Annals of Pediatric Gastroenterology and Hepatology ISPGHAN
Volume 5 | Issue 4 | Year 2023

Approach to a Child with Massive Hepatomegaly

Arghya Samanta1, Moinak Sen Sarma2

1,2Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India

Corresponding Author: Moinak Sen Sarma, Department of Pediatric Gastroenterology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, Uttar Pradesh, India, Phone: +91 9956620668, e-mail:

Received: 07 November 2023; Accepted: 28 November 2023; Published on: 19 January 2024


Pediatricians/pediatric gastroenterologists should be aware of the causes of massive hepatomegaly in children and be able to differentiate benign diseases from those with a worse prognosis and evaluate accordingly. Clinical evaluation is of extreme importance, with keen attention to agewise etiologies and clinical pointers. Most disorders causing massive hepatology in children are potentially treatable with favorable outcomes if detected and treated early. This review discusses the approach for the evaluation of a child presenting with massive hepatomegaly.

How to cite this article: Samanta A, Sarma MS. Approach to a Child with Massive Hepatomegaly. Ann Pediatr Gastroenterol Hepatol 2023;5(4):61–64.

Source of support: Nil

Conflict of interest: None

Keywords: Hepatic malignancy, Massive hepatomegaly, Storage disorder


In pediatric hepatology practice, a child presenting with hepatomegaly is a common scenario where hepatomegaly may be a part of a systemic problem. However, massive hepatomegaly usually requires workup for an underlying primary liver pathology. In this review, we discuss a stepwise approach to a child presenting with massive hepatomegaly and focus mainly on the common etiologies.


By and large, the common differential diagnosis for massive hepatomegaly in a child comes under three broad categories: (1) abnormal storage of different material (lipid or glycogen or fructose or cholesterol); (2) primary or metastatic hepatic malignancies; and (3) hepatic vascular congestion [acute Budd–Chiari syndrome (BCS)] (Table 1). Figure 1 provides a pragmatic algorithm for evaluating a child with massive hepatomegaly.

Table 1: Common causes of massive hepatomegaly in children
Storage disease Carbohydrate storage diseases: GSD, HFI
Lysosomal storage disease: Gaucher’s disease, Niemann–Pick disease
CESD/Wolman disease, mucopolysaccharidosis
Malignancy Primary hepatic malignancy: hepatoblastoma, hemangioendothelioma, HCC, embryonal sarcoma, rhabdoid tumor, angiosarcoma, leiomyosarcoma
Metastatic/systemic: metastatic neuroblastoma, Langerhans cell histiocytosis
Lymphoreticular malignancy: leukemia, lymphoma
Congestion Acute BCS

Fig. 1: Approach to a child with massive hepatomegaly

Clinical Approach

Massive hepatomegaly with glycopenic symptoms (early morning irritability, voracious appetite, hypoglycemic seizure) should indicate carbohydrate storage diseases like glycogen storage disease (GSD) and hereditary fructose intolerance (HFI). HFI has a further history of aversion to sweets, juices, and fruits and gastrointestinal symptoms (vomiting, abdominal distension, or diarrhea after exposure to fructose), polyuria, or rickets. The presence of splenohepatomegaly (larger spleen as compared to the liver) and pancytopenia should raise the suspicion of an infiltrative disorder such as Gaucher’s disease and Niemann–Pick’s disease. If a child presents with a relatively shorter duration of illness with constitutional symptoms (fever, night sweating, and weight loss) with rapid liver expansion, then malignant infiltration, such as leukemia and lymphoma, should be suspected with prompt evaluation. One of the major reasons for massive hepatomegaly is liver tumors. During infancy, hepatoblastoma, metastatic neuroblastoma, and rhabdoid tumors are the most common tumors, while in children between 1 and 3 years, hepatoblastoma and rhabdomyosarcoma are common. In older children and adolescents, embryonal sarcoma, angiosarcoma, and hepatocellular carcinoma (HCC) are more commonly seen. HCC is more frequently encountered in the setting of cirrhosis, although de novo HCC is also seen in children.1 Hemangioendothelioma presents as massive hepatomegaly with severe anemia and cardiac failure. In addition, there may be features of hypothyroidism (constipation and lethargy). There is a high expression of type III iodothyronine deiodinase activity within the tumor. This enzyme is responsible for the conversion of T4 and T3 to inactive metabolites. Sudden onset of pain in the right upper quadrant and recurring ascites with prominent dilated abdominal veins can be seen in acute BCS.

Clues in Physical Examination

If there is soft hepatomegaly, then the possibility of storage disorder is stronger, while firm to hard hepatomegaly with irregular border is usually due to cirrhosis or malignant infiltration. The presence of splenomegaly in association with massive hepatomegaly can be seen in GSD type IV or HFI (due to portal hypertension) or malignancies (lymphoreticular malignancies or hepatic tumors with tumor infiltration of portal vein). Lymphoreticular malignancies usually present with hepatosplenomegaly. Splenohepatomegaly is a feature of lysosomal storage diseases (LSD) like Gaucher’s disease or Niemann–Pick disease. Cherry red spot-on ophthalmological examination is found in approximately 50% of patients with Niemann–Pick disease.2 If a child has chubby cheeks, it points towards GSD, while the absence of caries teeth may suggest HFI. Signs of overt rickets in the setting of massive hepatomegaly suggest HFI. Children with GSD type III may additionally have features of myopathy. As mentioned earlier, the presence of tense/reaccumulating ascites, tender hepatomegaly, and prominent abdominal or back veins may suggest acute BCS. Cutaneous vascular lesions or presentation with congestive cardiac failure can be harbingers of hemangioendothelioma, while hypertension (due to paraneoplastic activity) can be seen in hepatoblastoma and neuroblastoma. Liver consistency will be bosselated in malignancies. Seborrheic dermatitis, skin lesions, or ear discharge may suggest Langerhans cell histiocytosis. Opsoclonus myoclonus and hypertension are found in patients with neuroblastoma (Table 2).

Table 2: Clinical evaluation of a child with massive hepatomegaly
Clinical features Laboratory parameters Definitive diagnosis
GSD Hypoglycemia, voracious appetite, chubby cheeks Hyperuricemia, hyperlipidemia, hyperlactatemia, nephromegaly (GSD 1), elevated creatine kinase (GSD 3) Micro and macrovesicular steatosis, glycogen-laden vacuoles (GSD 1), fibrosis (GSD 3); genetic testing
HFI Postprandial hypoglycemia, sweet aversion, vomiting, diarrhea on exposure to sucrose, absence of caries, rickets Hypophosphatemia, renal tubular acidosis Genetic testing for aldolase B mutation
Gaucher’s disease Splenohepatomegaly Pancytopenia Gaucher cell in liver/bone marrow biopsy,
β-glucosidase enzyme assay
Niemann–Pick disease Splenohepatomegaly, cherry red spot in retinal Pancytopenia, lung lesions on X-ray/CT chest Foamy macrophages in biopsy; Filipin staining for Niemann–Pick disease type C (not available in India), genetic testing
Wolman disease/cholesterol ester storage Malabsorption, growth failure, premature atherosclerosis Very low HDL, high LDL, adrenal calcification (50%) Microvesicular steatosis, luminal (cathepsin D), and membrane lysosomal markers (LAMP1, LAMP2, and lysosomal integral membrane protein 2) around the lipid vacuoles; genetic testing for lysosomal acid lipase mutation
BCS Reaccumulating ascites, prominent abdominal/back veins USG shows block in hepatic vein ± inferior vena cava
Hepatoblastoma Age <2 years, hypertension Thrombocytosis, elevated alpha-fetoprotein Radioimaging, histopathology
Hemangioendothelioma Cutaneous vascular lesion, congestive heart failure Kasabach–Merritt phenomenon, peripheral hypothyroidism Radioimaging
Neuroblastoma Hypertension, opsoclonus myoclonus Elevated urinary vinyl mandelic acid Histopathology
HCC Underlying cirrhosis Elevated α-fetoprotein Radioimaging
Embryonal sarcoma Age of >5 years Histopathology
Lymphoreticular malignancies Night sweats, generalized lymphadenopathy, bone pain Pancytopenia Bone marrow biopsy

CT, computed tomography; HDL, high-density lipoprotein; LDL, low-density lipoprotein; USG, ultrasonography

Laboratory Evaluation

In patients with carbohydrate storage disorders like GSD and HFI, isolated increases in liver enzymes without derangement of bilirubin, albumin, or international normalized ratio (INR) are found in liver function tests. Metabolic derangements like elevated serum lactate, triglyceride, uric acid, and nephromegaly on ultrasonography (USG) are seen in cases of GSD type I. In the case of GSD type III with muscle involvement, creatine phosphokinase will be high. Hyperketotic hypoglycemia is seen in both GSD and HFI, while postprandial hypoglycemia is seen only in HFI.3 Lipid profile can be useful—very low high-density lipoprotein (HDL) and high total and low-density lipoprotein cholesterol are seen in children with Wolman disease/cholesterol ester storage disease (CESD).4

Ultrasonography (USG) of the abdomen is a useful imaging modality. Fatty liver can be found in patients of GSD, HFI, Wolman disease, and CESD. Bilateral nephromegaly points towards GSD type I, while nephrocalcinosis can be found in HFI. Adrenal calcification on abdominal X-ray or ultrasound in around 50% of cases of Wolman disease.5

Electrocardiography may show conduction defects, while echocardiography might show changes in dilated cardiomyopathy. The diagnosis of all storage diseases is based on enzymatic activity, tissue histology, and genetic testing. Enzyme assay is not accessible everywhere. Liver/bone marrow biopsy shows typical Gaucher cells in Gaucher’s disease. Liver histopathology in Niemann–Pick disease shows microvesicular steatosis with foamy macrophages with variable degrees of fibrosis. Filipin staining under fluorescent microscopy is the gold standard for diagnosing Niemann–Pick disease type C, although it is not routinely available. Along with microvesicular steatosis, the presence of luminal (cathepsin D) and membrane lysosomal markers [lysosomal-associated membrane protein (LAMP)1, LAMP2, and lysosomal integral membrane protein 2] around the lipid vacuoles facilitated the diagnosis of Wolman disease/CESD.2

Detection of nonglucose-reducing substances in the urine sample while on a fructose-containing diet is a bedside screening test. Liver biopsy in patients with HFI shows macrovesicular steatosis with or without changes in inflammation and fibrosis. For confirmation, a genetic test is favored over the measurement of aldolase B activity in liver biopsy specimens as later is invasive and not widely available. Histopathologic findings of the liver in GSD I include distention of the liver cells by glycogen, while in GSD type III, the liver and/or muscle biopsy demonstrate a vacuolar accumulation of nonmembrane-bound glycogen primarily located in the cytoplasm. Lipid vacuoles are less frequent in GSD 3 than in GSD I, while fibrosis is noted in GSD III and not in GSD I.6 Genetic testing will confirm the diagnosis.

Routine blood tests can provide a few vital diagnostic clues in the evaluation of liver tumors. Thrombocytosis is common in children with hepatoblastoma, while disseminated intravascular coagulopathy, as seen in the picture, may be found in hemangioendothelioma due to consumption of platelet and coagulation factors within the vascular lesions. Imaging plays a fundamental role in characterizing lesions, staging, and evaluating the adequate treatment and the outcome. Although the radiological findings of some tumors can overlap, knowledge of the specific radiological features of each liver tumor is helpful in assessing the correct diagnosis. USG represents the first-level imaging modality in a child with a suspected abdominal mass because of its lack of ionizing radiation and no need for sedation. Of course, the finding of a hepatic tumor is an indication for further imaging evaluation. Lesions in hemangioendothelioma usually appear hypervascular, while other hepatic malignant tumors usually appear as a well-delineated, multilobulated, and septated hypoechoic mass. Serum α-fetoprotein is almost always elevated, often to very high levels (>105 ng/mL) and HCC, while it is normal (agewise cut-off) in other hepatic malignancies. Computed tomography or magnetic resonance angiography (CTA or MRA) is the next investigation. On CTA, lesions of hemangioendothelioma show marked peripheral enhancement in the arterial phase and central enhancement in the portal venous and delayed phases (target sign) and enlarged, persistently enhancing blood vessels seen within the tumor. Hepatic lesions in HCC show hyperenhancement in the arterial phase and rapid washout in the venous phase. The CTA/MRA findings are interpreted using imaging diagnostic algorithms, namely, Liver Imaging Reporting and Data System, for HCC diagnosis. In most cases, it is mandatory to obtain a tissue diagnosis before starting chemotherapy. Urinary vinyl mandelic acid will be elevated in cases of neuroblastoma.

For BCS, Doppler USG will be able to diagnose in >90% of cases. In those with inconclusive reports, computed tomography or magnetic resonance angiography might be required.


Children presenting with massive hepatomegaly have diverse etiologies. Thorough history taking and careful physical examination can provide vital clues toward underlying etiology. Focussed investigations and their proper interpretation will clinch the diagnosis in most cases.


Arghya Samanta

Moinak Sen Sarma


1. Khanna R, Verma SK. Pediatric hepatocellular carcinoma. World J Gastroenterol 2018;24(35):3980–3999. DOI: 10.3748/wjg.v24.i35.3980

2. Sen Sarma M, Tripathi PR. Natural history and management of liver dysfunction in lysosomal storage disorders. World J Hepatol 2022;14(10):1844–1861. DOI: 10.4254/wjh.v14.i10.1844

3. Singh SK, Sarma MS. Hereditary fructose intolerance: a comprehensive review. World J Clin Pediatr 2022;11(4):321–329. DOI: 10.5409/wjcp.v11.i4.321

4. Burton BK, Deegan PB, Enns GM, et al. Clinical features of lysosomal acid lipase deficiency. J Pediatr Gastroenterol Nutr 2015;61(6):619–625. DOI: 10.1097/MPG.0000000000000935

5. Bay L, Canero Velasco C, Ciocca M, et al. Liver disease and dyslipidemia as a manifestation of lysosomal acid lipase deficiency (LAL-D). Clinical and diagnostic aspects, and a new treatment. An update. Arch Argent Pediatr 2017;115(3):287–293. DOI: 10.5546/aap.2017.eng.287

6. Kishnani PS, Austin SL, Arn P, et al. Glycogen storage disease type III diagnosis and management guidelines. Genet Med 2010;12(7):446–463. DOI: 10.1097/GIM.0b013e3181e655b6

© The Author(s). 2023 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (, which permits unrestricted use, distribution, and non-commercial reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( applies to the data made available in this article, unless otherwise stated.