Hepatic involvement as an initial presentation of acute lymphoblastic leukemia (ALL) in adults is rare and may delay the diagnosis.
Material and methodsA case series of adult patients with confirmed B-cell ALL (B-ALL) and altered liver function tests at disease onset was conducted. Clinical, biochemical, imaging, and flow cytometry data were collected, ruling out infectious, autoimmune, and toxic etiologies.
ResultsThree men, 68, 36, and 38 years of age, presented with cholestasis and hepatosplenomegaly with no biliary tract dilation. Flow cytometry showed high percentages of B lymphoblasts. One patient died shortly after starting chemotherapy and the other two remain on active treatment.
ConclusionHepatic infiltration due to ALL should be considered in the differential diagnosis of cholestasis with a normal biliary tract in adults.
El compromiso hepático como forma de presentación inicial de la leucemia linfoblástica aguda (LLA) en adultos es infrecuente y puede retrasar el diagnóstico.
Material y métodosSerie de casos de pacientes adultos con diagnóstico confirmado de leucemia linfoblástica aguda de células B y alteración del perfil hepático al debut. Se recolectaron datos clínicos, bioquímicos, de imágenes y citometría de flujo, descartándose etiologías infecciosas, autoinmunes y tóxicas.
ResultadosSe incluyeron tres varones de 68, 36 y 38 años que presentaron colestasis y hepatoesplenomegalia sin dilatación de la vía biliar. La citometría de flujo evidenció altos porcentajes de linfoblastos B. Un paciente falleció tras iniciar quimioterapia; los otros dos permanecen en tratamiento activo.
ConclusiónLa infiltración hepática por LLA debe considerarse en el diagnóstico diferencial de colestasis con vía biliar normal en adultos.
Acute lymphoblastic leukemia (ALL) is a hematologic malignancy characterized by the clonal proliferation of immature lymphoblasts in the bone marrow, blood, and extramedullary tissues, due to genetic and chromosomal alterations.1,2 Leukemia is more frequent in childhood but its presentation in adults is a therapeutic challenge, with elevated morbidity and mortality.3
Hepatic involvement in ALL is infrequent and associated with poorer prognosis.4,5 Leukemic infiltration into the hepatic parenchyma may cause cholestatic jaundice, markedly elevated alkaline phosphatase and gamma-glutamyl transferase (GGT), and even liver failure.6 Given the scant literature on this form of presentation, early clinical recognition continues to be a diagnostic challenge.
The present work describes 3 cases of B-cell ALL (B-ALL) in adults with hepatic involvement at disease onset, highlighting their clinical presentation, biochemical findings, and diagnostic implications (Table 1).
Laboratory exams of patients with first presentation of acute lymphoblastic leukemia.
| Parameter | Case 1 | Case 2 | Case 3 |
|---|---|---|---|
| Hemoglobin (g/dL) | 10.9 | 8.5 | 16.9 |
| Leukocytes (×10³/μL) | 3.5 | 3.87 | 23.32 |
| Blasts (%) | 47 | 98 | 43 |
| Platelets (×10³/μL) | 110 | 90 | 80 |
| INR | 1.1 | 0.9 | 0.9 |
| PT | 12 | 13 | 13 |
| Total bilirubin total (mg/dL) | 23.8 | 12.8 | 1.6 |
| Direct bilirubin (mg/dL) | 21.3 | 11.0 | 1.0 |
| Alkaline phosphatase (U/L) | 1509 | 628 | 652 |
| GGT (U/L) | 460 | 242 | 687 |
| Albumin (g/dL) | 3.39 | 2.9 | 3.0 |
| AST (U/L) | 53 | 52 | 137 |
| ALT (U/L) | 61 | 61 | 99 |
| LDH (U/L) | 1337 | 453 | 1869 |
Study design and setting: A retrospective, descriptive, epidemiologic study designed as a case series was conducted on 3 adult patients treated at the Gastroenterology Service of the Hospital Nacional Cayetano Heredia (Lima, Peru), between January 2023 and March 2024.
Inclusion and exclusion criteria: Inclusion criteria: (a) age ≥ 18 years; (b) diagnosis of B-ALL confirmed by flow cytometry; and (c) evidence of hepatic involvement (clinical and/or biochemical) at disease onset, prior to starting chemotherapy.
Exclusion criteria: (a) a previous diagnosis of leukemia or exposure to chemotherapy, (b) known chronic liver disease (cirrhosis, chronic viral hepatitis, or other), (c) extrahepatic biliary obstruction or biliary tract dilation identified by ultrasound, tomography, or magnetic resonance cholangiopancreatography, (d) confirmed alternative diagnosis explaining the cholestasis (acute viral hepatitis, autoimmune hepatopathy, or drug-induced liver injury), or (e) insufficient clinical/laboratory information for making the evaluation.
Operational definition of hepatic involvement: Hepatic involvement was considered present with the coexistence of (1) cholestatic biochemical pattern (elevated alkaline phosphate and/or GGT, with or without a predominance of direct hyperbilirubinemia), (2) hepatomegaly or hepatosplenomegaly on physical examination and/or imaging studies, and (3) absence of intra or extrahepatic biliary tract dilation on imaging studies. No liver biopsies were performed in the setting of thrombocytopenia/cytopenias and the need to promptly start oncohematologic treatment.
Variables and analysis: Demographic data, clinical manifestations, complete blood count with peripheral blood smear, liver function tests, lactate dehydrogenase (LDH), coagulation parameters, findings on imaging studies, and percentage of lymphoblasts through cytometry were recorded. A descriptive analysis was carried out.
Ethical considerations: All patients signed statements of informed consent and the study complied with the principles of the Declaration of Helsinki.
ResultsCase descriptionsCase 1 A 68-year-old man with diabetes and high blood pressure, presented with progressive jaundice, choluria, and weight loss of 6 kg over 20 days. There were no signs of hepatic encephalopathy. Tomography identified hepatosplenomegaly (liver 186 mm, spleen 157 × 64 mm), with no biliary tract dilation. Flow cytometry revealed 84.3% B lymphoblasts. Chemotherapy (vincristine, methotrexate, l-asparaginase) was started immediately following diagnosis and the patient died shortly thereafter. A 36-year-old man with no comorbidities, presented with jaundice and choluria for 30 days, hepatosplenomegaly, and retroperitoneal lymphadenopathy. There were no signs of hepatic encephalopathy. Peripheral blood smear revealed 98% blasts, and cytometry revealed 89% pathologic B lymphoblasts. Chemotherapy (vincristine, methotrexate, l-asparaginase) was started and the patient had good clinical progression. He is currently under periodic follow-up. A 38-year-old man with an unremarkable past medical history presented with pain in the right hypochondrium, choluria, nausea, and vomiting for 3 weeks. There were no signs of hepatic encephalopathy. Magnetic resonance imaging identified hepatosplenomegaly. Peripheral blood smear revealed 55% blasts and cytometry confirmed common B-ALL. Chemotherapy (vincristine, methotrexate, l-asparaginase) was started, with favorable progression. The patient is currently under periodic follow-up.
Infectious (viral hepatitis A, B, and C, human immunodeficiency virus [HIV], cytomegalovirus [CMV], Epstein-Barr virus [EBV]), autoimmune, and toxic (medications or herbal products) causes were ruled out in all cases.
Discussion and conclusionsHepatic involvement as the initial manifestation of B-ALL in adults is rare, with few cases reported in the literature.2,4,7
From the pathophysiologic perspective, the cholestatic pattern may be explained by the infiltration of lymphoblasts into the sinusoids and portal spaces, with canalicular compression and altered bile flow, in addition to cytokine-mediated inflammation and hepatocellular dysfunction. Sinusoidal/portal infiltration with canalicular cholestasis has been described in hematologic disorders when there is hepatic involvement, even in the absence of extrahepatic obstruction.3,4,8 In extreme, albeit rare, settings, acute liver injury and liver failure secondary to massive infiltration have been reported.9
Our three cases show that ALL may initially present with altered liver function tests (direct hyperbilirubinemia with intrahepatic cholestasis → R factor below 2, and hepatosplenomegaly, even with no marked cytopenia or biliary tract dilation. Such a pattern should alert us to the possibility of an underlying hematologic disease, especially when the more frequent etiologies have been ruled out. In adults, the more aggressive disease biology and elevated leukemic burden could contribute to a more complicated clinical course.2
Previous studies by Siddique et al.6 and Venvertloh et al.9 reported similar presentations with obstructive jaundice and altered liver function tests, in which B-ALL was identified through flow cytometry. Early recognition is key to preventing diagnostic delays that worsen outcomes.
The differential diagnosis of intrahepatic cholestasis includes viral hepatitis (A, B, C), autoimmune hepatitis, small duct primary sclerosing cholangitis, sepsis-associated cholestasis, and drug or herbal product-induced liver injury. The additional presence of hepatosplenomegaly increases the probability of other more specific diseases, such as EBV, CMV, tuberculosis, primary biliary cholangitis, leukemia/lymphoma, sarcoidosis, and amyloidosis. In our case series, negative viral and autoimmune studies, the absence of drug/herbal exposure, and especially the presence of blasts in the peripheral blood and elevated LDH, were key elements guiding the evaluation toward hematologic malignancy. We recommend routine complete blood count with peripheral blood smear in all patients with unexplained cholestasis and organomegaly.
One of the patients in our case series died shortly after starting chemotherapy, whereas the other 2 remain on active treatment. None of the three developed liver failure but the literature indicates that extensive hepatic infiltration may lead to fulminant liver failure and high mortality.3,4,9
In conclusion, an altered liver profile may be the initial manifestation of a hematologic disease, such as ALL. Leukemic hepatic infiltration should be suspected in adults presenting with cholestasis and hepatosplenomegaly, especially when imaging studies of the biliary tract are normal.
CRediT authorship contribution statementThe authors have participated in the concept and design of the article and the writing and approval of the final version to be published.
Ethical considerationsThe authors declare that no experiments on humans were conducted for this study. We utilized patient data collection formats of our work center, maintaining patient anonymity and obtaining informed consent.
Financial disclosureNo financial support was received in relation to this article.
The authors declare that there is no conflict of interest.
