert Lázaro F, Pérez Monjardín E, Pérez AP. Hypertransaminasemia as a manifestation of Shwachman-Diamond syndrome. An Pediatr (Barc) 2006;64:481—4. [5] Vajro P, Maddaluno S, Veropalumbo C. Persistent hypertransaminasemia in asymptomatic children: a stepwise approach. World J Gastroenterol 2013;19:2740—51. [6] Wilschanski M, van der Hoeven E, Phillips J, Shuckett B, Durie P. Shwachman-Diamond syndrome presenting as hepatosplenomegaly. J Pediatr Gastroenterol Nutr 1994;19:111—3. [7] Reif S, Arav-Boger R, Diamant S, Burstein Y, Fatal A. Shwachman-Diamond syndrome associated with autoimmune phenomena. J Med 1999;30:259—65. [8] Lehmann HP, Block D, Markert-Hahn C, Zolg JW. New concepts in systemic autoimmunity testing. Scand J Clin Lab Invest Suppl 2001;235:84—90. [9] Shah N, Cambrook H, Koglmeier J, Mason C, Ancliff P, Lindley K, et al. Enteropathic histopathological features may be associated with Shwachman-Diamond syndrome. J Clin Pathol 2010;63:592—4. [10] Hagiwara S, Watanabe A. A case of Shwachman-Diamond syndrome distinguished from celiac disease. Pediatr Rep 2012;4:e30. [11] Maglio M, Tosco A, Paparo F, Auricchio R, Granata V, Colicchio B, et al. Serum and intestinal celiac disease-associated antibodies in children with celiac disease younger than 2 years of age. J Pediatr Gastroenterol Nutr 2010;50:43—8. [12] Vajro P, Paolella G, Fasano A. Microbiota and gut-liver axis: a mini-review on their influences on obesity and obesity related liver disease. J Pediatr Gastroenterol Nutr 2013;56: 461—8.
Available online at
ScienceDirect www.sciencedirect.com
CASE REPORT
Shwachman-Diamond syndrome with autoimmune-like liver disease and enteropathy mimicking celiac disease Claudio Veropalumbo a, Angelo Campanozzi b, Fabiola De Gregorio a, Antonio Correra c, Valeria Raia a, Pietro Vajro d,e,∗ a
Pediatrics Section, University of Naples ‘‘Federico II’’, Naples, Italy Department of Scienze Mediche e del Lavoro, Pediatrics Section, University of Foggia, Foggia, Italy c Pediatric Hospital Santobono-Annunziata, Naples, Italy d Department of Medicine and Surgery, Chair of Pediatrics, University of Salerno, Baronissi-Salerno, Italy e European Laboratory for Food Induced Disease (ELFID), Naples, Italy b
Available online 14 August 2014
Summary Liver abnormalities that normalize during infancy as well an enteropathy are reported in Shwachman-Diamond syndrome (SDS). The pathogenesis of both conditions is unknown. We report two SDS cases with autoimmune-like (antismooth muscle and/or antinuclear antibody positivity) liver disease and antigliadin antibody positive inflammatory enteropathy. Hypertransaminasemia did not resolve after immunosuppressive therapy and/or a gluten-free diet. These transient autoimmune phenomena and gut-liver axis perturbations may have played a role in transient SDS hepatopathy and enteropathy. Our report may stimulate other studies to define the relationship between the SDS genetic defect and intestinal permeability as the pathogenic mechanism underlying SDS related liver and intestinal inflammation. © 2014 Published by Elsevier Masson SAS.
∗ Corresponding author at: Department of Medicine and Surgery, Chair of Pediatrics, University of Salerno, Via Allende, 84081 BaronissiSalerno, Italy. Tel.: +39 089 965016; +39 089 672409; Mobile: +39 339 236 1008. E-mail addresses: [email protected] (C. Veropalumbo), [email protected] (A. Campanozzi), [email protected] (F. De Gregorio), [email protected] (A. Correra), [email protected] (V. Raia), [email protected] (P. Vajro).
http://dx.doi.org/10.1016/j.clinre.2014.06.017 2210-7401/© 2014 Published by Elsevier Masson SAS.
e2
Introduction Shwachman-Diamond syndrome (SDS) is an autosomal recessive genetic syndrome with variable and pleiotropic phenotypes which may hamper its rapid recognition [1,2]. It is caused by mutations in the gene encoding Shwachman-Bodian-diamond syndrome protein (SBDS), involved in several pathways which deal with ribosomal RNA metabolism, apoptosis, and mitotic spindle stabilization. Transient hepatic injury of unknown origin may be an early SDS manifestation [2—4]. In this report we propose transient autoimmune phenomena and gut-liver axis perturbation as the etiologic cause.
Case report 1 C. was born from unrelated healthy parents after an uneventful pregnancy; birth weight (W) and length (L) were 2.9 kg and 47 cm, respectively. Weaning occurred at 4 months of age. At age 5 months hepatomegaly (lower edge 3 cm below the right costal margin), isolated hypertransaminasemia (aspartate aminotransferases [AST], and alanine aminotransferase [ALT] up to 4 and to 10 × UNV, respectively) (Fig. 1A) were noted during a routine visit. W, L, and head circumference (HC) were < 5th percentile with a W/L ratio at 50th percentile. Positive antigliadin antibodies (AGA) (IgA and IgG up to 400 AU and 277 AU, respectively; upper normal values [UNV] < 30), and abnormal intestinal histology (mild villus atrophy with normal intraepithelial lymphocytes count [16%]) without Giardia infestation suggested possible celiac disease (CD). However, anti-endomesial (EMA) and anti-transglutaminase antibodies (TGase) tested negative. After starting a gluten-free diet (GFD), at 8 months, serum transaminases did not improve, but AGA serum levels markedly decreased (AGA IgA × 2 UNV, AGA IgG × 3 UNV). Because DQ2/DQ8 haplotypes were absent, gluten was reintroduced at 14 months. AGA relapsed to initial values, while EMA and TGase remained persistently negative. Laboratory tests to exclude other viral, genetic-metabolic, autoimmune, and muscular causes of elevated transaminases [5] revealed hypergammaglobulinemia with mildly elevated IgG (13.2 g/dl, UNV < 10.7), 1:80 positive antismooth muscle antibodies (ASMA) and 1:80 antinuclear antibodies (ANA), suggesting a diagnosis of autoimmune hepatitis (AIH) type I. Liver biopsy showed a mild active hepatitis (Fig. 2A), and corticosteroids and azathioprine were started at age 9 months. Hepatic enzymes (Fig. 1A) nearly doubled initial values, so immunosuppressive treatment was prudently tapered, and then stopped after 4 months. Mild neutropenia appeared within 5 months after prednisone decrease. At age 12 months, low levels of serum amylase (10 mol/l, normal values 28—100) and fecal elastase were repeatedly noted. Sweat test was normal, while molecular analysis of SBDS gene revealed causative mutations (c.258+2T/c.258+2T + c.183—1847A> CT). X-rays and magnetic resonance imaging demonstrated SDS typical ribs abnormalities and pancreatic lipomatosis, respectively. Pancreatic enzyme supplements were prescribed. During follow-up, serum transaminases progressively decreased to complete and persistent normalization at age 4 years (Fig. 1A). Neutropenia progressed requiring granulocyte
C. Veropalumbo et al. colony stimulating factor (G-CSF) which was successfully stopped after 1 year, when values of neutrophils reached 1000/mm3 . Current neutrophil count (age 2) is 1300/mm3 .
Case report 2 F. was born from unrelated healthy parents after an uneventful pregnancy. Birth W and L were 2.550 kg, and 49 cm, respectively. Weaning occurred at 4 months of age. She was seen by pediatric gastroenterologists at age 10 months for longstanding failure to thrive, mild hepatomegaly, neutropenia (600 neutrophils/mm3 ), and isolated hypertransaminasemia (AST and ALT 5 × UNV and 10 × UNV, respectively) which began at 2 months of age (Fig. 1B). She was diagnosed with possible CD based on increased AGA values (IgA 115—741 AU, IgG 111—2727 AU [UNV < 30]), and subtotal villus atrophy and increased intraepithelial lymphocytes on intestinal histology, without Giardia ova or parasites. After starting a GFD, AGA normalized, but hypertransaminasemia did not resolve. Negative DQ2 and/or DQ8 haplotypes eliminated the initial CD diagnosis, and gluten was reintroduced into the diet. Screening for the most common causes of age related hypertransaminasemia was negative, but there were borderline-increased total serum IgG (12.2 g/l: UNV < 10.6), and positive ASMA (1:80). Liver histology showed mild steatohepatitis (Fig. 2B). AIH therapy with prednisone was started at age 12 months. After initial improvement, liver enzymes rose sharply necessitating discontinuation of prednisone therapy after 3.5 months. Bone marrow biopsy demonstrated a defect of maturation of neutrophils with erythrophagocytosis. Investigation of SBDS gene revealed causative mutations (c.258+2T>C+c.183—184TA>CT). X-Rays revealed subclinical SDS skeletal abnormalities, namely short ribs with flared and irregular metaphyseal ends. Fecal elastase was low and pancreatic enzyme supplementation was prescribed. Serum transaminases normalized over a period of 3 years. Neutrophil values improved after G-CSF therapy, which was continued up to 10 years of age. Currently, at age 19, neutrophils are 1900/mm3 , while AST and ALT, EMA and TGase, IgA values remain normal (Fig. 1B).
Discussion Our report describes 2 pediatric SDS cases presenting with hypertransaminasemia, mild hypergammaglobulinemia, positive autoantibodies (ASMA and/or ANA), and histological liver activity, resembling type I autoimmune hepatitis, unresponsive to corticosteroids (AIH scores 10 for both, i.e., possible AIH). Fifteen percent of SDS patients have hepatomegaly, and 50 to 75% have elevated serum transaminases, and increased serum bile acids [3], with a wide range of histopathologic hepatic patterns [2,6]. The pathogenesis of the liver involvement remains poorly understood. Accelerated hepatocyte apoptosis through the Fas-pathway has been proposed. Autoimmune phenomena has been associated in one instance with SDS, but not specifically with SDS related liver disease [7]. The true functional roles and diagnostic significance of autoantibody positivity
Shwachman-Diamond syndrome hepatopathy, autoimmunity and enteropathy
e3
Figure 1 Trend of AST and ALT serum values over time in patients C (Panel A) and patient F (Panel B). Periods of immunosuppressive (IS) therapy and of gluten-free diet are reported. AST: aspartate aminotransferase; ALT: alanine aminotransferase. Normal values of aminotransferases are indicated by marked horizontal line at 35 U/l.
Figure 2 A and B show histologically mild active hepatitis with mild steatosis, and portal inflammation in patient C and patient F, respectively (Hematoxylin Eosin staining).
observed in our patients are difficult to define since differentiating irrelevant autoimmune phenomena from substantial autoimmune disease at an early stage is not possible [8]. During the first year of life, both patients had received an erroneous diagnosis of CD, the result of varying degrees of duodenal inflammatory enteropathic features described in more than half of symptomatic children with SDS [9]. A recent report described a 2-year-old girl with hypertransaminasemia, and hyperimmunoglobulinemia G similar to our patients. She had a few endoscopic characteristics of CD, was unresponsive to a gluten-free diet, and four years later, low serum pancreatic enzyme levels led to the correct diagnosis of SDS [10]. In SDS a subtle link between impaired ribosomal RNA, translational arrest, gut epithelial damage and loss of the intestinal barrier with increased intestinal permeability
probably exist. An isolated increase of AGA levels as observed in our patients could be an indicator of CD in a child of less than 2 years old [11]. However, it could also indicate other intestinal alterations causing a nonspecific increased permeability to macromolecules. Impaired gutliver axis is currently an emerging factor involved in non alcoholic fatty liver disease/steatohepatitis through lipid and carbohydrate metabolism alterations, translocation of endotoxins and pro-inflammatory cytokines leakage from the gut to the portal venous system [12] which are associated with progression from hepatic steatosis to hepatitis, which were both present in one of our patients. Further studies are required to support this hypothesis. We suggest that a high index of suspicion for SDS is necessary in a young child who presents with ‘‘autoimmune’’ hepatic and/or intestinal phenomena, requiring an accurate search for more typical SDS signs like neutropenia or pancreatic insufficiency or
e4 subclinical skeletal abnormalities to avoid misdiagnoses and potentially harmful therapies [2].
Disclosure of interest The authors declare that they have no conflicts of interest concerning this article.
Acknowledgements We are grateful to Professor Olivier Bernard (Bicêtre, France) and Professor Phil Rosenthal (San Francisco, California, USA) for helpful discussion in preparing the manuscript.
References [1] Shwachman-Diamond syndrome. Online mendelian inheritance in man, OMIM® . Baltimore, MD: Johns Hopkins University; 2010 [MIM Number: 260400; http://omim.org/]. [2] Dror Y, Donadieu J, Koglmeier J, Dodge J, Toiviainen-Salo S, Makitie O, et al. Draft consensus guidelines for diagnosis and treatment of Shwachman-Diamond syndrome. Ann N Y Acad Sci 2011;1242:40—55. [3] Toiviainen-Salo S, Durie PR, Numminen K, Heikkilä P, Marttinen E, Savilahti E, et al. The natural history of Shwachman-Diamond syndrome-associated liver disease from childhood to adulthood. J Pediatr 2009;155:807—11.
C. Veropalumbo et al. [4] Revert Lázaro F, Pérez Monjardín E, Pérez AP. Hypertransaminasemia as a manifestation of Shwachman-Diamond syndrome. An Pediatr (Barc) 2006;64:481—4. [5] Vajro P, Maddaluno S, Veropalumbo C. Persistent hypertransaminasemia in asymptomatic children: a stepwise approach. World J Gastroenterol 2013;19:2740—51. [6] Wilschanski M, van der Hoeven E, Phillips J, Shuckett B, Durie P. Shwachman-Diamond syndrome presenting as hepatosplenomegaly. J Pediatr Gastroenterol Nutr 1994;19:111—3. [7] Reif S, Arav-Boger R, Diamant S, Burstein Y, Fatal A. Shwachman-Diamond syndrome associated with autoimmune phenomena. J Med 1999;30:259—65. [8] Lehmann HP, Block D, Markert-Hahn C, Zolg JW. New concepts in systemic autoimmunity testing. Scand J Clin Lab Invest Suppl 2001;235:84—90. [9] Shah N, Cambrook H, Koglmeier J, Mason C, Ancliff P, Lindley K, et al. Enteropathic histopathological features may be associated with Shwachman-Diamond syndrome. J Clin Pathol 2010;63:592—4. [10] Hagiwara S, Watanabe A. A case of Shwachman-Diamond syndrome distinguished from celiac disease. Pediatr Rep 2012;4:e30. [11] Maglio M, Tosco A, Paparo F, Auricchio R, Granata V, Colicchio B, et al. Serum and intestinal celiac disease-associated antibodies in children with celiac disease younger than 2 years of age. J Pediatr Gastroenterol Nutr 2010;50:43—8. [12] Vajro P, Paolella G, Fasano A. Microbiota and gut-liver axis: a mini-review on their influences on obesity and obesity related liver disease. J Pediatr Gastroenterol Nutr 2013;56: 461—8.
