A 52-year-old man with medical history marked by obesity (body weight 112 Kg, body mass index 33.7 kg/m2) and acute myocardial infarction (20 years ago), presented to our Institution in June 2013 with fever and dental pain. There was no more tobacco intoxication, nor alcohol consumption. Clinical examination was normal. Blood tests displayed hyperleukocytosis with 74% of circulating blasts, anemia, and thrombocytopenia. Hepatic tests showed moderate cytolysis and cholestasis: L-aspartate aminotransferase (AST) level at 59 IU/l, (N<40), L-alanine aminotransferase (ALT) at 44 IU/l, (N<56), gamma-glutamyltransferase (gammaGT) at 69 IU/l, (N<42), alkaline phosphatase (APL) at 49 IU/l, (N<120), and total bilirubinemia (TBIL) at 35 mumol/l, (N<20). An abdominal ultrasound was performed and revealed mild steatosis and absence of hepatomegaly. Because of fever, a piperacillin/tazobactam treatment (4 g/6 h) was rapidly initiated. Bone marrow aspirate confirmed the diagnosis of ALL with medullary infiltration by 90% of blastic cells immunophenotypically of B cell lineage (CD19+, CD22+, CD10-, CD20-). Molecular and cytogenetic analyses showed initial features of high-risk ALL (Ikaros deletion and t(4;11) with MLL rearrangement).
After a 1-week prephase with steroids, induction chemotherapy was started according to the GRAALL 2005 trial, including daunorubicin 50 mg/m2/day on days 1 to 3 and 30 mg/m2/day on days 15 and 16; vincristine 2 mg total dose on days 1, 8, 15, and 22; cyclophosphamide 750 mg/m2/day on days 1 and 15; and (theoretically) 8 injections of L-aspa 6000 IU/m2/day on days 8, 10, 12, 20, 22, 24, 26, and 28. Neuromeningeal prophylaxis was performed by intra-thecal injections of methotrexate (15 mg), methylprednisolone (40 mg), and cytarabine (40 mg). Granulocyte colony-stimulating factor (G-CSF) was planned from day 18 to the ultimate neutrophil recovery. During neutropenia, Candida albicans was isolated twice from systematic stool examination, without any digestive symptoms. At day 19, the patient presented abdominal tenderness, especially in the right upper quadrant, and hepatomegaly. While recovering neutrophils on day 22, he experienced fever again and an increase of biological inflammatory markers (grey zone, Figure 1). On day 25, after 5 injections of L-aspa (day 10 injection was not performed), hepatic enzyme levels significantly increased, showing cholestasis and to a lesser extend cytolysis (AST level at 168 IU/l, ALT at 148 IU/l, gammaGT at 735 IU/l, APL at 148 IU/l, and TBIL at 128 mumol/l). Another L-aspa injection was done on day 26, but the last one was not prescribed, as hepatic enzymes still increased. At that time, bone marrow aspirate showed achievement of complete remission. A large and systematic diagnosis strategy, including screening for viral infections (HBV, HCV, HAV, HEV, VZV, EBV, HSV, CMV, HIV, PVB19), and autoantibodies (anti nuclear, anti-neutrophil cytoplasmic, anti-mitochondria, anti-actin, anti-endoplasmic reticulum, anti-LKM1, and anti-GP210), was negative. Lipid profile only revealed an isolated hypertriglyceridemia (3.3 g/l). A second abdominal echography, and contrast computed tomography were performed, this time showing homogeneous hepatomegaly (hepatic arrow at 22.2 cm) with signs of major steatosis (Cf Figure 2A), and no sign of biliary obstruction or vascular abnormality. There were no hypodense nodular lesions. Bacterial and mycological blood cultures remained negative. A liver biopsy was performed at J34 (AST level at 179 IU/l, ALT at 266 IU/l, gammaGT at 1425 IU/l, APL at 266 IU/l, and TBIL at 124 mumol/l) by transjugular route. Pathology examination revealed macro- and microvesicular severe steatosis, affecting more than 50% of hepatocytes, with a moderate hepatocyte necrosis, and a mild portal and lobular inflammatory infiltration, including rare neutrophils (Figure 2B). Gomori-Grocott coloration was negative, and bacterial assessment remained sterile. All running treatments were stopped except acetyl salicylic acid because of the cardiac history.
Concomitantly, the patient presented a cough related to an interstitial pneumonia. Pneumocystis jirovecii infection was documented by PCR from bronchoalveolar lavage products. Arterial oxygen pressure was at 58 mmHg (without oxygen therapy). A curative treatment, combining atovaquone with systemic corticosteroids (0.5 mg/kg/day for 10 days), was initiated on day 36 (CRP level at 50 mg/l, AST at 200 IU/l, ALT at 292 IU/l, gammaGT at 1755 IU/l, APL at 260 IU/l, and TBIL at 123 mumol/l), yielding to a rapid decrease of the inflammatory syndrome. Antioxidant therapy with N-acetyl cysteine was concomitantly started. Prothrombin time was maintained at about 60-70% with daily intravenous vitamin K supplementation.
No clinical or biological evidence of hepatic failure was observed. Finally, biological cholestasis and hepatic cytolysis progressively decreased. A control abdominal ultrasound also revealed the regression of hepatomegaly. On day 68, hepatic tests tended to be in normal range (AST level at 43 IU/l, ALT at 79 IU/l, gammaGT at 80 IU/l, APL at 47 IU/l, and TBIL at 19 mumol/l). Consolidation chemotherapy could therefore be administered, but L-aspa was definitively banned. After 3 months, hepatic test results were in normal range, except for gammaGT level at 85 IU/l. Intensification by allogeneic stem cell transplantation is ongoing.