Hepatic hemangioma (HH) is a common asymptomatic, self-limiting benign vascular tumor of the liver in neonates. Although complicated HHs are rare, they have significant risks of morbidity and mortality, especially during the perinatal period. Because of the high risks of complications from surgical interventions, there is an unmet need for effective medical therapy. We report 2 neonates with life-threatening HH who were evaluated for a liver transplant before being treated successfully with combined medical therapy, which included sirolimus, corticosteroids, and propranolol.
Hepatic hemangiomas (HHs) are the most common benign vascular tumors of the liver in neonates. Historically, the nomenclature has included both HH and hemangioendothelioma, which is a misnomer. More recently, 3 variants have been identified on the basis of imaging characteristics: focal, multifocal, and diffuse. These distinct lesions have unique clinical and pathologic features that follow traits noted with the more common dermal, congenital, and infantile hemangioma. The focal lesions have been found to be negative for glucose transporter 1 (GLUT-1), such that these are considered to be congenital hepatic hemangiomas (CHHs), analogous to a rapidly involuting congenital hemangioma (RICH) lesion found elsewhere. Currently, there are no reports of congenital hemangiomas responding to medical therapy. The multifocal and diffuse subtypes are positive for GLUT-1 and therefore are considered infantile hepatic hemangiomas (IHHs).1,2 IHHs are small or undetectable at birth. These lesions grow rapidly during the first few months of life before they spontaneously involute. IHHs are more likely to be associated with hemangiomas on the skin as well as hypothyroidism.2
According to International Society for the Study of Vascular Anomalies classification, both CHH and IHH are classified as a benign vascular tumor, and most of the cases are asymptomatic and self-limiting, but life-threatening complications can occur, especially with large HHs.3 The mortality rate is estimated at 11% to 18% because of acute congestive heart failure (CHF) and abdominal compartment syndrome.2 Other reported complications include intramural bleeding, coagulopathy, consumptive hypothyroidism, and liver failure. Currently, guidelines exist for HH evaluation and monitoring, but standard medical management recommendations are limited.1 Here, we present 2 neonates with life-threatening HH that required urgent surgical or angiographic intervention. Both were considered for a liver transplant; however, after acute stabilization, both patients were successfully treated with medical therapy by using sirolimus in combination with corticosteroids and propranolol.
A term male newborn was transferred to our hospital because of a prenatal diagnosis of liver vascular malformation with CHF. There was no cutaneous vascular abnormality on examination. A laboratory examination revealed mild coagulopathy without thrombocytopenia (platelet count: 135 000 platelets per μL; prothrombin time [PT] :19.1 seconds; international normalized ratio [INR]: 1.7; partial thromboplastin time [PTT]: 40 seconds; fibrinogen level: 121 mg/dL; aspartate aminotransferase level: 34 U/L; alanine aminotransferase level: 13 U/L; ALP level: 104 U/L; total bilirubin level: 2.2 mg/dL; ALB level: 2.5 g/dL). The echocardiogram revealed a severely dilated right atrial and right ventricle due to high volume returning from liver mass. The postnatal abdominal computer tomography angiogram (CTA) revealed multifocal hypervascular hepatic masses consistent with the diagnosis of IHH (Fig 1 A and B). Arterial embolization for high-output heart failure is included in the clinical practice algorithm presented by Christison-Lagay et al.4 This expertise was not available at the time of presentation, and therefore arterial ligation was performed successfully at 27 hours postdelivery to reduce life-threatening intravascular shunting. The intention of arterial ligation initially was to reduce fast blood flow, improve cardiac function, and obtain a tissue biopsy. Tissue acquisition was aborted because of clinical volatility and high risk of massive bleeding. He was started on methylprednisolone at 2 mg/kg per day at day of life (DOL) 6, which subsequently was increased to 5 mg/kg per day at DOL 11 because of disease progression. Although a liver transplant was anticipated, medical management was maximized with the addition of sirolimus and propranolol on DOL 12. Sirolimus was started at 0.8 mg/kg/m2 every 12 hours and then gradually increased to a target therapeutic trough level of 10 to 15 ng/mL. Propranolol was started at 0.5 mg/kg per day, divided 3 times daily. Because of hemodynamic instability, propranolol dosing was increased slowly by 0.1 mg/kg per dose every 2 doses until reaching the goal of 1 mg/kg per day at DOL 17. Because the patient tolerated combination therapy well, propranolol was increased to 3 mg/kg per day within the next 3 days. The patient had marked improvement the following week after combined medical initiation and was able to discontinue inotropic cardiac medication. The follow-up echocardiogram on DOL 26 revealed only mild dilation of RV, with normal systolic function. An abdominal ultrasound revealed notable tumor reduction and decreased blood flow at 1 month of age. The patient was discharged from the hospital at 2 months of age. Systemic steroids were subsequently weaned, and his cardiac function normalized by 4 months of age. Propranolol and sirolimus tapering was initiated at 12 months of age. By 2 years of age, the patient no longer required any medical therapy, and the IHH lesions were only faintly visible on an ultrasound, with no evidence of regrowth on sequential ultrasounds.
The second patient was a term female infant born with notable abdominal distension without acute pulmonary or cardiac dysfunction. She had no cutaneous vascular anomaly (Fig 2A). A laboratory examination revealed mild anemia (hemoglobin level: 12.3 g/dL), thrombocytopenia (platelet count: 75 000 platelets per μL), and coagulopathy (PT: 25.9 seconds; INR: 2.4; PTT: 52.3 seconds; fibrinogen level: 37 mg/dL). An abdominal MRI was obtained and revealed a large, focal lobulated vascular mass with progressive peripheral-to-central contrast enhancement, consistent with HH (Fig 2 B and C). Propranolol was initiated at 1 mg/kg per day, divided every 8 hours, then increased to 3 mg/kg per day. A serial abdominal ultrasound revealed a persistent increase in tumor size and blood flow after 2 weeks of propranolol treatment. Oral feeding was not possible because of abdominal distention. Methylprednisolone was therefore added at 2 mg/kg per day. Unfortunately, soon after her first dose of steroids, the child had intraabdominal hemorrhage resulting in hemorrhagic shock, abdominal compartment syndrome, and cardiac arrest. She underwent emergent abdominal decompression, followed immediately by left hepatic artery embolization. Although a surgical resection and liver transplant were planned, the immediate surgical risks as well as long-term morbidities were concerning because of the location and size of the mass. Therefore, additional medical therapy was started by using sirolimus (initial dosage of 0.8 mg/kg/m2 every 12 hours and gradually increased to the target 10- to 15-ng/mL trough level). One week after we started combination therapy, the platelet count and coagulogram results became normal (platelet count: 267 000 platelets per μL; PT: 14.0 seconds; INR: 1.1; PTT: 27.8 seconds; fibrinogen level: 373 mg/dL). A weekly ultrasound revealed stabilization in the size of the tumor after 2 weeks of treatment by using combination therapy, and steady volume reduction was noted after 4 weeks (Fig 2D). The patient was started on oral feeds and discharged from the hospital soon after. Prednisolone was tapered off slowly because of hypertension and adrenal suppression. She tolerated propranolol and sirolimus well without any side effects noted. Sirolimus was subsequently tapered at 5 months of age because of hospital admission for bronchiolitis related to respiratory syncytial virus. A sequential follow-up ultrasound revealed further reduction in the size of the mass after terminating sirolimus therapy, with the patient maintained on propranolol.
HH is the most common benign tumor of the liver during infancy. Most patients have spontaneous involution without any sequelae. Although complicated HHs are rare, they do pose significant risks of morbidity and mortality, especially during the perinatal period. Surgical interventions are often attempted to preserve cardiac function. However, the immediate surgical risks and long-term morbidities have to be carefully considered.2 Here we reported 2 children with life-threatening HH who were treated without resection but required urgent surgical or interventional therapy and were then successfully treated with combination medical therapy during their first year of life.
Systemic corticosteroids have been the traditional first-line therapy for HH. Lack of response, however, has been reported at as high as 25%.5 Patients with complicated HH are often referred for arterial embolization, surgical resection, or liver transplantation. Since the introduction of propranolol for the treatment of infantile hemangioma in 2008, the rate of surgical intervention has decreased by nearly 90%. The lower cost of propranolol treatment and long-term lack of sequelae are favorable, especially in comparison with liver transplantation.6 Most multifocal and diffuse HHs, like infantile HHs elsewhere in the body, respond well to propranolol; therefore, it is considered as a first-line therapy.7
CHHs are typically focal lesions that have the characteristic peripheral enhancement and often reveal high flow. This is associated with the risk of CHF and, rarely, life-threatening hemorrhage.8 Standard treatment of symptomatic hepatic RICH is embolization or surgical intervention, which sometimes is not feasible because of an unstable clinical condition. There are few reports of successful use of propranolol in the treatment of CHH; however, corticosteroids and propranolol have not been proven effective in treating RICH in other locations.8,9 Recent studies revealed somatic mutations of GNAQ and GNA11 in congenital hemangioma, which lead to constitutive activation of mitogen-activated protein kinase signaling.10 Mammalian target of rapamycin inhibitor is known to tamper the activity of the mitogen-activated protein kinase pathway11 and therefore should be considered when CHH does not respond to conventional treatments.
Sirolimus (rapamycin), a mammalian target of rapamycin inhibitor, has been used broadly for many vascular tumors and malformations in recent years because of its antiangiogenic effects.12 Greenberger et al13 showed that sirolimus reduces self-renewal capacity of cells derived from IH and causes tumor regression. Synergistic effects were observed when sirolimus and corticosteroids were used in combination to reduce angiogenesis and tumorigenesis in vitro. This was likely due to their differences in mechanism of action. Corticosteroids block vascular endothelial growth factor A expression, whereas sirolimus downregulates angiogenin and placental growth factor-1.12 Combined use of the 2 medications may improve therapeutic efficacy and shorten treatment duration, therefore minimizing side effects.
In practice, it is extremely difficult to obtain a liver biopsy for GLUT-1 immunostaining from a patient who is critically ill; therefore, diagnostic and management decisions can be challenging. Despite that, our report revealed the efficacy of using sirolimus, especially in combination with corticosteroids and propranolol. Both of our patients tolerated and responded to treatment well, without evidence of recurrence.
Although many large HHs may involute spontaneously, life-threatening complications can occur during the neonatal period. On the basis of our anecdotal experience with these 2 cases of life-threatening HH, we believe that combination therapy may have synergistic effects and maximize the benefit of treatment. Timely initiation of treatment with all 3 medications combined may allow patients to avoid radical surgeries or avoid being subjected to lifetime immunosuppression from a liver transplant. A large-scale randomized study in the future may be helpful to address the role of each agent in the management of CHH and IHH. Randomized initiation of these treatments may be only feasible for neonates who are not critically ill.
The cases presented here reveal the importance of interdisciplinary collaboration in management of complicated HH. Early referral to a vascular anomalies specialist is important for the early initiation of medical therapy and may improve outcomes.
Dr Lekwuttikarn conducted the initial analyses, drafted the initial manuscript, and completed the subsequent revision; Dr Josephs participated in data collection and critical review of the manuscript for its intellectual content; Dr Teng conceptualized and designed the study, coordinated and supervised data collection, and reviewed the manuscript for its intellectual content; and all authors approved the final manuscript as submitted and agree to be accountable for all aspects of the work.
FUNDING: No external funding.
congestive heart failure
congenital hepatic hemangioma
computer tomography angiogram
day of life
glucose transporter 1
infantile hepatic hemangioma
international normalized ratio
partial thromboplastin time
rapidly involuting congenital hemangioma
POTENTIAL CONFLICT OF INTEREST: The authors have indicated they have no potential conflicts of interest to disclose.
FINANCIAL DISCLOSURE: The authors have indicated they have no financial relationships relevant to this article to disclose.