Acute liver failure as a presenting feature in an adolescent with acute lymphoblastic leukemia: A case report with review of literature

Simran Bhatnagar; Bharat Kumar; Nitish Kumar; Alok Hemal

doi:10.4103/ipcares.ipcares_59_23

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CASE REPORT WITH REVIEW OF LITERATURE

Year : 2023 | Volume : 3 | Issue : 3 | Page : 146-149

Acute liver failure as a presenting feature in an adolescent with acute lymphoblastic leukemia: A case report with review of literature

Simran Bhatnagar, Bharat Kumar, Nitish Kumar, Alok Hemal
Department of Pediatrics, ABVIMS and Dr. Ram Manohar Lohia Hospital, New Delhi, India

Date of Submission	20-Mar-2023
Date of Decision	12-Jul-2023
Date of Acceptance	18-Jul-2023
Date of Web Publication	14-Aug-2023

Correspondence Address:
Dr. Nitish Kumar
Department of Pediatrics, ABVIMS and Dr. Ram Manohar Lohia Hospital, New Delhi
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/ipcares.ipcares_59_23

Abstract

Background: Acute lymphoblastic leukemia (ALL) is a common pediatric malignancy, typically manifesting with symptoms of bone marrow and hematolymphoid organ infiltration. Although hepatic involvement in the form of hepatosplenomegaly is seen in nearly two-thirds of the patients, primary presentation as acute liver failure is rare. Clinical Description: A 12-year-old boy presented with complaints of abdominal distention with jaundice for the past 15–20 days, associated with transient fever of 6 days. Examination revealed pallor, icterus, and hepatosplenomegaly. A possibility of acute infectious or autoimmune hepatitis or hemolytic anemia was considered. Management: Liver function tests were deranged with hyperbilirubinemia with modest increase in transaminases and serum alkaline phosphatase along with deranged prothrombin time. The complete blood count showed pancytopenia with normal peripheral smear. Investigations for common infectious causes were noncontributory, as also those for autoimmune hepatitis. The direct Coombs test was also negative. In view of persistent pancytopenia with hyperbilirubinemia and hepatosplenomegaly, a bone marrow evaluation was done, which revealed B-cell ALL (B-ALL). Thus, the child was diagnosed with a case of ALL presenting with acute liver failure. The child was initially managed as a case of acute liver failure and on diagnostic confirmation, he was started on the B-ALL chemotherapy protocol as per his risk stratification with hepatic dose modification of chemotherapy. The child showed complete normalization of the liver functions by about 4 weeks of induction chemotherapy and achieved remission. Conclusions: A child presenting with acute liver failure may be having an underlying undiagnosed, clinically silent ALL. After ruling out common causes of acute liver failure, one must not forget the possibility of leukemic blast infiltration of the liver as a cause of liver failure. With early initiation of advanced chemotherapeutic induction regimens, there can be dramatic resolution of liver injury and remission of ALL.

Keywords: Child, hepatic failure, hepatitis, India, leukemic infiltration

How to cite this article:
Bhatnagar S, Kumar B, Kumar N, Hemal A. Acute liver failure as a presenting feature in an adolescent with acute lymphoblastic leukemia: A case report with review of literature. Indian Pediatr Case Rep 2023;3:146-9

How to cite this URL:
Bhatnagar S, Kumar B, Kumar N, Hemal A. Acute liver failure as a presenting feature in an adolescent with acute lymphoblastic leukemia: A case report with review of literature. Indian Pediatr Case Rep [serial online] 2023 [cited 2023 Sep 30];3:146-9. Available from: http://www.ipcares.org/text.asp?2023/3/3/146/383629

Acute lymphoblastic leukemia (ALL) is one of the most common childhood malignancies.^[1],[2],[3] Conventionally, ALL presents with features of bone marrow infiltration and failure, including fever due to repeated infections, easy fatigability owing to anemia, and excessive bruising due to thrombocytopenia. Another set of clinical symptoms occurs due to leukemic infiltration of the organs of the reticuloendothelial system (lymphadenopathy and hepatosplenomegaly) as well as other organs.

The most common form of liver involvement in ALL is asymptomatic hepatosplenomegaly, seen in 68% of all ALL patients.^[3] Transaminitis might be seen but liver function abnormalities are usually mild, without clinical manifestations. Hyperbilirubinemia is uncommon. A primary presentation of ALL with a picture of frank jaundice and acute liver failure is rarely reported.^[4],[5],[6] With recent advances in chemotherapeutic agents for ALL, the prognosis of the condition, despite complications, has been quite favorable.^[7] Thus, liver involvement in ALL may also have a fair possibility of reversal, if curative treatments focused on the etiology are provided timely. We describe an adolescent boy presenting with acute-onset liver failure, which turned out to be a complication of an undiagnosed underlying ALL.

Clinical Description

A 12-year-old boy reported to the hospital's emergency department with complaints of abdominal distention for 20 days and yellowish discoloration of the skin, sclera, and dark urine for around 15 days. He also had a fever lasting for 5–6 days, 2 weeks ago. The abdominal distention was insidious in onset, gradually progressive, associated with some physical discomfort. After about 5 days, he was noticed to have yellowish discoloration of the skin, sclera, and urine, which gradually deepened. The patient also developed fever along with jaundice, subsiding within a week. The child had a single, transient episode of small volume of bleeding from his nose, in the following week. There was no history of any skin rash, hematemesis, passage of black-colored, tarry stools, or bleeding from any other site. There was no history of any blood transfusion. He did not have any alteration of sensorium or abnormal sleep-wake pattern nor was there any history of loose stools, vomiting, recent travel, joint pains, rash, exposure to rice fields, rainwater, or rats.

The boy did not have any significant medical or surgical illness in the past. The birth, antenatal, and postnatal periods were uneventful. The child had been immunized for age and had attained all developmental milestones at appropriate times. There is no significant family history of any chronic illness.

On examination, the patient was sick-looking and appeared to be deeply agonized due to a severe abdominal pain. He was conscious and oriented with temperature of 37.3°C, heart rate of 108/min, respiratory rate of 22/min, SpO₂ of 97% on room air, blood pressure of 116/72 mmHg, and normal volume pulses. Weight for age (54 kg), height for age (160 cm), and body mass index (21) were between +1 and +2 standard deviation. Child had pallor, deep icterus, and isolated pedal edema. There was no lymphadenopathy, clubbing, or cyanosis. There was no stigmata of chronic liver disease or of any vitamin or other nutritional deficiencies. The abdomen was distended with diffuse tenderness. The liver was palpable 10 cm below the right costal margin and the spleen was palpable 5 cm along the splenic axis. Bowel sounds were present. There was no fluid thrill or shifting dullness. Other systemic examination findings were within the normal limits.

Management and Outcome

Based on the history and examination findings, the differential diagnoses considered were infectious causes, including viral hepatitis, leptospirosis, scrub typhus, complicated malaria, and complicated enteric fever; autoimmune hepatitis; hemolytic anemia; malignancies like Langerhans cell histiocytosis and acute leukemia; hemophagocytic lymphohistiocytosis (HLH); and storage disorders. Since the history was short, of only about 20 days, chronic causes and storage disorders were less likely, and investigations for other causes were carried out.

The child was initially managed as a case of acute liver failure, and all relevant investigations were sent. Complete blood count showed pancytopenia with a hemoglobin of 5.7 g/dL, an absolute neutrophil count of 0.9 × 10³/L, and a platelet count of 80 × 10⁶/L. Liver function tests were deranged with total serum bilirubin of 5.5 mg/dL, direct bilirubin of 3.12 mg/dl, aspartate aminotransferase of 178 U/L, alanine transaminase of 52 U/L, and serum alkaline phosphatase of 639 U/L along with deranged prothrombin time of 17.8 s and international normalized ratio of 2.6. Total protein and serum albumin were 5.7 g/dL and 2.7 g/dL, respectively. Serum ammonia (60 g/dl) and lactate levels (5.7 mmol/L) were elevated. No atypical cells were found on peripheral smear. Renal function and serum electrolytes were found to be within the normal limits. On the peripheral smear, red blood cells were predominantly normocytic and normochromic, with anisopoikilocytosis and a reticulocyte count of 2% with a corrected reticulocyte count of 0.87%. Direct and indirect Coomb's test was negative. The serum iron was 215 μg/dl, total iron-binding capacity was 231 μg/dl, transferrin saturation was 93%, serum Vitamin B12 was 1329 pg/ml, and folate was 3.92 ng/ml.

Dengue serology, leptospira, and scrub typhus antibodies, serology for human immunodeficiency virus, hepatitis A, B, C, and E, Cytomegalovirus, Epstein–Barr virus, and parvovirus B19 were negative. Blood and urine cultures were sterile, and serum Widal and Typhidot were negative. Tuberculosis was ruled out as the Mantoux was negative, a chest X-ray was normal, and in the gastric aspirate GeneXpert, no bacilli were detected.

Autoimmune workup, including antinuclear antibody, antiliver-kidney microsomal antibody, and anti-Smith antibody, was negative. Serum triglyceride (106 mg/dl), fibrinogen (199 mg/dl), and ferritin (698 ng/ml) levels did not fulfill the criteria for HLH. An ultrasound of the whole abdomen was suggestive of hepatosplenomegaly, with normal echotexture.

Having ruled out common infectious and autoimmune causes, a bone marrow aspiration with biopsy was done which showed the presence of excess blasts. 1-2 prominent nucleoli were seen with no Auer rods. Bone marrow flow cytometry showed the presence of 30% blasts with positivity for CD19, CD10, CD22, Tdt, and HLA DR. Blasts were negative for CD3, CD5, CD7, CD13, CD14, CD33, CD64, and MPO confirming B-cell ALL.

Thus, the child was diagnosed as a case of ALL with acute liver failure, possibly due to leukemic infiltration.

The family of the patient was counseled and after sending all baseline investigations, chemotherapy was started by the 7^th day of hospitalization, according to the Indian Collaborative Childhood Leukaemia Group (ICiCLe) Intermediate Risk Protocol, along with drug dose modification in view of hepatic failure. Induction phase with prednisolone was started. Transaminitis resolved, and serum bilirubin levels decreased to the normal range by 28 days of chemotherapy initiation [Figure 1]. The size of the liver and spleen regressed, and the general condition of the patient improved. On the 8^th day of induction therapy, blood and cerebrospinal fluid examinations showed the absence of blasts. At present, the patient is on regular follow-up and receiving chemotherapy as per the ICiCLe protocol.

Figure 1: Pattern of bilirubin levels (mg/dL) during the course of treatment

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Discussion with Review of Literature

ALL is one of the most common pediatric malignancies with an overall survival rate approaching up to 90% with the latest advanced treatment protocols.^[8] The most common presenting signs and symptoms are often nonspecific, including fever and infections caused by neutropenia, fatigue, and progressive pallor due to anemia, and bleeding manifestations due to decreased platelet counts. Other manifestations may include lymphadenopathy, hepatomegaly, splenomegaly, and bone pains.^[8]

Asymptomatic hepatosplenomegaly is one of the most common presenting features of pediatric ALL occurring in up to 68% cases.^[3] Published literature suggests that approximately one-third of children with ALL have increased aminotransferase levels at the time of diagnosis with a mere 3.4% having conjugated hyperbilirubinemia.^[3] Acute liver failure as a presenting complaint of ALL has only rarely been reported.^{[3],[4],[5],[6],[8],[9]} It is also seen that ALL - induced hepatitis is more common in patients with T cell ALL, in those with higher white blood cell count, uric acid and lactate dehydrogenase levels, suggesting higher leukemic burden in such patients.^[3]

Several mechanisms have been proposed for hepatic involvement in a case of ALL.^[3] These include (i) leukemic infiltration of the liver: sinusoidal as well portal infiltration by leukemic blasts leading to nonspecific portal inflammation; (ii) paraneoplastic manifestation of acute leukemia; (iii) liver injury secondary to administration of hepatotoxic chemotherapeutic drugs; (iv) development of concomitant hepatitis, particularly hepatitis B or C infection due to recurrent blood transfusions; and (v) development of concomitant sepsis and viral infections due to underlying immunocompromised state.

Acute liver failure results from acute-onset massive hepatic necrosis with severe impairment of liver function in a previously healthy liver. If untreated, it can lead to hepatic encephalopathy within 8 weeks. Therefore, it is very important to determine the cause of liver failure and treat the same. Timely identification of ALL as a cause of acute liver failure can lead to appropriate management and improved survival.

There are very few case reports that describe a child presenting initially with acute liver failure but turning out to be ALL [Table 1].^{[3],[4],[5],[6],[8],[9]} Most of these case reports where acute liver failure was a presenting feature of ALL have reported dramatic improvement with the initiation of chemotherapy. However, treatment of ALL with acute liver failure is not straightforward, as many of the first-line chemotherapy drugs used in the induction phase of ALL (anthracyclines, vincristine, and L-asparaginase) are potentially hepatotoxic or have hepatic route of metabolism and/or excretion.^[10] As a result, either dose modification of the required chemotherapy drugs or delay in their administration may be required. There have been studies that showed that the addition of steroids can decrease the liver enzymes.^[10] In our case too, glucocorticoids as a part of initial induction therapy showed improvement in the general and clinical condition of the patient and a sudden decrease in bilirubin and transaminases was seen. Although, in our case, initial hepatic dose modification of chemotherapy was done, the rapid improvement of transaminitis and hyperbilirubinemia following steroid therapy allowed us to reinstate full dose of chemotherapeutic drugs early in the course of treatment.

Table 1: Review of literature summarizing case reports of children with acute lymphoblastic leukemia, presenting with acute liver failure

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To conclude, a child presenting with acute liver failure may be having an underlying unsuspected, clinically silent, ALL. After ruling out common causes of acute liver failure, one must not forget the possibility of leukemic blast infiltration of the liver as a causative factor. Early initiation of advanced strategies of chemotherapy for ALL has proven to be very successful in the resolution of such a complication of ALL.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form, the legal guardian has given his consent for images and other clinical information to be reported in the journal. The guardian understands that names and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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