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Persistent hyperaminotransferasemia resolving after weight reduction in obese children
The Journal of Pediatrics Volume 125, Number 2
Vajro et al.
239
Persistent hyperaminotransferasemia resolving after weight reduction in obese children Pietro Vajro, MD, Angiola Fontanella, MD, Clelia Perna, ME), G i u s e p p e Orso, MD, Mariangela Tedesco, MD, and A n n a De Vincenzo, MD From the Department of Pediatrics, School of Medicine, Universityof Naples "Federico I1," Italy Nine obese children were referred to our liver disease unit because of asymptomatic, long-standing (range, 4 to 49 months) hyperaminotransferasemia of unknown origin. Ultrasonography showed a "bright" liver in most patients. A hypocaloric diet was prescribed, and the hepatic abnormalities of the compliant patients showed a prompt and persistent improvement that paralleled the loss of excess weight. (J PEDIATR1994;125:239-44)
Slightly elevated and fluctuating serum aminotransferase values caused by steatosis and steatohepatitis, and leading to fibrosis and cirrhosis of the liver, are more common in otherwise healthy obese populations than previously appreciated.I, 2 Recognition is important because the liver abnormalities are often reversible after treatment of obesity. 3 This association in childhood is often not considered, and in obese children an erroneous diagnosis of cryptogenic chronic hepatitis may be made, with a consequent delay of the appropriate treatment. 46 We describe the clinical and laboratory features of several obese children who were referred to our institution for the evaluation of prolonged hyperaminotransferasemia of unknown cause, and discuss the response of the liver abnormalities to weight loss. METHODS Nine consecutive children (six boys) with long-standing, asymptomatic hyperaminotransferasemia of unknown origin were admitted to our institution during the years 1987 to 1992 (Table). Measurements of aminotransferase levels had been done because of hepatomegaly in one patient, as a part of routine laboratory studies in three patients, before minor surgery in two patients, and before vaccination against hepatitis B in the remaining three patients. No patient had a history of acute liver disease, transfusion of either blood or blood products, or ingestion of hepatotoxic
Submitted for publication June 28, 1993; accepted March 4, 1994. Reprint requests: Pietro Vajro, MD, Department of Pediatrics, Medical School of the University, Via Pansini, 5, 80131 Naples, Italy. Copyright © 1994 by Mosby-Year Book, Inc. 0022-3476/94/$3.00 + 0 9/22/55715
Table. Characteristics of the nine patients at study entry
Age (yr) Weight z score (SD units) Relative median weight (%) ALT (mU/ml)* AST (mU/ml)* Duration of hyperaminotransferasemia (too)
Mean _+ SD
Range
8,7 _+ 2.1 4.6 _+ 2.0
4.9-11.9 2.6-7.9
156 _+ 24
136-203
84 _+ 28 59 _+ 15 14 + 12
50-115 33-83 4-49
AST, Aspartateaminotransferase.
*Normal values <40 mU/ml.
drugs. The parents' aminotransferase serum levels were reported to be normal. Physical examination on admission showed hepatomegaly (lower margin palpable 4 cm below the right costal margin, with normal consistency) in 0nly one patient. All of the patients were obese (weight/height ratios >95th percentile). Weight z scores ([weight - mean weight for sex ALT
Alanine aminotransferase
and age]/standard deviation) and relative median weight ([weight × 100]/median weight for sex and age) were computed in reference to the regional population standard.7 All patients underwent the usual liver function tests: antigens or antibodies (or both) to hepatitis viruses A, B, and C, cytomegalovirus, Epstein-Barr virus, and toxoplasma; and determinations of the following: serum al-antitrypsin, serum glucose and lactic acid, blood gases, urinary reduc-
240
Vajro et al.
The Journal of Pediatrics August 1994
18+,,,71 " ~2+.,,Jl
0-
I
I
t-14o
I
1-12o
I I I t,oo+
~ +8:
60 "<
+6"
.~ +2" .
I
1
2
3
4
5
PATIENTS COMPLIANT TO DIET
6
7
8
9
PATIENTS NOT COMPLIANT TO DIET
Figure. Changes of weight z scores (black areas) and ALT serum values (gray areas) after start of a hypocaloric diet and physical exercise program in nine obese children. Dotted lines indicate upper normal values of ALT. Note relation between decline of serum ALT activity and loss of weight with time in the first seven patients. ing substances, serum ceruloplasmin and urinary copper, serum ferritin, sweat chloride, non-organ-specific autoantibodies, anti-gliadin antibodies, and serum creatine kinase and lactic dehydrogenase- Other tests chosen on the basis of the clinical findings were performed to rule out the most frequent causes of chronic hyperaminotransferasemia in children. Some tests, such as detection of antibodies against hepatitis C virus, were repeated one or two times. Liver ultrasonography at entry was obtained in seven patients. Needle biopsy of the liver was performed after parental consent in the first patient of the series and was repeated after 12 months; this patient had moderate hepatomegaly. After obesity was identified as a likely cause, a balanced individualized hypoealoric diet and physical exercise were prescribed for all children, to obtain a loss of weight of about 500 gm/wk. Weight and liver function tests were repeated at 2- to 6-month intervals. Ultrasound studies were repeated after 5 to 12 months. Comparisons between means were calculated by paired Student t test; correlations between variables were calculated by the Pearson correlation test. Two-tailed p values greater than 0.05 were considered not significant: RESULTS As shown in the Table, weight z scores and relative median weights of patients ranged from 2.6 to 7.9 and from 136 to 203, respectively. Hyperaminotransferasemia was confirmed in all patients; the alanine aminotransferase values were significantly higher than the aspartate aminotransferase values and ranged from 1.2 to 3.5 times the upper
normal values. No relation between ALT values and age of patients or degree of obesity at entry was found. Except for elevated values of serum 3,-glutamyl transpeptidase in two children (1.5 and 2.1 times upper normal values, respectively), results of the other liver function tests were normal. Results of laboratory test to investigate the causes of chronic hyperaminotransferasemia were negative or within normal limits in all patients. In six of seven patients liver ultrasonography showed a "bright" liver appearance with numerous hyperechoic areas within the parenchyma. Moderate hepatomegaly was present in one of these six patients; needle biopsy of the liver showed steatohepatitis. Seven patients were compliant to the prescribed diet and lost at least 10% of their excess of weight, expressed as z score (see Figure). A parallel decrease of the relative median weight and of the weight/height ratios was also observed. Liver size decreased in the patient who had hepatomegaly. In all of these patients, aminotransferase values significantly decreased (p <0.01) and were persistently normal after the second to sixth months of diet. A significant positive correlation between weight and ALT values during and after diet was found (r --- 0.41; p = 0.02). Ultrasonographic evidence of liver brightness decreased in four of the five children who had had a previous study, and was close to normal in the other two patients who had not undergone ultrasonography before the diet. Results of a liver biopsy repeated after 1 year were normal in one patient. Follow-up studies up to 30 months (mean ___ SD = 24 _+ 9 months; range, 10 to 30 months) confirmed the persistence of normal aminotransferase values in all pa-
The Journal of Pediatrics Volume 125, Number 2
tients. No relapses of hyperaminotransferasemia were observed, even in the three patients who tended to gain weight and to reach the original weight z score. Two patients, who had clinical and laboratory characteristics overlapping those of the remaining seven patients, were not compliant with the prescribed diet or the recommended exercise program. Their weight continued to increase and no amelioration of liver function test results or of the ultrasonographic pattern was observed. DISCUSSION Childhood simple obesity causes psychologic, respiratory, orthopedic, biliary, and, later in life, cardiovascular consequences,8 but liver damage has rarely been reported at this age. 4"6 The close correlation between the decline of serum aminotransferase activity and loss of weight after successful use of a hypocaloric diet suggests a causal role for obesity in the liver involvement of our patients. The relation is even more striking when the long persistence of the hyperaminotransferasemia before dietary treatment is considered. Most viral, metabolic, and autoimmune chronic liver diseases and myopathies were ruled out by appropriate tests. Further investigation was not warranted, particularly because the patients' condition would be closely observed. The mechanisms underlying the development of steatohepatitis with or without fibrosis in obese people are still unknown; in adults the amount of fat deposited in the liver does not closely correlate with the degree of obesity but might depend on the duration of the obesity. 3 In our pediatric series, the degree Of basal ALT abnormalities had no relation to the degree of obesity. Unfortunately, duration of obesity before admission to our hospital could not be calculated accurately because the problem of overweight had never been of concern to parents or the attending physicians. This association seems to be much less frequent in children than in adults; Kinugasa et al. 4 reported an incidence of 12% of liver involvement in childhood obesity. In the obesity clinic of our department, a recent survey revealed that 22 (10%) of 228 otherwise healthy obese children had unsuspected elevated aminotransferase values. The nine patients reported here, on the contrary, came to medical attention because of their long-standing hyperaminotransferasemia rather than because of their obesity. Our patient who underwent liver biopsy had steatohepa-
Vajro et al.
241
titis. This lesion reverted to normal after weight loss, in keeping with data reported both in adults 2 and in children.4 It seems reasonable to assume that a marked improvement of aminotransferase values and changes of ultrasonographic abnormalities indicate a parallel improvement of morphologic liver changes in those patients of our series who did not undergo liver biopsies.6, 9 We conclude that obesity should be considered in evaluation of a child with persistent hyperaminotransferasemia of unknown origin and a bright appearance of the liver on ultrasonography. Early recognition and treatment of obesity in these children may avoid more invasive or expensive investigations and prevent the progression of liver damage, in addition to lowering the risk of other consequences of childhood obesity. We thank the dietitians of our department of pediatrics, Dr. Luigi Greco for statistical help, and Dr. Adriana Franzese for gathering preliminary data on abnormal liver function test results in children attending the obesity clinic. REFERENCES 1. Golik A, Rubio A, Weintraub M, Byrne L. Elevated serum liver enzymes in obesity: a dilemma during clinical trials. Int J Obes 1991;15:797-801. 2. Morgan MY. Nutritional aspects of liver and biliary disease. In: Mclntyre N, Benhamou JP, Bircher J, Rizzetto M, Rodes J, eds. Oxford textbook of clinical hepatology. Oxford: Oxford University Press, 1991:1359-60. 3. Palmer M, Schaffner F. Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology 1990; 99:1408-13. 4. Kinugasa A, Tsunamoto K, Furukawa N, Sawada T, Kusunoki T, Shimada N. Fatty liver and its fibrous changes found in simple obesity of children. J Pediatr Gastroenterol Nutr 1984;3:408- 14. 5. Moran JR, Ghishan FK, Halter SA, Greene HL. Steatohepatitis in obese children: a cause of chronic liver dysfunction. Am J Gastroenterol 1983;78:374-7. 6. Coche G, Gottrand F, Sevenet F, Ducrocq C. Steatose hepatique par surcharge ponderale chez l'enfant. J Radiol 1991; 72:235-7. 7. Capozzi G, Vitiello N, Granato L, et al. Weight and obesity analysis in Campania's school children. Ital J Pediatr 1989;15:429-37. 8. Barness LA. Nutrition and nutritional disorders. In: Behrman RE, Kliegman RM, Nelson WE, Vaugham VC lII, eds. Nelson textbook of pediatrics. Philadelphia: WB Saunders, 1992:133-4. 9. Galambos JT, Willis CE. Relationship between 505 paired liver tests and biopsiesin 242 obese patients. Gastroenterology 1978;74:1191-3.
Vajro et al.
239
Persistent hyperaminotransferasemia resolving after weight reduction in obese children Pietro Vajro, MD, Angiola Fontanella, MD, Clelia Perna, ME), G i u s e p p e Orso, MD, Mariangela Tedesco, MD, and A n n a De Vincenzo, MD From the Department of Pediatrics, School of Medicine, Universityof Naples "Federico I1," Italy Nine obese children were referred to our liver disease unit because of asymptomatic, long-standing (range, 4 to 49 months) hyperaminotransferasemia of unknown origin. Ultrasonography showed a "bright" liver in most patients. A hypocaloric diet was prescribed, and the hepatic abnormalities of the compliant patients showed a prompt and persistent improvement that paralleled the loss of excess weight. (J PEDIATR1994;125:239-44)
Slightly elevated and fluctuating serum aminotransferase values caused by steatosis and steatohepatitis, and leading to fibrosis and cirrhosis of the liver, are more common in otherwise healthy obese populations than previously appreciated.I, 2 Recognition is important because the liver abnormalities are often reversible after treatment of obesity. 3 This association in childhood is often not considered, and in obese children an erroneous diagnosis of cryptogenic chronic hepatitis may be made, with a consequent delay of the appropriate treatment. 46 We describe the clinical and laboratory features of several obese children who were referred to our institution for the evaluation of prolonged hyperaminotransferasemia of unknown cause, and discuss the response of the liver abnormalities to weight loss. METHODS Nine consecutive children (six boys) with long-standing, asymptomatic hyperaminotransferasemia of unknown origin were admitted to our institution during the years 1987 to 1992 (Table). Measurements of aminotransferase levels had been done because of hepatomegaly in one patient, as a part of routine laboratory studies in three patients, before minor surgery in two patients, and before vaccination against hepatitis B in the remaining three patients. No patient had a history of acute liver disease, transfusion of either blood or blood products, or ingestion of hepatotoxic
Submitted for publication June 28, 1993; accepted March 4, 1994. Reprint requests: Pietro Vajro, MD, Department of Pediatrics, Medical School of the University, Via Pansini, 5, 80131 Naples, Italy. Copyright © 1994 by Mosby-Year Book, Inc. 0022-3476/94/$3.00 + 0 9/22/55715
Table. Characteristics of the nine patients at study entry
Age (yr) Weight z score (SD units) Relative median weight (%) ALT (mU/ml)* AST (mU/ml)* Duration of hyperaminotransferasemia (too)
Mean _+ SD
Range
8,7 _+ 2.1 4.6 _+ 2.0
4.9-11.9 2.6-7.9
156 _+ 24
136-203
84 _+ 28 59 _+ 15 14 + 12
50-115 33-83 4-49
AST, Aspartateaminotransferase.
*Normal values <40 mU/ml.
drugs. The parents' aminotransferase serum levels were reported to be normal. Physical examination on admission showed hepatomegaly (lower margin palpable 4 cm below the right costal margin, with normal consistency) in 0nly one patient. All of the patients were obese (weight/height ratios >95th percentile). Weight z scores ([weight - mean weight for sex ALT
Alanine aminotransferase
and age]/standard deviation) and relative median weight ([weight × 100]/median weight for sex and age) were computed in reference to the regional population standard.7 All patients underwent the usual liver function tests: antigens or antibodies (or both) to hepatitis viruses A, B, and C, cytomegalovirus, Epstein-Barr virus, and toxoplasma; and determinations of the following: serum al-antitrypsin, serum glucose and lactic acid, blood gases, urinary reduc-
240
Vajro et al.
The Journal of Pediatrics August 1994
18+,,,71 " ~2+.,,Jl
0-
I
I
t-14o
I
1-12o
I I I t,oo+
~ +8:
60 "<
+6"
.~ +2" .
I
1
2
3
4
5
PATIENTS COMPLIANT TO DIET
6
7
8
9
PATIENTS NOT COMPLIANT TO DIET
Figure. Changes of weight z scores (black areas) and ALT serum values (gray areas) after start of a hypocaloric diet and physical exercise program in nine obese children. Dotted lines indicate upper normal values of ALT. Note relation between decline of serum ALT activity and loss of weight with time in the first seven patients. ing substances, serum ceruloplasmin and urinary copper, serum ferritin, sweat chloride, non-organ-specific autoantibodies, anti-gliadin antibodies, and serum creatine kinase and lactic dehydrogenase- Other tests chosen on the basis of the clinical findings were performed to rule out the most frequent causes of chronic hyperaminotransferasemia in children. Some tests, such as detection of antibodies against hepatitis C virus, were repeated one or two times. Liver ultrasonography at entry was obtained in seven patients. Needle biopsy of the liver was performed after parental consent in the first patient of the series and was repeated after 12 months; this patient had moderate hepatomegaly. After obesity was identified as a likely cause, a balanced individualized hypoealoric diet and physical exercise were prescribed for all children, to obtain a loss of weight of about 500 gm/wk. Weight and liver function tests were repeated at 2- to 6-month intervals. Ultrasound studies were repeated after 5 to 12 months. Comparisons between means were calculated by paired Student t test; correlations between variables were calculated by the Pearson correlation test. Two-tailed p values greater than 0.05 were considered not significant: RESULTS As shown in the Table, weight z scores and relative median weights of patients ranged from 2.6 to 7.9 and from 136 to 203, respectively. Hyperaminotransferasemia was confirmed in all patients; the alanine aminotransferase values were significantly higher than the aspartate aminotransferase values and ranged from 1.2 to 3.5 times the upper
normal values. No relation between ALT values and age of patients or degree of obesity at entry was found. Except for elevated values of serum 3,-glutamyl transpeptidase in two children (1.5 and 2.1 times upper normal values, respectively), results of the other liver function tests were normal. Results of laboratory test to investigate the causes of chronic hyperaminotransferasemia were negative or within normal limits in all patients. In six of seven patients liver ultrasonography showed a "bright" liver appearance with numerous hyperechoic areas within the parenchyma. Moderate hepatomegaly was present in one of these six patients; needle biopsy of the liver showed steatohepatitis. Seven patients were compliant to the prescribed diet and lost at least 10% of their excess of weight, expressed as z score (see Figure). A parallel decrease of the relative median weight and of the weight/height ratios was also observed. Liver size decreased in the patient who had hepatomegaly. In all of these patients, aminotransferase values significantly decreased (p <0.01) and were persistently normal after the second to sixth months of diet. A significant positive correlation between weight and ALT values during and after diet was found (r --- 0.41; p = 0.02). Ultrasonographic evidence of liver brightness decreased in four of the five children who had had a previous study, and was close to normal in the other two patients who had not undergone ultrasonography before the diet. Results of a liver biopsy repeated after 1 year were normal in one patient. Follow-up studies up to 30 months (mean ___ SD = 24 _+ 9 months; range, 10 to 30 months) confirmed the persistence of normal aminotransferase values in all pa-
The Journal of Pediatrics Volume 125, Number 2
tients. No relapses of hyperaminotransferasemia were observed, even in the three patients who tended to gain weight and to reach the original weight z score. Two patients, who had clinical and laboratory characteristics overlapping those of the remaining seven patients, were not compliant with the prescribed diet or the recommended exercise program. Their weight continued to increase and no amelioration of liver function test results or of the ultrasonographic pattern was observed. DISCUSSION Childhood simple obesity causes psychologic, respiratory, orthopedic, biliary, and, later in life, cardiovascular consequences,8 but liver damage has rarely been reported at this age. 4"6 The close correlation between the decline of serum aminotransferase activity and loss of weight after successful use of a hypocaloric diet suggests a causal role for obesity in the liver involvement of our patients. The relation is even more striking when the long persistence of the hyperaminotransferasemia before dietary treatment is considered. Most viral, metabolic, and autoimmune chronic liver diseases and myopathies were ruled out by appropriate tests. Further investigation was not warranted, particularly because the patients' condition would be closely observed. The mechanisms underlying the development of steatohepatitis with or without fibrosis in obese people are still unknown; in adults the amount of fat deposited in the liver does not closely correlate with the degree of obesity but might depend on the duration of the obesity. 3 In our pediatric series, the degree Of basal ALT abnormalities had no relation to the degree of obesity. Unfortunately, duration of obesity before admission to our hospital could not be calculated accurately because the problem of overweight had never been of concern to parents or the attending physicians. This association seems to be much less frequent in children than in adults; Kinugasa et al. 4 reported an incidence of 12% of liver involvement in childhood obesity. In the obesity clinic of our department, a recent survey revealed that 22 (10%) of 228 otherwise healthy obese children had unsuspected elevated aminotransferase values. The nine patients reported here, on the contrary, came to medical attention because of their long-standing hyperaminotransferasemia rather than because of their obesity. Our patient who underwent liver biopsy had steatohepa-
Vajro et al.
241
titis. This lesion reverted to normal after weight loss, in keeping with data reported both in adults 2 and in children.4 It seems reasonable to assume that a marked improvement of aminotransferase values and changes of ultrasonographic abnormalities indicate a parallel improvement of morphologic liver changes in those patients of our series who did not undergo liver biopsies.6, 9 We conclude that obesity should be considered in evaluation of a child with persistent hyperaminotransferasemia of unknown origin and a bright appearance of the liver on ultrasonography. Early recognition and treatment of obesity in these children may avoid more invasive or expensive investigations and prevent the progression of liver damage, in addition to lowering the risk of other consequences of childhood obesity. We thank the dietitians of our department of pediatrics, Dr. Luigi Greco for statistical help, and Dr. Adriana Franzese for gathering preliminary data on abnormal liver function test results in children attending the obesity clinic. REFERENCES 1. Golik A, Rubio A, Weintraub M, Byrne L. Elevated serum liver enzymes in obesity: a dilemma during clinical trials. Int J Obes 1991;15:797-801. 2. Morgan MY. Nutritional aspects of liver and biliary disease. In: Mclntyre N, Benhamou JP, Bircher J, Rizzetto M, Rodes J, eds. Oxford textbook of clinical hepatology. Oxford: Oxford University Press, 1991:1359-60. 3. Palmer M, Schaffner F. Effect of weight reduction on hepatic abnormalities in overweight patients. Gastroenterology 1990; 99:1408-13. 4. Kinugasa A, Tsunamoto K, Furukawa N, Sawada T, Kusunoki T, Shimada N. Fatty liver and its fibrous changes found in simple obesity of children. J Pediatr Gastroenterol Nutr 1984;3:408- 14. 5. Moran JR, Ghishan FK, Halter SA, Greene HL. Steatohepatitis in obese children: a cause of chronic liver dysfunction. Am J Gastroenterol 1983;78:374-7. 6. Coche G, Gottrand F, Sevenet F, Ducrocq C. Steatose hepatique par surcharge ponderale chez l'enfant. J Radiol 1991; 72:235-7. 7. Capozzi G, Vitiello N, Granato L, et al. Weight and obesity analysis in Campania's school children. Ital J Pediatr 1989;15:429-37. 8. Barness LA. Nutrition and nutritional disorders. In: Behrman RE, Kliegman RM, Nelson WE, Vaugham VC lII, eds. Nelson textbook of pediatrics. Philadelphia: WB Saunders, 1992:133-4. 9. Galambos JT, Willis CE. Relationship between 505 paired liver tests and biopsiesin 242 obese patients. Gastroenterology 1978;74:1191-3.