- Email: [email protected]
Aminotransferase activity in celiac disease
The Journal o f Pediatrics Volume 123, Number 6
tory measure such as lactate and lactic acid levels to identify patients who will benefit from transfusions. J. C. MOiler, MD U. Schwarz, MD L Reiss, MD E. Nitsche, MD Department of Pediatrics Medical University o f Lfibeck 23583 Lfibeck, Germany 9/35/49481
E d i t o r i a l correspondence
10 17
rocytes, together with prospective collection of clinical and laboratory data, will be required to prove our hypothesis. Shai Izraeli, MD Shmuel Davidson, MD Department o f Neonatology Beilinson Medical Center Petach- Tiqva 49100, Israel 9/35/49482
REFERENCES REFERENCES
1. Izraeli S, Ben-Sira L, Harell D, Naor N, Ballin A, Davidson S. Lactic acid as a predictor for erythrocyte transfusion in healthy preterm infants with anemia of prematurity. J PED~ATR 1993;122:629-31. 2. Meyer J, Sive A, Jacobs P. Empiric red cell transfusion in asymptomatic preterm infants. Acta Paediatr 1993;82:30-4. 3. Levy GI, et al. National Survey of Neonatal Transfusion Practices. I and II. Pediatrics 1993;91:523-36.
Reply To the Editor: "True" anemia results from a deficient supply of "available oxygen" to the tissues relative to the tissues' demand for oxygen. I The amount of available oxygen depends only partially on hemoglobin concentration and is influenced by the hemoglobin-oxygen affinity as well. The most important factors regulating this affinity are changes related to the concentration of erythrocytic 2,3-diphosphoglycerate and fetal hemoglobin. 2 Therefore the very weak correlation between cardiac output or lactate level and hemoglobin concentration in young, healthy very low birth weight infants is not surprising. We wholeheartedly agree that hemoglobin level could not serve by itself as an indicator for blood transfusion, and hence we looked for another measure, namely lactic acid. Our interpretation of the data of M611er et al. is that determination of serum lactate levels, a feasible and easy-to-perform test in any neonatal intensive care unit, may be a good way to predict anemia (tissue hypoxemia) requiring blood transfusion. In their group of infants with symptoms, the elevated pretransfusion lactate level decreased significantly after transfusion. This decline occurred simultaneously with a significant drop in physiologic values such as heart rate and cardiac output. If the serum lactate level accurately reflects tissue hypoxemia, a rising lactate level may be an alarming sign preceding hemodynamic decompensation. In that case, blood transfusion, even in the absence of symptoms, might prevent the development of hemodynamic deterioration. The observation of M611er et al. in very low birth weight infants with symptoms and our own findings in symptom-free infants support the hypothesis that serum lactate determinations may help to identify growing "anemic" premature infants who will benefit from transfusions. Random assignment of symptom-free premature infants with low hematocrit and high lactate values to transfusion with eryth-
1. Stockman JA III. Anemia of prematurity: current concepts in the issue of when to transfuse. Pediatr Clin North Am 1986;33:111-28. 2. Delavoria-Papadopoulos M, Roncevic NP, Oski FA. Postnatal changes in oxygen transport of term, premature and sick infants: the role of red cell 2,3-diphosphoglyccrate and adult hemoglobin. Pediatr Res 1971;5:235-45.
Aminotransferase activity in celiac disease To the Editor: Vajro et al. 1 reported persistently elevated serum aminotransferase levels in six children with celiac disease. No child had gastrointestinal symptoms, and all were extensively investigated for liver disease. The only additional abnormalities detected were mild inflammatory changes from liver biopsy tissue. The diagnosis of celiac disease was made by the presence of antigliadin antibodies and typical villous atrophy on small bowel biopsy. The tissue and biochemical abnormalities resolved after gluten withdrawal and returned after a gluten challenge. The authors conclude that celiac disease results in hepatic injury heralded by elevated serum aminotransferase values. An alternative explanation for the increase in serum aminotransferase values is that these enzymes are of gut origin. We have reported the presence of raised aspartate aminotransferase (AST) levels in acute sera from 8 of 39 children with rotavirus gastroenteritis. 2 No child had any clinical evidence of liver disease, and no other liver function abnormalities were detected. The AST values measured in convalescent sera from these children were within the normal range. However, 6 of the remaining 31 children had a rise in serum AST values between acute and convalescent samples. Four of these six children had gastrointestinal symptoms at the time of collection of the second serum sample, from either persistent carbohydrate malabsorption or a second episode of gastroenteritis. The raised serum AST values during the acute illness, and rises observed in children with symptoms of persisting gut injury, suggested that the source of the elevated serum AST values may have been injured enterocytes in the small bowel mucosa rather than damaged hepatocytes. Serum levels of aminotranferases reflect activity in a number of different organs. 3 It is possible that a significant proportion of the serum aminotransferase levels in the patients reported by Vajro et al. originated from damaged enterocytes as a result of their celiac disease. Irrespective of the origin of these enzymes, we agree that
10 18
Editorial correspondence
The Journal of Pediatrics December 1993
celiac disease should be considered in any child with unexplained persistent hyperaminotransferasemia.
K. Grimwood, MD, FRACP G. L. Barnes. MD, FRACP University of Melbourne Department of Paediatrics Department of Gastroenterology Royal Children's Hospital, Parkville, Victoria 3052, Australia
two more patients with gluten-sensitive enteropathy. We suggest that patients with chronic, unexplained liver dysfunction without associated overt symptoms of malabsorption might be evaluated for celiac disease. Atypical cases of gluten-sensitive enteropathy may lead to severe liver disease that can be easily treated by dietary restrictions. Although diagnosis of these exceptional cases may require detailed investigations, celiac disease should always be considered as a "preventable" cause of chronic liver disease.
Ender Pehlivanoglu, MD Associate Professor of Pediatrics Evin Ozguven,. MD Department of Pediatrics Division of Pediatric Gastroenterology and Nutrition Salih Guran, MD Assistant Professor of Radiology Department of Radiology Marmara University Faculty of Medicine Istanbul, Turkey
9/35/50217
REFERENCES
1. Vajro P, Fontanetla A, Mayer M, et al. Elevated serum aminotransferase activity as an early manifestation of gluten-sensitive enteropathy. J PEDIA~rR 1993;122:416-9. 2. Grimwood K, Coakley JC, Hudson IL, Bishop RF, Barnes GL. Serum aspartate aminotransferase levels after rotavirus gastroenteritis. J PEDIATR 1988;112:597-600. 3. Gautier PE, Richterich R. Valeur diagnostique d'activites enzymatiques du serum en pediatrie. II. Constance et specificite des anomalies enzymatiques. Helv Paediatr Acta 1963;18:3279.
To the Editor: Vajro et al.1 suggested a relationship between serum aminotransferase activity and gluten-sensitiveenteropathy. We report the case of an 11-year-old girl with a 4-year history of pallor, weakness, and mild abdominal distention associated with short stature. She had a mildly enlarged liver and spleen, and follicular hyperkeratosis. Laboratory investigations revealed normal trace elements, serum amino acid concentrations, and essential fatty acid levels. Results of antigliadin antibody, stool, and viral serologic tests were also negative. Serum alanine aminotransferase and aspartate aminotransferase levels were within the normal ranges. Abdominal tomography revealed a chain of enlarged lymph nodes. Histopathologic examination of small-bowel biopsy specimens revealed mildly shortened villi. The patient was put on a gluten-free diet but had no histopathologic improvement (determined by biopsy performed during the sixth month of dietary therapy). Three years later the patient was reinvestigated because of marked growth failure and abdominal distention. The stool pattern was unremarkable, levels of alanine aminotransferase and aspartate aminotransferase were moderately elevated, and the spleen and liver were markedly enlarged. Intestinal biopsy revealed total villous atrophy and hypertrophic crypts. Electron microscopy showed a flattened mucosa with enlarged cryptal openings. Liver biopsy revealed infiltration of portal spaces by polymorphonuclear neutrophils and mononuclear cells with parenchymal necrosis and advanced fibrosis. Corticosteroid therapy and a gluten-free diet were initiated. Liver function returned to normal within 3 months and remained within the normal range after cessation of prednisolone treatment. Control biopsy of the small bowel revealed complete healing of the villi by the seventh month of the dietary therapy. We have also observed elevation of aminotransferase levels in
9/35/50216 REFERENCES
1. Vajro P, Fontanella A, Mayer M, et al. Elevated serum aminotransferase activity as an early manifestation of gluten-sensitive enteropathy. J PEOIATR 1993;122:416-9. 2. Leonardi S, Bottaro G, Patene R, et al. Hypertransaminasemia as the first symptom in infant celiac disease. J Pediatr Gastroenterol Nutr 1990;11:404-6.
Reply To the Editor: Pehlivanoglu et al. support our suggestion that patients with chronic unexplained liver dysfunction might be evaluated for celiac disease. However, we do not agree that these cases should be considered "exceptional." As a matter of fact, diagnoses of "typical" celiac disease are decreasing in all centers and are increasingly being replaced by diagnoses of "atypical" cases.1 Our cases have been diagnosed during the past 5 years. In the same period, at our institution, 40 new cases of celiac disease per year have been diagnosed, many of them being atypical cases, particularly those with onset at the age of 4 years or more. Hepatic damage should be considered one of the atypical manifestations of the disease. Drs. Grimwood and Barnes place attention on the source of the elevated serum aminotransferase vatues in patients with celiac disease. We agree that serum levels of aminotransferases reflect activity in a number of different organs2 and that an accurate search for their source is often necessary. We ruled out possible renal, erythrocytic, neurologic, pancreatic, and muscular origin on clinical grounds or on the basis of appropriate investigations (e.g., determination of serum levels of creatine kinase, lactate dehydrogenase, and their isoenzymes). The simultaneous rise of both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) did not suggest "macro AST" in our patients.3 Available technology unfortunately does not allow us to distinguish between "'hepatocyte" and "enterocyte" origin of aminotransferases. Moreover, the liver has been considered by us to be the most probable source
tory measure such as lactate and lactic acid levels to identify patients who will benefit from transfusions. J. C. MOiler, MD U. Schwarz, MD L Reiss, MD E. Nitsche, MD Department of Pediatrics Medical University o f Lfibeck 23583 Lfibeck, Germany 9/35/49481
E d i t o r i a l correspondence
10 17
rocytes, together with prospective collection of clinical and laboratory data, will be required to prove our hypothesis. Shai Izraeli, MD Shmuel Davidson, MD Department o f Neonatology Beilinson Medical Center Petach- Tiqva 49100, Israel 9/35/49482
REFERENCES REFERENCES
1. Izraeli S, Ben-Sira L, Harell D, Naor N, Ballin A, Davidson S. Lactic acid as a predictor for erythrocyte transfusion in healthy preterm infants with anemia of prematurity. J PED~ATR 1993;122:629-31. 2. Meyer J, Sive A, Jacobs P. Empiric red cell transfusion in asymptomatic preterm infants. Acta Paediatr 1993;82:30-4. 3. Levy GI, et al. National Survey of Neonatal Transfusion Practices. I and II. Pediatrics 1993;91:523-36.
Reply To the Editor: "True" anemia results from a deficient supply of "available oxygen" to the tissues relative to the tissues' demand for oxygen. I The amount of available oxygen depends only partially on hemoglobin concentration and is influenced by the hemoglobin-oxygen affinity as well. The most important factors regulating this affinity are changes related to the concentration of erythrocytic 2,3-diphosphoglycerate and fetal hemoglobin. 2 Therefore the very weak correlation between cardiac output or lactate level and hemoglobin concentration in young, healthy very low birth weight infants is not surprising. We wholeheartedly agree that hemoglobin level could not serve by itself as an indicator for blood transfusion, and hence we looked for another measure, namely lactic acid. Our interpretation of the data of M611er et al. is that determination of serum lactate levels, a feasible and easy-to-perform test in any neonatal intensive care unit, may be a good way to predict anemia (tissue hypoxemia) requiring blood transfusion. In their group of infants with symptoms, the elevated pretransfusion lactate level decreased significantly after transfusion. This decline occurred simultaneously with a significant drop in physiologic values such as heart rate and cardiac output. If the serum lactate level accurately reflects tissue hypoxemia, a rising lactate level may be an alarming sign preceding hemodynamic decompensation. In that case, blood transfusion, even in the absence of symptoms, might prevent the development of hemodynamic deterioration. The observation of M611er et al. in very low birth weight infants with symptoms and our own findings in symptom-free infants support the hypothesis that serum lactate determinations may help to identify growing "anemic" premature infants who will benefit from transfusions. Random assignment of symptom-free premature infants with low hematocrit and high lactate values to transfusion with eryth-
1. Stockman JA III. Anemia of prematurity: current concepts in the issue of when to transfuse. Pediatr Clin North Am 1986;33:111-28. 2. Delavoria-Papadopoulos M, Roncevic NP, Oski FA. Postnatal changes in oxygen transport of term, premature and sick infants: the role of red cell 2,3-diphosphoglyccrate and adult hemoglobin. Pediatr Res 1971;5:235-45.
Aminotransferase activity in celiac disease To the Editor: Vajro et al. 1 reported persistently elevated serum aminotransferase levels in six children with celiac disease. No child had gastrointestinal symptoms, and all were extensively investigated for liver disease. The only additional abnormalities detected were mild inflammatory changes from liver biopsy tissue. The diagnosis of celiac disease was made by the presence of antigliadin antibodies and typical villous atrophy on small bowel biopsy. The tissue and biochemical abnormalities resolved after gluten withdrawal and returned after a gluten challenge. The authors conclude that celiac disease results in hepatic injury heralded by elevated serum aminotransferase values. An alternative explanation for the increase in serum aminotransferase values is that these enzymes are of gut origin. We have reported the presence of raised aspartate aminotransferase (AST) levels in acute sera from 8 of 39 children with rotavirus gastroenteritis. 2 No child had any clinical evidence of liver disease, and no other liver function abnormalities were detected. The AST values measured in convalescent sera from these children were within the normal range. However, 6 of the remaining 31 children had a rise in serum AST values between acute and convalescent samples. Four of these six children had gastrointestinal symptoms at the time of collection of the second serum sample, from either persistent carbohydrate malabsorption or a second episode of gastroenteritis. The raised serum AST values during the acute illness, and rises observed in children with symptoms of persisting gut injury, suggested that the source of the elevated serum AST values may have been injured enterocytes in the small bowel mucosa rather than damaged hepatocytes. Serum levels of aminotranferases reflect activity in a number of different organs. 3 It is possible that a significant proportion of the serum aminotransferase levels in the patients reported by Vajro et al. originated from damaged enterocytes as a result of their celiac disease. Irrespective of the origin of these enzymes, we agree that
10 18
Editorial correspondence
The Journal of Pediatrics December 1993
celiac disease should be considered in any child with unexplained persistent hyperaminotransferasemia.
K. Grimwood, MD, FRACP G. L. Barnes. MD, FRACP University of Melbourne Department of Paediatrics Department of Gastroenterology Royal Children's Hospital, Parkville, Victoria 3052, Australia
two more patients with gluten-sensitive enteropathy. We suggest that patients with chronic, unexplained liver dysfunction without associated overt symptoms of malabsorption might be evaluated for celiac disease. Atypical cases of gluten-sensitive enteropathy may lead to severe liver disease that can be easily treated by dietary restrictions. Although diagnosis of these exceptional cases may require detailed investigations, celiac disease should always be considered as a "preventable" cause of chronic liver disease.
Ender Pehlivanoglu, MD Associate Professor of Pediatrics Evin Ozguven,. MD Department of Pediatrics Division of Pediatric Gastroenterology and Nutrition Salih Guran, MD Assistant Professor of Radiology Department of Radiology Marmara University Faculty of Medicine Istanbul, Turkey
9/35/50217
REFERENCES
1. Vajro P, Fontanetla A, Mayer M, et al. Elevated serum aminotransferase activity as an early manifestation of gluten-sensitive enteropathy. J PEDIA~rR 1993;122:416-9. 2. Grimwood K, Coakley JC, Hudson IL, Bishop RF, Barnes GL. Serum aspartate aminotransferase levels after rotavirus gastroenteritis. J PEDIATR 1988;112:597-600. 3. Gautier PE, Richterich R. Valeur diagnostique d'activites enzymatiques du serum en pediatrie. II. Constance et specificite des anomalies enzymatiques. Helv Paediatr Acta 1963;18:3279.
To the Editor: Vajro et al.1 suggested a relationship between serum aminotransferase activity and gluten-sensitiveenteropathy. We report the case of an 11-year-old girl with a 4-year history of pallor, weakness, and mild abdominal distention associated with short stature. She had a mildly enlarged liver and spleen, and follicular hyperkeratosis. Laboratory investigations revealed normal trace elements, serum amino acid concentrations, and essential fatty acid levels. Results of antigliadin antibody, stool, and viral serologic tests were also negative. Serum alanine aminotransferase and aspartate aminotransferase levels were within the normal ranges. Abdominal tomography revealed a chain of enlarged lymph nodes. Histopathologic examination of small-bowel biopsy specimens revealed mildly shortened villi. The patient was put on a gluten-free diet but had no histopathologic improvement (determined by biopsy performed during the sixth month of dietary therapy). Three years later the patient was reinvestigated because of marked growth failure and abdominal distention. The stool pattern was unremarkable, levels of alanine aminotransferase and aspartate aminotransferase were moderately elevated, and the spleen and liver were markedly enlarged. Intestinal biopsy revealed total villous atrophy and hypertrophic crypts. Electron microscopy showed a flattened mucosa with enlarged cryptal openings. Liver biopsy revealed infiltration of portal spaces by polymorphonuclear neutrophils and mononuclear cells with parenchymal necrosis and advanced fibrosis. Corticosteroid therapy and a gluten-free diet were initiated. Liver function returned to normal within 3 months and remained within the normal range after cessation of prednisolone treatment. Control biopsy of the small bowel revealed complete healing of the villi by the seventh month of the dietary therapy. We have also observed elevation of aminotransferase levels in
9/35/50216 REFERENCES
1. Vajro P, Fontanella A, Mayer M, et al. Elevated serum aminotransferase activity as an early manifestation of gluten-sensitive enteropathy. J PEOIATR 1993;122:416-9. 2. Leonardi S, Bottaro G, Patene R, et al. Hypertransaminasemia as the first symptom in infant celiac disease. J Pediatr Gastroenterol Nutr 1990;11:404-6.
Reply To the Editor: Pehlivanoglu et al. support our suggestion that patients with chronic unexplained liver dysfunction might be evaluated for celiac disease. However, we do not agree that these cases should be considered "exceptional." As a matter of fact, diagnoses of "typical" celiac disease are decreasing in all centers and are increasingly being replaced by diagnoses of "atypical" cases.1 Our cases have been diagnosed during the past 5 years. In the same period, at our institution, 40 new cases of celiac disease per year have been diagnosed, many of them being atypical cases, particularly those with onset at the age of 4 years or more. Hepatic damage should be considered one of the atypical manifestations of the disease. Drs. Grimwood and Barnes place attention on the source of the elevated serum aminotransferase vatues in patients with celiac disease. We agree that serum levels of aminotransferases reflect activity in a number of different organs2 and that an accurate search for their source is often necessary. We ruled out possible renal, erythrocytic, neurologic, pancreatic, and muscular origin on clinical grounds or on the basis of appropriate investigations (e.g., determination of serum levels of creatine kinase, lactate dehydrogenase, and their isoenzymes). The simultaneous rise of both aspartate aminotransferase (AST) and alanine aminotransferase (ALT) did not suggest "macro AST" in our patients.3 Available technology unfortunately does not allow us to distinguish between "'hepatocyte" and "enterocyte" origin of aminotransferases. Moreover, the liver has been considered by us to be the most probable source