Early Pre-B Acute Lymphoblastic Leukemia Presenting as Fulminant Liver Failure

Abstract

Liver involvement is most often mild and clinically silent in children with hematological malignancies. Hepatomegaly may be present at the time of diagnosis; however, it is rare to find impairment of liver function. Four cases of adult with fulminant hepatic failure due to massive infiltration of the liver by malignant cells have been reported by Zafrani et al. (1). Severe hepatocellular dysfunction has also been reported in association with extensive metastatic liver disease (2). Fulminant hepatic failure in children with acute lymphoblastic leukemia is uncommon and, to our knowledge, only two cases have been previously reported (3,4). We describe the case of a child with fulminant liver failure who was transferred to the pediatric liver transplant unit for emergency liver transplantation. The child was found to have early pre-B acute lymphoblastic leukemia. The hepatic failure was due to infiltration of the liver with blast cells and ischemic necrosis of the hepatocytes. This case illustrates how malignant blood disorders may present as severe primary liver disease in children. This uncommon cause of acute liver failure must be recognized prior to making the decision of emergency liver transplantation. CASE REPORT A previously healthy 14-year-old boy was admitted to the hospital because of jaundice and fever (38°C). Four days before admission, he experienced intense abdominal pain with nausea and fatigue. There was no history of drug or toxic intake. On admission, physical examination revealed marked hepatomegaly and splenomegaly. There was no lymphadenopathy. Neurologic examination was normal. Laboratory studies showed hemoglobin 12.2 g/dl, white blood cell count 2.5 × 109/L (with a differential of 16% polymorphonuclears and 63% lymphocytes), and platelet count 85 × 109/L. Liver function tests showed an increase in serum transaminase activities: AST, 3000 IU/L (normal <50); ALT, 3500 IU/L (normal <40); and serum total bilirubin, 35.3 μmol/dl. Coagulation studies showed factor V 27% of normal and prothrombin time 60 s (normal 14 s). The patient was transferred 6 h later to the pediatric intensive care unit for evaluation of an emergency liver transplantation. On admission, there was no fever. Vital signs were unremarkable. The patient was icteric and had clinical grade 1 hepatic encephalopathy. The liver was markedly enlarged, measuring 15 cm. There was no ascites at physical examination. On ultrasound examination the liver appeared homogeneous, and there was no compression or thrombosis of the hepatic artery and portal vein. The acid-base balance was normal. Liver function tests showed an increase in serum transaminase activities: AST, 3321 IU/L; and ALT, 4620 IU/L. Serum total bilirubin was 42.0 mmol/dl (normal <1.7 mmol/dl), serum alkaline phosphatase activity was 641 IU/L, and gammaglutamyltranspeptidase was 76 IU/L (normal <25). Arterial ammonia was 198 mmol/L (normal <50). Blood coagulation studies showed: fibrinogen, 0.1 g/dl; factor II, 17% of normal; factor V, 31%; factor VII + X, 11%; prothrombin time, 72 s (normal 14 s); and activated partial thromboplastin time, 73 s (normal 40 s). Fibrin degradation products dosage was negative. Platelet count and white blood cell count showed thrombocytopenia (66 × 109/cL) and leukopenia (1.8 × 109 cells/L). No leukemic cells were noted on peripheral blood smear. A bone marrow smear examination was performed and showed massive infiltration of the bone marrow with lymphoblastic cells. These leukemic cells expressed an early pre-B immunophenotype: cell markers were positive for HLA DR, CD10, CD19, and negative for CD20; no surface immunoglobulins were found. Serum markers for hepatitis A (IgM HAV-Ab), hepatitis B (HBs-Ag, IgM HBc-Ab, HBe-Ab, HBs-Ab), hepatitis C (IgG HCV-Ab), Epstein-Barr virus, (IgG and IgM VCA-Ab, IgG EBNA-Ab), adenovirus (IgG Ab), herpes simplex (IgG and IgM Ab), herpes type 6 (IgG Ab), and CMV (IgG and IgM Ab) were negative. Polymerase chain reaction for HCV was negative. Viral cultures of stools, urine, blood, and bone marrow were negative. Blood and urine cultures were negative. Non-organ-specific autoantibodies (anti-smooth muscle Ab, anti-nuclear factor, anti-microsomal membrane Ab) were negative. Acetaminophen dosage was negative. Serum alphafetoprotein was negative by a radioimmunologic method. The child was treated supportively. The airways were intubated and the patient artificially ventilated. Corticosteroid therapy was started (hydrocortisone sodium succinate 500 mg/m2/day i.v.). The child's condition continuated to deteriorate within a few hours after admission. Hepatic encephalopathy worsened to grade 3 hepatic encephalopathy. The patient became anuric. An arteriovenous hemofiltration with dialysis using a highly permeable membrane (Gambro FH 77 Hemofilter, Gambro, Hechingen, Germany) was then started. Episodes of hypoglycemia occurred and continuous infusion of hypertonic glucose was necessary to maintain an adequate level of glycemia. Over the subsequent 48 h, hepatic encephalopathy worsened to grade 4 hepatic encephalopathy. Twelve hours before death, he presented with septic shock, and vasopressor agent infusion was necessary to maintain normal systemic blood pressure. The patient died of multiple organ failure on hospital day 4. Four blood cultures drawn immediately before the patient's death were positive for Escherichia coli. An autopsy was not performed because of parents' refusal. A liver biopsy was performed immediately after the patient died. The cultures of liver specimen were negative for bacteria, fungi, and viruses. Immunofluorescence assay on liver tissue was negative for HSV I, HSV II, CMV, and adenovirus antigens. Histological findings were as follows: There was scanty infiltration of the sinusoids and portal tract by leukemic infiltrates with massive area of necrosis (liver cell hydropic degeneration, coagulation necrosis, cell dropout). The necrosis was more marked in the mediolobular and centrilobular zones and was surrounded by a narrow rim of intact hepatocytes or duct-like structures (Fig. 1). Dilated proliferated ductules seen at the junction of portal tracts and hepatocytes contained bile plugs as well as neutrophils. There were no viral inclusions in the liver. DISCUSSION Liver involvement is most often moderate in patients with hematological malignancies. Hepatomegaly may be present at the time of diagnosis but only rarely does liver dysfunction dominate (5). Several authors have reported on adult patients with malignancies presenting as fulminant hepatic failure (6-8). Zafrani et al. reported on four adults with acute monoblastic leukemia, acute phase of chronic myelogenous leukemia, or lymphoma presenting as fulminant hepatic failure (1). Harrison et al. reported on three patients with metastatic liver disease who presented with a clinical course compatible with fulminant hepatic failure (2). In both reports, liver examination at autopsy showed a similar histologic picture with extensive infiltration of the liver by blast cells. Some cases of primary liver carcinoma, metastatic carcinoma, and malignant hemangioendothelioma associated with fulminant hepatic necrosis have also been described (6-9). To our knowledge, only two cases of children with acute lymphoblastic leukemia (ALL) and hepatic failure secondary to massive leukemic infiltrate have been reported. One child was a 5-year-old boy with ALL who was terminal at the time of presentation (3). Another publication reported the case of a 5-year-old girl with ALL on maintenance chemotherapy, who developed a viral-like syndrome and died within 7 days as the result of fulminant hepatic failure (4). In all cases, postmortem examination of the liver showed extensive leukemic infiltration of the liver and liver cells necrosis. The hepatic failure observed in these patients shares common features with those described in the present report. In all three cases, the clinical course was extremely rapid. The three children had acute lymphoblastic leukemia. In two of them, fulminant hepatic failure led to the discovery of the leukemia. However, the histological findings in the two published cases and the case reported here are different. In the cases previously reported, the striking histological abnormality consisted of a massive leukemic infiltration of the liver by the tumor cells leading to the loss of hepatic ultrastructure. By contrast, in the case reported here, liver infiltration was moderate but hepatocyte necrosis was massive. This finding suggests that several mechanisms may explain fulminant hepatic failure in leukemia. To date, these mechanisms remain speculative. The possible etiologies of liver failure include added viral infection, sepsis, and hepatic ischemia. In the present case, viral serologies and cultures were all negative. Moreover, there were no viral inclusions identified on histopathologic studies of the liver. Sepsis was not apparently the cause of liver failure. In this patient, septic shock was a terminal event, and hepatic failure was preexistent to the sepsis. Finally, it seems reasonable to relate the liver failure, observed in this case, to acute hepatocellular ischemia. The centrilobular localization of necrosis suggests such a mechanism because it is well known that centrilobular areas are more susceptible to circulatory failure and especially to portal hypotension (10). Ischemia, could be related to interruption of the portal blood flow and (or) to systemic hypotension. In this child, extrahepatic portal vein obstruction had been excluded by ultrasound examination. Intrahepatic portal veins studied on the liver biopsy specimen were permeable but complete histopathological study of the liver was not possible, and the specimen examined may not be representative of the whole liver. Nevertheless, the histopathological study of the liver biopsy showed infiltration of the portal tracts by leukemic cells. We suggest that the necrosis could be the result of reduced portal blood supply. Lastly, circulatory failure with systemic hypotension, as the patient became terminal, could have led to further reduction in liver perfusion precipitating liver failure. Fig. 2 The possibility of leukemia should be kept in mind in children with fulminant hepatic failure. The case presented here simulated fulminant viral-induced or toxin-induced hepatic necrosis, which are the main causes of fulminant hepatic failure in children. The current treatment of fulminant hepatic failure is emergency liver transplantation (11). The importance of recognizing cases like the one we have presented is obvious because extrahepatic malignancy is currently regarded as an absolute contraindication to liver transplantation. The clinician should be alerted if the liver is enlarged because it is usually small or not palpable in viral-induced or toxin-induced fulminant liver necrosis. Complete blood cell leukocyte differential counts and blood smear examination should guide the diagnosis, but peripheral blood cells are sometimes normal in leukemia. Finally, bone marrow smear or liver biopsy should be performed in case of doubt, before putting the child on an emergency transplantation list. Acknowledgments: The authors thank Dr. J. C. Fellouse (Hôpital de Bayeux, France) for referring the child to our unit.FIG. 1.: A monomorphic leukemic infiltrate (arrows) fills and expands the portal tracts (PT) and tends to infiltrate from the portal triads into the adjacent parenchyma. Necrosis is accompanied by proliferating bile ducts (PBD) in portal tracts and within the confines of former lobules. There is dilatation and congestion of sinusoids. Trichrome stain, original magnification, ×25.FIG. 2.: Leukemic cells (arrows) can be identified in the portal tract (PT) and in some hepatic sinusoids. Dilated proliferating biles ducts (PBD) are seen at the junction of the portal tract and hepatocytes. There is a coagulative degeneration of liver cells. Macrophages containing ceroid pigment are present in necrotic areas. Hematoxylineosin, original magnification, ×46.