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).

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.