SHORT COMMUNICATION
Acute Leukemia Presenting as Acute Hepatitis Without Liver Failure
Christine Rivet, yGuy Leverger, Emmanuel Jacquemin, and Olivier Bernard
ABSTRACT A diagnosis of acute lymphoblastic or myeloblastic leukemia was made in 6 children ages 4 to 14 years who presented with a clinicobiochemical picture of acute hepatitis without liver failure. Standard chemotherapy, including 1 week pretreatment with steroids in children with lymphoblastic leukemia, allowed complete remission of the leukemia and normalization of serum liver tests. Key Words: acute hepatitis, acute lymphoblastic leukemia, acute myeloblastic leukemia, chemotherapy, hemophagocytic syndrome
(JPGN 2014;59: 640–641)
H
epatic involvement is usually mild in children with acute leukemia and consists mostly of liver enlargement and sometimes of a moderate increase in serum aminotransferase levels (1). On the contrary, there have been reports, both in adults and in children, of leukemia presenting as fulminant liver failure, and the importance of a proper diagnosis of malignancy to provide specific treatment and avoid liver transplantation has been emphasized (2–5). The possibility of acute leukemia presenting as acute hepatitis with no signs of liver failure has been mentioned or reported in a limited number of children, and its implications in terms of management of the leukemia are debated (1). Here, we report our experience with 6 such children; the results indicate that the search for leukemia should be added to the list of the investigations in a child presenting with features of what could be initially considered acute hepatitis of viral or autoimmune origin and suggest that standard chemotherapy can be given.
RESULTS Between 1991 and 2007, 6 children (4 girls, 1 with Down syndrome) presented with a clinicobiochemical picture suggesting acute hepatitis. The main clinical, biochemical, and hematological data and the outcome are presented in Table 1. There was a mean interval of 23 days (range 10–41) between the first symptom and diagnosis of leukemia by means of bone marrow examination; symptoms were general fatigue in all children and fever in 3, Received March 17, 2014; accepted June 28, 2014. From the He´patologie Pe´diatrique and Centre de Re´fe´rence National de l’Atre´sie des Voies Biliaires, Hoˆpital Biceˆtre AP-HP, the INSERM U757 Orsay, and Universite´ Paris-Sud 11, Le Kremlin-Biceˆtre, and the yHe´matologie-Immuno-Oncologie Pe´diatrique, Hoˆpital d’Enfants Armand Trousseau, AP-HP, Paris, France. Address correspondence and reprint requests to Olivier Bernard, He´patologie Pe´diatrique, Hoˆpital Biceˆtre, Le Kremlin-Biceˆtre Cedex 94275, France (e-mail: [email protected]). The authors report no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000484
followed by jaundice in 5 of 6 children after a median interval of 8 days. At the time of diagnosis, jaundice was present in 5 children, clinically significant lymph nodes were detected in 1 child only, and raised serum aminotransferase levels (mean 32 N) and normal prothrombin time were present in all. Serologic tests for hepatitis A, hepatitis B, hepatitis C, Epstein-Barr virus, cytomegalovirus, herpes simplex virus, parvovirus B19, and adenovirus were negative. Abdominal ultrasonography examination performed in 5 children showed an increased thickness of the gallbladder wall in 2 children and significant abdominal lymph nodes in 1. There was no dilation of the bile ducts. In patient 3, who did not display liver or spleen enlargement nor blast cells on blood smears, 3 bone marrow examinations were necessary during a period of 40 days before the diagnosis was made; in this child, the first 2 bone marrow examinations and a transjugular liver biopsy had shown signs of hemophagocytosis syndrome without blasts. In the other 5 children, bone marrow examination displayed blast cell infiltration at the first assessment in our unit. Leukemia was of the most common type in children, pre-B, in 5 children and myeloblastic in 1. All of the children underwent chemotherapy according to standard protocols used in France and without any modification in the dates or doses because of the liver condition. Complete remission of the leukemia was observed after a mean interval of 36 days (range 27–40) after the onset of chemotherapy. Serum aminotransferase levels were found to be normal after a mean interval of 34 days (range 23–45) after onset of chemotherapy. At the last follow-up visit, 4 children were in complete remission 6 to 16 years after the first sign of disease. The other 2 died during a relapse of the leukemia. During the same time, 2 other children presented with fulminant liver failure related to acute lymphoblastic leukemia and died after a few days in intensive care; in one, acute liver failure led to the initial diagnosis of leukemia; in the other, acute liver failure led to the diagnosis of a relapse of the leukemia.
DISCUSSION The 6 patients reported here, with acute liver disease clinically and biochemically similar to acute hepatitis with or without jaundice, a high increase in serum aminotransferase levels, and a normal prothrombin time, and the 8 children mentioned or reported previously (1,6–9) indicate that the possibility of acute leukemia should be considered to be the first cause of acute hepatitis in children when the blood cell counts show anemia with low reticulocyte count, neutropenia, and/or thrombocytopenia, because treatment is urgent. When blast cells are not visible on the smears, other diagnoses may be considered such as viral or autoimmune hepatitis combined with pancytopenia, hepatitis-associated aplastic anemia syndrome, or poisoning. Rapid and, if necessary, repeat bone marrow examination is therefore essential. Acute lymphoblastic leukemia of the pre-B type is the most commonly observed, but other types are possible, as shown by patient 6. The improvement in liver biochemical results in the course of chemotherapy indicates that the liver condition is the consequence of the leukemia. Whereas
640 JPGN Volume 59, Number 5, November 2014 Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN
Volume 59, Number 5, November 2014
Acute Leukemia Presents as Acute Hepatitis Without Liver Failure
TABLE 1. Clinical and laboratory results at the time of diagnosis by means of bone marrow examination, and outcome in 6 children with acute leukemia who presented with signs of acute hepatitis Patients Age, y Physical signs Serum liver tests Bilirubin, mmol/L (conjugated) ALT, IU/L Prothrombin time, % Gamma GT, U/L g-Globulins, g/L Blood cell count Hemoglobin, g/dL White blood cells mm3 Neutrophils mm3 Platelets mm3 Blast cells mm3 (smear) Bone marrow Blast cells, % Type Treatment Induction ALT after 1 wk of steroids, IU/L Normal ALT, daysy Outcome Follow-up, y Status
1 11 J, H, S
2 15 J, H
3 8 None
4 4 J, H
5 13 J, H, S
6 14 J, S, LN
125 (113) 1530 98 250 10
193 (130) 810 89 35 8
14 585 82 145 15
176 (125) 4500 74 320 5
51 (37) 405 70 n.d. n.d.
85 (74) 800 76 290 8
8 1000 80 70,000 190
10 4500 310 54,000 4100
8 1500 550 53,000 0
11 3200 1470 41,000 60
9 5600 560 95,000 3400
6 2600 100 20,000 700
96 L
92 L
38 L
87 L
82 L
94 M
P, D, V, A 135 31
P, D, V, A 320 28
P, D, V, A 160 39
P, D, V, A 192 38
P, D, V, A 150 23
AraC, Mi n.a. 45
6 Alive
16 Alive
6 Alive
4 Death (relapse)
13 Alive
3 Death (relapse)
Results of bone marrow examination for patient 3 are those of the third examination; 2 previous examinations and liver histology failed to show blast infiltration (see text). No liver biopsies were performed in the other children because the first marrow examinations showed blast cells infiltration. Normal laboratory values are as follows: bilirubin 17 mmol/L, conjugated bilirubin
Acute Leukemia Presenting as Acute Hepatitis Without Liver Failure
Christine Rivet, yGuy Leverger, Emmanuel Jacquemin, and Olivier Bernard
ABSTRACT A diagnosis of acute lymphoblastic or myeloblastic leukemia was made in 6 children ages 4 to 14 years who presented with a clinicobiochemical picture of acute hepatitis without liver failure. Standard chemotherapy, including 1 week pretreatment with steroids in children with lymphoblastic leukemia, allowed complete remission of the leukemia and normalization of serum liver tests. Key Words: acute hepatitis, acute lymphoblastic leukemia, acute myeloblastic leukemia, chemotherapy, hemophagocytic syndrome
(JPGN 2014;59: 640–641)
H
epatic involvement is usually mild in children with acute leukemia and consists mostly of liver enlargement and sometimes of a moderate increase in serum aminotransferase levels (1). On the contrary, there have been reports, both in adults and in children, of leukemia presenting as fulminant liver failure, and the importance of a proper diagnosis of malignancy to provide specific treatment and avoid liver transplantation has been emphasized (2–5). The possibility of acute leukemia presenting as acute hepatitis with no signs of liver failure has been mentioned or reported in a limited number of children, and its implications in terms of management of the leukemia are debated (1). Here, we report our experience with 6 such children; the results indicate that the search for leukemia should be added to the list of the investigations in a child presenting with features of what could be initially considered acute hepatitis of viral or autoimmune origin and suggest that standard chemotherapy can be given.
RESULTS Between 1991 and 2007, 6 children (4 girls, 1 with Down syndrome) presented with a clinicobiochemical picture suggesting acute hepatitis. The main clinical, biochemical, and hematological data and the outcome are presented in Table 1. There was a mean interval of 23 days (range 10–41) between the first symptom and diagnosis of leukemia by means of bone marrow examination; symptoms were general fatigue in all children and fever in 3, Received March 17, 2014; accepted June 28, 2014. From the He´patologie Pe´diatrique and Centre de Re´fe´rence National de l’Atre´sie des Voies Biliaires, Hoˆpital Biceˆtre AP-HP, the INSERM U757 Orsay, and Universite´ Paris-Sud 11, Le Kremlin-Biceˆtre, and the yHe´matologie-Immuno-Oncologie Pe´diatrique, Hoˆpital d’Enfants Armand Trousseau, AP-HP, Paris, France. Address correspondence and reprint requests to Olivier Bernard, He´patologie Pe´diatrique, Hoˆpital Biceˆtre, Le Kremlin-Biceˆtre Cedex 94275, France (e-mail: [email protected]). The authors report no conflicts of interest. Copyright # 2014 by European Society for Pediatric Gastroenterology, Hepatology, and Nutrition and North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition DOI: 10.1097/MPG.0000000000000484
followed by jaundice in 5 of 6 children after a median interval of 8 days. At the time of diagnosis, jaundice was present in 5 children, clinically significant lymph nodes were detected in 1 child only, and raised serum aminotransferase levels (mean 32 N) and normal prothrombin time were present in all. Serologic tests for hepatitis A, hepatitis B, hepatitis C, Epstein-Barr virus, cytomegalovirus, herpes simplex virus, parvovirus B19, and adenovirus were negative. Abdominal ultrasonography examination performed in 5 children showed an increased thickness of the gallbladder wall in 2 children and significant abdominal lymph nodes in 1. There was no dilation of the bile ducts. In patient 3, who did not display liver or spleen enlargement nor blast cells on blood smears, 3 bone marrow examinations were necessary during a period of 40 days before the diagnosis was made; in this child, the first 2 bone marrow examinations and a transjugular liver biopsy had shown signs of hemophagocytosis syndrome without blasts. In the other 5 children, bone marrow examination displayed blast cell infiltration at the first assessment in our unit. Leukemia was of the most common type in children, pre-B, in 5 children and myeloblastic in 1. All of the children underwent chemotherapy according to standard protocols used in France and without any modification in the dates or doses because of the liver condition. Complete remission of the leukemia was observed after a mean interval of 36 days (range 27–40) after the onset of chemotherapy. Serum aminotransferase levels were found to be normal after a mean interval of 34 days (range 23–45) after onset of chemotherapy. At the last follow-up visit, 4 children were in complete remission 6 to 16 years after the first sign of disease. The other 2 died during a relapse of the leukemia. During the same time, 2 other children presented with fulminant liver failure related to acute lymphoblastic leukemia and died after a few days in intensive care; in one, acute liver failure led to the initial diagnosis of leukemia; in the other, acute liver failure led to the diagnosis of a relapse of the leukemia.
DISCUSSION The 6 patients reported here, with acute liver disease clinically and biochemically similar to acute hepatitis with or without jaundice, a high increase in serum aminotransferase levels, and a normal prothrombin time, and the 8 children mentioned or reported previously (1,6–9) indicate that the possibility of acute leukemia should be considered to be the first cause of acute hepatitis in children when the blood cell counts show anemia with low reticulocyte count, neutropenia, and/or thrombocytopenia, because treatment is urgent. When blast cells are not visible on the smears, other diagnoses may be considered such as viral or autoimmune hepatitis combined with pancytopenia, hepatitis-associated aplastic anemia syndrome, or poisoning. Rapid and, if necessary, repeat bone marrow examination is therefore essential. Acute lymphoblastic leukemia of the pre-B type is the most commonly observed, but other types are possible, as shown by patient 6. The improvement in liver biochemical results in the course of chemotherapy indicates that the liver condition is the consequence of the leukemia. Whereas
640 JPGN Volume 59, Number 5, November 2014 Copyright 2014 by ESPGHAN and NASPGHAN. Unauthorized reproduction of this article is prohibited.
JPGN
Volume 59, Number 5, November 2014
Acute Leukemia Presents as Acute Hepatitis Without Liver Failure
TABLE 1. Clinical and laboratory results at the time of diagnosis by means of bone marrow examination, and outcome in 6 children with acute leukemia who presented with signs of acute hepatitis Patients Age, y Physical signs Serum liver tests Bilirubin, mmol/L (conjugated) ALT, IU/L Prothrombin time, % Gamma GT, U/L g-Globulins, g/L Blood cell count Hemoglobin, g/dL White blood cells mm3 Neutrophils mm3 Platelets mm3 Blast cells mm3 (smear) Bone marrow Blast cells, % Type Treatment Induction ALT after 1 wk of steroids, IU/L Normal ALT, daysy Outcome Follow-up, y Status
1 11 J, H, S
2 15 J, H
3 8 None
4 4 J, H
5 13 J, H, S
6 14 J, S, LN
125 (113) 1530 98 250 10
193 (130) 810 89 35 8
14 585 82 145 15
176 (125) 4500 74 320 5
51 (37) 405 70 n.d. n.d.
85 (74) 800 76 290 8
8 1000 80 70,000 190
10 4500 310 54,000 4100
8 1500 550 53,000 0
11 3200 1470 41,000 60
9 5600 560 95,000 3400
6 2600 100 20,000 700
96 L
92 L
38 L
87 L
82 L
94 M
P, D, V, A 135 31
P, D, V, A 320 28
P, D, V, A 160 39
P, D, V, A 192 38
P, D, V, A 150 23
AraC, Mi n.a. 45
6 Alive
16 Alive
6 Alive
4 Death (relapse)
13 Alive
3 Death (relapse)
Results of bone marrow examination for patient 3 are those of the third examination; 2 previous examinations and liver histology failed to show blast infiltration (see text). No liver biopsies were performed in the other children because the first marrow examinations showed blast cells infiltration. Normal laboratory values are as follows: bilirubin 17 mmol/L, conjugated bilirubin
